Medical Device Quality Systems Manual

Medical Device Quality Systems Manual
HHS Publication FDA 97-4179
MEDICAL DEVICE QUALITY SYSTEMS MANUAL:
A SMALL ENTITY COMPLIANCE GUIDE
First Edition
(Supersedes the Medical Device Good Manufacturing Practices
Manual)
Andrew Lowery, Judy Strojny, and Joseph Puleo
Division of Small Manufacturers Assistance
Office of Health and Industry Programs
CENTER FOR
DEVICES AND
RADIOLOGICAL HEALTH
CDRH
December 1996
(This publication supersedes FDA 91-4179)
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Center for Devices and Radiological Health
Rockville, Maryland 20850
FOREWORD
The Center for Devices and Radiological Health (CDRH) of the Food and Drug
Administration (FDA), develops and implements national programs to protect the public
health in the fields of medical devices and radiological health. These programs are intended to
assure the safety, effectiveness, and proper labeling of medical devices, to control unnecessary
human exposure to potentially hazardous ionizing and non-ionizing radiation, and to assure
the safe, efficacious use of such radiation.
The Center publishes the results of its work in scientific journals and in its own technical
reports. These reports disseminate results of CDRH and contractor projects. They are sold by
the Government Printing Office and/or the National Technical Information Service. Many are
available via the FDA home page on the World Wide Web at: http:\\www.fda.gov.
We welcome your comments and requests for further information.
D. Bruce Burlington, M.D.
Director
Center for Devices and
Radiological Health
ii
PREFACE
The Medical Device Amendments of 1976 mandated the establishment of "an identifiable office to
provide technical and other nonfinancial assistance to small manufacturers of medical devices to
assist them in complying with the requirements of the Federal Food, Drug, and Cosmetic Act." The
Division of Small Manufacturers Assistance (DSMA) in the Office of Health and Industry
Programs (OHIP) was established to meet this requirement. DSMA develops educational materials
and sponsors workshops and conferences to provide firms with a firsthand working knowledge of
medical device requirements and compliance policies.
This manual covers the Quality System regulation and the basic Good Manufacturing Practices
(GMP) requirements that all manufacturers and distributors must consider when they plan to
manufacture medical devices, including medical device kits, trays or packs, for distribution in the
United States. Model procedures and sample forms are also included in the manual to assist
manufacturers.
Adherence to the medical device Quality System regulation makes good business sense and also
serves public health aims -- two very good reasons for the Food and Drug Administration (FDA) to
encourage compliance. However, a prerequisite to complying with a regulation is a clear
understanding of its content. Recognizing this fact, the Division of Small Manufacturers Assistance
(DSMA) developed this manual to help manufacturers increase their knowledge of medical device
GMP requirements and FDA compliance policies. DSMA also uses this manual at quality system
workshops conducted throughout the country.
The Quality System regulation outlines the minimum elements of a system for designing and
producing a medical device. Manufacturers of medical devices commonly find that their quality
needs are broader than these basic elements because of the additional need to meet company
quality claims as required by paragraph 501(c) of the Federal Food, Drug, and Cosmetic (FD&C)
Act and to meet customer needs and requirements.
The DSMA staff and the Office of Compliance (OC) in the Center for Devices and Radiological
Health (CDRH) provided valuable assistance in preparing this manual.
For further information, contact the appropriate office within CDRH or call DSMA at 800-6382041, 301-443-6597 or FAX 301-443-8818. Comments on this manual, related workshops, and other
DSMA activities are always welcome.
Lireka P. Joseph, Dr.P.H.
Director
iii
Office of Health and Industry Programs
NOTE TO MANUFACTURERS OF MEDICAL DEVICES
The Quality System (QS) regulation indicates the required end result rather than specifically
prescribing how a manufacturer is to comply with this regulation. It is the responsibility of the
manufacturer to use good judgment when developing a quality system which appropriately applies
the QS regulation to their specific products and operations. The manufacturer, not FDA, bears
overall responsibility for the production of high-quality products.
Nevertheless, FDA recognizes that manufacturers may benefit from having guidance, model
procedures, and sample forms that others have developed or adopted in an effort to comply with
the intent of the regulation. The guidance in this manual includes discussion on the entire QS
regulation, plus it provides multiple examples of procedures and forms which can be adopted and
modified by manufacturers as appropriate.
We have included a variety of model procedures and sample forms in this manual. However,
these are not meant to be official statements of FDA policy. Rather, they represent a compilation of
examples that firms may find useful in understanding how some manufacturers have successfully
complied with QS and/or GMP requirements. Before any model procedure or form is adopted into
a quality system program, the applicability and suitability to a particular device and
manufacturing operation should be carefully examined. This manual will assist you in developing a
quality system that meets the intent of the FDA Quality System regulation.
FDA also recognizes the continuing need to use innovative approaches, particularly in dealing
with small businesses that could be unnecessarily adversely affected by federal regulations. It is
hoped that the information in this manual will assist manufacturers in their efforts to establish and
maintain a quality system that enhances business. The Office of Compliance at 301- 594-4692 or
DSMA at 800-638-2041, FAX 301-443-8818, can be contacted for additional assistance and
information.
This manual can be purchased from the Superintendent of Documents, U.S. Government
Printing Office, Washington D.C. 20402, telephone 202-512-1800, and from the National Technical
Information Service, U.S. Department of Commerce, 5285 Port Royal Road, Springfield, VA
22161, telephone 703-487-4650. This manual is also available to all manufacturers through the
World Wide Web at: http:\\www.fda.gov.
Sincerely yours,
iv
John F. Stigi
Director
Division of Small Manufacturers Assistance
v
ABSTRACT
A. Lowery, J. Strojny, and J. Puleo, Project Officers. Division of Small Manufacturers Assistance,
Office of Health and Industry Programs. Medical Device Quality Systems Manual: A Small Entity
Compliance Guide. HHS Publication FDA 97-4179 (December 1996).
This manual covers requirements of the Quality System regulation that
manufacturers of medical devices must consider when they design devices, or
when they manufacture, contract manufacture, remanufacture, process, repack,
or relabel finished medical devices intended to be commercially distributed. The
manual contains articles that explain the various good manufacturing practices
(GMP) requirements such as design controls, process validation, calibration,
device master records, component control, etc., along with related topics such as
labeling. It also contains examples of forms, procedures, decals, etc.
Manufacturers may use this guidance when developing their quality system.
This manual incorporates changes required by the Safe Medical Devices Act of
1990 and the Medical Device Amendments of 1992. This manual is an update of
HHS publication FDA 91-4179, “Medical Device Good Manufacturing Practices
Manual, Fifth Edition.”
This manual is used in the Division of Small Manufacturers Assistance (DSMA)
medical device workshops.
The mention of commercial products, their sources, or their use in connection with material
reported herein is not to be construed as either an actual or implied endorsement of such
products by the Department.
The educational information in this manual is not an official statement binding FDA.
Although this guidance document does not create or confer any rights for or on any
person and does not operate to bind FDA or the public, it does represent the agency’s
current thinking on guidance for quality systems.
Where this document reiterates a requirement imposed by statute or regulation, the
force and effect as law of the requirement is not changed in any way by virtue of its
inclusion in this document.
1-vi
CONTENTS
Foreword ...................................................................................................................................... ii
Preface .................................................................................................................................... iii
Abstract ..................................................................................................................................... iv
Note to Manufacturers of Medical Devices .................................................................................v
1.
The Quality System Regulation .................................................................................... 1-1
2.
Quality Systems ................................................................................................................ 2-1
3.
Design Controls ................................................................................................................ 3-1
4.
Process Validation ............................................................................................................ 4-1
5.
Personnel .......................................................................................................................... 5-1
6.
Buildings and Environment ............................................................................................ 6-1
7.
Equipment and Calibration ............................................................................................ 7-1
8.
Device Master Record ..................................................................................................... 8-1
9.
Document and Change Control....................................................................................... 9-1
10. Purchasing and Acceptance Activities ............................................................................ 10-1
11. Labeling .......................................................................................................................... 11-1
12. Product Evaluation ........................................................................................................ 12-1
13. Packaging ........................................................................................................................ 13-1
14. Storage, Distribution and Installation ......................................................................... 14-1
15. Complaints ...................................................................................................................... 15-1
16. Servicing ......................................................................................................................... 16-1
17. Quality Systems Audits .................................................................................................. 17-1
18. Factory Inspections......................................................................................................... 18-1
Appendixes
Quality System Regulation ..................................................................................................... 19-1
Application of the Medical Device GMPs to Computerized Devices
and Manufacturing Processes ............................................................................................ 19-21
1-vii
1
THE QUALITY SYSTEM REGULATION
INTRODUCTION ................................................................................................................ 1-1
FLEXIBILITY OF THE GMP ........................................................................................... 1-2
MANUAL CONTENTS ....................................................................................................... 1-3
GMP APPLICATIONS AND EXEMPTIONS ................................................................. 1-4
Exemptions ..................................................................................................................... 1-4
Component Manufacturers ........................................................................................... 1-5
Remanufacturers ........................................................................................................... 1-6
Custom Device Manufacturers ..................................................................................... 1-6
Contract Manufacturers ............................................................................................... 1-6
Contract Testing Laboratories ..................................................................................... 1-6
Repackagers, Relabelers, and Specification Developers ............................................ 1-7
Initial Distributors of Imported Devices ...................................................................... 1-8
INTRODUCTION
The current Good Manufacturing Practices (GMP) requirements set forth in the Quality System
(QS) regulation are promulgated under section 520 of the Food, Drug and Cosmetic (FD&C) Act.
They require that domestic or foreign manufacturers have a quality system for the design and
production of medical devices intended for commercial distribution in the United States. The
regulation requires that various specifications and controls be established for devices; that devices
be designed under a quality system to meet these specifications; that devices be manufactured under
a quality system; that finished devices meet these specifications; that devices be correctly installed,
checked and serviced; that quality data be analyzed to identify and correct quality problems; and
that complaints be processed. Thus, the QS regulation helps assure that medical devices are safe
and effective for their intended use. The Food and Drug Administration (FDA) monitors device
problem data and inspects the operations and records of device developers and manufacturers to
determine compliance with the GMP requirements in the QS regulation.
The QS regulation is in Part 820 of Title 21 of the Code of Federal Regulations (CFR). This
regulation covers quality management and organization, device design, buildings, equipment,
purchase and handling of components, production and process controls, packaging and labeling
control, device evaluation, distribution, installation, complaint handling, servicing, and records. The
preamble describes the public comments received during the development of the QS regulation and
describes the FDA Commissioner's resolution of the comments. Thus, the preamble contains
valuable insight into the meaning and intent of the QS regulation.
The QS regulation is reprinted in the appendix of this manual.
1-1
FLEXIBILITY OF THE GMP
Manufacturers should use good judgment when developing their quality system and apply those
sections of the QS regulation that are applicable to their specific products and operations. Section
820.5 of the QS regulation requires that, "Each manufacturer shall establish and maintain a quality
system that is appropriate for the specific device(s) designed or manufactured, and that meets the
requirements of this part." The word "appropriate" means that the rule is a flexible regulation.
However, if manufacturers decide to not implement certain GMP requirements which are qualified
by the term “where appropriate,” they should document their justification for nonimplementation.
The justification should show that not implementing a requirement is not reasonably expected to
result in product that does not meet specifications or failure to carry out any necessary corrective
action [820.1(a)(30]. Operating within this flexibility, it is the responsibility of each manufacturer to
establish requirements for each type or family of devices that will result in devices that are safe and
effective, and to establish methods and procedures to design, produce, and distribute devices that
meet the quality system requirements. FDA has identified in the QS regulation the essential elements
that a quality system shall embody for design, production and distribution, without prescribing
specific ways to establish these elements. Because the QS regulation covers a broad spectrum of
devices and production processes, it allows some leeway in the details of quality system elements. It
is left to manufacturers to determine the necessity for, or extent of some quality elements and to
develop and implement specific procedures tailored to their particular processes and devices. For
example, if it is impossible to mix up labels at a manufacturer because there is only one label or one
product, then there is no necessity for the manufacturer to comply with all of the GMP requirements
under device labeling.
The medical device QS regulation requires an "umbrella" quality system intended to cover the
design, production, and distribution of all medical devices from simple surgical hand tools to very
complex computerized axial tomography (CAT) scanners. It is not practical for a regulation to
specify details of quality system elements for such a wide range of products. Rather, the QS
regulation specifies general objectives such as use of trained employees, design reviews, design
validation, calibrated equipment, process controls, etc., rather than methods, because a specific
method would not be appropriate to all operations.
In most cases, it is left to the manufacturer to determine the best methods to attain quality
objectives. In some cases, however, the QS regulation does specify the particular type of method to
be used, such as written procedures or written instructions. This does not mean, however, that
manufacturers cannot vary from the method specified if the intent of the GMP requirement can be
met by another method such as using an engineering drawing plus a model device as manufacturing
instructions. Written procedures are not restricted to paper copies. Written procedures may be
filed and distributed by automated data processing equipment. This flexibility is allowed by section
820.180.
Typically, large manufacturers will have a quality system that exceeds the medical device QS
regulation. Small manufacturers will typically have a proportionally simpler system. FDA
recognizes: that a small manufacturer may not need the same amount of documentation that a large
manufacturer does in order to achieve a state-of-control; and, that some of records maintained to
fulfill the GMP requirements for written procedures may not be as long and complex for a small
manufacturer.
1-2
After a manufacturer establishes a quality system, it should be maintained. Each manufacturer
should assure that with growth and process or product changes their quality system is still adequate.
This assurance is obtained through change control, day-to-day observance of operations, and by
periodic audits of the quality system. The auditor should first identify the elements of the company's
quality system. Next the audit should determine how well each element is functioning, and then
determine its adequacy with respect to the intent of the device GMP requirements and meeting the
company's quality claims.
MANUAL CONTENTS
To aid auditors, QA managers, and others, this manual provides guidance in the interpretation
of the GMP requirements, and demonstrates the flexibility of the QS regulation in its application to
diverse devices, manufacturing processes, and manufacturers. In the absence of guidance from FDA,
manufacturers may rely on industry, national, and international consensus standards or guidances
to meet GMP requirements.
This manual was also developed to aid manufacturers in completing, maintaining, or expanding
their quality system. Contents include educational materials, aids, and examples of how to
implement elements of a quality system, together with detailed examples of procedures, control
forms, and associated data. The examples of typical procedures, drawings, and forms found in this
manual were derived from quality systems in the device industry. These materials are not meant to
describe universally applicable elements of a quality system that can be used unchanged by any
manufacturer. Of course, a form or aid as presented in this manual may be suitable for direct use
for a specific device and operation; however, in general, manufacturers will need to use care in
adopting and modifying a selected form or procedure to meet the specific quality system needs of
their devices and operations.
This manual is arranged as if the reader were starting a new business. That is, as if an entrepreneur
were sequentially:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
obtaining information on GMP requirements;
determining the appropriate quality system needed to control the design, production and
distribution of the proposed device;
designing products and processes;
training employees;
acquiring adequate facilities;
purchasing and installing processing equipment;
drafting the device master record;
noting how to change the device master records;
procuring components and materials;
producing devices;
labeling devices;
evaluating finished devices;
packaging devices;
distributing devices;
processing complaints and analyzing service and repair data;
servicing devices;
auditing and correcting deficiencies in the quality system; and
1-3
18. preparing for an FDA inspection.
If manufacturers perform these activities as required by the QS regulation and as expounded in
this manual, they should be prepared for a GMP inspection of their operations by an FDA
investigator.
Manufacturers and importers of medical devices shall also comply with the Medical Device
Reporting (MDR) regulation, 21 CFR Part 803, which requires that serious complaints be reported
to FDA. MDR is related to the GMP complaint and failure investigation requirements, which are
covered in Chapter 15. If manufacturers comply with the QS regulation and guidance in this manual
and in other sources, there is a high probability that they will reduce the frequency of reportable
events.
GMP APPLICATIONS AND EXEMPTIONS
The QS regulation applies to finished devices intended to be commercially distributed for human
use unless there is an approved exemption in effect. GMP exemptions are codified in the
classification regulations 21 CFR 862 to 892. The exemption of most Class I devices from design
controls is in section 820.30(a).
Certain components such as blood tubing and major diagnostic x-ray components are considered
by FDA to be finished devices because they are accessories to finished devices. The manufacturer of
such accessories is subject to the QS regulation when the accessory device is labeled and sold
separately from the primary device for a health-related purpose to a hospital, physician, or other
user.
The designation of a device as a "custom" or “customized” device does not confer a GMP
exemption.
Contract manufacturers and specification developers shall comply with the sections of the QS
regulation that apply to the functions they perform.
Contract test laboratories are considered an extension of a manufacturer's quality system and
presently are not routinely scheduled for GMP inspections. The finished device manufacturer shall
meet the requirement of the QS regulation, particularly 820.50, Purchasing, when they obtain
products or services. Internal test laboratories, however, that are part of a corporate manufacturer
that provides services to individual corporation factories should meet GMP requirements. Internal
laboratories are inspected as part of the FDA GMP inspection of the member factories.
Situations are discussed in the remainder of this chapter where various manufacturers are
exempt from the QS regulation or are not routinely inspected. However, these manufacturers are
still subject to the FD&C Act. If these manufacturers or any manufacturer render devices unsafe or
ineffective, the devices are adulterated and/or misbranded and the manufacturers are subject to the
penalties of the FD&C Act.
Exemptions
1-4
FDA has determined that certain types of establishments are exempt from GMP requirements;
and
FDA has defined GMP responsibilities for others. Exemption from the GMP requirements does not
exempt manufacturers of finished devices from keeping complaint files (820.198) or from general
requirements concerning records (820.180). Sterile devices are never exempted from GMP
requirements. A device that normally would be subject to GMP requirements may be exempt under
the following conditions:
•
When FDA has issued an exemption order in response to a citizen's petition for exemption,
•
When FDA, in the absence of a petition, has exempted the device and published the
exemption in the Federal Register,
•
When the device is exempted by FDA classification regulations published in the Federal
Register and codified in 21 CFR 862 to 892,
•
When the device is an investigational intraocular lens (IOL) and meets the requirements of
the investigational device exemption (IDE) regulation for IOL's, and
•
Through a policy statement, FDA may decide not to apply GMP requirements to some types
of devices and processes although the devices may not have been exempted from GMP
requirements.
Manufacturers should be aware of the GMP exemption status of their devices. In addition,
manufacturers should keep on file records of any specific GMP exemption granted to them by FDA.
Upon request during a factory visit, the exemption records need to be shown during normal business
hours to the FDA investigator in order to verify that an exemption has been granted.
Component Manufacturers
A "component" is defined by 820.3(c) as "any raw material, substance, piece, part, software,
firmware, labeling, or assembly which is intended to be included as part of the finished, packaged,
and labeled device.” Component manufacturers are excluded from the QS regulation by 820.1(a)(i).
Current FDA policy is to rely upon the finished device manufacturer to assure that components are
acceptable for use. Component manufacturers are not routinely scheduled for GMP inspections;
however, FDA encourages them to use the QS regulation as guidance for their quality system.
When finished device manufacturers produce components specifically for use in medical devices
they produce, whether in the same building or another location, such production of components is
considered part of the device manufacturing operations, and the production should comply with the
QS regulation.
1-5
Accessory devices [807.20(a)(5)] such as hemodialysis tubing or major diagnostic x-ray
components, that are packaged, labeled, and distributed separately to a hospital, physician, etc., for
health-related purposes are sometimes inappropriately referred to as components. However, FDA
considers them finished devices because they are suitable for use or capable of functioning and are
distributed for health-related purposes; and the QS regulation applies to their manufacture.
Similarly, a device or component including software that is sold as an addition to a finished medical
device to augment or supplement its performance is also termed an accessory. An accessory to a
medical device is considered a finished device and, therefore, is subject to the QS regulation.
Remanufacturers
A remanufacturer is any person who processes, conditions, renovates, repackages restores or
does any other act to a finished device which has been previously distributed to significantly change
the finished device’s performance or safety specifications or intended use from that established by
the original finished device manufacturer. Remanufacturers are considered manufacturers. As such,
these manufacturers are subject to inspection by FDA and shall meet the applicable requirements of
the medical device QS regulation. These manufacturers shall establish and implement quality
systems to assure the safety and effectiveness of the devices that are distributed. Such activities
include drafting of master records, rebuilding per the master records, inspection and testing,
calibration of measurement equipment, control of components, updating of labeling, processing of
complaints, and any other GMP requirement applicable to the activities being performed.
Remanufacturers are also required to comply with the labeling requirements of 21 CFR 801.1(c).
This labeling regulation requires that where the person or manufacturer named on the label of the
device is not the original manufacturer, the name shall be qualified by an appropriate phrase which
reveals the connection that person has with the device, e.g., remanufactured by XYZ Company.
Custom Device Manufacturers
Section 520(b) of the FD&C Act and the IDE regulation (21 CFR Part 812) define a custom
device. Custom devices are exempt from certain statutory requirements. For example,
manufacturers of custom devices are not required to comply with premarket approval requirements
(Section 515) and are exempt from premarket notification requirements [Section 510(k)]. Custom
devices are NOT exempt from the GMP requirements. Current FDA policy, however, is to not
inspect manufacturers of custom devices. Manufacturers of custom devices should comply with the
GMP requirements while considering the flexibility allowed.
Contract Manufacturers
A person(s) that manufactures a finished device under the terms of a contract with another
manufacturer is a contract manufacturer. The agreement between the manufacturers should be
documented in a written contract. Contract manufacturers of finished devices shall comply with
applicable requirements of the quality system and shall register their establishment with FDA.
Depending on the circumstances, both the contractor and manufacturer may be held jointly
responsible by FDA for the activities performed.
Contract Testing Laboratories
1-6
Contract laboratories that designs or test components or finished devices for a manufacturer are
considered an extension of the manufacturer's quality system. These laboratories may provide
services to a number of customers, many of which are not medical device manufacturers. These
contract laboratories are not subject to routine GMP inspections. Through the conduct of quality
audits or other means, the finished device manufacturer is responsible for assuring that equipment
and procedures used by a lab are adequate and appropriate (820.50). However, an internal test
laboratory, if part of a manufacturer that does testing for various facilities within the corporation, is
subject to inspection when FDA GMP inspections are conducted at the individual manufacturing
facilities. That is, the test laboratory is simply a part of a medical device manufacturer of which all
device-related divisions shall comply with the QS regulation.
Repackagers, Relabelers, and Specification Developers
Repackaging and relabeling of a device and specification development are defined as
manufacturing in 21 CFR Part 807, Establishment Registration and Device Listing for
Manufacturers of Devices. Some definitions from 807.3(d) are reprinted below because they affect
the applications of the QS regulation.
(d) "Manufacture, preparation, propagating, compounding, assembly, or processing" of a device
means the making by chemical, physical, biological, or other procedures of any article that meets the
definition of a device in section 201(h) of the Act.
These terms include the following activities:
(1) Repackaging or otherwise changing the container, wrapper, or labeling of any device
package in furtherance of the distribution of the device from the original place of
manufacture to the person who makes final delivery or sale to the ultimate consumer;
(2) Initial distribution of imported devices; or
(3) Initiation of specifications for devices that are manufactured by a second party for
subsequent commercial distribution by the person initiating specifications.
As defined above, repackaging and relabeling are manufacturing operations. Further, a
repacker, repackager or relabeler is a manufacturer per 820.3(o) and subject to the applicable
requirements of the QS regulation. Individuals are repackers or relabelers if they:
•
package and/or label previously manufactured finished devices or accessories;
•
receive finished devices in bulk (e.g., surgical tubing, syringes, media, etc.,) and repacks them
into individual packages and label them;
•
receive previously manufactured devices that have been packaged and labeled by another
manufacturer, and combine them into a kit with other unpackaged devices which are
received in bulk.
Individuals are not considered repackers or relabelers or a manufacturer for purposes of
applying the QS regulation if they pack only previously packaged and labeled individual devices into
1-7
packages for the convenience of the user. (Note that this activity is essentially the same as a drug
store employee placing packaged items into a bag labeled with the name of the drug store.)
A distributor who only adds a label bearing their name and address is exempt from the GMP
requirements. A manufacturer simply affixing a sticker label bearing the distributor's name and
address would not require record keeping demonstrating compliance with labeling controls
requirements.
Specification developers provide specifications to contract manufacturers, who produce devices
to meet the specifications. The contract manufacturer may package and label the device, or the
finished device may be shipped to the specification developer for packaging and labeling.
Specification developers are manufacturers and are subject to the GMP requirements that apply
to the activities they conduct, such as various design controls including correct transfer of the design
information to a contract manufacturer [820.30(h)]. This activity, in turn, requires an adequate
device master record (820.181) and adequate change control [820.40(b)]. Further, if the product
carries the specification developer's label, the developer is responsible for maintaining a complaint
file and processing complaints, plus maintaining the device specifications and other appropriate
documents in the device master record.
Initial Distributors of Imported Devices
The initial distributor is the foreign manufacturer’s official correspondent with the FDA. With
regards to the GMP, this initial distributor is responsible for maintaining complaint files and
general record keeping requirements. A procedure shall be established and maintained for
receiving, reviewing, and evaluating complaints. All complaints, including oral complaints, are to be
processed in a uniform and timely manner. These complaints shall be evaluated to determine
whether or not they require reporting to FDA under 21 CFR part 804 or 803, Medical Device
Reporting. The initial distributor is also required to evaluate all complaints to determine whether
an investigation is necessary, as well as complying with all other requirements in 820.198, Complaint
Files. See Chapter 15 in this manual for more complete guidance on handling complaints.
1-8
2
QUALITY SYSTEMS
INTRODUCTION .................................................................................................................... 2-1
QUALITY SYSTEM PRACTICES ........................................................................................ 2-3
Design Controls .................................................................................................................... 2-3
Component Selection ........................................................................................................... 2-5
Labeling Content .................................................................................................................. 2-5
Process Quality ..................................................................................................................... 2-5
Management Responsibility ................................................................................................ 2-6
Formal and Documented Quality System .......................................................................... 2-7
Approval of Product ............................................................................................................ 2-8
Quality Acceptance Activities ............................................................................................. 2-8
Quality System Audits ......................................................................................................... 2-8
Employee Training .............................................................................................................. 2-8
QUALITY SYSTEM MAINTENANCE ................................................................................ 2-9
MEDICAL DEVICE REPORTING ..................................................................................... 2-10
INTRODUCTION
The Quality System (QS) regulation requires that each manufacturer shall establish and maintain
a quality system that is appropriate for the specific medical device(s) designed or manufactured
(820.5 and 820.20). The GMP requirements are harmonized with the International Organization for
Standards (ISO) 9001:1994 and ISO DIS 13485. The quality system should be an integrated effort -a total systems approach, to satisfy the particular safety and performance needs of a specific
manufacturer, product, and user-market. The quality assurance (QA) activities do not simply
consist of inspection and testing spot solutions or "fire-fighting,” no matter what the product is or
how small the manufacturer. In all cases, quality should be considered at the earliest stages in every
significant area that has an effect on the quality, safety, and effectiveness of the device. These areas
include product development, design verification and validation, component and/or supplier
selection, documentation, development of labeling, design transfer, process development and
validation, pilot production, routine manufacturing, test/inspection, device history record
evaluation, distribution, service or repair, and complaints. Complaints and, of course, favorable
comments constitute customer feedback that may result in improvements in the device, labeling,
packaging or quality system.
Most important of all is management commitment. Management and employees should have the
correct attitude if their quality system program is to be effective. Quality consciousness should be
developed in every employee. Each person should be made aware of the importance of his or her
individual contributions in the overall effort to achieve an acceptable level of quality.
After a quality system is in place and checked, it should not be allowed to stagnate -- it should
continue to be dynamic. The system remains dynamic through continuous feedback, "big-picture"
monitoring by system audits, management review, and corrective and preventive action. Sufficient
2-1
personnel with necessary education, background, and experience should be in all departments to
ensure that quality system activities are properly and adequately performed.
The result is an organization that is operating in a known state-of-control for the device design,
process design, manufacturing processes, and records. A properly functioning quality system results
in increased safety and effectiveness of the device, reduced liability exposure, reduced regulatory
exposure, increased customer satisfaction, less scrap, lower costs, much less confusion, higher
employee morale, and, as a result, higher profits.
There are several QA systems in common use, including quality control, good manufacturing
practices, product design assurance, the ISO 9000 series of international QA standards, and total
quality assurance. Quality control is a minimal system which emphasizes test and inspection. The QS
regulation is a government mandated QA system for medical device manufacturers. It emphasizes
device, labeling, packaging and process design and all aspects of production: facilities, equipment,
design development, design and production documentation, correct design transfer, production
control, production records and feedback. Total quality assurance is a system which emphasizes
that: all employees and suppliers are responsible for their activities; design requirements are
established and met; process requirements are established and met; all production activities are
controlled; finished product specifications are met; and feedback results in appropriate corrections.
Product design assurance is a QA system which assures that customer needs are determined, and
that product design requirements are established and met. The ISO 9000 series of QA standards
ranges from basic quality control to very significant design and production systems.
ISO 9001 is the most comprehensive because it covers design, production, servicing and
corrective/preventive activities. The FDA GMP requirements are slightly more extensive because
they include extensive coverage of labeling, and complaint handling.
FEEDBACK
An ideal system for quality assurance is discussed in order to explain the concept of a system. An
ideal QA system is composed of an organization that executes a QA program according to
documented policy and specifications in order to achieve stated objectives as shown in Figure 2.1.
1.
Management Policies
2.
Objectives
3.
Organization
4.
Documentation
o
Perform task per policy
o
Monitor
o
Customer
Figure 2.1 Elements of a Quality System
The written policies and objectives are set by management and are influenced by outside factors
such as customer requirements, standards, and regulations. For example, the customer requirements
and needs and resulting device specifications should be known to be correct, as these are based on
market
2-2
research, technical and medical considerations, consensus standards, review of existing devices,
environmental and compatibility considerations, and design review. The objectives are to produce
safe and effective devices at a profit. Ideally, the quality system includes everyone in the company as
everyone is fully committed to the quality system program. In addition, however, quality assurance
departments such as design QA and production QA are established to help achieve specific
objectives. Tasks to be performed to meet these objectives are described in procedures and other
documents.
Documentation for a quality system is composed of: product-specific technical documentation
such as engineering drawings, component purchase specifications, procedures for manufacturing
processes and testing; labels, etc.; and general quality system documentation, such as standard
operating procedures (SOP's) for employee training, audits, etc., that are applicable for all products.
All activities and product quality are monitored; and any deviations from device and process
specifications and company policies are fed back into the system where the deviations are corrected.
Likewise, complaint and service information are processed and fed back for appropriate corrections.
If the required activities including the feedback are performed, the quality system is self correcting
and, thus, the manufacturer is operating in a state-of-control. FDA requires manufacturers of
medical devices to operate in a state-of-control.
QUALITY SYSTEM PRACTICES
An adequate and properly implemented quality system such as the one required by the QS
regulation or ISO 9001, because of its broad scope, has a high likelihood of preventing the design,
manufacture, and shipment of defective products. Basic quality controls such as inspection and
testing, are important parts of a quality system because they provide information that should be fed
back into the program where action can be taken to correct root causes of quality problems.
Identifying and solving quality problems is a core requirement of the QS regulation. This approach
is in contrast to merely applying superficial corrections by pass/fail quality-control inspection
including rework of finished product or in-process assemblies.
Feedback is necessary to verify the adequacy of the design, manufacturing processes, and the
controls used. It also helps trigger corrective action to solve root causes of quality problems rather
than just performing rework.
Design Controls
Each manufacturer is required by regulation to establish and maintain design control procedures
for any class III or class II device, and a selected group of class I devices. The class I devices subject
to design controls are devices automated with computer software and the following specific devices:
SECTION
DEVICE
868.6810
Catheter, Tracheobronchial Suction
878.4460
Glove, Surgeon’s
880.6760
Restraint, Protective
892.5650
System, Applicator, Radionuclide, Manual
892.5740
Source, Radionuclide Teletherapy
Because the intrinsic quality level of devices and processes is established during the design phase,
the quality system program should include this phase if the program is to assure overall quality,
2-3
meet customer requirements, meet company quality claims, and comply with the intent of the FD&C
Act. The terms "product assurance" and "design QA" are often used to identify the quality system
activities related to product design. The QS regulation uses the term “design controls.” A product
assurance system or design QA system combined with a production QA system constitutes a total
quality system.
Quality system, production, regulatory, and other appropriate personnel should participate in the
review, evaluation, and documentation of the components, device, and process design. It is from data
established during this preproduction phase that all other activities derive such as, purchasing,
processing, and testing. Development and validation data are also useful in cases of regulatory or
product liability actions to show that the design and manufacturing processes were well conceived
and properly validated, reviewed, and documented.
Total quality systems extend from customer requirements through development and production
to customer use and feedback. Thus total quality systems encompass the medical device law and
regulations, particularly the QS regulation. The FD&C Act, and its implementing regulations such
as those for Labeling, Premarket Notification, Investigational Device Exemptions (IDE), Premarket
Approval (PMA), and GMP requirements impact the quality of devices at various times during the
design product life-cycle. The IDE, PMA, 510(k), labeling and QS regulation with their
preproduction and production requirements constitute a total quality system. For example, Section
501(c) of the Act states that a product is adulterated if it does not have a quality equal to the quality
stated or implied by the product labeling. Analysis of device recall problem data by FDA has shown
that such problems are divided almost equally between design and production. Thus, a production
quality assurance program is not sufficient to produce safe and effective devices -- design shall also
be covered. A design quality assurance system is required by the QS regulation.
Two other reasons for having a total quality system are 21 CFR Part 803, Medical Device
Reporting (MDR), and product liability. MDR requires manufacturers of medical devices to report
to FDA certain adverse events that they receive from any source. Product liability actions are often
the result of poor design, labeling, and manufacturing. Reporting and liability exposure are reduced
by using a total quality system.
Intrinsic or desired quality is established by the design specifications for the product, its
components, and the manufacturing processes. Complying with the QS regulation assures that the
manufacturing processes can consistently achieve desired levels of quality and that the finished
device meets its device master record specifications. This result is a significant quality step.
However, if the device as designed is of poor quality, the GMP production controls will only assure
that a poor quality device is manufactured. Thus, the QS regulation requires an overall quality
system program, which embraces evaluation of customer needs; product design; verification and
validation; labeling development and control; all manufacturing and control activities; and
customer feedback.
Component Selection
Component and raw material specifications developed during the design phase should be well
conceived and adequate for their intended purpose. New components or components for an unusual
application need to be verified (qualified) for the intended use. In some cases, where large quantities
of components or raw materials are involved, the specifications should include valid and well
2-4
understood methods of sampling and acceptance. These specification and sampling/acceptance plans
should also be accessible and acceptable to suppliers. The specifications are device master record
(DMR) spec document or the specifications appear in a DMR drawing or procedure.
Manufacturers shall establish and maintain procedures to ensure their purchased and otherwise
received products and services conform to their specified requirements. The manufacturers shall
then assess their suppliers, contractors, and consultants based on their ability to meet the established
specifications. When possible, an agreement shall be established to include that the suppliers,
contractors, and consultants will notify the manufacturer of any changes in the product or service
that may affect the quality of a finished device.
Labeling Content
The regulations in 21 CFR Part 801, Labeling; Part 809, In Vitro Diagnostic Products for Human
Use; and Part 812, Investigational Device Exemptions, are intended to control the content of
labeling. Likewise, 21 CFR Part 807, Premarket Notification; and Part 814, Premarket Approval
and 820.30, Design Controls, help control the content of labeling by design and premarket
submissions. The intent of these regulations and the FD&C Act is for manufacturers to have a
labeling control program such that their labeling always complies with the regulations and meets the
needs of the users. By a formal process under a total quality system during the design phase, clear
and concise printed and/or software labeling are written and reviewed; and the ink substrate and
attachment methods for printed labeling are developed. Such labeling is designed to meet customer
and regulatory requirements. Thereafter, the procurement, use of the correct label, and the correct
attachment of labels is assured under a manufacturer's quality system elements for these activities.
Process Quality
Manufacturing methods and processes to be used should be developed, equipment selected, and
processes and methods qualified. For all significant processes such as welding, molding, lyophilizing,
sterilizing, and packaging/sealing where the output cannot be fully verified, the qualification should
include a full validation of the processes. The output may not be fully verified for economic,
technical, or practical reasons and thus validation is needed. Production specifications and methods
employed in manufacturing should result in standard in-process and finished products without
excessive sorting or reprocessing. Inspection and test methods should be developed that will
adequately monitor product characteristics to make certain these are within the acceptable
specifications. These methods should be developed, evaluated, validated where necessary, and
documented during the product and process development phase. The methods should be
implemented at the beginning of routine production.
Any adverse effects the manufacturing processes, manufacturing materials, or equipment may
have on device safety and performance should be identified. Where necessary, procedures have to be
developed, implemented, and monitored to control these characteristics. Quality system personnel
should participate in the timely (i.e., early) development of special controls, test or inspection
methods, or training programs needed to insure product quality. Acceptance methods should be
developed for accurate measurement of outgoing product quality.
Management Responsibility
2-5
As set forth by the QS regulation (820.20), one of the most important responsibilities of
management when developing a quality system is to establish its policy and objectives for, and
commitment to, quality. Management with executive responsibility shall ensure that the quality
policy is understood, implemented, and maintained at all levels of the organization. This means each
manufacturer shall establish the appropriate responsibility, authority, and interrelation of all
personnel who manage, perform, and assess work affecting quality, and provide the independence
and authority necessary to perform these tasks. The QS regulation also requires that each
manufacturer shall establish and maintain an adequate organizational structure to ensure that
devices are designed and produced in accordance with the GMP requirements. To meet these
regulatory requirements, manufacturers are required to provide adequate resources, including the
assignment of trained personnel for management, performance of work, and assessment activities,
including internal quality audits.
Management with executive responsibility shall appoint a member of management who will have
authority over and responsibility for:
•
•
Ensuring that quality system requirements are effectively established and effectively
maintained; and
Reporting the performance of the quality system to management with executive responsibility
for review.
Thus, the QS regulation requires that management with executive responsibility shall review the
suitability and effectiveness of the quality system at defined intervals and with sufficient frequency
according to established procedures to ensure that the quality system satisfies the regulatory
requirements and the manufacturer’s established quality policy and objectives. The dates and
results of quality system reviews shall be documented.
The quality assurance personnel should be able to identify system problems, to recommend and
provide solutions, and to verify implementation of the solutions. Other personnel may also identify
and solve quality problems. The quality system should support such activities by all personnel.
Feedback from quality assessment activities is necessary to verify the adequacy of the
manufacturing process and the controls used. It also helps trigger corrective action to solve root
causes of quality problems rather than just performing rework.
Typically, a quality system identifies problems with device quality through review of verification
and validation data, inspection/test data, analysis of device history and service records, failure
analysis, analysis of complaints, and review of other objective data. In this regard, reduction in
productivity is often an indicator of quality problems. Low morale and confusion are indicators of
inadequate procedures, and/or training and poor management. Also, measurement of scrap and
rework is an effective method of detecting quality problems and reducing costs. These are examples
of sources that provide feedback to the quality system.
In conclusion, each manufacturer is required to establish a quality plan which defines the quality
practices, resources, and activities relevant to the devices that are designed and manufactured. The
manufacturer shall establish how the requirements for quality will be met [820.20(d)]. Each
manufacturer shall establish quality system procedures and instructions. To facilitate the
understanding, use, review, and updating of the quality system, an outline of the structure of the
documentation used in the quality system shall be established where appropriate [820.20(e)].
2-6
Formal and Documented Quality System
The QS regulation requires that each manufacturer prepare and implement quality system
procedures adequate to assure that a formally established and documented quality system is
implemented The system should include not only formal documentation, but also an obvious
commitment to quality from top management. There should be manifest indications that
management recognizes the need for a quality system in order to assure quality products. In many
manufacturers, this commitment is accomplished through means such as: a management policy;
assignment of responsibilities and authorities; and general statements and actions such as employee
training that define goals of the quality system. This policy is supported by a number of more
detailed quality system documents such as verification methods, sampling procedures,
inspection/test procedures, product audits, and records indicating that measurement and monitoring
of quality has occurred. The number of documents needed depends on the size and complexity of the
operation and the characteristics of the product. The QS regulation requires the manufacturer to
maintain various records such as:
•
•
•
•
•
•
•
•
design history files,
device master records,
device history records,
maintenance schedules and records,
complaint files and failed device/component files,
audit reports,
distribution records, and
personnel training records.
Most of these records are discussed in more detail in later chapters. In each case, the records
should be appropriate for the device and the operation involved. Any changes to device master
records should be made by a formal procedure and be formally approved.
Among other records, the device master record contains manufacturing procedures and
standard operating procedures (SOP's). Some manufacturers tend to write an excessive number of
general SOP's. Manufacturers should not generate and use procedures that are not needed. Also,
standard operating procedures tend to not match actual operations because the operations gradually
change as the company grows or as products are added without amending the procedures. Such
procedures may require operations that have no benefit, or require excessive collection of data, or
collection of data that is never used. Thus, manufacturers need to occasionally flow chart and
analyze their operations to determine, among other things, if the existing procedures are inadequate,
correct, or excessive. Flow-charting is a tool that directs a detailed audit of an operation. Flowcharting to analyze operations is an excellent method for improving operations and the associated
quality system activities. At the end of Chapter 10, Purchasing and Acceptance Activities, an
example of a flow-chart is contained in PA-1004, Procedure for Receiving and Inspection of
Material, integral page 4 of 9.
Approval of Product
The quality system includes procedures for assuring that all products such as components,
packaging, labeling, manufacturing materials, and finished devices have been approved for use; and
2-7
that contracted items and services are suitable [820.50, 820.80]. Likewise, the quality system shall
assure that rejected items are identified and properly disposed [820.90]. Additionally, the quality
system shall assure that production records are reviewed before the product is distributed
[820.80(d)]. These records are part of the device history record. Device history records shall be
reviewed to verify that the operations represented have been properly conducted and that the
records are complete.
Quality Acceptance Activities
The quality system shall determine that all tests and inspections are performed correctly (see
820.80, 820.181, and 820.20). Some of the methods used to accomplish this are adequate test and
inspection procedures, training of test personnel, quality system audits, review of quality system
records, and product audits. However, simply instituting a quality system and checking that it is
conducted correctly is not enough to satisfy the QS regulation. The regulation also requires that the
quality system be appropriate and adequate for the purpose. This determination should be done
during final product development, pilot production, and, of course, whenever product and/or
processes are modified. In cases where conformance to specifications cannot be adequately measured
by in-process or finished product testing and inspection, the system should include validation of
processes.
Quality System Audits
The QS regulation requires (820.20) that each manufacturer shall prepare and implement
quality system procedures adequate to assure that a formally established and documented quality
system program is performed. Many activities are required to fulfill this requirement. As
management performs their assigned routine duties, they should be aware of the obvious aspects of
the quality system. However, to make sure that all aspects, obvious, hidden or subtle, of the required
program exist and are operating correctly, the QS regulation requires planned and periodic audits
(820.22) of the quality system. Management with executive responsibility reviews audit reports as
part of their review of the suitability and effectiveness of the quality system.
Employee Training
QS regulation requires quality awareness training for manufacturing and quality system personnel
[820.25(b)]. Personnel involved in quality system activities shall be properly trained, both by
education and experience. No matter how effective quality system and production systems are as
concepts, people still play the major role in producing a quality product. Lack of training -- as
reflected in instances of negligence, poor operating techniques, or inability of employees to discharge
their functions properly -- can lead to defective products and, sometimes, to regulatory or liability
problems. Management should be diligent in looking for factors that indicate a need for employee
training.
A quality system should include an ongoing formal program for training and motivating all
personnel. All employees should be made aware that product quality is not solely the responsibility
of management. Quality is the responsibility of every employee -- any employee can potentially
generate a quality problem through negligence. It is extremely important to understand the
following points with respect to typical quality-related functions.
2-8
•
Top management sets the quality attitude for the company.
•
Research and development has primary responsibility for designing quality into the device.
•
Technical services or an equivalent functional group has primary responsibility for
documenting the design.
•
Manufacturing, process or "scale-up" engineering has primary responsibility for designing
quality into the manufacturing processes.
•
Manufacturing personnel have primary responsibility for producing devices that have the
maximum level of quality that can be achieved based on the product and process designs.
•
Quality system personnel have primary responsibility for the program’s management, status
reports, audits, problem identification, data analysis, etc., as described in the QS regulation
and in this manual.
A medical device manufacturer should NEVER try to operate on the basis that only the quality
system organization has primary and direct responsibility for the quality of the products. To do so
means that quality problems will not be solved in a timely manner because attention is directed
toward the wrong organization. In reality, it is part of the responsibility of the quality system to see
that attention is directed toward the correct department if a quality problem arises.
Where necessary, employees should be certified to perform certain manufacturing or quality
system procedures. Records of training and/or certification shall be maintained. Personnel
performing quality system functions should:
•
•
•
•
have sufficient, well-defined responsibilities and authority;
be afforded the organizational freedom to identify and evaluate quality problems;
be able to formulate, obtain, and recommend possible solutions for quality system problems;
and,
verify implementation of solutions to quality problems.
QUALITY SYSTEM MAINTENANCE
After the quality system is operational, personnel should continue to look for problem areas or
factors that can have an impact on product quality. Many factors that can have an impact on
product quality include:
•
changes in, or absence of, personnel;
•
uncomfortable working conditions (e.g., breakdowns in air conditioning);
•
increases in workload or production rates;
•
introduction of new production or inspection equipment;
2-9
•
changes in company incentive techniques (e.g., placing hourly employees on piecework can
cause deterioration of product quality); and
•
changes in sources for purchased components and materials, as well as changes in
components, devices, or process techniques.
As noted, quality system audits and flow-charting of operations are excellent methods for
determining the detailed status of the system. Correcting problems or responding to conditions
identified by audits, operational analyses, and customer feedback data can result in quality system
improvements.
MEDICAL DEVICE REPORTING
FDA has promulgated regulations [803] for manufacturers, distributors, and initial distributor(s)
requiring them to establish and maintain reports, including the Medical Device Reporting (MDR)
reports for serious injuries, death, or certain other adverse incidents. If a manufacturer has a
quality system as required by the QS regulation, the frequency of MDR reporting should be
minimized.
2-10
3
DESIGN CONTROLS
INTRODUCTION ............................................................................................................... 3-1
Coverage ........................................................................................................................ 3-2
QUALITY SYSTEM .......................................................................................................... 3-2
Personnel Training ....................................................................................................... 3-3
DESIGN AND DEVELOPMENT PLANNING ............................................................... 3-3
Interface ......................................................................................................................... 3-4
Structure of Plans ......................................................................................................... 3-4
DESIGN INPUT................................................................................................................... 3-5
Input Checklists ............................................................................................................ 3-6
DESIGN REVIEW............................................................................................................... 3-7
Combination Devices .................................................................................................... 3-8
Preparation For Reviews .............................................................................................. 3-8
Why Design Reviews ..................................................................................................... 3-9
Types Of Design Review Meetings .............................................................................. 3-9
Design Review Requirements ..................................................................................... 3-10
End Of Initial Design .................................................................................................. 3-11
DESIGN OUTPUT............................................................................................................. 3-12
Documenting Design Output ...................................................................................... 3-13
Acceptance Criteria .................................................................................................... 3-13
Design Output Approval ............................................................................................ 3-14
DESIGN VERIFICATION AND VALIDATION........................................................... 3-14
Design Evaluation versus Specifications ................................................................... 3-15
Software Validation .................................................................................................... 3-17
Labeling Verification .................................................................................................. 3-18
DESIGN TRANSFER ....................................................................................................... 3-19
DESIGN CHANGES ........................................................................................................ 3-19
DESIGN HISTORY FILE ............................................................................................... 3-20
EXHIBITS ......................................................................................................................... 3-22
Design Input Requirements Procedure ..................................................................... 3-22
INTRODUCTION
The Safe Medical Devices Act of 1990 added design validation requirements to the GMP
requirements in section 520(f) of The Act. Section 820.30 of the Quality System (QS) regulation lists
the design control requirements that manufacturers should satisfy to be in compliance. This chapter
describes design controls and provides guidance to assist manufacturers in complying with design
control requirements.
“Design Control Guidance for Medical Device Manufacturers” is another document that may
assist manufacturers in understanding the intent of the design control requirements. This manual
interprets the language of the QS regulation and explains the underlying concepts in practical terms.
“Do It By Design: An Introduction to Human Factors in Medical Devices” is a document that
3−1
contains background information about human factors as a discipline, describes and illustrates
device problems and discusses human factors principles and methods as a part of the design control
system. Both of these manuals are possible resources for manufacturers who are either developing
or improving their design control system. These manuals are also available through DSMA.
Coverage
The design controls section 820.30 of the QS regulation applies to the design of products, and
processes and changes to existing designs and processes. Changes to existing designs should be made
in accordance with design control requirement even if the original design was not subject to these
requirements. Design controls are not retroactive to completed portions of ongoing design programs.
Each manufacturer of any class III or class II device, and class I devices automated with
computer software and those listed below shall establish and maintain procedures to control the
design of the device in order to make certain that specified design requirements are met.
Manufacturers of other Class I devices should develop and document their devices under their own
design control system because the documentation is needed to help meet the device master record
requirements in 820.181 and marketing submission requirements. Thus, manufacturers of exempt
Class I devices are encouraged to use 820.30, Design Controls, as guidance.
Classification
Section
868.6810
878.4460
880.6760
892.5650
892.5740
All Sect.
Class I Devices Subject to Design Controls Listed in Paragraph 820.30(a)(2)
Catheter, Tracheobronchial Suction
Glove, Surgeon's
Restraint, Protective
System, Applicator, Radionuclide, Manual
Source, Radionuclide Teletherapy
Devices automated with computer software
The design requirements for the device are primarily specified by the manufacturer; however,
FDA has a few design requirements in the 21 CFR Part 801 labeling regulations and in Parts 10001050 which cover radiological and electronic products. A few of the FDA design requirements are in
standards. For example, some parameters for medical gloves are in standards by the American
Society for Testing and Materials (ASTM). (That is, medical gloves are required to meet these
standards in order to be substantially equivalent to gloves already in commercial distribution.)
QUALITY SYSTEM
Each manufacturer is required to establish and maintain a quality system that is appropriate for
the specific medical device(s) designed or manufactured [820.5 and 820.1(a)(3)], and that meets the
requirements of Part 820. Therefore, the details of design control systems will vary depending on the
complexity of the product or process being designed. However, all non-exempt manufacturers
including very small manufacturers and manufacturers that design less complex devices or processes
are expected to define, document and implement design control procedures and other quality system
procedures as called for in the regulation. One of these, a sample design input procedure, is
exhibited at the end of this chapter.
3−2
Manufacturers may establish one design control procedure to cover the various design control
sections in 820.30; or, they may use one or more procedures for each topic. Multiple procedures may
be easier to develop, update and implement. Medium to large manufacturers may have several
additional procedures to support their main design control procedures. Design control procedures
may be part of the quality system records (QSR) noted in section 820.186.
Personnel Training
Personnel training in 820.25 is one of the quality system requirements, which applies to employees
that perform any activity covered by the QS regulation including all design activities.
Manufacturers are required to establish procedures for identifying training needs and making
certain that all personnel are trained to adequately perform their assigned responsibilities. Design
personnel shall be made aware of device defects which may occur from the improper performance of
their specific jobs. In particular, personnel who perform verification and validation activities shall
be made aware of defects and errors that may be encountered as part of their job functions.
Most technical employees need various degrees of training, as appropriate, in the medical device
regulations, safety, labeling, human factors, verification, validation, design review techniques, etc.
DESIGN AND DEVELOPMENT PLANNING
Developing a new device and introducing it into production are very complex tasks. For many
new devices and associated manufacturing processes that use software, these tasks are further
complicated because of the importance of software, and the possibility of subtle software errors.
Without thorough planning, program control, and design reviews, these tasks are virtually
impossible to accomplish without errors or leaving important aspects undone. The planning exercise
and execution of the plans are complex because of the many areas and activities that should be
covered. Some of the key activities are:
•
•
•
•
•
•
•
•
•
•
•
•
and,
•
determining and meeting the user/patients requirements;
meeting regulations and standards;
developing specifications for the device;
developing, selecting and evaluating components and suppliers;
developing and approving labels and user instructions;
developing packaging;
developing specifications for manufacturing processes;
verifying safety and performance of prototype and final devices;
verifying compatibility with the environment and other devices;
developing manufacturing facilities and utilities;
developing and validating manufacturing processes;
training employees; •
documenting the details of the device design and processes;
if applicable, developing a service program.
To support thorough planning, the QS regulation requires each manufacturer to establish and
maintain plans that describe or reference the design and development activities and define
responsibility for implementation.
3−3
The plans should be consistent with the remainder of the design controls. For example, the design
controls section of the quality system requires a design history file (DHF) [820.30(j)] that contains or
references the records necessary to demonstrate that the design was developed in accordance with
the:
1. approved design plan, and
2. regulatory requirements.
Thus, the design control plans should agree with, and require meeting, the quality system design
control requirements. One of the first elements in each design plan should be how you plan to meet
each of the design control requirements for the specific design you plan to develop; that is, the design
plans should support all of the required design control activities. Such plans may reference the
quality system procedures for design controls in order to reduce the amount of writing and to assure
agreement.
Interface
Design And Development Planning section 820.30(b) states:
“The plans shall identify and describe the interfaces with different groups or activities that provide,
or result in, input to the design and development process...”
If a specific design requires support by contractors such as developing molds, performing a
special verification test, clinical trials, etc., then such activities should be included or referenced in
the plan and proactively implemented in order to meet the interface and general quality system
requirements. Of course, the interface and general requirements also apply to needed interaction
with manufacturing, marketing, quality assurance, servicing or other internal functions.
Proactive interface is a important aspect of concurrent engineering. Concurrent engineering is
the process of concurrently, to the maximum feasible extent, developing the product and the
manufacturing processes. This valuable technique for reducing problems, cost reduction and time
saving cannot work without proactive interface between all involved parties throughout all stages of
the development and initial production program.
Structure of Plans
Each design control plan should be broad and complete rather than detailed and complete. The
plan should include all major activities and assignments such as responsibility for developing and
verifying the power supplies rather than detailing responsibility for selecting the power cords,
fuseholders and transformers. Broad plans are:
•
•
•
•
easier to follow;
contain less errors;
have better agreement with the actual activities; and
will require less updating than detailed plans.
3−4
Over the years, several manufacturers have failed to follow this advice and opted for writing
detailed design control procedures. They reported being unable to finish writing the over-detailed
procedures and were unable to implement them.
Regardless of the effort in developing plans, they usually need updating as the development
activities dictate. Thus, the QS regulation requires in 820.30(a) that the plans shall be reviewed,
updated, and approved as the design and development evolves. The details of updating are left to the
manufacturer; however, the design review meetings are a good time and place to consider, discuss
and review changes that may need to be made in the design development plan.
DESIGN INPUT
Design input means the physical and performance requirements of a device that are used as a
basis for device design [820.3(f)].
Section 820.30(c) Design Input, requires that each manufacturer shall establish and maintain
procedures to make certain that the design requirements relating to a device are appropriate and
address the intended use of the device, including the needs of the user and patient. Also, a design
requirement in 820.130 requires that each manufacturer shall make certain that device packaging
and shipping containers are designed and constructed to protect the device from alteration or
damage during the customary conditions of processing, storage, handling, and distribution. The
intent of 820.130 is to add the broad conditions that are considered for a package design. Packaging
design activities should be done according to design controls. Likewise, the design of the content and
physical parameters of labeling are covered by design controls. Manufacturers that are exempt from
design controls shall labeling and packaging specifications in the DMR (820.181) and are encouraged
to use the QS design controls as guidance.
The input procedures shall address incomplete, ambiguous, or conflicting requirements. The
design input requirements shall be documented and shall be reviewed and approved by a designated
individual(s). The approval, including the date and signature of the individual(s) approving the
requirements, shall be documented.
Under a design control system, manufacturers should identify device requirements during the
design input phase or beginning of the design activity. Design input includes determining customer
needs, expectations and requirements plus determining regulatory, standards, and other appropriate
requirements. These various requirements are documented by the manufacturer in a set of device
requirements. A set of design input requirements, when converted to engineering terminology,
finalized and accepted as part of the device master record is called a device or product specification.
The design input phase usually is a continuum because intensive and formal input requirements
activities usually occur near the beginning of the feasibility phase and continue to the early physical
design activities. After the initial design input phase there are also intensive and formal activities to
reduce the input requirements to engineering-type input specifications -- usually called a product or
device specification.
At the opposite end of the design program, the last event is initial production which may be pilot
production or the beginning of routine production. Whether a manufacturer starts with pilot or
routine production depends on the nature of the new device and associated production. Pilot devices
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may be distributed after design validation of initial units is completed if they meet all of the device
master record and other GMP requirements. Some manufacturers, however, use the pilot models in
training programs for technical writers, production and service personnel, etc. Pilot models are also
commonly used in early marketing displays.
After the concept of the new device design is established, the following basic design input
questions should have been answered:
1.
2.
3.
4.
5.
6.
7.
What is the real need for the new device?
Where will the new device be used?
Who will use the new device?
How will the new device be used?
With what devices will the new device be used?
How long will the new device be used? and
Other questions related to the specific device to be developed.
Designing a device and verifying that it meets customer requirements are expensive and time
consuming activities. Therefore, to control these activities and increase the probability of achieving
desired safety and performance characteristics, device, software, and process requirements and
specifications should be thoroughly reviewed and approved before physical design and development
begins. As the design evolves, the hardware, software, packaging, labeling, etc., shall be verified
[820.30(f)] and reviewed [820.30(e)] versus their latest specifications to verify that design input
requirements have been met.
Input Checklists
Device requirements should identify all of the desired performance, physical, safety and
compatibility characteristics of the proposed device and, ultimately, the finished device. Design input
also includes requirements for labeling, packaging, manufacturing, installation, maintenance and
servicing. The final device specifications should cover ALL of the device characteristics. The device
specifications may incorporate other specifications by reference such as reference to the
manufacturer’s list of specifications for a type of device, to specific paragraphs in standards, or to all
of a standard, etc. with respect to a referenced specification. It should be very clear exactly what is
going to be met. A failure to properly address characteristics or factors such as immunity from
transients in the power source, thermal stress, electromagnetic compatibility (EMC), packaging
protection, shipping stability, proper maintenance, etc., can have disastrous consequences.
It is possible to diligently develop device requirements and still forget one or more elements in the
final specification. Hopefully, no key factors will be left out. To reduce the probability of a
requirement or characteristic being left out, a specification checklist(s) may be used during the
design input phase. A checklist should be developed that is broad based but also germane to the
product line of the manufacturer. If used, a checklist should be part of a standard operating
procedure such as a Design Input Specification Procedure.
The input requirements should cover any standards that the manufacturer plans for the device to
meet. In the United States, information about essentially all national and international standards
may be obtained from the American National Standards Association (ANSI), 11 West 42nd Street,
New York, New York, 10036, phone 212-642-4900. ANSI is a private organization, which monitors
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most of the standards activity in the United States and foreign activity in which U.S. citizens
"officially" participate. Thus, ANSI can supply addresses and other information about all well
established standards writing groups. Also, ANSI has for sale many different types of standards
including quality system standards. For example, the International Electrotech Commission has a
draft design review standard, "Guide on Formal Design Review” (plus a supplement), which should
be helpful to product assurance/design control personnel.
The QS regulation requires that the input procedures shall address incomplete, ambiguous, or
conflicting requirements. Thus, every reasonable effort should made to collect all of the
requirements from which the designers can generate detailed design specifications that are clear,
correct and complete.
At the end of the major aspects of the design input stage, the design input requirements shall be
documented and shall be reviewed and approved by a designated individual(s). The approval,
including the date and signature of the individual(s) approving the requirements, shall be
documented.
A documented device specification or set of specifications derived from the input requirements
should exist at the beginning of the physical design project. The device and other related
specifications should be kept current as the design of the device, packaging, labeling and
manufacturing processes evolve during the development program. As the physical design evolves,
the specifications usually become more specific and more detailed.
The device specification will undergo changes and reviews as the device design evolves. However,
one goal of market research and initial design reviews is to establish complete device requirements
and specifications that will minimize subsequent changes.
Old versions of the input requirements and later the input specifications are put in the design
history file (DHF) or indexed in the computer as part of the DHF to help show that the design plan
was followed.
DESIGN REVIEW
Design review [820.30(e)] is one of the key design control elements in a quality system. The
objectives of design review are stated in the definition of design review in 820.3(h) as follows:
Design review means a documented, comprehensive, systematic examination of a design to evaluate
the adequacy of the design requirements, to evaluate the capability of the design to meet these
requirements, and to identify problems.
To meet the systematic design review requirement, device design and design reviews should
progress through defined and planned phases starting with the design input phase and continuing
through validation of initial production units or lots. Subsequent activities are usually design
changes.
To meet the design review comprehensive requirement, assessments should include a formal
review of the main device and subsystems, including accessories, components, software, labeling, and
packaging; production and resource needs; and installation and service, if needed. The scope
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includes performance, physical safety, compatibility with other devices, overall device system
requirements, human factors, and environmental compatibility.
Even though users or medical practitioners will be aware of direct medical requirements, they
may not be fully aware of physical safety, compatibility, system, human factors, and environmental
requirements. Thus, the reviews of the design input and the design should extend beyond merely
satisfying user-stated requirements in order to assure that safety and effectiveness goals are met.
As the development program progresses, the reviews should cover producibility and production
documentation such as assembly drawings, manufacturing instructions, test specifications, test
procedures, etc.
The extent and frequency of design reviews depends on the complexity and significance of the
device being evaluated.
When the design program is a redesign of an existing device, a special effort should be made to
assure that data obtained from previous failures, complaints, and service records are made available
and reviewed by those responsible for design, design input and design review.
Combination Devices
Marketing submissions to FDA for drug delivery, drug coated, etc., devices are required to have
appropriate data that supports combination claims. The verification of combination devices requires
interaction between device, drug or other manufacturers. Records of this interaction, such as design
review meeting minutes, are required in order to meet the interface requirements of 820.30(b),
Design and Development Planning. The labeling and particularly the cross-labeling of combination
devices should be carefully analyzed during verification and validation activities, and design review
meetings.
Preparation For Reviews
The designated moderator or other designated employee should announce the formal review
meetings with appropriate lead time and include an agenda.
Persons who are making presentations should prepare and distribute information to help clarify
review issues and help expedite the review. However, the intent of the quality system is not that
presentations be so formal and elaborate that designers are spending excessive time on presentations
rather than on designing a safe and effective device.
Persons who plan to attend a review meeting should come prepared to discuss the key issues on
the agenda and issues related to the current design phase. Design review meetings are a great
educational forum. However, design review meetings should not be used as a primary tool to educate
or bring new employees or unprepared employees up-to-speed. To do so detracts from the intent of
the meeting and detracts from the intent of the GMP requirements. Obviously, design review is also
an excellent educational tool. However, new, or new-to-the-project employees should be primarily
oriented by other means that do not detract from the primary function of design review meetings.
Why Design Reviews
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Design reviews are conducted for design definition, selection and adequacy; communication; and
resolution of problems and issues. For example, the design review of the design input requirements
and subsequent design input specifications for the device, labeling, packaging and accessories is
performed to help select the best and/or needed characteristics and requirements, usually from
among many available and sometimes conflicting inputs.
The design review of the initial requirements allows input from all parties. Various people may
participate and "buy in" or "become part of the program." As the design input and review activities
progress, any conflicts are resolved and the preliminary specifications for the device, accessories,
labeling, and packaging are established. Herein, the device, accessories, labeling and packaging is
called the device system. Because of the establishment of these input requirements and subsequent
specifications, plus interface and communication during the reviews, all personnel are directed
toward the goal of developing the "exact" same device system.
As the development progresses and the design and production processes evolve, design reviews
reduce errors, help avoid problems, help find existing problems, help propose solutions, increase
producibility and reduce production transfer problems. The relentless inquiry during design reviews
will expose needed design input requirements and/or design corrections that otherwise may have
been overlooked.
Throughout the design program and particularly toward the end of the development cycle, design
reviews help assure that the final design of the device system meets the current design requirements
and specifications.
Types Of Design Review Meetings
Design review meetings may be grouped into two levels such as:
•
•
total or major program review meetings, and
sub-program or team review meetings.
Some of the review meetings need to be total or major program review meetings because this is
the only type of review meeting that will satisfy all of the GMP review requirements, particularly the
interface requirement for interaction between or among different organizational groups. However,
sub-program, team and contractor review meetings are design review meetings, are subject to
quality system design controls, and should be conducted in a manner that meets the GMP
requirements. Sub-program or team meetings are encouraged as these can be very effective and
efficient in reviewing and resolving sub-program issues.
The records of total program and team meetings are part of the device design history file. The
team review records or a summary of team records and the current design documentation are to be
available, as appropriate, at total program review meetings.
Design review meetings are called under two scenarios:
•
first are the meetings that are preplanned and called at least on a per design phase;
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•
second are ad hoc meetings that are covered in the broad plans and are called to review or
resolve a specific problem or issue.
The preplanned design review meetings and ad hoc meetings are part of the planning and
interaction that are required in 820.30(b), Design and Development Planning. That is, the
manufacturer should expect, plan for, and encourage appropriate ad hoc meetings as well as the
major design review meetings. Reasonable notes and copies of significant engineering documents
discussed during total device system, ad hoc, contractor, and other review meetings are part of the
device design history file.
Design Review Requirements
The objectives of design review are stated in the definition noted above. How these objectives are
to be achieved are presented in the design review requirements. The main design review
requirements are in 820.30(e) of the QS regulation as follows:
Each manufacturer shall establish and maintain procedures to ensure that formal documented
reviews of the design results are planned and conducted at appropriate stages of the device's design
development. The procedures shall ensure that participants at each design review include
representatives of all functions concerned with the design stage being reviewed and an individual(s)
who does not have direct responsibility for the design stage being reviewed, as well as any specialists
needed. The results of a design review, including identification of the design, the date, and the
individual(s) performing the review, shall be documented in the design history file.
There are four requirements related to design reviews:
1. The meetings should be formal. That is, key attendees are designated and the meetings are
conducted at least once per stage/phase, are planned, are announced or are periodic, have an
appropriate agenda, notes are recorded, etc., according to the manufacturer procedure for design
reviews.
The design review procedure should be broad and complete in that it contains information about
all of the requirements. However, the procedure should not be so detailed that it cannot be
followed. Over the years, several manufacturers have failed to follow this advice, tried to write
detailed design QA procedures, and have reported that they were unable to finish writing the
over-detailed procedures and were unable to implement them.
2. To meet the definition of design review in 820.3(h), the review should include persons who are
intimately knowledgeable about the technical characteristics of the design such as performance,
safety, compatibility, etc. In many manufacturers this can only be done by those persons
responsible for the design. However, reviews are to be objective, unbiased examinations by
appropriately trained personnel which should include an individual(s) not responsible for the
design. The moderator of the review meeting may be one of the persons not responsible for the
design.
To meet interface and other review requirements, the review meetings should, as appropriate,
include representatives of R&D, Engineering, Technical Support Services, Production
Engineering, Manufacturing, Quality Assurance, Marketing, Installation and Servicing,
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Purchasing and contractors. Design review should, as applicable and at the appropriate phase,
include those responsible for coordinating or managing preclinical and clinical studies.
3. Pre- and post-review meeting significant responsibilities and assignments should be documented
[820.30(b)]. These assignments are not unusual -- they are simply ordinary work required to
develop a new product or modify an existing product. The progress and/or results of such
assignments would typically be reported at the next review meeting. Documentation is not
required for detailed day-to-day development activities that are part of the designers routine job.
4. The design review meeting results are made a part of the device design history file. The results
should include minutes and should include notes, or annotated draft drawings and annotated
draft procedures that played a significant role during the design review. Such documents help
show that plans were followed, verification/validation was reviewed, and, to some extent, how the
design evolved.
The QS regulation does not require that every document mentioned, referenced or used during a
design review be placed in the design history file.
The device design review meeting minutes should include information such as:
•
•
•
•
•
•
moderator and attendees,
date and design phase/stage,
plans and/or agenda,
problems and/or issues to identify and solve,
minutes and reports, and
follow-up report(s) of solutions and/or the next review covers the solutions and remaining
issues.
Manufacturers may use a form to capture some of this information for minutes such the device,
date, moderator, attendees, major phase, problems, assignments, etc. The device design review
minutes are a key and required part of the design history file. The minutes also help consolidate
development information and the current minutes are also a brief record of some of the immediate
development tasks to be done.
End Of Initial Design
The design control requirements, particularly design validation, give clear insight into when the
initial dsign effort is completed. The end of the total design effort has not been reached until it is
known that the initial production devices, when transferred to production and produced per the
device master record, meet all of the current design specifications. This fact can only be determined
by performing design validation on one or more samples of the finished production units as required
by 820.30(g). Initial production and subsequent validation are well defined stages; and, therefore,
design review(s) shall be performed as required by 820.30(e), Design Review.
Thus the design validation of initial production should be followed by a "final" design review to
meet the design review requirement. If the validation of the final design and subsequent design
review(s) reveal design problems, then design changes are required to correct these problems.
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Design changes require another design verification and, where appropriate, validation and review of
all parts or the affected parts of the device system.
DESIGN OUTPUT
Design output per 820.3(g) means the results of a design effort at each design phase and at the end
of the total design effort. The finished design output is the basis for the device master record. The
total finished design output consists of the device, its packaging and labeling, and the device master
record.
Device master record (DMR) means a compilation of records containing the procedures and
specifications for a finished device.
The design output at each phase are documents and physical design elements that are either
complete or are used to move the design effort into the next phase. For example, the first design
output will usually be the design requirements document. From the requirements and their
engineering knowledge, the designers will derive the preliminary design specifications. Then the
physical design begins. For example, the designers may begin the selection of known routine
components that are part of the design and begin documenting their purchasing and acceptance
requirements documented to meet 820.50 Purchasing Controls, (b) Purchasing Data which requires
that each manufacturer shall establish and maintain data that clearly describe or reference the
specified requirements, including quality requirements, for purchased or otherwise received product
and services.
Other components will be selected as the design evolves. The design output for some special or
new components, or components in unusual applications, will include verification protocols,
purchasing and acceptance requirements.
Many of the design output documents are documents that directly form part of the DMR. The
remaining DMR documents are created by quality assurance, production engineering, process
engineering, technical writing, installation and servicing, etc., using design output data and
information. For example, the finished device final-test methods and some installation and/or
servicing test methods and data forms may be derived from the design verification protocol(s).
When all of these design and documentation activities are completed, the DMR is complete. When
the DMR is complete and initial production units, including packaging, meets all specifications, the
total finished design output exists.
To generate the design output per the QS regulation in 820.30(d), three activities are required.
Each of these is listed and discussed below.
1. Each manufacturer shall establish and maintain procedures for defining and documenting design
output in terms that allow an adequate evaluation of conformance to design input requirements.
2. Design output procedures shall contain or make reference to acceptance criteria and ensure that
those design outputs that are essential for the proper functioning of the device are identified.
3. Design output shall be documented, reviewed, and approved before release. The approval,
including the date and signature of the individual(s) approving the output, shall be documented.
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Documenting Design Output (1)
Documenting design output in terms that allow an adequate evaluation of conformance to design
input requirements is a significant requirement and design activity. A common technique for
achieving this conformance is listed below.
• Convert the general input requirements to specific design engineering specifications and give each
item a line/paragraph number.
• Develop the design to meet all of the parameters and characteristics in the design engineering
specification.
• Generate a verification requirement document(s) and test method(s) for the design and give each
requirement/parameter/characteristic the same line/paragraph number that it has in the design
engineering specification.
• Generate a verification data form that lists each requirement/parameter/characteristic and give
each requirement/parameter/characteristic the same line/paragraph number that it has in the
design engineering specification.
Each of these documents has a different drawing number but the line/paragraph numbers are the
same. The first of these documents may be used as the beginning format for the next one. Therefore,
it is almost impossible to leave out an element. Thereafter, when the verification is performed and
documented, conformance or lack of conformance from input to output is known.
Acceptance Criteria (2)
The verification documents and data contain more information than is typically needed for
production evaluation and acceptance of components, in-process items and finished devices.
Therefore, it is easy to copy and modify verification documents to meet the quality system
requirement that: design output procedures shall contain or make reference to acceptance criteria
and ensure that those design outputs that are essential for the proper functioning of the device are
identified. In fact, this technique of deriving test procedures from the verification protocols also
yields the test method(s) and data form(s) needed to meet the DMR requirements for QA procedures
and acceptance criteria in 820.181(c).
Design Output Approval (3)
The third and final output requirement is that: design output shall be documented, reviewed, and
approved before release. The approval, including the date and signature of the individual(s)
approving the output, shall be documented. This means that:
• Manufacturers may choose to have a group review certain documents and have individuals
review other documents.
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• Output documents that are directly part of the DMR are reviewed, dated and signed by the
author which is current practice; and reviewed, dated and approved by individual(s) designated
by the manufacturer. As appropriate, these reviews should cover technical issues as well as
adequacy for use in production, purchasing, servicing, etc. DMR documents that are generated
and approved under 820.30 automatically meet the approval requirements of 820.40, Document
Controls and do not have to be re-approved under 820.40.
• Design output reports, data and any other document that will be used to create documents in the
DMR are reviewed, dated and signed by the author which is current practice; and reviewed,
dated and approved by individual(s) designated by the manufacturer.
Design output also includes the physical design which, of course, is not intended to be signed, and
dated. The approval for the physical design is the validation that is done on initial production units.
DESIGN VERIFICATION AND VALIDATION
Each manufacturer shall establish and maintain procedures for verifying the device design.
Design verification [820.30(f)] shall confirm that the design output meets the design input
requirements. The results of the design verification, including identification of the design, method(s),
the date, and the individual(s) performing the verification, shall be documented in the DHF.
Validation [820.30(g)] means confirmation by examination and provision of objective evidence
that the particular requirements for a specific intended use can be consistently fulfilled.
Process validation means establishing by objective evidence that a process consistently produces a
result or product meeting its predetermined specifications.
Design validation means establishing by objective evidence that device specifications conform
with user needs and intended use(s).
Verification means confirmation by examination and provision of objective evidence that
specified requirements have been fulfilled.
Each manufacturer shall establish and maintain procedures for validating the device design.
Design validation shall be performed under defined operating conditions on initial production units,
lots, or batches, or their equivalents. Design validation shall ensure that devices conform to defined
user needs and intended uses and shall include testing of production units under actual or simulated
use conditions. Design validation shall include software validation and risk analysis, where
appropriate. The results of the design validation, including identification of the design, method(s),
the date, and the individual(s) performing the validation, shall be documented in the DHF.
Design verification is always done versus specifications. Therefore, to control the specifications
and increase the probability of achieving desired safety and performance characteristics, device,
software, labeling, packaging and any other specifications should be complete and thoroughly
reviewed before development commences. As the hardware and software designs evolve, they should
be evaluated versus their current specifications.
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Verification and validation should be done with test equipment calibrated and controlled
according to quality system requirements. Otherwise, there is limited confidence in the data.
Verification and validation should also be done according to a written protocol(s). The protocol(s)
should include defined conditions for the testing. The protocol(s) should be approved before being
used. Test protocol(s) are not perfect for a design, particularly a new design. Therefore, the
designers and other verification personnel carefully annotate any ongoing changes to a protocol.
Likewise, the verification personnel should record technical comments about any deviations or other
events that occurred during the testing. The slightest problem should not be ignored. During design
reviews, the comments, notes and deviations may be as important as test data from the formal
protocol(s).
Design Evaluation versus Specifications
The original design of devices and any subsequent changes should be verified by appropriate and
formal laboratory, animal, and in vitro testing. Risk analysis should be conducted to identify
possible hazards associated with the design. Failure Mode Effects Analysis and Fault Tree Analysis
are examples of risk analysis techniques.
Appropriate laboratory and animal testing followed by analysis of the results should be carefully
performed before clinical testing or commercial distribution of the devices. The manufacturer
should be assured that the design is safe and effective to the extent that can be determined by
various scientific tests and analysis before clinical testing on humans or use by humans. For
example, the electrical, thermal, mechanical, chemical, radiation, etc., safety of devices usually can
be determined by laboratory tests.
Clinical testing is not needed for many substantially equivalent devices (See 21 CFR Part 807
Subpart E - Premarket Notification Procedure). Where it is needed, such as for complex
substantially equivalent devices or new devices, clinical testing on humans should meet the
applicable requirements in the Investigational Device Exemption (IDE) regulations (21 CFR Parts
812 and 813).
The general IDE regulation (21 CFR Part 812) exempts a manufacturer during the
"premarketing phase" from the following provisions of the FD&C Act:
•
•
•
•
•
•
•
•
•
Misbranding,
Registration of the Establishment,
Premarket Notification [510(k)],
FDA Performance Standards,
Premarket Approval,
Production sections ONLY of the Good Manufacturing Practices,
Color Additives,
Banned Devices, and
Restricted Devices.
Don't be misled by this list of exemptions -- being exempted from these provisions does not mean
that a manufacturer may develop a new device under uncontrolled conditions and then test it on
humans. Devices being clinically tested are not exempt from section 501(c) of the FD&C Act, which
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states that a device is adulterated if it does not meet a manufacturer’s quality claims. Devices being
manufactured for use in clinical studies under an IDE are exempt ONLY from the production
section of the QS regulation. They are not exempt from design controls listed in 820.30. In addition,
the IDE regulation has labeling requirements in 812.5 and quality assurance requirements in
812.20(b)(3) that shall be met. Further, manufacturers should remember that human subjects are
also protected through the courts via product liability laws and actions. In summation, protection of
manufacturer interests, human test subjects, practitioners, and patients requires that all medical
devices be developed, evaluated, and manufactured under a total quality system.
Laboratory testing to force a failure takes considerable time and the "culprit" may not fail
during the testing. Another evaluation technique is Failure Mode and Effects Analysis (FMEA) in
which failures are assumed to occur. FMEA is useful for evaluating reliability, safety, and general
quality where, for example, the evaluator assumes that:
•
•
•
•
each component fails,
each subsystem or subassembly fails,
the operator makes errors, and
the power source is interrupted and immediately restarted.
The probability of each failure actually occurring and, if it does, the resulting effect are analyzed.
Then, where needed and feasible, hazards and faulty performance are designed out of the device or
reduced; or compensated or prevented/reduced by interlocks, warning signs, explicit instructions,
alarms, etc. Risks, of course, cannot always be removed from medical devices, but they should be
known and controlled to the extent feasible with existing technology.
Failure Mode and Effects Analysis (FMEA) is a very powerful and cost-effective technique. Note
that it takes very little time to assume that a component or subsystem is going to fail versus the time
required to test to failure. The idea is not to promote one method above the other because a
reasonable amount of both actual testing and failure mode and effects analysis should be done before
a device is clinically tested and/or placed into production.
Besides using FMEA there are also other human factor and validation process techniques that
can be used in developing an overall risk analysis. These techniques include: timelines, workload
analysis, failure analysis, alternative calculations, testing including animal testing, auditing the
design output, design reviews, demonstrations, and comparing a new design to a proven design etc.
The users should be considered components when developing a fault tree and failure mode effects
analysis.
All evaluation results should be reviewed by product development personnel who compare the
tests and FMEA results with specifications, including safety and performance standards, to make
certain that the desired level of intrinsic quality has been designed into the device. Also, the
appropriate design of manufacturing processes, including validation where appropriate, is needed to
assure that production can achieve the level of quality designed into the device.
Software Validation
Software is evaluated and reviewed versus the software specifications during the ongoing
development of the device design. When a "final" prototype(s) is available, the software and
hardware are validated to make certain manufacturer specifications for the device and process are
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met. Some aspects of hardware evaluation were discussed above. Aspects specific to software are
covered below.
Before testing the software in actual use, the detailed code should be visually reviewed versus flow
charts and specifications. All cases, especially decision points and error/limit handling, should be
reviewed and the results documented.
In all cases, algorithms should be checked for accuracy. Recalls have occurred because algorithms
were incorrectly copied from a source and, in other cases, because the source algorithm was
incorrect. During the development phase, complex algorithms may need to be checked by using a
test subroutine program written in a high-order language, if the operational program is written in a
low-level language.
The validation program is planned and executed such that all relevant elements of the software
and hardware are exercised and evaluated. The testing of software usually involves the use of an
emulator and should include testing of the software in the finished device.
The testing includes normal operation of the complete device; and this phase of the validation
program may be completed first to make certain that the device meets the fundamental
performance, safety and labeling specifications. Concurrently or afterward, the combined system of
hardware and software should be challenged with abnormal inputs and conditions. As appropriate,
these inputs and conditions include such items as:
•
•
•
•
•
•
•
operator errors;
induced failure of sensors and cables or other interconnects;
induced failure of output equipment;
exposure to static electricity;
power loss and restart;
simultaneous inputs or interrupts; and,
as appropriate, deliberate application of none, low, high, positive, negative, and extremely
high input values.
The results of the software and combined device system validation are included in the design
reviews.
Labeling Verification
During verification, the complete device is exercised such that all labeling, displays, and outputs
are generated, reviewed, and the results documented. During the verification, all displayed prompts
and instructions are checked versus the manufacturer’s and FDA’s labeling requirements and
versus the operator manual.
Printed labeling and screen displays should be checked to see if they are directed to the user and
not to the system designers, which is a common fault found in labeling. Displayed text should be
short and to the point. Because displays are brief, keywords should be carefully selected to match
system characteristics, yet transfer the maximum information to the user. The text of references to
controls or other parts of the system should match the labeling on the device. Data, identifications,
or other key information displayed should be current, complete, unambiguous, and accurate.
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During verification, all prompts and instructions should be followed exactly by the device test or
other operators and such action should result in correct operation of the device. Prompts and
instructions should appropriately match the instructions in the operator's manual. The evaluation
should include verification that any screen or other displays meet the requirements of, and have
been approved per, the manufacturer’s policy/procedure for design of labeling.
Patient and procedure data on printouts should be correct; therefore, printouts should undergo a
verification similar to that performed for the screen or other displays. In addition, the printouts
should be evaluated with respect to their "cold" information transfer characteristics. Will the
printouts be quickly and clearly understood a few weeks later when the reader is not reading the
displays, operating the device, or looking at the patient? All printouts should also meet the
manufacturer’s design control policy/procedure requirements for labeling. Likewise, patient data or
other key information transmitted to a remote location should be correct; therefore, it should be
checked for accuracy, completeness, and identification. Annotated copies of verified labeling,
printouts, etc. and associated notes and any checklists should be placed in the design history file.
The overall device specifications usually have requirements that cover user/operator error
prevention and control. Along with operator training, such errors are controlled by:
• adequate instruction manuals,
• adequate device labels,
• display of adequate prompts and correct instructions,
• status (history) reports,
• exclusion of certain erroneous inputs or actions, and
• adequate human factors design.
Also, for some devices, it may be important to control the order in which data can be entered by
the operator. In emergency situations or because of distractions, it may be important to present the
operator with a brief history or status report of recent actions. During the verification, the listed
items should be evaluated versus the specifications, and checked for completeness and appropriateness. A checklist or matrix may be used to aid in the review of labeling.
DESIGN TRANSFER
The design controls require that each manufacturer shall establish and maintain procedures to
ensure
that the device design is correctly translated into production specifications.
It is common practice for sections of a design to be transferred before the entire design is
completed. The QS regulation does not prevent such split or multiple transfers. Transfer is to be
performed only for completed elements of the design -- multiple transfers may not be used to bypass
any design, labeling or other GMP requirements.
A significant part of the transfer requirement is met when the design output is being created.
That is, some of the design output documents are part of the DMR and are used directly for
production. The remaining DMR documents are based on design output information. A procedure is
needed to cover the generation of the remaining device master record documents based on
information in the design output documents.
3−18
Design transfer should assure that the section of the design being transferred:
•
•
•
•
•
•
meets input requirements;
contains acceptance criteria, where needed;
contains design parameters which have been appropriately verified;
is complete and approved for use;
is fully documented in the DMR or contains sufficient design output information to support
the generation of remaining DMR documents; and
is placed under change control if not already done.
Design transfer may include training of production, installation and service employees and such
training should be covered by or referenced by the transfer procedure.
DESIGN CHANGES
Changes to a design element are controlled per 820.30(i) Design Changes which states that: each
manufacturer shall establish and maintain procedures for the identification, documentation,
validation or where appropriate verification, review, and approval of design changes before their
implementation.
The original design activities and subsequent change control activities for the design are both
done under the full set of the quality system design controls. A manufacturer may not use a design
change control procedure to bypass part of the design controls. Thus, it is difficult to describe
change control before design transfer because both activities are done under design controls.
Most of the details of the change control system are left to the manufacturer to develop, document
and implement. As the design activity progresses toward the final stage, it is expected that the degree
of change control will increase.
Those elements of the design that have been verified and accepted obviously should be under
change control. A design that has been submitted to FDA for marketing clearance should be under
change control. A design undergoing clinical trials should be under change control or the clinical
data may not be accepted by FDA. A design that is released for production should be under design
and general change control.
After design activities are begun and the physical design evolves into an accepted entity,
subsequent changes to the device specification(s) are proposed, evaluated, reviewed, approved, and
documented per all of 820.30. The revised specification(s) becomes the current design goal in
accordance with the manufacturer procedures for: design control, design change control, and
document control.
A design change control procedure should at least cover:
•
under what conditions change control is required;
•
documenting the reason for the change;
3−19
•
any differences in the change control process when outside parties are involved;
•
analysis of the design to identify other elements that are impacted by the change; and
•
for significant changes which includes any change requiring verification and/or validation,
placing the reason for the change in the design history file along with the required design
verification, validation and review documentation.
DESIGN HISTORY FILE
Design history file (DHF) means a compilation of records which describes the design history of a
finished device [820.3(e)].
The DHF covers the design activities used to develop the device, accessories, major components,
labeling, packaging and production processes.
The design controls in 820.30(j) require that each manufacturer shall establish and maintain a
DHF for each type of device. Each type of device means a device or family of devices that are
manufactured according to one DMR. That is, if the variations in the family of devices are simple
enough that they can be handled by minor variations on the drawings, then only one DMR exists. It
is common practice to identify device variations on drawings by dash numbers. For this case, only
one DHF could exist because only one set of related design documentation exists. Documents are
never created just to go into the DHF.
The QS regulation also requires that the DHF shall contain or reference the records necessary to
demonstrate that the design was developed in accordance with the approved design plan and the
requirements of this part. As noted, this requirement cannot be met unless the manufacturer
develops and maintains plans that meet the design control requirements. The plans and subsequent
updates should be part of the DHF. In addition, the QS regulation specifically requires that:
3−20
•
the results of a design review, including identification of the design, the date, and the
individual(s) performing the review, shall be documented in the DHF.
•
design verification shall confirm that the design output meets the design input requirements.
The results of the design verification, including identification of the design, method(s), the
date, and the individual(s) performing the verification, shall be documented in the DHF.
Typical documents that may be in, or referenced in, a DHF are listed below:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
design plans;
design review meeting information;
sketches;
drawings;
procedures;
photos;
engineering notebooks;
component qualification information;
biocompatibility (verification) protocols and data;
design review notes;
verification protocols and data for evaluating prototypes;
validation protocols and data for initial finished devices;
contractor / consultants information;
parts of design output/DMR documents that show plans were followed; and
parts of design output/DMR documents that show specifications were met.
The DHF contains documents such as the design plans and input requirements, preliminary input
specs, validation data and preliminary versions of key DMR documents. These are needed to show
that plans were created, followed and specifications were met.
The DHF is not required to contain all design documents or to contain the DMR, however, it will
contain historical versions of key DMR documents that show how the design evolved.
Does the DHF have value for the manufacturer? Yes, when problems occur during re-design and
for new designs, the DHF has the "institutional" memory of previous design activities. The DHF also
contains valuable verification and validation protocols that are not in DMR. This information may
be very valuable in helping to solve a problem; pointing to the correct direction to solve a problem;
or, most important, preventing the manufacturer from repeating an already tried and
found-to-be-useless design.
EXHIBITS
Design Input Requirements Procedure
A sample Design Input Requirements procedure is presented which covers basic activities for
obtaining data on requirements that is needed for employees to develop device specifications. This
procedure uses the multiple specification approach; however, a single combined specification would
3−21
use a very similar procedure. This procedure should be modified to meet specific needs before being
adopted by a manufacturer.
3−22
COMPANY LOGO
Title: Design Input Requirements Procedure
Prepared by:
Prep. Date:
ECN History:
SOP #:
App:
Rev:
Page: 1 of 2
Date:
Date:
POLICY - Design specifications covering all design requirements shall be established for all proposed devices
before any significant physical design activities are started.
SCOPE - This policy applies to all devices and accessories developed by the manufacturer or developed by a
contractor for us. For purchase of completed designs, refer to SOP ####. The device specification(s) must exist
or be generated regardless of the source of the design.
CONFIDENTIALITY - Device development plans and activities are always confidential. Market research
reports and documents such as specifications with parameter data shall be marked confidential.
Design control procedures, standard SOPs, blank forms, and required design review and design
verification/validation records may be shown to, and may be copied by, FDA investigators as required by the
QS regulation. Design parameters are not covered by the QS regulation. Therefore, confidential specification
characteristics and parameters in the copies of these documents shall be blacked out unless the document is
being collected during an inspection related to a marketing submission.
RESPONSIBILITY
Marketing and Engineering have the primary responsibility for determining safety and performance
requirements and developing input specifications; however, all departments are expected to support the
development of input requirements and subsequent specifications.
MARKETING - Marketing shall plan and conduct all customer contacts to obtain information on customer
desires, needs, expected pricing, opinions about existing devices, etc.
To the maximum extent feasible, market research shall be conducted in a manner to reduce leaking of
manufacturer confidential information and plans.
Design review meetings shall normally precede and follow all significant outside market research activities.
Initial market research activities shall be previewed with top management.
Market research results are to be documented and marked confidential.
PRODUCTION - Production has primary responsibility for assuring producibility and establishing
manufacturing requirements. Some of these requirements may be general during the early design stages.
ENGINEERING - Engineering is expected to supply design input information on most requirements. Such
inputs may parallel data obtained by market research.
Engineering has primary responsibility for specifying what technology to use.
Engineering shall analyze input data on requirements and reduce it to preliminary specifications.
Engineering has primary responsibility for addressing incomplete, ambiguous, or conflicting requirements
and shall see that such issues are appropriately discussed at design reviews.
3−23
Page 2 of 2
RA & QA - RA and QA managers or their designees shall attend all design input or specification review
meetings to provide input on, and to assure that, regulatory, manufacturer, quality, safety, performance, etc.,
procedures are followed and that requirements are met.
SPECIFICATIONS
STRUCTURE - Multiple specifications shall be used except for very simple devices. A separate specification
shall be developed for accessories, labeling, packaging, etc. An overall device specification shall be developed
and shall include an index that points to supporting specifications. The specifications, among other factors,
shall address:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Performance and Efficacy;
Human Factors;
Chemical Safety;
Electrical Safety;
Mechanical Safety;
Radiation Safety;
Thermal Safety;
Biocompatibility;
Device Compatibility;
System Compatibility;
Environmental Compatibility;
Packaging (in a separate specification document);
Any FDA design requirements in the Part 801 and Part 1000-1050 regulations; and
Labeling in a separate document and, as appropriate, in the device primary specification.
CHECKLISTS - Checklists of requirements germane to our product line may be used to develop and support
specifications. If used, such checklists become part of this procedure and part of the design documentation.
DESIGN REVIEW - Each specification shall undergo design review before it is approved for physical design
activities or is used as a background document to support further market research. Such reviews shall be
documented.
APPROVAL - The Marketing manager and Engineering manager shall approve all input specifications after
these have been subjected to design review.
DOCUMENTATION - The approved specifications shall be given document numbers and become part of the
device master record for the new device.
CHANGE CONTROL - The Engineering manager shall decide when design activities have progressed to the
stage that the various specifications shall be subject to our Design Change Control Procedure. However, for
our organization, design change control can start NO later than the FIRST of the following events:
-
clearance of a 510(k), or
start of a clinical investigation.
3−24
4
PROCESS VALIDATION
INTRODUCTION ............................................................................................................................ 4-1
TERMS AND DEFINITIONS ......................................................................................................... 4-2
WHY VALIDATE PROCESSES .................................................................................................... 4-2
WHAT PROCESSES SHOULD BE VALIDATED ...................................................................... 4-3
TYPES OF PROCESS VALIDATION ........................................................................................... 4-3
Prospective Validation ................................................................................................................. 4-3
Retrospective Validation ............................................................................................................. 4-4
PROCESS VALIDATION STUDIES ............................................................................................. 4-5
Planning the Process Validation Study ...................................................................................... 4-5
Installation and Operation Qualification .................................................................................. 4-6
Process Performance Qualification ............................................................................................ 4-8
Product Performance Qualification ........................................................................................... 4-9
DOCUMENTATION ....................................................................................................................... 4-9
REVALIDATION ............................................................................................................................. 4-9
REFERENCES ............................................................................................................................... 4-10
INTRODUCTION
The Quality System (QS) regulation defines process validation as establishing by objective
evidence that a process consistently produces a result or product meeting its predetermined
specifications [820.3(z)(1)]. The requirement for process validation appears in section 820.75 of the
Quality System (QS) regulation. The goal of a quality system is to consistently produce products that
are fit for their intended use. Process validation is a key element in assuring that these principles and
goals are met.
The process validation requirements stated in the QS regulation and the guidance offered here
have general applicability to manufacturing processes for medical devices. Many technologies are
used in the production of medical devices. The details of process validation will vary according to the
nature of the medical device (e.g., sterile or non-sterile) and the nature and complexity of the process
being validated.
Processes are developed according to the design controls in 820.30 and validated according to
820.75. The process specifications, hereafter called parameters, are derived from the specifications
for the device, component or other entity to be produced by the process. The parameters are
documented in the device master record per 820.30, 820.40 and 820.181. The process is developed
such that the required parameters are achieved. To ensure that the output of the process will
consistently meet the required parameters during routine production, the process is validated.
The basic principles for validation may be stated as follows:
•
Establish that the process equipment has the capability of operating within required
parameters;
4−1
•
Demonstrate that controlling, monitoring, and/or measuring equipment and instrumentation
are capable of operating within the parameters prescribed for the process equipment;
•
Perform replicate cycles (runs) representing the required operational range of the equipment
to demonstrate that the processes have been operated within the prescribed parameters for
the process and that the output or product consistently meets predetermined specifications for
quality and function; and
•
Monitor the validated process during routine operation. As needed, requalify and recertify
the equipment.
TERMS AND DEFINITIONS
Terms other than those used herein may be found in the literature.
Validation: confirmation by examination and provision of objective evidence that the particular
requirement for a specific intended use can be consistently fulfilled.
Process validation: establishing by objective evidence that a process consistently produces a result
or product meeting its predetermined specifications.
Installation qualification: establishing documented evidence that process equipment and ancillary
systems are capable of consistently operating within established limits and tolerances.
Process performance qualification: establishing documented evidence that the process is effective
and reproducible.
Product performance qualification: establishing documented evidence through appropriate testing
that the finished product produced by a specified process(es) meets all release requirements for
functionality and safety.
Prospective validation: validation conducted prior to the distribution of either a new product, or
product made under a revised manufacturing process, where the revisions may affect the product's
characteristics.
Retrospective validation: validation of a process for a product already in distribution based upon
accumulated production, testing and control data.
Validation protocol: a written plan stating how validation will be conducted, including test
parameters, product characteristics, production equipment, and decision points on what constitutes
acceptable test results.
WHY VALIDATE PROCESSES
There are many reasons, in addition to the regulatory requirements, for validating processes. A
manufacturer can assure through careful design of the device and packaging, careful design and
validation of processes, and process controls, that there is a high probability that all manufactured
4−2
units will meet specifications and have uniform quality. The dependence on intensive in-process and
finished device testing can be reduced. However, in-process and finished product testing still play an
important role in assuring that products meet specifications. A properly validated and controlled
process will yield little scrap or rework, resulting in increased output. Consistent conformance to
specifications is likely to result in fewer complaints and recalls. Also, when needed, the validation
files contain data to support improvements in the process or the development of the next generation
of the process.
WHAT PROCESSES SHOULD BE VALIDATED
Where process results cannot be fully verified during routine production by inspection and test,
the process must be validated according to established procedures [820.75(a)]. When any of the
conditions listed below exist, process validation is the only practical means for assuring that
processes will consistently produce devices that meet their predetermined specifications:
•
Routine end-product tests have insufficient sensitivity to verify the desired safety and efficacy
of the finished devices;
•
Clinical or destructive testing would be required to show that the manufacturing process has
produced the desired result or product1;
•
Routine end-product tests do not reveal all variations in safety and efficacy that may occur in
the finished devices2;
•
The process capability is unknown, or it is suspected that the process is barely capable of
meeting the device specifications.
TYPES OF PROCESS VALIDATION
Process validation may be conducted at different points during the life cycle of a product. The
types of process validation are defined in terms of when they occur in relation to product design,
transfer to production and release of the product for distribution.
Prospective Validation
Prospective validation is conducted before a new product is released for distribution or, where the
revisions may affect the product's characteristics, before a product made under a revised
manufacturing process is released for distribution.
Concurrent validation is a subset of prospective validation and is conducted with the intention of
ultimately distributing product manufactured during the validation study. Concurrent validation is
1
For example, USP 23 states: "Absolute sterility cannot be practically demonstrated without complete
destruction of every finished article."
[Added note: Also, a positive test result may be caused by operator error rather than non sterility.]
2
For example, visual inspections usually are not capable of detecting defects in structural welds. Such defects
may be detectable only by using destructive testing, expensive test equipment, or very slow test methods.
4−3
feasible when nondestructive testing is adequate to verify that products meet predetermined
specifications and quality attributes. If concurrent validation is being conducted as the initial
validation of a new process or a process which has been modified, product should be withheld from
distribution until all data and results of the validation study have been reviewed, and it has been
determined that the process has been adequately validated.
Concurrent validation may be conducted on a previously validated process to confirm that the
process is validated. If there have been no changes to the process and no indications that the process
is not operating in a state of control, product could be released for distribution before revalidation of
the process is completed. There is some risk to early release of product in that subsequent analysis of
data may show that the process is not validated.
Retrospective Validation
Retrospective validation is the validation of a process based on accumulated historical
production, testing, control, and other information for a product already in production and
distribution. This type of validation makes use of historical data and information which may be
found in batch records, production log books, lot records, control charts, test and inspection results,
customer complaints or lack of complaints, field failure reports, service reports, and audit reports.
Historical data must contain enough information to provide an in-depth picture of how the process
has been operating and whether the product has consistently met its specifications. Retrospective
validation may not be feasible if all the appropriate data was not collected, or appropriate data was
not collected in a manner which allows adequate analysis.
Incomplete information mitigates against conducting a successful retrospective validation. Some
examples of incomplete information are:
•
Customer complaints which have not been fully investigated to determine the cause of the
problem, including the identification of complaints that are due to process failures;
•
Complaints were investigated but corrective action was not taken;
•
Scrap and rework decisions that are not recorded, investigated and/or explained;
•
Excessive rework;
•
Records that do not show the degree of process variability and/or whether process variability
is within the range of variation that is normal for that process, for example, recording test
results as "pass" or "fail" instead of recording actual readings or measurements results in the
loss of important data on process variability; and
•
Gaps in batch records for which there are no explanations. (Retrospective validation cannot
be initiated until the gaps in records can be filled or explained.)
If historical data is determined to be adequate and representative, an analysis can be conducted
to determine whether the process has been operating in a state of control and has consistently
produced product which meets its predetermined specifications and quality attributes. The analysis
must be documented.
4−4
After a validated process has been operating for some time, retrospective validation can be
successfully used to confirm continued validation of that process if no significant changes have been
made to the process, components, or raw materials.
Statistical process control is a valuable tool for generating the type of data needed for
retrospective analysis to revalidate a process and show that it continues to operate in a state of
control.
PROCESS VALIDATION STUDIES
Planning the Process Validation Study
Careful planning of a validation study is essential to ensure that the process is adequately
validated. The plan should include design reviews. The plan for the validation study is documented
in the validation protocol. A copy of the protocol and validation results are placed in the Design
History File (DHF) [820.30 (j)] or quality system record file (820.186). The operational, monitoring,
and other production-related procedures are part of the device master record (DMR) (820.181).
Planning for the validation should include the following elements as well as any other relevant issues
that must be addressed to conduct the validation study:
•
identification of the process to be validated;
•
identification of device(s) to be manufactured using this process;
•
criteria for a successful study;
•
length and duration of the study;
•
assumptions (shifts, operators, equipment, components);
•
identification of equipment to be used in the process [820.75(b)(2)];
•
identification of utilities for the process equipment and quality of the utilities;
•
identification of operators and required operator qualifications [820.75(b)(2)];
•
complete description of the process {may reference the DMR [820.181(b)]};
•
relevant specifications including those for the product, components, manufacturing materials,
the environment, etc. [may reference the DMR and quality system files {820.181(a) and (b);
820.186};
•
any special controls or conditions to be placed on preceding processes during the validation;
•
process parameters to be controlled and monitored, and methods for controlling and
monitoring [820.70(a); 820.75(b)(2)];
4−5
•
product characteristics to be monitored and method for monitoring [820.70(a)(2);
820.75(b)(2); 820.80(c)];
•
any subjective criteria used to evaluate the product;
•
definition of what constitutes nonconformance for both measurable and subjective criteria;
•
statistical methods for data collection and analysis (820.250);
•
consideration of maintenance and repairs [820.72(a)];
•
conditions that may indicate that the process should be revalidated [820.75(c)];
•
stages of the study where design review is required; and
•
approval(s) of the protocol.
The validation plan should also cover the installation and operation qualification of any equipment
used in the process, process performance qualification, and product performance qualification.
Installation and Operation Qualification
After process equipment is designed or selected, it should be installed, reviewed, calibrated,
challenged, and evaluated to ensure that it is capable of operating within established limits and
tolerances as well as throughout all anticipated operating ranges. Installation and operation
qualification studies establish confidence that all equipment used in the manufacturing process
meets specified requirements and is appropriately designed, constructed, placed, and installed to
facilitate maintenance, adjustment, cleaning, and use [820.70(g)].
The installation and operation qualification phases of process validation include:
•
examining equipment design and supplied documentation;
•
determining installation requirements;
•
establishing any needed environmental controls and procedures;
•
assuring that the work area has sufficient space to perform the processing and associated
activities;
•
installing the equipment;
•
verifying correct installation;
•
establishing manufacturing procedures for the monitoring, operation, and control of the
equipment including the minimum number of operators;
4−6
•
determining calibration, cleaning, maintenance, adjustment, and expected repair
requirements;
•
identifying important elements of the equipment that could affect the output or finished
device;
•
verifying that the system or subsystem performs as intended throughout all anticipated
operating ranges; and
•
documenting the above information.
Equipment fabricators may perform qualification runs at their facilities and analyze the results to
determine that the process equipment is ready for delivery to the medical device manufacturer.
Device manufacturers should obtain copies of the suppliers' qualifications studies to use as guides, to
obtain basic data, and to supplement their own qualification studies. However, it is usually
insufficient to rely solely upon the representations and studies of the equipment supplier. The device
manufacturer is ultimately responsible for evaluating, challenging, and testing the equipment and
deciding whether the equipment is suitable for use in the manufacture of a specific device(s). The
evaluations may result in changes to the equipment or process. Such changes must meet QS
requirements in 820.30, Design Control; 820.40, Document Controls; 820.50, Purchasing Controls;
820.70, Process Controls; 820.72, Inspection, Measuring, and Test Equipment; 820.75, Process
Validation; 820.181, Device Master Record.
Installation and operation qualifications should include establishing pertinent methods,
procedures, and schedules for calibration, cleaning, and maintenance, and establishing a repair
parts list for each piece of equipment. Planning for eventual maintenance and repairs can reduce or
prevent confusion during emergency repairs which could lead to improper repairs such as the use of
the wrong replacement part. Post-repair cleaning, calibration, and re-start requirements should be
established if necessary to prevent inadvertent manufacture of nonconforming devices. The objective
is to assure that all repairs can be performed in a way that will not affect the characteristics of
material processed or devices manufactured after repairs.
Process and monitoring equipment (instruments) should be calibrated at the beginning of the
validation study, and the calibration should be checked at the end of the study to establish
confidence in the validation of the process. Equipment found out of calibration at the end of a
process validation study may indicate that the process has not been operating in a state of control
and cannot be considered validated. More frequent calibration or more robust equipment may be
necessary, or you may wish to use stand-alone instruments in parallel with the built-in process
monitoring equipment.
It is important to document installation and operation qualification studies. Such documentation
can substitute for part of the requalification of equipment in future process validation studies. When
equipment is moved to a new location, installation and operation should be requalified. By
comparing data from the original installation and operation qualification and the requalification,
the manufacturer can determine whether there have been any changes in equipment performance as
a result of the move. Changes in equipment performance should be evaluated to determine whether
it is necessary to revalidate the process.
4−7
Process Performance Qualification
The purpose of process performance qualification is to rigorously test the process to determine
whether it is capable of consistently producing an output or in-process or finished devices which
meet specifications. In entering the process performance qualification phase of validation, it is
understood that the:
•
device, packaging, and process specifications have been established, documented, and
essentially proven acceptable through engineering, laboratory or other verification methods
[820.30; 820.70(a)]; and
•
process and ancillary equipment and the environment have been judged acceptable on the
basis of installation and operation qualification studies [820.70(g)].
Challenges to the process should simulate conditions that will be encountered during actual
production. Challenges should include the range of conditions allowed in written standard operating
procedures and should be repeated enough times to assure that the results are meaningful and
consistent. Challenges may need to include forcing the preceding process to operate at its allowed
upper and lower limits.
Process and product data should be analyzed to determine what the normal range of variation is
for the process output. Knowing what is the normal variation of the output is crucial in determining
whether a process is operating in a state of control and is capable of consistently producing the
specified output.
Process and product data should also be analyzed to identify any variation due to controllable
causes. Depending on the nature of the process and its sensitivity, controllable causes of variation
may include:
•
•
•
•
•
•
•
•
temperature,
humidity,
variations in electrical supply,
vibration,
environmental contaminants,
purity of process water,
light, and
inadequate employee training.
Appropriate measures should be taken to eliminate controllable causes of variation. For example,
extreme variations in temperature can be eliminated by installing heating and air conditioning.
Employee training can be improved and conducted more frequently, and employees can be
monitored more closely to assure that they are properly performing the process. Eliminating
controllable causes of variation will reduce variation in the process output and result in a higher
degree of assurance that the output will consistently meet specifications.
After routine production begins, data derived from monitoring the process and output product
can be analyzed for variation and compared to the normal range of variation. Such analyses can
detect when the process output is shifting so that corrections can be made before, or soon after,
nonconforming product is produced.
4−8
Product Performance Qualification
The purpose of product performance qualification is to demonstrate that the process has not
adversely affected the finished product and that the product meets its predetermined specifications
and quality attributes. Product performance qualification and design validation of initial finished
devices are closely related. According to the design control requirements, design validation shall be
performed under defined operating conditions on initial production units, lots, or batches, or their
equivalents [820.30(g)]. Products used for design validation should be manufactured using the same
production equipment, methods and procedures that will be used in routine production. Otherwise,
the product used for design validation may not be representative of production units and cannot be
used as evidence that the manufacturing process will produce a product that meets pre-determined
specifications and quality attributes.
Design validation can be conducted using finished products made during process validation
studies and will satisfy the need for product performance qualification. Design validation shall
ensure that devices conform to defined user needs and intended uses and shall include testing
production units under actual or simulated use conditions [820.30(g)]. Original designs and design
changes are subject to design control requirements [820.30(i)]. The results of design validation are
subject to review under the design control review requirements [820.30(e)].
DOCUMENTATION
The requirements for process validation are described in section 820.75 and include
documentation requirements for the process validation study phase as well as for routine production
using a validated process. Records of validation activities and results must be maintained
[820.75(a)]. Validation protocols and results may be filed in the DHF [820.30(j)] or in the QS files
(820.186). Records must include the date and signature of the individual(s) approving the validation
and, where appropriate, the major equipment validated [820.75(a)]. Procedures for monitoring and
control of process parameters must be established and maintained for validated processes
[820.75(b)]. Procedures for the operation, monitoring and control of processes are part of the DMR
(820.181).
When a validated process is used for manufacturing finished devices, the process must be
performed by a qualified individual [820.75(b)(1)]. Records must be maintained of the monitoring
and control methods and data; where appropriate, the individual(s) performing the process; the date
performed; and major equipment used. The records should be maintained in the DHR (820.184).
REVALIDATION
As long as the process operates in a state of control and no changes have been made to the process
or output product, the process does not have to be revalidated. Whether the process is operating in a
state of control is determined by analyzing day-to-day process control data and any finished device
testing data for conformance with specifications and for variability.
When changes or process deviations occur, the process must be reviewed and evaluated, and
revalidation must be performed where appropriate [820.75(c)]. Review, evaluation, and revalidation
activities must be documented.
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Processes may be routinely validated on a periodic basis; however, periodic validation may not be
adequate. More important is appropriate monitoring so that if problems develop or changes are
made, the need for immediate revalidation is considered.
REFERENCES
1. Guideline on General Principles of Process Validation, May 1987, FDA, CDRH/CDER
2.
Journal of Validation Technology, Vol. 1, No. 4, August 1995
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5
PERSONNEL AND TRAINING
INTRODUCTION ...................................................................................................................... 5-1
FDA Observations .................................................................................................................. 5-2
GMP REQUIREMENTS ........................................................................................................... 5-2
Employee Selection ................................................................................................................ 5-3
Production Personnel ............................................................................................................ 5-4
Technical Personnel ............................................................................................................... 5-4
Process Validation .................................................................................................................. 5-5
Quality Assurance Personnel ................................................................................................ 5-6
Complaint Handling .............................................................................................................. 5-7
Management ........................................................................................................................... 5-7
Training Methods .................................................................................................................. 5-7
Training Indicators ................................................................................................................ 5-8
Audits ...................................................................................................................................... 5-8
EXHIBITS ................................................................................................................................. 5-10
Employee Training Procedure ............................................................................................ 5-10
Employee Training Record ................................................................................................. 5-10
INTRODUCTION
Establishing a quality system should be an integrated and universal effort. A total quality systems
approach should be designed to satisfy the particular quality, safety, and performance needs of a
specific manufacturer, product, and user-market. Employees play a vital role in achieving these
objectives. Obviously, employees need to be aware of the details of the quality system and how to
meet them. The Quality System (QS) regulation supports these goals by requiring that a
manufacturer have sufficient qualified personnel and by requiring quality awareness training for
personnel [820.25(a)]. Management with executive responsibility shall ensure their quality policy is
understood, implemented, and maintained at all levels of the organization. This should be
accomplished by supplying sufficient resources, training, responsibility, and authority to all
managing personnel that will enable them to perform their tasks.
Personnel involved in design, manufacturing, quality assurance, auditing, complaint processing,
servicing, etc., should be properly trained, both by education and experience. No matter how
effective quality assurance and production systems are as concepts, people still play the major role in
designing and producing a quality product. Lack of training -- as reflected in instances of negligence,
poor operating techniques, or the inability of employees to discharge their functions properly -- can
lead to defective products and, sometimes, to regulatory or liability problems.
Employee attitude is the most important personnel factor that can assure an effective quality
system. By management setting an excellent example and through effective training, quality
consciousness should be developed in every employee. Each person should be made aware of the
importance of his or her individual contributions in the overall effort to achieve an acceptable level
of quality.
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The role of management in this vital awareness effort cannot be passive -- management should be
diligent in looking for factors that indicate a need for employee training [820.25(b)]. A quality
system should include an ongoing formal program for training all personnel. All personnel should be
made aware that product quality is not solely the responsibility of management or any other single
group. Quality is the responsibility of every employee -- any employee can generate a quality
problem through ignorance of their job requirements or negligence.
FDA Observations
It is not unusual for FDA investigators to conduct factory inspections and observe employees who
are clearly unaware of situations that can result in poor device quality. These employees obviously
have not been properly instructed on what activities or conditions will directly cause defective
devices or that can lead to mixups, contamination, or other problems that can cause non-conforming
devices. For example, an improperly maintained piece of manufacturing equipment may eventually
have disastrous consequences on finished devices. Therefore, the employee charged with maintaining
the equipment, as well as the operator of the equipment, should be made aware of conditions that
reflect a need for maintenance.
FDA investigators have observed employees: smoking near or sweeping dust into open processing
tanks where the smoke and dust would destroy the usefulness of the device; blowing smoke or
sweeping dust onto devices to be sterilized; handling delicate devices while wearing rings or other
jewelry; wearing gloves with holes or rubbing their nose and continuing to handle devices that need
to comply with bioburden requirements; wearing cleanroom clothing into uncontrolled areas; and
other poor practices such as leaving windows or doors open in controlled environmental areas.
FDA investigators were advised by management that it is the manufacturer's policy not to allow
the above situations to occur. The implementation of this policy is questionable. Are these employees
originally and then periodically reminded of the reason: for not smoking, eating, and wearing rings;
and for personal cleanliness, and other employee requirements? People respond better when they
know why they are allowed or not allowed to do certain activities - not just being told that it is
company policy.
GMP REQUIREMENTS
The QS regulation requires in section 820.25 that each manufacturer shall have sufficient
personnel with the necessary education, background, training, and experience to assure that all
activities required by this part are correctly performed. [The requirement for sufficient trained
personnel is also covered by resource requirements in 820.20(b)(2) as follows. Each manufacturer
shall provide adequate resources, including the assignment of trained personnel, for management,
performance of work, and assessment activities, including internal quality audits, to meet the
requirements of this part.]
Each manufacturer shall establish procedures for identifying training needs and ensure that all
personnel are trained to adequately perform their assigned responsibilities. Training shall be
documented.
As part of their training, personnel shall be made aware of device defects which may occur from
the improper performance of their specific jobs. [In addition to training, personnel also have to be
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notified if they are responsible for nonconforming product. The intent is to prevent or reduce
nonconforming product. Each manufacturer shall establish and maintain procedures to control
product that does not conform to specified requirements [820.90(a)]. The procedures shall
address the identification, documentation, evaluation, segregation, and disposition of
nonconforming product. The evaluation of nonconformance shall include a determination of the
need for an investigation and notification of the persons or organizations responsible for the
nonconformance. The evaluation and any investigation shall be documented.]
Personnel who perform verification and validation shall be made aware of defects and errors that
may be encountered as part of their job functions. There are also personnel requirements in
820.70(d) and 820.75(b)(1) as follows. Each manufacturer shall establish and maintain requirements
for the health, cleanliness, personal practices, and clothing of personnel if contact between such
personnel and product or environment could reasonably be expected to have an adverse effect on
product quality. The manufacturers shall ensure that maintenance and other personnel who are
required to work temporarily under special environmental conditions are appropriately trained or
supervised by a trained individual.
Each manufacturer shall ensure that validated processes are performed by qualified individual(s)
[870.75(b)(1)].
Employee Selection
As the first step in meeting GMP personnel requirements, manufacturers should select or hire
appropriate employees for the tasks to be performed. The initial selection of employees for a specific
job is made based on a combination of education, experience, personal habits, interests, etc. For
example, education alone is not a good indicator of whether a recent graduate with a scientific
degree can design a product.
New employees should be informed that they are working in a regulated industry and should be
initially trained to perform their specific jobs and be made aware of any defects or problems that
may occur from:
•
•
•
•
•
improper performance of their assigned tasks;
using incorrect tools or incorrect use of a tool;
poor hygiene, poor health, or smoking or eating on the job;
poor work habits or being in the wrong location; and
other detrimental factors.
Production Personnel
Section 820.70(d) requires that personnel in contact with a device or its environment shall be
clean, healthy, and suitably attired where lack of cleanliness, good health, or suitable attire could
adversely affect the device. Personnel who, by medical examination or supervisory observation,
appear to have a condition which could adversely affect the device should be excluded from affected
operations until the adverse condition is corrected. Personnel should be instructed to report such
conditions to their supervisor. Such actions by management could create problems unless employees
are instructed about work practices and requirements when they are hired or initially assigned to
the task in an environmentally controlled area.
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If eating, drinking, or smoking could have an adverse affect on the devices' fitness for use, then
employees should be informed that these activities are to be done only in designated areas.
Employees need to be informed why certain personnel and work practices are required. Basic
instructions about invisible microorganisms and particulates will make the company requirements
much more meaningful. People respond better when they know why they are allowed or not allowed
to do certain activities rather than just being told it is company policy.
Some factors that should be considered when teaching employees about working in a controlled
environment include:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
proper attire and dressing anteroom;
controlled use of, and entry into, controlled areas;
minimizing body movements;
locating the body and hands with respect to product and airflow;
prohibiting eating, drinking, smoking, or gum chewing;
reducing of coughing, sneezing and other objectionable health related conditions;
preventing use of lead pencils and certain cosmetics;
bathing and hand washing requirements;
preventing or controlling the cutting, tearing or storage of cardboard, paper, debris, etc.;
eliminating electrostatic charges by selection of clothing, grounding, etc.;
ensuring cleanliness of raw materials, components and tools; etc.
using correct furniture and eliminating use of extra furniture;
regulating the storage of tools, glassware and containers;
cleaning the room and production equipment per written procedure; and
cleaning of work surfaces and chairs.
Technical Personnel
The manufacturer should assure that they have sufficient properly trained personnel, or
programs to train technical personnel, to design, validate, develop processes, and produce the new or
modified device. Scientific and technical personnel usually need training in:
•
•
•
•
•
•
•
•
•
•
regulatory requirements;
company documentation systems;
verification and validation techniques;
consensus standards;
human factors;
labeling;
safety;
reliability;
producibility; and,
other peripheral design topics.
New design personnel may be introduced to manufacturing methods and producibility issues by
being assigned to various manufacturing areas before starting their design activities. The resulting
5−4
knowledge and experience is as valuable as their technical education -- remember that the ultimate
objective of a design and manufacturing operation is to produce a safe and effective device.
In another valuable training technique, manufacturing personnel are assigned to assist
development personnel in verifying components, and assembling and verifying subassemblies and
prototype devices.
These training techniques:
•
improve communications and technology transfer between the various departments;
•
help meet the interface requirements in 820.30(b), Design and Development Planning;
•
help promote concurrent engineering;
•
help research and development personnel understand that the goal is to produce a device -not just design a device;
•
achieve advance training for manufacturing personnel about a forthcoming design;
•
reduce production problems by improving the producibility of the device based on the
expertise and input of the manufacturing personnel into the design of the device; and
•
reduce production problems based on the expertise and input of the device design personnel
into the design of processes and production tools, jigs, molds, in-house standards, and test
methods.
All of these are important and valuable side benefits to these simple cross-training techniques.
Such training should be documented.
Process Validation
The above discussion for technical personnel also applies to technical employees that perform
process validation. After the processes are validated, these technical personnel should use their
expertise and experience to develop training methods or help train production employees on how to
monitor, control, and operate validated processes. Section 820.75(b) requires a manufacturer to
establish and maintain procedures for monitoring and control of process parameters for validated
processes to ensure that specified requirements continue to be met. Further, 820.75(b)(1) requires
that validated processes be performed by qualified individuals. Obviously, operators that are trained
to operate each specific validated process are needed to meet these requirements.
During the development and validation of a process, planning for eventual maintenance can
reduce or prevent confusion during emergency repairs. An emergency could lead to improper
repairs, such as use of a wrong replacement part. Therefore, the installation qualification should
include a review of pertinent training requirements, maintenance procedures, repair parts lists, and
calibration of measuring equipment.
Quality Assurance Personnel
5−5
QA or product acceptance employees shall meet the GMP personnel requirements for
manufacturing employees AND shall be made aware of defects and errors likely to be found in
nonconforming components and devices. Usually, it is easier and more effective to teach all of the
GMP personnel requirements to all appropriate employees.
Production or QA personnel performing quality assurance or acceptance functions should :
•
Maintain requirements for health, cleanliness, and clothing standards which will prevent an
adverse effect on product quality.
•
Adequately train and/or supervise temporary personnel working in special environmental
conditions.
The production department shall have sufficient personnel with the necessary education,
background, training, and experience to assure that all production activities are correctly
performed. Employees are selected and/or trained for their assigned tasks. These tasks may be
janitorial, receiving, pulling parts, production, labeling, acceptance test and inspection, packaging,
painting, welding, mixing, specific technical tests, etc.
To meet this requirement, each manufacturer shall establish procedures for identifying training
needs and ensure that all personnel are trained to adequately perform their assigned responsibilities.
As part of their training, personnel shall be made aware of device defects which may occur from
the improper performance of their specific jobs. Employees should be informed that they may need
to be qualified or certified to perform certain tasks such as welding, operating a validated process or
working in controlled areas. Likewise, employees need to be told that where necessary, they will be
informed about improper performance of their assign tasks with the intent of improving their
performance and reducing the likelihood of producing nonconforming product. Where necessary,
employees should be certified to perform manufacturing or quality acceptance procedures where a
high degree of specialized skill is required. Training shall be documented.
Complaint Handling
It is a good idea for most of the company personnel to receive basic training in complaint
handling techniques. Appropriate employees such as receptionists, salespersons, representatives,
secretaries, service personnel, and other employees who talk with users should receive training on
their responsibilities in regard to complaint handling requirements in section 820.198. If these
employees receive a device complaint, they need to know they have a responsibility to report it to the
company person(s) assigned to handle complaints. Likewise, importers and distributors should be
made aware of the complaint requirements, and they should be requested to forward complaints to
the manufacturer.
Management
Proper job performance by employees as required by the QS regulation dictates that
management have a good knowledge of the QS regulation and resulting quality system. Therefore,
management should also have appropriate education, training, and experience. As part of their
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review of the quality system, management should make certain that adequate "how to do"
documentation is available to employees. Proper job performance should be supported by correct
and complete quality system and device master records. These records should be written in such a
manner that the intended employees can understand and properly use them.
Management should show their commitment to training by providing a training room such as a
cafeteria and training equipment such as chalkboards, flip charts, video cameras, VCRs, television
monitors, slide projectors, overhead projectors, screens, workbooks, etc.
Training Methods
Training for employees may be achieved by many methods such as:
•
•
•
•
•
•
•
•
device regulatory and GMP seminars;
individual consultations with managers, consultants, FDA personnel, etc.;
on-the-job training with appropriate instructors;
cross-training details between R&D and production;
video tapes and movies;
slide shows with an appropriate instructor;
reading GMP/QA manuals and textbooks; and
formal college QA courses.
To meet GMP requirements, all training should be documented as noted above.
Training Indicators
A proactive approach to training is required by 820.25(b) where each manufacturer is required to
establish procedures for identifying training needs. Thus, management should diligently look for
factors that indicate a need for additional training or retraining. Some of these training indicators
are:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
verification failures due to basic problems,
post-submission technical and labeling information required by ODE for 510(k) submissions,
validation problems due to routine problems,
excessive design transfer problems or delays,
inadequate device master record,
excessive device defects,
excessive process equipment or line down-time,
improper labeling or packaging,
employee confusion,
employees ignoring environmental control requirements,
process or sterilization failures,
incorrect ordering or shipment information,
customer complaints, and
excessive or basic items on a FDA list of observations.
5−7
This information is derived from management observations, analysis of device history records,
analysis of complaint records, quality assurance audits, etc.
Audits
As management performs their daily activities they are aware of the obvious aspects of personnel
workmanship and work practices. However, to make sure that all aspects, obvious, hidden, or subtle,
of the required quality system exist and are operating correctly, the QS regulation in 820.20(b)
requires planned and periodic audits of the quality system. This audit covers:
•
•
•
noting personnel practices in areas being audited,
looking for training indicators as listed above, and
whether the company approach to training programs is proactive.
The audit also includes an inspection and review of training:
•
•
•
•
programs and content,
facilities,
equipment, and
records.
A report should be made of each quality audit, including any reaudits(s) of deficient matters such
as incorrect performance of work, lack of training, failure to update training, the training program
not being proactive for all of the personnel that receive complaints, part of the training equipment is
not functioning, on-the-job training not adequately supervised or documented, etc. Audit reports
that cover training activities and personnel practices should be reviewed by management responsible
for these factors in their department. Corrective actions for deficient training and personnel
practices shall be taken where necessary (820.22).
5−8
EXHIBITS
Reprinted on the following pages is an example of an employee general training procedure and an
example of associated employee training record. These may be used to comply with the training
requirements of the QS regulation.
The Buildings and Environment Chapter 6 has a procedure with many details about employee
practices in clean rooms.
Employee Training Procedure
This procedure is an example of a general employee training procedure that may be used by
manufacturers to assure that all employees receive basic training when they are hired and are
qualified for the assigned tasks. The procedure is used with the following training form.
Employee Training Record
This employee training record is a basic form for noting training activities for each employee. A
few training requirements are preprinted on the form because new hires should immediately receive
this basic training. The training record is used with a general training procedure as described above.
*** SAMPLE PROCEDURE ***
COMPANY LOGO
Page 1 of 2
Title Employee Training
SOP Number
Prepared by
Date Prepared
Approved by
Date
Rev
ECN Notes
Policy - Employees shall be trained as needed to perform their assigned tasks and shall be made aware that
we produce medical devices in accordance with various regulations and standards.
Scope - This procedure applies to all employees.
Hiring - The education, background, training, and experience of prospective employees shall be considered
with respect to the requirements of the job to be filled.
Responsibility - Managers are responsible for assuring that the employees assigned to them are trained or
otherwise qualified for the assigned jobs. Before assigning an employee for the first time to a new job,
managers shall check their training to verify that the employee has been trained or qualified for the new job.
The QA department is responsible for training facilities, equipment, and supplies.
Training - All inexperienced employees shall be trained to perform their assigned jobs. On-the-job training
shall be monitored closely by a supervisor. All employees shall be made aware of design and/or production
defects, visible and invisible, in the device, labeling, and packaging that may occur from the improper
performance of their jobs and defects that they should look for and detect. Our cleanliness (environmental
control) and safety procedures shall be explained to all employees.
5−9
Quality Assurance Employees - QA or product acceptance employees shall receive the training noted above
and shall be made aware of errors and defects, visible and invisible, likely to be encountered as part of their
quality assurance functions.
Customer Complaints - Receptionists, managers, representatives, salespersons, and other employees likely to
receive complaints are trained in complaint handling procedures applicable to their functions.
Change Control - All employees are to be advised that they are to perform their jobs as instructed or as
covered by standard operating procedures (SOP's). They are NOT allowed to change cleaning, compounding,
processing, testing, packaging, labeling, or tasks covered by SOP's until the change is approved according to
our change control SOP.
Documentation - All classroom and on-the-job training shall be documented by the supervisor and trainer of
the employee on the form as shown on sheet 2. A separate form for each employee with a record of their
training shall be filed and shall be updated at the end of each training session.
*** SAMPLE RECORD ***
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EMPLOYEE TRAINING RECORD
Page 2 of 2
Employee Name
DATE
EMPLOYEE
SIGNATURE
Hire Date
PRESENT JOB
TYPE OF
TRAINING
safety
defect awareness
environment control
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SUPERVISOR /
TRAINER SIGN.
6
BUILDINGS AND ENVIRONMENT
INTRODUCTION ............................................................................................................... 6-1
PERSONNEL TRAINING ................................................................................................. 6-1
BUILDINGS ........................................................................................................................ 6-1
Repackers, Remanufacturers, Contract Sterilizers, and Relabelers .............................. 6-2
Contamination Control ................................................................................................ 6-2
Orderly Operations ....................................................................................................... 6-2
ENVIRONMENTAL CONTROL ..................................................................................... 6-3
General Controls ........................................................................................................... 6-3
Analyze Operation ........................................................................................................ 6-3
Specifications ................................................................................................................. 6-4
Monitoring ..................................................................................................................... 6-5
CONTAMINATION CONTROL ...................................................................................... 6-5
Personnel Sanitation Practices .................................................................................... 6-6
Prevent Contamination by Hazardous Substances .................................................... 6-6
Personal Practices ......................................................................................................... 6-6
EXHIBITS ........................................................................................................................... 6-7
Clean Room and Work Station Procedure ....................................................................... 6-7
Cleaning Procedure for the Aseptic Filling Room ..................................................... 6-7
INTRODUCTION
The buildings and environment in which components, devices, and records are received,
processed, built, or stored, and the personnel that perform these operations should be controlled so
that finished devices will consistently meet the specifications established by the manufacturer. The
degree of control should allow for appropriate changes in such elements as temperature, humidity,
bioburden, particles, personnel, components, devices, and records.
PERSONNEL TRAINING
Personnel play an important role in orderly operations and environmental control. They can
reduce or increase contamination. Thus, personnel can positively or negatively impact most of the
points made in this chapter. To reduce problems and increase the state-of-control, employees shall
be appropriately trained regarding orderly operations and environmental control as required by
820.25 and as discussed in Chapter 5.
BUILDINGS
Facilities of medical device manufacturers and their contractors in which components, in-process
devices, accessories, and finished devices are handled, processed, and stored shall have sufficient
space and be designed to allow proper cleaning, maintenance, and other necessary operations in
order to meet the requirements of 21 CFR 820.70 of the Quality System (QS) regulation. Buildings
should be suitably designed so that there is adequate space for manufacturing, receiving,
packaging/labeling, storage, etc., to: minimize contaminants; assure orderly handling procedures;
and prevent mixups. As the company grows or the product line is changed, existing facilities may
6−12
become inadequate. Thus, as part of the quality assurance program audit, existing buildings should
be reviewed to determine if space and facilities are adequate in light of growth or changes in
production
Repackers, Remanufacturers, Contract Sterilizers, and Relabelers
The GMP requirements for buildings extend to manufacturers that repackage and/or relabel
unpackaged bulk devices, contract sterilizers, and remanufacturers that change the original
condition of devices. The number of operations needed to repackage or relabel a product may be less
than for actual manufacturing of a product; nevertheless, there is a need to design and arrange
facilities so that repackaging and/or relabeling operations, particularly for sterile devices, can be
performed in a controlled manner. Because remanufacturing of devices is manufacturing, the GMP
requirements for buildings and facilities extend to areas where modifications are performed. In
some manufacturers these modifications are done in cluttered repair shops. Under these conditions,
there is an increased probability for contamination or mixup, hence such manufacturers should take
appropriate precautions as required by the QS regulation.
Contamination Control
Typical problems in manufacturing and storage facilities include environmental contamination
and insufficient space for receiving and holding incoming products before testing and inspection
[820.70(c) and 820.70(e) and 820.70(f)]. For each area in the building where products are processed,
any elements such as particulates from cardboard dust, by-products from slitting or cutting
operations, microorganisms, humidity, temperature, static electricity, etc., which a manufacturer
has determined might cause contamination should be controlled. Buildings should be appropriately
constructed to prevent, reduce, and control potential contaminants and support the environmental
control program as discussed later. For example, the control of dust may require that driveways and
parking lots be paved. Crowding causes mixups and can result in contamination or in the use of
unapproved or rejected products. Designated areas should be assigned for various production
activities such as receiving, inspection/testing, manufacturing, labeling, packaging, record keeping,
etc. Traffic by personnel who do not work in or manage the designated areas should be held to a
minimum.
Orderly Operations
In addition to having sufficient space, the facility shall be designed and arranged so that all
operations can be performed in an orderly manner [820.70(f)]. This will facilitate the satisfactory
performance of all operations. In manufacturing areas, it prevents confusion that can lead to
unsatisfactory job performance and mixups. The goal is for a smooth flow of operations.
To preclude mixups, distinct operations or processes should be separated either physically, by
walls or partitions, or spatially, by providing enough room between operations to indicate that
separate activities are being performed. An appropriate degree of separation, or walls, curtains, etc.,
should exist so that no activity will spray, dust, or otherwise have an adverse effect on other adjacent
activities. For example, there should be a handling and storage system to preclude the mixup of
labeled "sterile" but not-yet-sterilized devices from the same type of devices that have been
sterilized. Manufacturers that have more than one labeling operation should maintain adequate
separation of these to prevent any mixups occurring between various products and their specified
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labeling. Labeling mixups are a major cause of product recalls and a number of these mixups can be
traced to inadequate separation of operations during the labeling of devices.
ENVIRONMENTAL CONTROL
One of the variables that can significantly affect product quality and employee performance is the
environment. A controlled environment is, to various degrees, an integral part of most production
facilities. Some environmental factors to be considered are lighting, ventilation, temperature,
humidity, pressure, particulates, and static electricity. Section 820.70(c), Environmental Control, of
the QS regulation, is considered by FDA to be a "discretionary" requirement; that is, the degree of
environmental control to be maintained should be consistent with the intended use of the device and
details of how to achieve this control are left to the manufacturer to decide. "Discretionary quality
system requirements" are those which may or may not apply to the manufacturer of a specific
device. In these cases the manufacturer should decide whether implementing such requirements is
necessary to assure the quality of the finished device. These requirements are modified in the QS
regulation by phrases such as "where environmental conditions could reasonably be expected to
have an adverse affect" and "adequately control."
General Controls
General air conditioning is normally not regarded as an environmental control; however, changes
in temperature and lighting can have an adverse effect on employee performance and, in turn, on
assuring that the device is properly assembled, inspected, and tested. Air conditioning can control
humidity which, in turn, can affect the generation of static charges. Static charges can damage some
electronic components and, in such situations, need to be controlled [820.70(c)]. Production workers
are a major source of particulate contamination and standard operating procedures for personnel
are often necessary in order that employees not adversely affect the environment.
Analyze Operation
If the environment in which devices are manufactured or held can have an adverse effect on the
devices' fitness for use, that environment shall be controlled [820.70(c)]. For each operation, the
manufacturer should analyze the manufacturing operations to identify controls needed for the
finished device to meet the device specifications and be fit for the intended use; and to control costs.
For example, in the manufacture of sterile devices such as implants, or diagnostic media that
requires aseptic filling, the environment should be controlled to reduce viable microorganisms and
particulate matter. The packaging for sterile devices should be stored in a clean, dry, insect-free
area. Components that support bacterial growth should be stored in a controlled environment
which, in some cases, will include refrigeration.
Because particles can bridge across sub-micron circuits and static electricity can rupture
semiconductor junctions, microcircuits for use in devices should be manufactured in a stringent
clean-room environment where particulates and humidity are controlled. When analyzing the
production of a device to determine the degree of control needed, the manufacturer should identify
exactly what needs to be controlled:
•
•
•
the device itself;
the area for one task; or
the large production area.
6−14
For example, if the device can be cleaned after production, there usually is no need for extensive
environmental control during production. If the cleaned devices are stored in clean containers or
are immediately packaged, the environment usually should be controlled where the device is being
packaged. If the work area needs to be controlled, how much should be controlled -- a work bench,
room, or factory? For example, a HEPA filtered laminar-flow bench maintains a low-particulate
environment that is large enough for many small tasks or operations. If a larger area is needed, then
it may be possible to set a broad environmental specification for most of the room or area. A small
laminar-flow unit and curtains can create a small, but very clean area. Considerations such as these
can reduce environmental facility and equipment costs and reduce the activities required to
maintain and monitor the controlled area and operations.
Specifications
When it is necessary to control the environment, specifications for parameters such as
temperature, humidity, colony forming units (CFU's), and particulates per cubic foot, etc. should be
established. No FDA guidances for these parameters presently exist for environmentally controlled
areas such as clean rooms. “Federal Standard Airborne Particulate Cleanliness Classes In Clean
room and Clean Zones” (FED-STD-209E) with its appendices is suggested as a resource for
developing clean room standards such as particle counts per cubic foot. Federal Standard 209E
defines various levels of environmental control such as Class 1000. A Class 1000 room contains no
more than 1000 particles 0.5 micron diameter or larger per cubic foot of air. Information may also
be obtained from manufacturers of clean room equipment. Aseptic manufacturing and filling are
usually done in a Class 100 or better clean room or bench. The Class 100 status is maintained during
routine operations. During idle periods the particle count will generally be much lower than 100.
Some manufacturers use a Class 10,000 clean room for the assembly and packaging of devices that
will be terminally sterilized and where a low particulate count on the devices is desired. The
specifications for such a room could be:
Particulates:
Humidity:
Temperature:
Air Velocity:
Air Pressure:
Maximum of 10,000 of 0.5 micron diameter or larger per cubic foot
45 +/- 5 percent
72 +/- 2.5 degrees F
90 feet/minute +/- 2 percent
0.05 inches water between the clean room and other areas
For assembly of many types of convenience kits and assembly of medical devices that need to be
free of visible particles, many manufacturers use an "industrially clean area or controlled
environment area." Such rooms are air conditioned and use furnace filters and, in some cases, prefilters of much finer porosity than furnace filters are also used. The temperature is controlled by a
standard room thermostat. Humidity variations are limited by common air conditioning. True air
conditioning with cooling below the dewpoint and reheat are not necessarily used. Air velocity is
determined for the air conditioning; and the room is known to have positive pressure with respect to
other areas by a flow or pressure indicator. A particle class is not specified. However, these
manufacturers have established a controlled environment and appropriate specifications for
temperature, cleaning, and contamination controls are in place. For example, filters should be
replaced per schedule or as needed based on scheduled inspections. Any practices or factors from
the following list that the manufacturer has deemed appropriate and elected to use should be
specified and routinely performed or followed. Some additional factors that should be considered
when planning and using a controlled environment include:
6−15
•
•
•
•
•
•
•
•
•
•
•
•
•
•
proper attire and dressing anteroom;
controlled use of, and entry into, controlled areas;
prohibiting eating, drinking, smoking, or gum chewing;
preventing use of lead pencils;
regulating the storage of glassware and containers;
preventing or controlling the cutting, tearing or storage of cardboard, debris, etc.;
cleaning the room and production equipment per written procedure;
the original design and cleaning of work surfaces and chairs;
selecting correct furniture and eliminating all nonessential equipment;
controlling room air quality (amount of particulates, pressure, velocity, and exchange rate);
eliminating electrostatic charges by controlling work surface composition or grounding;
ensuring cleanliness of raw materials, components and tools;
controlling the purity, sterility, and non-pyrogenicity of process water; and
maintaining prefilters, HEPA filters, and electrostatic precipitators.
Also see at the end of this chapter the procedure, "Clean Room and Work Station Procedure,”
which covers work practices, dress codes, and hygiene for employees working in clean rooms or at
laminar-flow benches.
Monitoring
An appropriate system for regular monitoring should be established and maintained for each of
these factors to be controlled for a given operation. This will ensure that equipment is performing
properly and that the quality of the environment is within specifications. When a particle count
Class is specified, monitoring of airborne particulates is usually done with an air sampler.
Monitoring of work surfaces for microbes [colony forming units] may be done with surface contact
plates or settling plates. However, settling plates should not be used for monitoring when horizontal
laminar air flow is used as they are ineffective for this type of flow.
All sampling should be done per written procedure, and the data should be recorded. Further,
periodic inspections of environmental controls and documentation of the inspections are required by
the QS regulation. The inspection checkoff form or other record should be kept simple.
CONTAMINATION CONTROL
The QS regulation requires in 820.70(e) that every manufacturer establish and maintain
procedures to prevent contamination of product or equipment. These process specifications are
established by the manufacturer to ensure that finished devices will meet the company's quality
claims. Typical device examples are: in vitro devices that are not contaminated with microbes,
detergents or rodenticides; circuits that are not contaminated with flux; implants that are not
contaminated with body oils and certain implants that are not contaminated with pyrogens.
Pyrogens are substances that cause fever in humans, and they arise primarily from cellular debris of
gram-negative bacteria.Certain implants such as orthopedic implants are not required or expected
to be pyrogen free. Other devices are required to be nonpyrogenic including: transfusion and
infusion assemblies, devices that come in contact with circulating blood or cerebrospinal fluid,
intraocular lenses and the surgical instruments used in their implantation, and any device labeled as
“nonpyrogenic”. Manufacturers should carefully control the environment in which such devices are
6−16
manufactured and processed to minimize contamination with bacteria or establish a procedure for
cleaning the devices.
If necessary for the device to meet company product specifications or labeling claims, cleaning
procedures and schedules to meet the requirements of section 820.70 may need to be written. Each
operation should be analyzed in order to write an appropriate procedure or determine that one is
not needed. For example, written procedures are usually not required for cleaning floors and work
benches in areas where non-sterile and non-growth promoting components or devices are processed
and packaged. An example of a procedure and schedule for cleaning an aseptic filling room is
exhibited at the end of this chapter. Records related to facilities, the environment and personnel
practices need to be kept simple as shown by this example. Note that the schedule and record of
cleaning are both on page 4 of the procedure. The record of cleaning may be a checkmark, initial, or
signature. Where a checkmark is used for repetitive work, companies commonly require that the
person's name be on the record at least once. The schedule for cleaning may be posted or filed as
long as it is in a convenient location. As appropriate, manufacturers may use this procedure as is,
modify it, or use it as a guide to develop a procedure to meet specific needs.
Personnel Sanitation Practices
Adequate bathroom, dressing, storage, and waste facilities should be provided, as appropriate, for
personnel to maintain the needed level of cleanliness [820.70(d)]. Such facilities should be
maintained on a regularly scheduled basis. Where necessary, such as in a clean room, special
clothing and an area to don and store the garments should be provided. Clean room clothing is not
be worn into uncontrolled rooms or outside the facility.
Prevent Contamination by Hazardous Substances
If rodenticides, insecticides, or other hazardous substances are used, written procedures to limit
their use or for their removal from work surfaces and devices should be established to prevent any
adverse affect on the manufacturing process or the device [820.70(e)].
Personal Practices
If eating, drinking, or smoking could have an adverse affect on the devices' fitness for use,
manufacturing procedures should include instructions on how to avoid such adverse effects
[820.70(d)]. For example, these activities could be confined to specially designated areas such as a
lunch room or employees lounge. Directions and containers or equipment should be provided for
timely and safe disposal of trash, by-products, effluents and other refuse.
EXHIBITS
Reprinted on the following pages are two examples of procedures that may be used to comply
with the cleaning or contamination control requirements of the QS regulation. Both of these
procedures deal with sensitive areas of the plant: clean room and aseptic filling rooms. Therefore,
these are more comprehensive than is normally needed for general plant cleaning.
Note that these procedures follow good labeling practices in that the tasks or rules are broken
into numbered steps; and only one or two activities or rules are included in each step. Thus, the
directions or rules are easy to read, remember, and execute or obey.
6−17
Clean Room and Work Station Procedure
This procedure is divided into general requirements, non-laminar airflow clean rooms, and
workstations, laminar airflow clean rooms and workstations, and clean room personnel rules. The
first part of this procedure contains useful information for any area of a plant were moderate
control is needed to reduce particulate contamination. The level of control needed increases as the
procedure goes from non-laminar airflow to laminar airflow. The final section contains additional
requirements for personnel working in a clean room.
Cleaning Procedure for the Aseptic Filling Room
This is a standard operating procedure used by personnel that are charged with cleaning an
aseptic filling area and not for personnel that generally work in this area. This cleaning procedure is
divided into two sections, daily and weekly tasks, thus giving personnel guidance on when, as well as,
how to perform these tasks. Please note that many manufacturers will alternate the germicide in
their cleaning solution to minimize the likelihood of resistant organisms developing. There are two
items of interest in this procedure that should help to minimize entering and exiting this area: the
equipment list at the beginning, and the maintenance information at the end. The equipment list is
important because it alerts personnel to obtain the proper equipment before beginning work. The
maintenance procedures allow the personnel to perform maintenance tasks without calling in a
special crew or having to exit and re-enter the room unnecessarily.
Sheet 1 of 3
PROCEDURE TITLE: Clean Room and Work Station Procedure
No.______ Rev._________
Prepared by__________________________App. by____________________Date________
A. General Requirements
1.
No eating, drinking, smoking, or chewing gum.
2.
Specified garments must be worn when entering and inside the clean area. These shall be stored
in the anteroom and not worn in non-clean areas.
3.
Only approved clean room paper shall be allowed in the area.
4.
Use only ballpoint pens (fine point preferred).
5.
Rouge, lipstick, eye shadow, eyebrow pencil, mascara, and false eyelashes shall not be worn by
any worker while in any clean area.
6−18
6.
No cosmetics of any kind are to be applied or removed in the clean area.
7.
Skin lotions or lanolin-base soaps are in the restrooms for employees to use to guard against
flaking due to dry skin.
8.
Solvent contact with the bare skin should be avoided, as most solvents will remove the natural
skin oils and cause excessive skin flaking.
9.
The use of paper or fabric towels is not recommended -- washrooms should have electrically
powered, warm-air dryers.
10. Approved pliers, tweezers or lint-free gloves must be used to handle manufacturing materials,
components, or finished devices.
11. Do not touch with gloves or finger cots any covered or uncovered part of the body, or any item
or surface that has not been thoroughly cleaned.
12. All containers, racks, jigs, fixtures, and tools should be cleaned to the same level of cleanliness
specified for the device being processed.
6−19
Sheet 2 of 3
B.
Non-laminar Airflow Clean rooms and Work Stations
1.
Garments shall be pocket-less, lint-free coveralls, with snug fitting fasteners at the neck, wrist,
and ankles.
2.
Lint-free caps must be worn and must completely cover the hair and head except for the eyes,
nose, mouth, and chin.
3.
Shoes shall be cleaned and covered with a non-shedding boot-type cover or changed to
approved clean room footwear. If special footwear is provided, it shall not be worn outside the
clean room and dressing room.
4.
Janitorial services shall be performed only by adequately trained and supervised personnel,
each of whom must be properly garbed.
5.
All equipment to be brought into the clean room shall be qualified for clean room use and first
be thoroughly cleaned. Use only equipment that will minimize the generation of contaminants.
6.
Traffic into and within the clean room shall be restricted to authorized and properly garbed
personnel, and unnecessary movements by these personnel shall be minimized.
C. Laminar Airflow Clean Rooms and Work Stations
1.
Garments may vary with the operation being performed, but the minimum garment shall be a
pocket-less, lint-free smock which extends to at least 15 inches below the work surface. The
collar and cuffs shall have fasteners.
2.
Head covering shall be worn, and shall completely cover the hair. If the operation requires the
wearer to lean over the work, or move into the airstream between the filter bank and the work
piece, the front, sides, and rear neck areas of the head shall also be covered.
3.
Shoe covers are not necessary for vertical or horizontal laminar airflow facilities except when
the work is being performed less than 24 inches from the floor.
4.
A face mask may be needed if an operator has a cold, or if the nose and mouth must be brought
very close to the work piece for work on miniature components or devices. Check with your
supervisor for instructions.
6−20
Sheet 3 of 3
D. Clean Room Personnel Rules
Personnel will be asked to cooperate in maintaining a low contaminant emission rate by observing
the following rules.
1.
Bathe at night, instead of in the morning, to allow the build-up of normal body oils which
reduces skni shedding. Also, use skin lotions.
2.
Wear clean, unstarched, low-shedding garments.
3.
Where appropriate, shave daily and be clean shaven or wear appropriate hair covering.
4.
Avoid touching, rubbing, and scratching exposed areas of the body.
5.
Exercise extra care to rid the hands of normal residue from home duties such as starching,
baking, plastering, wallpapering, painting, concrete work, carpentering or other particulate
generating activity.
6.
Request duty outside the or away from the clean room area when you have a cold or other viral
or bacterial infection.
6−21
Page 1 of 4
STANDARD OPERATING PROCEDURE: Number G021 Revision A
TITLE: Cleaning Procedure for the Aseptic Filling Room
APPROVED BY:__________________________Date:___________________
PURPOSE: Control of surface contamination within the Aseptic Filling Room.
EQUIPMENT NEEDED:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Cleaning solution: See SOP G044
Non-linting wiping cloths
Stainless-steel basins and pails
Dry-wet vacuum cleaner for floors
(should be equipped with a HEPA filter on the exhaust air port to filter the exhaust air)
Sponge mops with replaceable sterile heads
Mop buckets
Stainless-steel sponges
Powder free latex surgical gloves, sterile
Head and shoe covers, sterile
Face masks and gowns, sterile
Stainless-steel cart
Sprayer
Trash can plastic liners
Stepladder
DAILY CLEANING REQUIREMENTS:
CAUTION: Be careful when using stepladder and when walking in wet areas. USE EXTREME
CARE WHEN CLEANING ELECTRICAL FIXTURES AND OUTLETS. USE DAMP (NOT WET)
CLOTH TO WIPE ELECTRICAL ITEMS.
A. Gowning Room:
Shoe and head covers are required in this area. Begin all cleaning at the top and finish at the
bottom of any equipment or surface to be cleaned.
1.
2.
3.
4.
Empty trash containers and replace plastic liners.
Replenish stock of shoe covers, masks, head covers, gowns, gloves and put into proper areas.
Fill dispenser with 0.45 u filtered 70% Isopropyl alcohol.
Mix cleaning solution of XXXXXXXX using process water (SOP G044).
6−22
Page 2 of 4
5. Fill a stainless-steel basin with cleaning solution and begin wiping in this order: the boot
box;
stool; wash station; top and outsides of all cabinets; counter tops; and the tops of the
trash
containers.
6. Remove excess debris and wet mop the floor with cleaning solution.
7. Fill sprayer with cleaning solution and wet the floor; allow it to air dry.
8. Gown according to gowning procedures and go into the filling area (SOP G014).
B.
Filling Room:
1. Move any remaining products (devices) to appropriate areas as directed by your supervisor.
2. Empty all trash containers and replace liners.
3. Remove particulate matter from ledges, cabinets and external surfaces of laminar-flow
benches
with a wiping cloth and cleaning solution.
4. Perform general cleaning and organization of shelves.
5. Remove debris and wet mop the floor with cleaning solution.
6. Spray the entire floor in the filling room with cleaning solution, using the provided sprayer.
Allow the floor to air dry.
WEEKLY CLEANING REQUIREMENTS:
All daily cleaning requirements are included in the weekly cleaning requirements. The additions
to the weekly cleaning are ceilings, walls, and the internal work surfaces of the laminar-flow work
benches. Rodac plate measurements are taken after cleaning and before the next production
shift.
A. Gowning Room:
1. Use only one entrance and one exit when cleaning. The cleaning direction will flow from
entrance to exit.
2. Remove all non-essential equipment from the room and clean it. Return the equipment after
the
entire area is cleaned.
3. Begin cleaning the room by wiping the entire ceiling area with the cleaning solution.
Frequent changes of the cleaning solution and the wiping cloths are needed for effective cleaning
of large areas such as the ceilings and walls. Make new solution and change wiping cloths when
dirty.
1. Clean air vents, lighting fixtures, and sprinkler heads.
6−23
Page 3 of 4
1. Clean the walls next, starting at the top and cleaning toward the floor.
2. When the ceilings and walls are cleaned, follow steps 1, 2, 3 and 5 of the Daily Cleaning
Requirements for the gowning room.
3. Remove debris and wet mop the floor with cleaning solution.
4. Fill the sprayer with cleaning solution and wet the floor. Allow to air dry.
5. Gown according to procedure and go into the Filling room (SOP G014).
B.
Filling Room:
1. Follow steps 1, 2, 3 and 4 of Daily Cleaning Requirements for Filling Room.
2. Begin cleaning operation by wiping the entire ceiling area with cleaning solution. Make new
cleaning solution and change wiping cloth when visibly dirty.
3. Clean air vents, ultraviolet and fluorescent lighting fixtures and sprinkler heads.
4. Clean the ultraviolet bulb since any oil or dust on the bulb drastically reduces its germicidal
properties.
5. Clean the walls next, starting at the top and cleaning toward the floor. Make new cleaning
solution, and change wiping cloth when dirty.
6. Empty all shelves and wipe with the cleaning solution. Wipe the removed materials and put
them back onto the cleaned shelf.
7. Wipe all cabinets and equipment with the cleaning solution from top to bottom.
8. Wipe all ledges and surfaces with the cleaning solution.
9. Pay particular attention to the laminar-flow workbenches because the cleaning operation
should start in the internal work surface of the hood as it is the cleanest area.
Use a fresh wiping cloth and cleaning solution for the internal work surfaces. Do not use the same
cloth or solution which was used for the external cleaning. Discard solution and wiping cloths after
cleaning each hood.
1. First, switch off the laminar-flow hood, then clean all outside surfaces from top of hood to
bottom stand. Discard cleaning cloth.
2. Second, clean all internal work surfaces with a new cleaning cloth in this order:
a.
b.
c.
d.
Air diffuser screen
Workbench top.
Plexiglas sides
Light covers
3. Clean the floors. Scrub stains or spills first, with stainless-steel sponges, to loosen debris. Use
the sponge mop to clean the loosened debris. Fill the sprayer with cleaning solution and wet
the entire floor area. Allow to air dry. Rodac plate measurements are made after cleaning
and
before the next production shift.
4. Complete the documentation ledger and sign it. See Attachment A.
Page 4 of 4
6−24
C. Maintenance of Cleaning Equipment After Daily and Weekly Cleaning:
1. Use the same solution as used for general cleaning.
2. Wipe stepladder from top to bottom, in that order, and put it into storage cabinet.
3. Wipe stainless-steel basins and pails with cleaning solution, allow to air dry, and put into
storage cabinet.
4. Rinse mops and buckets with cleaning solution. Do not leave dirty solution in buckets or
vacuum cleaner.
5. Rinse sponge mops with warm water. If mop head needs replacing, replace it and put mop
into
storage cabinet.
6. Wipe stainless-steel cart with cleaning solution and put into storage cabinet.
7. Rinse sprayer with cleaning solution and put into storage cabinet.
8. Rinse vacuum cleaner with cleaning solution. Remove filters and clean with cleaning
solution.
Replace filters and clean nozzle. Put into storage cabinet.
9. Autoclave mop heads and buckets per procedure GAC 09.
6−25
PTIC FILL DEPARTMENT CLEANING RECORD
A
ITEM
NING ROOM
Empty waste containers
ROOM
LOCKS
AN FILL RM
LING AREA
Week of
SUN
Remove dirty uniforms
Wipe ceilings
Clean UV lights
Wipe walls
Clean floors
Empty waste containers
Straighten shelves
Wipe ceilings, walls & ledges
Clean UV lights
Clean floors
Wipe ceiling & walls
Clean floors
Empty waste containers
Wipe ceilings & walls
Clean floors
Empty waste containers
Wipe ceilings, walls & ledges
Clean UV lights
Clean floors
e task completed each day by a check mark in appropriate box. Shift Supervisor:
6−26
MON
TUE
WED
THU
FRI
SAT
WKLY
7
EQUIPMENT AND CALIBRATION
INTRODUCTION ................................................................................................................ 7-1
EQUIPMENT GMP CONTROLS ..................................................................................... 7-2
Maintenance 7-2
Records ........................................................................................................................... 7-3
MANUFACTURING MATERIALS ................................................................................. 7-3
Analyze Use .................................................................................................................... 7-3
Control Use .................................................................................................................... 7-4
AUTOMATED PRODUCTION AND QA SYSTEMS .................................................... 7-4
Software Validation Guidances ................................................................................... 7-5
Employee Responsibility and Training ....................................................................... 7-5
Formal Development of Software ................................................................................ 7-5
Commercial Software and Equipment ...................................................................... 7-6
Validation of Automated Equipment and Processes ................................................ 7-7
Automated Data Collection and Processing ............................................................... 7-7
Equipment Controls and Audits .................................................................................. 7-8
MEASURING EQUIPMENT CALIBRATION .............................................................. 7-8
Calibration Requirements ............................................................................................ 7-9
Equipment Selection ................................................................................................... 7-12
Procedures ................................................................................................................... 7-12
Management of Metrology ............................................................................................... 7-13
Calibration Records .......................................................................................................... 7-13
Schedules 7-17
Standards ........................................................................................................................... 7-18
Calibration Environment ........................................................................................... 7-18
AUDIT OF CALIBRATION SYSTEM .......................................................................... 7-18
INTEGRATING MEASUREMENTS INTO THE QA SYSTEM ............................... 7-19
EXHIBITS ......................................................................................................................... 7-20
P.C. Board Cleaning ................................................................................................... 7-20
Calibration Procedures for Mechanical Measuring Tools ............................................ 7-20
INTRODUCTION
The Quality System (QS) regulation requires that each manufacturer develop, conduct, control,
and monitor production processes to ensure that the end device conforms to its specifications
[820.70]. All equipment used to manufacture a device shall be appropriately designed, constructed,
placed, and installed to facilitate maintenance, adjustment, cleaning, and use [820.70(g)]. The degree
of maintenance on equipment and the frequency of calibration of measuring equipment will depend
upon the type of equipment, frequency of use, and importance in the manufacturing process. Where
deviations from device specifications could occur as the result of manufacturing processes, the
manufacturer shall establish and maintain process control procedures. This chapter addresses the
7−1
steps necessary to ensure that manufacturing equipment continuously operates within the
parameters necessary to produce a product that meets specifications.
EQUIPMENT GMP CONTROLS
The selection, purchase, and installation of the most appropriate manufacturing equipment is
important to successfully manufacture a medical device to specifications. After this manufacturing
equipment has been installed and placed in operation, it shall be maintained. This includes the
periodic inspection, adjustment, cleaning, and other maintenance of this equipment to insure that
product specifications continue to be met [820.70(g)(1), (2) and (3)]. If the manufacturing equipment
used in production includes computers or an automated data processing system, the manufacturer
shall validate the software for its intended use and the software changes using an established
protocol [820.70(i)]. In addition the manufacturer is responsible for ensuring the establishment of
routine calibration [820.72], inspection, and maintenance on all of their inspection, measuring, and
test equipment so this equipment will be suitable for its intended use(s).
Equally important to the purchasing and maintenance of manufacturing equipment is the
adequate training of personnel so they are able to operate the equipment correctly [820.25(b) and
820.70(d)]. This training shall be documented. Included in adequate personnel training is the
establishment and maintenance of requirements for health, cleanliness, personal practices, and
clothing of employees when contact between these people and the product or the environment could
reasonably be expected to adversely effect the finished product quality [820.70(d)].
Maintenance
Device manufacturers shall establish schedules to maintain, clean, and adjust equipment used in
the manufacture of medical devices where failure to do so could have an adverse effect on the
equipment's operation and hence the device. For example, failure to maintain, clean, and adjust a
sealing and/or packaging machine used for primary packaging of sterile devices will eventually
result in defective packages and thus nonsterile products.
A manufacturer should determine if the equipment requires maintenance and apply the
appropriate parts of the GMP requirements for equipment. The user usually can determine if
specific equipment requires maintenance by reviewing the equipment operations and maintenance
manuals usually supplied by the equipment manufacturer. Typically, a manufacturer will maintain
equipment simply because it prolongs equipment life and minimizes the need for major service.
If it is necessary to maintain, clean, or adjust equipment, the manufacturer should:
•
have a written schedule for performing these activities;
•
where adjustment is necessary to maintain proper operation, post the inherent limitations and
allowable tolerances of the equipment or make these readily available to personnel responsible
for making the adjustments;
•
document the maintenance activities including the date and individual(s) performing the
maintenance activity and the date and individual(s) conducting the inspections;
7−2
• have procedures for conducting periodic inspections to assure adherence to maintenance
schedules; and,
•
audit the activities and document the inspection.
Records
Manufacturers may find it helpful to establish and maintain maintenance procedures for
manufacturing equipment in order to ensure meeting the manufacturing specifications. These
procedures should include adjustment and cleaning, as well as other equipment maintenance.
Documentation should be kept on maintenance activities including: the activity performed, the date,
and the individual providing the maintenance [820.70(g)(1)]. An example of an operation and
maintenance procedure, "P.C. Board Cleaning," is exhibited at the end of this chapter. Maintenance
records and schedules are not needed for equipment such as lathes, presses, grinders, etc., that are
used in a machine shop and maintained by skilled employees on a daily basis. Automated machining
equipment will require maintenance schedules.
MANUFACTURING MATERIALS
The proper or optimum operation of manufacturing equipment often requires the use of
lubricants and other manufacturing materials. The QS regulation defines "manufacturing material"
as any material or substance used in or used to facilitate the manufacturing process, a concomitant
constituent, or a byproduct constituent produced during the manufacturing process, which is
present in or on the finished device as a residue or impurity not by design or intent of the
manufacturer [820.3(p)]. Manufacturing materials are often used with equipment. Manufacturing
materials include, but are not limited to: mold release compounds; cleaning agents; lubricating oils;
and other substances used to facilitate manufacturing. If any of these materials has an adverse effect
on the finished device, procedures shall be established and maintained for the removal or at least the
reduction of these manufacturing materials to an amount that will not adversely affect the device’s
quality.
Manufacturing materials are specified, procured, inspected/tested, etc., the same as components
[820.3(r), 820.50, and 820.80]. For details see Purchasing and Acceptance Activities, Chapter 10 of
this manual.
Analyze Use
The use of manufacturing materials that may adversely affect the finished device should be
carefully analyzed. Each process should be designed to use a minimum amount of adverse materials
so as to reduce costs, reduce removal efforts, and increase the intrinsic safety of the device. Whether
or not a manufacturing material has been removed or adequately limited may be determined by
using either of the two general approaches below.
•
The adverse material may be measured directly and compared to the process specification.
• If feasible, the component, in-process device, or finished device may be tested against its
specification. If the item passes, it follows that the residue is not affecting the performance.
7−3
The test specification should be appropriate for this method of evaluating residues and may need
to include tests for toxicity, pyrogens, material compatibility, etc.
Control Use
Section 820.70(h) requires a written procedure for the use and removal of manufacturing
materials that can have an adverse effect on devices. Usually, the procedure used for routine
cleaning of the device and its assemblies can be used for this purpose. If so, a special procedure is not
necessary. However, when residues from agents such as ethylene oxide should be reduced, special
instructions usually are necessary.
When manufacturing materials such as oils, mold-release compounds, gases, cleaning agents,
etc., are used on or in equipment, manufacturers should:
•
•
•
provide written procedures for the use and removal of materials; and
remove the material or limit it to a safe amount;
document the removal.
Where a manufacturing material residue is not or cannot be made safe for everyone such as for
sensitized individuals, the manufacture should meet limits set by regulation, standards, guidance,
etc. When appropriate, a caution label should be used to advise sensitized or atopic individuals
about the residue.
A sample procedure, "P.C. Board Cleaning", covering equipment used for removing adverse
manufacturing materials (flux and debris) is exhibited at the end of this chapter. This procedure
covers the removal of flux, finger oils, debris, etc., from printed circuit (PC) boards. In some cases,
flux is an adverse manufacturing material.
AUTOMATED PRODUCTION AND QA SYSTEMS
The hardware system, software program, and general quality assurance system controls
discussed below are essential in the automated manufacture of medical devices. The systematic
validation of software and associated equipment will assure compliance with the QS regulation; and
reduce confusion, increase employee morale, reduce costs, and improve quality. Further, proper
validation will smooth the integration of automated production and quality assurance equipment
into manufacturing operations.
Medical devices and the manufacturing processes used to produce them vary from the simple to
the very complex. Thus, the QS regulation needs to be and is a flexible quality system. This flexibility
is valuable as more device manufacturers move to automated production, test/inspection, and
record-keeping systems.
Software Validation Guidances
The QS regulation requires in 820.70(i) that software programs be validated for their intended
use according to an established protocol when computers are used as part of an automated
production or a part of the quality system. Software used in automated production and quality
systems consists of programs or codes that cause computerized equipment to perform desired tasks,
7−4
plus operator manuals and instructions. FDA has drafted an information document, "Application of
the Medical Device GMPs to Computerized Devices and Manufacturing Processes," which is
reprinted in the Appendix. Also, a document entitled, "Reviewer Guidance For Computer
Controlled Medical Devices Undergoing 510(k) Review," is available from DSMA. Both of these
documents can be used with the QS regulation to help establish a software QA and validation
program.
There are also standards, books, and articles that can be used for guidance. Military
Specification MIL-S-52779A and the Institute of Electrical and Electronic Engineers (IEEE)
"Standard for Software Quality Assurance Plan" (IEEE Std 730-1984) are examples.
Manufacturers, however, should not rely completely on such documents, but should examine their
software needs and develop whatever controls are necessary to assure software is adequate for its
intended use.
Employee Responsibility and Training
The device manufacturer should identify individuals or departments responsible for software
quality and clearly specify their responsibilities. These individuals and/or department personnel
should have sufficient training, authority, responsibility, and freedom of action to specify and
evaluate the design and use of software and associated equipment.
A manufacturer probably will experience problems if employees operating the automated system
or inputting data do not have adequate background and/or training. Employees should have
adequate knowledge of the system through both formal training and on-the-job experience. Those
responsible for data input should be able to recognize data errors (820.25). The QS regulation
requires that processes be controlled (820.70). Thus, automated systems should be designed
[820.70(a)] and employees trained (820.25) to help prevent inaccurate data input or adjustments.
This requirement can be accomplished by the aforementioned training and by software controls.
Where practical, software programs should have built-in error controls such as prompts, alpha-only
fields, numeric only fields, length limits, range limits, and sign (+or -) control to help eliminate
mistakes during data entry. These error-control or human-factors requirements, as appropriate,
should be part of the specifications for software being developed or purchased.
Formal Development of Software
Manufacturers that develop their own process control software shall follow the design controls in
820.30 and document each step of the development. The software should be appropriately structured
and documented so that any future changes can be accomplished, even by a different programmer,
with a minimum of difficulty and maximum reliability.
To validate software, it should be:
•
•
•
•
structured, documented and verified as it is developed;
checked to make sure that it meets specifications;
adequately tested with the assigned hardware systems; and
operated under varied conditions by the intended operators or persons of like training to
assure that it will perform consistently and correctly.
7−5
Each module or routine of the program should be verified to make sure it performs the specified
function. The main core of the program should be checked to make certain that all parameters are
correctly initialized and that data is correctly transferred between the routines. The input-output
routines should be checked for proper operation with the intended peripherals to the extent feasible
at this stage of the development. The testing is performed with real or simulated input data. The
input data should accurately represent the real data that will occur in the next phase of testing. This
input data should include data at the boundaries of acceptability, i.e., limit testing. The test protocol,
data and results should be documented. The documentation should be made available to the party,
who will evaluate the software with the automated production or quality assurance equipment to be
used in routine manufacturing.
The testing of the software with the actual medical device production or testing equipment should
exercise program functions under expected production conditions. The testing should include the
input of normal and abnormal (limited case) data to test program performance and error handling.
The validation should assure that the software and associated equipment meet the company
specifications. The test protocol, testing, results, and design review should be documented in the
design history file. Procedures for use and maintenance of the equipment and acceptance of the
output product are documented in the device master record. Any serious deficiencies should be
corrected.
Commercial Software and Equipment
When an outside contractor is engaged to develop software, the device manufacturer should make
sure that the contractor clearly understands the software requirements and translates them into
documented specifications with sufficient objectivity that compliance can be measured. FDA
recognizes that most of the validation may be done by the contractor, however, the device
manufacturer is still responsible for the adequacy and the validation of the software for its intended
use. Therefore, the contractor should be required to develop the software according to a quality
system plan that includes validation.
When possible, the purchaser also should conduct pre-award audits to verify adequacy of the
contractor's quality system. Two key elements that should be checked are the contractor's test plans
and system for controlling changes to documentation. Subsequent audits should be conducted as
needed to verify that the contractor is complying with the quality system plan. The manufacturer
who has custom software prepared and validated by a contractor should ensure the software
program is running properly and producing correct results before using the program to produce
medical devices for distribution.
Manufacturers who purchase commercial equipment with incorporated software should validate
the software and associated equipment for the intended applications. If, however, the software has
been validated by the developer and proven through use, the purchaser need not test it as
comprehensively as new software. For example, automated production and test equipment that is
controlled by software can usually be validated through use of a "dummy" device. This "dummy"
device should exercise functions and decisions in normal and limit-case situations that may
reasonably be expected during production. In some cases, suppliers provide test programs that may
be used to assure that the equipment will appropriately and accurately perform all intended
functions before it is used for routine production.
7−6
Validation of Automated Equipment and Processes
Validated, automated machine tools such as lathes, printed-circuit drills, and component inserters
usually can be monitored and maintained by conducting a first and last-piece inspection of
representative product lots. The record of this activity may be noted on the routine quality control
or production records for the machine. Validation of complex microprocessor-controlled equipment,
such as sterilizers or to verify satisfactory operation is generally a more extensive activity than the
validation of machine tools. Typically, verification should be done by using calibrated measurement
instruments to check the actual parameters achieved during trial runs, and comparing these
measurements with the set points and data outputs of the automated system. In all cases, under the
QS regulation the user is responsible for:
•
•
•
assuring the adequacy of automated equipment and software;
verifying that all intended functions will be correctly and reliably performed; and
maintaining appropriate records.
Validation records [820.70(i)] for software and automated equipment can be maintained by the
user in the design history file [820.30(j)], the device history record [820.184], or the quality system
record [820.186], depending on what works best for the manufacturer. Specifications for the
hardware and software including directions for their use, if any, shall be included or referenced in
the device master record [820.181]. The device master record [820.3(j)], as explained in Chapter 8, is
a compilation of records containing procedures and specifications for a finished device. The device
master record (DMR) contains or references the records covering the use of the equipment and the
specifications of the output product. Upon request, these records shall be made available to FDA
investigators for review and copying during their audit [820.180] of the manufacturer's GMP
system.
All changes to software programs shall be formally reviewed and approved before
implementation [820.30, 820.70 and 820.40]. Because changes in one part of software can affect other
parts of software, adequate consideration should be given to side-effects of these changes. Such
changes are much easier to make and evaluate when the original software is appropriately
structured and thoroughly documented.
Automated Data Collection and Processing
In addition to aiding the production of devices, computers may be used to collect and maintain
quality control and production records. These records are called the device history record in the QS
regulation. A device history record [820.3(i)] is a compilation of records containing the production
history of a finished device. When design history files, device history records, device master records,
or quality system records are maintained by computer, appropriate controls should be used to
assure that data is entered accurately, changes are instituted only by authorized personnel, and
records are secure. Hard copy or alternative systems such as backups [820.180], duplicates, tapes,
or microfilm should also be used to avoid losing records as a result of inadvertent erasure or other
catastrophe. As appropriate, access to records and data bases should be restricted to designated
individuals.
The increased use of computers and related input/output peripherals has affected FDA policy
regarding GMP signature requirements. In response to the use of electronic technology, FDA has
7−7
issued an advisory opinion stating that magnetically coded badges or other computer-compatible
identifiers may be used in lieu of signatures as long as there are adequate controls to prevent
inaccurate data input. If coded badges and the like are not controlled (i.e., not restricted to
designated employees), they will not meet the applicable GMP requirements.
Manufacturers may wish to keep appropriate records such as device master records and
complaint files at central or corporate offices. If the overall data handling system is controlled as
stated above, manufacturers may maintain appropriate quality system records at central locations if
they can transmit these records to the manufacturing establishment by computer plus modem, or
other high speed data transfer system.
Equipment Controls and Audits
Automated equipment and any peripheral equipment requiring maintenance and/or calibration
shall be included in a formal calibration and maintenance program [820.72]. Also, environmental
factors such as temperature, humidity, contamination, static electricity, magnetic fields, and powersupply fluctuations can adversely affect automated equipment and data storage equipment such as
magnetic discs, tapes, optical systems, etc. Consequently, necessary precautions, environmental
controls, and maintenance programs [820.70] shall be implemented to prevent adverse effects on the
equipment and stored data.
During the quality system audit [820.22], manufacturers shall audit the use and control of their
automated production and quality systems. The audit should include software and equipment
maintenance procedures and records, and should evaluate the adequacy of security measures,
change controls, and other controls necessary to maintain software quality and proper performance
of associated equipment. The audit shall be documented, important results reviewed with
management, and corrective action taken as appropriate.
MEASURING EQUIPMENT CALIBRATION
The QS regulation is intended to help assure that devices will be safe, effective, and in compliance
with the FD&C Act. To support this goal, each medical device manufacturer should develop and
implement a quality system that assures, with a high degree of confidence, that all finished devices
meet the company's device master record specifications. These specifications should, in turn, reflect
the company quality claims. Section 501(c) of the FD&C Act states a device shall be deemed to be
adulterated if its strength differs from, or its purity or quality falls below, that which it purports
(claims). Such assurance is obtained by many activities including the measurement of component,
device, and process parameters during design and production. These measurements shall be made
with appropriate and calibrated equipment as required by 820.72.
Each manufacturer should assure that production equipment and quality assurance
measurement equipment, including mechanical, electronic, automated, chemical, or other
equipment, are:
•
suitable for the intended use in the design, manufacture, and testing of components, in-process
devices and finished devices;
•
capable of producing valid results;
7−8
•
operated by trained employees; and
•
properly calibrated versus a suitable standard.
To succeed, the quality system shall include a calibration program that is at least as stringent as
that required by the QS regulation (820.72). The intent of the GMP calibration requirements is to
assure adequate and continuous performance of measurement equipment with respect to accuracy,
precision, etc. The calibration program implemented by a company may be as simple or as
sophisticated as required for the measurements to be made. Some instruments need only be checked
to see that their performance is within specified limits, while others may require extensive
calibration to a specification.
Manufacturers should determine which measurements are necessary to assure that finished
devices meet approved device master record specifications, and assure these measuring instruments
are included in a calibration program. Measurement equipment should be identified by label, tag,
color code, etc., when located in the same areas as instruments that are not part of the calibration
system. Identification can assure that proper equipment is employed to verify and determine
compliance to specification of a device component, in-process device, or finished device.
Sometimes equipment used only for monitoring a parameter need not be calibrated but should be
identified (e.g., for monitoring). A monitoring function might be to indicate if a voltage or other
parameter exists, but the exact value is not important.
Calibration Requirements
The QS regulation requires in section 820.72(b) that equipment be calibrated according to written
procedures that include specific directions and limits for accuracy and precision. Figure 5.1
illustrates bias, precision, and accuracy.
Precision has no unit of measure and only indicates a relative degree of repeatability, i.e., how
closely the values within a series of replicate measurements agree with each other. Repeatability is
the result of resolution and stability.
Bias is a measure of how closely the mean value in a series of replicate measurements approaches
the true value. The mean value is that number attained by dividing the sum of the individual values
in a series by the total number of individual values.
Accuracy is the measure of an instrument's capability to approach a true or absolute value.
Accuracy is a function of precision and bias. Because different manufacturers have different
accuracy requirements, each manufacturer should decide the level of accuracy required for each
measurement and provide equipment to achieve that accuracy.
7−9
large bias + high precision
= low accuracy
zero bias + high precision
= high accuracy
•
••••
••
••
•
••• •
••••••
••••
large bias + low precision
= low accuracy
zero bias + low precision
= low accuracy
7−10
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Figure 5.1 Bias, Precision and Accuracy
Proper and periodic calibration will assure that the selected equipment continues to have the
desired accuracy. GMP calibration requirements are:
• routine calibration according to written procedures;
• documentation of the calibration of each piece of equipment requiring calibration;
• specification of accuracy and precision limits;
• training of calibration personnel;
• use of standards traceable to the National Institute of Standards and Technology (NIST),
other recognizable standards, or when necessary, in-house standards; and
• provisions for remedial action to evaluate whether there was any adverse effect on the
device’s quality.
7−11
Remedial action includes recalibration and evaluation of the impact of out-of-tolerance measurements:
• on the device design or process validation parameters or data;
• on the quality of existing components, in-process, or finished devices; and
• appropriate corrective action.
Equipment Selection
The manufacturer should establish and maintain procedures to ensure that purchased and
otherwise received equipment and associated supplies conform to specified requirements (820.50).
The purchase of stable and accurate measuring equipment can reduce the frequency of calibration
and increase confidence in the company's metrology program. Where economically feasible,
equipment with more accuracy than needed for various measurements can be used longer without
recalibration than equipment that marginally meets the desired accuracy requirements. Delicate
instruments, however, that are "pushing the state-of-the-art" should not be used for routine
measurements unless no other approach is feasible.
Procedures
There are a number of sources of information from which calibration procedures can be
developed. Instrumentation manufacturers often include calibration instructions with their
instruction manuals. Although these instructions alone are not adequate to meet the QS
requirements for a calibration procedure, they usually can be used for the actual calibration process.
In some cases, voluntary standards exist such as those by the American Society for Testing and
Materials (ASTM), the American National Standards Institute (ANSI), and the Institute of Electrical
and Electronic Engineers (IEEE).
Information contained in calibration procedures should be adequate to enable qualified
personnel to properly perform the calibrations. An example of a calibration procedure for
mechanical measuring tools appears at the end of this chapter.
A typical equipment calibration procedure includes:
•
•
•
•
•
•
•
•
purpose and scope;
frequency of calibration;
equipment and standards required;
limits for accuracy and precision;
preliminary examinations and operations;
calibration process description;
remedial action for product; and
documentation requirements.
Management of Metrology
Managers and administrators should understand the scope, significance, and complexity of a
metrology program in order to effectively administer it.
7−12
The selection and training of competent calibration personnel is an important consideration in
establishing an effective metrology program. Personnel involved in calibration should ideally
possess the following qualities:
• technical education and experience in the area of job assignment;
• basic knowledge of metrology and calibration concepts;
• an understanding of basic principles of measurement disciplines, data processing steps,
and acceptance requirements;
• knowledge of the overall calibration program;
• ability to follow instructions regarding the maintenance and use of measurement equipment
and standards; and
• mental attitude which results in safe, careful, and exacting execution of his or her duties.
Calibration Records
Calibration of each piece of equipment shall be documented to include:
• equipment identification,
• the calibration date,
• the calibrator, and
• the date the next calibration is due.
Many manufacturers use a system where each device has a decal or tag which contains the date of
calibration, by whom calibrated, and date the next calibration is due. Examples of such decals are
shown on the next page.
7−13
These decals are examples of the types commonly used to identify the status of measuring
instruments and tools. They are available as catalog items or a manufacturer may use its own
artwork to purchase decals with specialized wording.
CALIBRATION DATE
BY
DUE
CAL. ID No.
Calibration Identification Number or its equivalent is
usually the minimum information that may be on equipment.
This information allows the manufacturer to read by finding
the associated calibration record\card\file.
Measuring equipment that is not calibrated or otherwise unsuitable for
use should be placed in a quarantine area or labeled with a "calibration
void" decal.
CALIBRATION VOID
DO NOT USE
CALIBRATION
VOID
IF BROKEN
Typical calibration decals have a write-on surface. A
tough paper or cloth stock and a pressure sensitive
adhesive are used for easy application and removal of
the decal. “Due” is the blank for the date when
recalibration is due.
A seal or protective cover for exposed, recessed calibration controls on
instruments. The calibration control cannot be adjusted without breaking the
seal or removing the instrument case.
NOT A
CALIBRATED
INSTRUMENT
A decal to be applied to measurement or monitoring instruments not
intended for use in determining conformance to device master
record specifications with respect to testing, manufacturing,
environmental control, etc.
Calibration information is entered onto cards or forms, one for each piece of equipment, or
entered into a computerized data system. Most data systems include the calibration date, by whom
calibrated, date recalibration is due, the reason for the calibration, comments, address of the
manufacturer and calibration laboratory, equipment specifications, serial number, use, etc. An
example of a typical card used to record calibration information follows.
CARD# ______ OF ______
7−14
CALIBRATION CARD
MANUFACTURER
SERIAL NO.
ASSIGNED
CAL. CYCLE
TYPE
MODEL
DATE OF PURCHASE
LOCATION
USE
DATE OF
LAST CAL.
! FREQUENT
! MODERATE
REASON FOR CAL.
(BROKEN, NORMAL, ROUGH USE)
TO BE CALIBRATED BY
! SELDOM
DATE NEXT
CAL. DUE
NAME
COMPANY AND ADDRESS
PHONE
FORM #1700
7−15
! NOT USED
CAL. INFO. ACCURACY, DEFECTS, LUBE,
CLEAN, ETC.
Schedules
Measuring instruments should be calibrated at periodic intervals established on the basis of
stability, purpose, and degree of usage of the equipment. Intervals between calibrations should be
shortened as required to assure prescribed accuracy as evidenced by the results of preceding
calibrations. Intervals should be lengthened only when the results of previous calibrations indicate
that such action will not adversely affect the accuracy of the system, i.e., the quality of the finished
product.
A manufacturer should use a suitable method to remind employees that recalibration is due. For
small manufacturers, calibration decals on the measuring equipment may be sufficient because
recalibration can be tracked by scanning the decals for the recalibration date. For other
manufacturers, a computerized system, calibration cycle cards, tickler file, or the like may be used.
Calibration cycle cards are maintained in a 12-month (12-section) tickler file. There is one card per
item of measuring equipment. The cards in the section of the file for the current month are pulled
and all of the equipment listed is calibrated. For example, in a 6-month calibration cycle, when an
instrument is calibrated in May, the card is moved from the May section to the November section of
the file. When the file is checked in November, the cycle card will be there to remind the
manufacturer that calibration is due. The process is repeated until an event such as instrument
wear-out occurs and the respective cycle card is removed from the file.
Cycle cards are used where a manufacturer has many instruments to be calibrated. It would be
rather difficult to keep track of the calibration of a large number of instruments by reviewing
calibration record cards or scanning the decal on each instrument. It is easier to use a cycle card file.
A cycle card file or equivalent also should be used if the calibration records are filed by type of
instrument or manufacturer rather than due date. A typical cycle card follows. The "calibration
card number" blank refers to the calibration record card for the same item of equipment.
CALIBRATION CYCLE CARD
FORM NO. 5-15
MANUFACTURER:
INSTRUMENT:
MODEL NO.
SERIAL NO.
CALIBRATION INTERVAL:
LOCATION OF EQUIPMENT:
CALIBRATION CARD NO.
7−16
Standards
Where practical, the QS regulation requires that standards used to calibrate equipment be
traceable to the National Institute of Standards and Technology (NIST), or other recognized
national or international standards. Traceability also can be achieved through a contract calibration
laboratory which in turn uses NIST services.
The meaning of traceability to NIST is not always self-evident. Two general methods commonly
used to establish and maintain traceability to NIST are:
• NIST calibration of standards or instruments: When this method is used, private standards
are physically sent to NIST for calibration and returned.
• Standard Reference Materials (SRM's): NIST provides reference materials to be used in
a user's calibration program. These SRM's are widely used in the chemical, biological,
medical, and environmental fields.
Information can be obtained from the "Catalog of NIST Standard Reference Materials,”
available free from the National Institute of Standards and Technology, Office of Standard
Reference Materials,
Gaithersburg, MD 20899, phone: (301)975-2016.
When in-house standards are used, they should be fully described in the device master record or
quality system record. Independent or in-house standards should be given appropriate care and
maintenance and should be used according to a written procedure as is required for other
calibration activities. FDA recommends that at least two in-house standards be maintained -- one
for routine use and one for a back up.
Calibration Environment
As appropriate, environmental controls should be established and monitored to assure that
measuring instruments are calibrated and used in an environment that will not adversely effect the
accuracy required. Consideration should be given to the effects of temperature, humidity, vibration,
and cleanliness when purchasing, using, calibrating, and storing instruments.
AUDIT OF CALIBRATION SYSTEM
The calibration program shall be included in the quality system audits required by the QS
regulation. These audits should determine the continuing adequacy of the calibration program and
assess compliance with the program.
Many manufacturers use contract calibration laboratories to calibrate their measurement and
test equipment. If this is the case, FDA views the contract laboratory as an extension of the
manufacturer's GMP program or quality system. Normally FDA does not inspect contract
laboratory facilities, but it does expect the manufacturer to assess the contract lab to verify that
proper procedures are being used. Generally, the manufacturer of the finished device is responsible
for assuring the device is manufactured under an acceptable quality system.
7−17
When a medical device manufacturer uses a contract calibration laboratory, FDA expects the
manufacturer to have evidence that the equipment was calibrated according to the GMP
requirements. The device manufacturer can do this by:
• requiring and receiving certification that the equipment was calibrated under controlled
conditions using traceable standards;
•
maintaining an adequate calibration schedule;
•
maintaining records of calibration; or
• periodically auditing the contractor to assure appropriate and adequate GMP procedures
are being followed. For example, the contractor should have:
•
•
•
•
written calibration procedures;
records of calibration;
trained calibration personnel; and
standards traceable to NIST or other independent reproducible standards.
Certification notes and data should include accuracy of equipment when received by the lab to
facilitate remedial action by the finished device manufacturer, if necessary. Certification should also
include accuracy after calibration, standards used, and environmental conditions under which the
equipment was calibrated. The certification should be signed and dated by a responsible employee of
the contract lab.
If in-house standards are used by a contractor to calibrate device-related measuring equipment,
these standards shall be documented, used, and maintained the same as other standards.
INTEGRATING MEASUREMENTS INTO THE QA SYSTEM
Proper and controlled calibration can contribute to overall quality by assuring that device design
and process parameters are accurately measured and that unacceptable items are not accepted, and
acceptable items are not rejected as a result of measurements. If the appropriate product-quality
parameters are not checked, however, calibrated equipment will have little impact on assuring
quality.
A good quality system shall include calibration activities. However, proper calibration will be of
little use unless the applications of the measurement equipment are properly developed and
qualified during the preproduction development of inspection test methods and procedures. As
stated, effectiveness depends on the participation and influence of QA and production management
at the preproduction stage. Calibration of equipment cannot correct poor design of products nor can
it compensate for poor applications of equipment and techniques. It is the continued use of a
complete, integrated quality system, which assures that safe and effective devices are produced.
EXHIBITS
Examples of calibration cards, decals, and cycle cards were presented above in the text. Examples
of a device cleaning procedure and a calibration procedure follow. Manufacturers may use these as
7−18
presented if they match the manufacturers operations; or may modify them to meet specific
requirements.
P.C. Board Cleaning
This procedure covers the cleaning of printed circuit boards by using an automatic washer. The
procedure covers operation, shut down, cleaning, and routine maintenance.
Calibration Procedures for Mechanical Measuring Tools
This is a calibration procedure for mechanical measuring tools. In actual use, the initial
accuracy of each tool is checked using the procedure and is recorded. Thereafter, each tool is
recalibrated (checked) versus the initial accuracy. Of course, the initial accuracy should meet or
exceed the requirements of the measurements to be made with the tool. Precision is checked by
making several measurements at various points on the tool's measuring face (surface).
7−19
TITLE: P.C. Board Cleaning
NO:__________________________________
REV:___________________________________________________________________Sheet: 1 of 2
DRAFT: ___________________________ APP: ________________________ DATE: _______
1.0
PURPOSE: The purpose of this procedure is to document production operations performed
on the XXXXXX printed circuit board washer.
2.0
SCOPE: This procedure sequentially identifies all operations necessary to properly operate
and maintain this equipment.
3.0
OPERATING PROCEDURES:
3.0.1 Switch the Exhaust Systems fan on.
3.0.2 Assure that the sump pump is on at the circuit breaker panel.
3.1
Turn the power switch to the "ON" position.
3.2
Push the main power "START" button (#21 on Control Panel Diagram).
3.3
Visually inspect all pump compartment and screen filters for debris - make sure they are
clean before continuing.
3.4
Push the fill buttons on the rear control panel to fill the wash and rinse sections with water.
Make sure all drain lines are closed. The incoming water will stop automatically when the
tanks are filled to the correct levels.
3.4.1 Add 4 gallons XXXXXX detergent to the wash tank.
3.5
Depress the center knob on the temperature controllers (#30 on control panel diagram) and
turn clockwise until the red pointer indicates 60°C (140°F) for the wash tank and 60° C
(140°F) for the rinse tank.
3.6
Wait about 10 min. for water temperature to rise in the wash and rinse tanks. Wait until the
red lights on the temperature controllers go off and the black needle aligns with the red
pointer.
3.7
Push the START-STOP button (#25 on diagram) on for the conveyer.
3.7.1 Adjust the "SPEED CONTROL" (#27 on diagram) to the correct setting for the boards
to be run. See the cleaning specifications for each family of boards for the set points.
3.8
Push the "START" button (#28 on diagram) on for the dryer cycle. NOTE: conveyer belt
MUST be moving when dryer section is on or the equipment will be damaged.
3.9
Turn Photocell Switch (on Rear Panel) to the "Automatic" position.
Sheet 2 of 2
7−20
4.0
SHUT DOWN PROCEDURES:
4.1
Push the dryer cycle "STOP" button for the Wash and Rinse sections (#29 on control panel).
4.2
Turn Photocell Switch (on Rear Panel) to the "OFF" position.
4.3
Push the conveyer "START - STOP" button (#25 on diagram) to stop the conveyer.
4.4
Pull the DRAIN buttons on the control panel for the wash and rinse sections. Using litmus
paper, take a reading on the wash tank before draining it. IF the wash water has a reading of
"10" or less drain it; otherwise, do not drain the wash tank. Always drain the rinse tank.
4.5P
Pull the FILL buttons on the control panel for the wash and rinse sections to let water flush
the equipment for five minutes. Using a soft cloth, wipe off any residue remaining on the
equipment.
4.6
Pull the drain buttons on the control panel for the wash and rinse sections to let the water
drain.
4.7
Remove the screen filter in the washer and remove any debris.
4.8
Wipe the exterior front section of the machine with a soft cloth.
4.9
Push the main power "STOP" button, (#33) to shut off the equipment.
5.0
MAINTENANCE:
5.1
Monthly
5.1.1 Lubricate the conveyer drive chain with high temperature grease.
5.1.2 Check the wear strips on the conveyer belt frame and replace if required. These are
two white plastic strips located at the front of the equipment.
5.1.3 Check conveyer belt tightness - using a wire cutter and needle nose pliers, remove links
to tighten if required.
5.2
Quarterly
5.2.1 Shut off power in main panel at rear of equipment.
5.2.2 Lubricate pump motor ball bearing using standard bearing grease.
5.2.3 Lubricate flange bearings on conveyer shafts with bearing grease.
5.2.4 Check all wiring for loose connections and tighten if necessary.
5.2.5 Check all heater contacts - replace worn contacts.
7−21
Sheet 1 of 1
TITLE: Calibration Procedures for Mechanical Measuring Tools No.________Rev.___________
ECN Notes ________________________________________________________________________
______________________________________________________________________________
Drafted by ____________________________________App.________________Date____________
PURPOSE:
This procedure establishes a standard method for the calibration and
maintenance
of mechanical
measuring tools such as micrometers, calipers, etc.
SCOPE:
All measuring tools used to set specifications or measure conformance to
specifications, such as micrometers, calipers, etc., will be included in the
calibration program. Each tool will be assigned a number and checked every six
months for accuracy. If you suspect a tool is damaged or out of calibration, it
should be removed from service and brought to the Quality Control Lab (QC)
for checking. To enter a tool in the program, take it to QC where a number will
be assigned and initial accuracy checked and recorded.
PROCEDURE:
1. Each measuring tool shall be kept clean and maintained in a protective container. As needed, all
threads and slides shall be lubricated with a fine tool oil to assure free movement.
2. The calibration shall be done by a comparison to standard gage blocks traceable to the National
Institute of Standards and Technology standard with an accuracy 3 to 10 times greater than that
of the measuring tool.
3. The comparisons shall be made at different points along the measuring range of the tool. The
gage blocks used shall be picked at random to assure that the measuring tool is not checked at
the same points on each calibration cycle. When a measurement is made, move the gage blocks
from one side of the tool's measuring face to the other on an X/Y axis to assure no wear or taper
exists on the measuring faces.
4. Measurement tools not intended for testing or manufacturing do not require calibration in
accordance with the QS regulation. These tools should be kept out of manufacturing or labeled
to avoid inadvertent use. Otherwise, they should be entered in this calibration program.
5. After calibration, the date of calibration and the next due date of calibration shall be recorded
on the Calibration Form No._______. Any adjustments and/or repairs to be recorded. The form
is placed in the tickler file according to the next calibration date.
6. If a tool is found to be out of calibration, the QC lab will immediately pass the out-of-calibration
information to the appropriate supervisor in the department where the tool is used. The
Department and QC management will take appropriate remedial action for affected in-process
or finished devices.
7−22
8
DEVICE MASTER RECORDS
INTRODUCTION ................................................................................................................... 8-1
Document For Intended Employees .................................................................................. 8-4
Adequate Information ........................................................................................................ 8-6
Preparation and Signatures ............................................................................................... 8-6
Location of Records ............................................................................................................ 8-7
Record Retention .............................................................................................................. 8-10
DEVICE MASTER RECORD CONTENTS ...................................................................... 8-10
Device Specification .......................................................................................................... 8-10
Specific Documents ........................................................................................................... 8-11
Records for In Vitro Diagnostic Products ...................................................................... 8-11
QUALITY SYSTEM RECORD DOCUMENTS ................................................................ 8-13
WRITTEN PROCEDURES .................................................................................................. 8-13
Developing Procedures ..................................................................................................... 8-14
Content of Procedures ...................................................................................................... 8-15
CHANGE CONTROL ........................................................................................................... 8-17
EXHIBITS .............................................................................................................................. 8-18
Documents That May Appear in a Device Master Record ........................................... 8-18
Device Master Record Index ............................................................................................ 8-18
Product Specification for a Portable Defibrillator ........................................................ 8-18
Zener Diode Specification ................................................................................................ 8-18
Label Example ................................................................................................................... 8-18
Handle Assembly and Parts List ..................................................................................... 8-18
Cable Assembly and Parts List ........................................................................................ 8-19
Device Master Record Index for Amylase ...................................................................... 8-19
Product Description ........................................................................................................... 8-19
Amylase Diluent Solution ................................................................................................. 8-19
Filling Record - Liquid, Non Freeze Dried .................................................................... 8-19
Finished Product Release Form ....................................................................................... 8-19
Production Sample Card .................................................................................................. 8-19
Shop Order Traveler ........................................................................................................ 8-19
INTRODUCTION
Device master record (DMR) is the term used in the Quality System (QS) regulation for all of the
routine documentation required to manufacture devices that will consistently meet company
requirements. Section 820.3(j) of the QS regulation defines device master record as a compilation of
records containing the procedures and specifications for a finished device. The detailed
requirements for device master records are contained in section 820.181, as well as throughout the
regulation.
The definition for design output in 820.3(g) gives the basis and/or origin of the device master
record for all Class II and III devices as follows:
Design output means the results of a design effort at each design phase and at the end of
the total design effort. The finished design output is the basis for the device master record.
8−1
The total finished design output consists of the device, its packaging and labeling, and the
device master record.
For some devices, many of the design output documents are the same as the device master record
documents. Other device output information is used to create a DMR drawing such as for a test or
an inspection procedure. Figure 6.1 shows the close relationship between design output and the
device master record.
Section 820.181, Device Master Record, lists some typical documents in a DMR as follows:
The DMR for each type of device shall include, or refer to the location of, the following
information:
(a) Device specifications including appropriate drawings, composition, formulation,
component specifications, and software specifications;
(b)
Production process specifications including the appropriate equipment
specifications, production methods, production procedures, and production environment
specifications;
(c) Quality assurance procedures and specifications including acceptance criteria and
the quality assurance equipment to be used;
(d) Packaging and labeling specifications, including methods and processes used; and
(e) Installation, maintenance, and servicing procedures and methods.
The definition for Design Output 820.3(g) and requirements for Design Output 820.30(d) do not
apply to most Class I devices. Therefore, the requirements for the DMR for most Class I devices are
in 820.181 Device Master Record. Of course, a manufacturer of Class I devices may use the design
output sections of the GMP as guidance.
However, almost all sections of the QS regulation have requirements related to the device master
record. The device master record contains specifications for the device, accessories, labeling, and
packaging, and contains a full description of how to procure the components and manufacture the
device including specifications for facilities, environment, and production equipment. In addition to
the device specifications, a device master record contains documents that cover typical
manufacturing activities such as:
•
•
•
•
•
•
procurement,
assembly,
labeling,
test and inspection,
packaging, and
where applicable, sterilization.
Note that the listed activities and records or documents are required to produce any product -medical, industrial, or consumer. There is nothing special about device master records except the
name!
Also, note that in common usage, the term "device master record" refers to the total record or any
of its individual records. Therefore, the term is singular for the total record, singular for a single
document, and plural for a group of single documents. The term also may refer to an original record
or a copy of a record.
8−2
INITIAL
PRODUCTION
VALIDATION
DESIGN
REVIEWS
PROCESS
DEVELOPMENT
(VAL)
INPUT
DEVICE
DEVELOPMENT
DESIGN DEVICE
OUTPUT MASTER
RECORD
(VER)
DHF
8−3
PRODUCTION
Device master records should be technically correct, contain and/or reflect the approved device
and process designs, be under change control, contain the release or other control date, contain an
approval signature, and be directed toward the intended user. These requirements are in the QS
regulation because the device master record is the "beginning and end" of a product -- errors in the
device master record will have a serious impact on the state-of-control of the manufacturing
operation and may have a serious impact on the safety and performance of the device. The device
master record should be accurate and complete because the essence of the QS regulation is a quality
system based on designing a device to meet user needs, documenting the design and production
procedures in the device master record and then producing a finished device that meets the device
master record requirements. Thus, the device master record shall accurately reflect the device
intended to be produced by a manufacturer.
Document For Intended Employees
The content, style, language, graphics, etc., of device master records should be directed toward
the needs of the intended employees and, if the record is a specification or text for labeling, it should
be directed toward users. A failure to consider the intended user leads to confusion and means that
the company has not achieved the state-of-control intended by the QS regulation. Therefore,
applicable records should be directed toward the needs of procurement, processing, and
test/inspection personnel, rather than the needs of drafting, technical services, or product
development departments. Likewise, installation instructions should be directed to installers.
Labeling is often prepared by the same employees that draft device master records; and, these
employees should also be aware that labeling shall meet the needs of the user as directed by 21 CFR
809.10, 801.6 and 820.30.
In any manufacturing activity such as assembly, labeling, processing, testing, etc., achieving and
maintaining a state-of-control is enhanced by appropriate personnel knowing:
•
•
•
•
•
what task is to be done,
how to do the task,
who is to do the task,
what task is being done, and
what task was done and/or the results of the activity.
In order for employees to perform a job correctly, they should know exactly what is to be done
and exactly how to do the work. Section 820.181 requires that what is done be documented in the
device master record. The device master record also contains test and inspection procedures and
data forms that are used to help determine and record what was done.
Documents that instruct people how to fabricate, assemble, mix, label, test, inspect, etc., or how to
operate equipment should:
•
be directed toward the needs of the employees who will be using them and not directed toward
the drafts-person or designer;
•
match the tools and equipment to be used;
•
be correct, complete, and current; and
•
depend on part numbers and basic drawings to transfer information rather than almost
photographic type drawings.
If a component is changed, the representations on pictorial/photographic type drawings are no
longer correct and may be very confusing to employees, particularly new employees.
8−4
The how-to-manufacture instructions should be adequate for use by the intended employees and
correct for the intended operation. In the medium-to-large company, the instructions tend to be
extensive technical (engineering) drawings and written procedures. In any company, particularly
small manufacturers, the work instructions may take several forms as discussed below.
•
Engineering drawings may be used if employees are trained to read and use them. Some of the
how-to information comes from employee training rather than from drawings.
•
Assembly drawings may contain parts list and quality acceptance criteria. A separate quality
acceptance test and/or inspection procedure is not always necessary. An example of an
engineering drawing for assembling a handle is exhibited at the end of this chapter. This
drawing also includes some of the quality acceptance criteria for evaluating the handle in
Notes 1 and 2. The parts list for the handle is on the page after the assembly drawing. Some
manufacturers that manufacture simple devices use large sheets of paper for assembly
drawings and include the parts list on it. The combination drawing results in instant
availability of the parts list and reduces the number of drawings to be controlled. An example
of an engineering drawing for assembling a cable and the associated parts list follows the
handle assembly drawings.
•
Exploded-view drawings are used when employees cannot read plan-view engineering
drawings. Exploded-view drawings tend to be more "how to" than plan-view drawings.
Exploded-view drawings are expensive to draft -- in some cases it may cost less to teach
employees how to read and use ordinary plan-view drawings.
•
Step-by-step written procedures may be used to detail how to perform specific tasks with
check-off blanks to show that each specific task was performed. This type of procedure is
commonly used for critical operations and where there is little or no visual indication of what
has been done, such as for cleaning operations and for mixing chemicals.
Documentation may be supported by production aids such as labeled photographs, video tapes,
slide shows, sample assemblies, or sample finished devices. All of these perform device master record
functions and should be identified, and be current, correct, and approved for the intended operation.
The most commonly used aids are models or samples. There are two conditions that should be
satisfied in order to use these aids. First, a written specification for the sample shall be contained in
the device master record. This specification, of course, may be the same as the specification for the
assembly or finished device to be manufactured. This specification shall be subject to a formal
change-control procedure. Even though a model is available, the specification is needed for present
and future product development, and for production control purposes. Second, the sample should:
•
adequately reflect the device master record specification;
•
be identified as an approved acceptable representative sample, which means it shall meet the
company required workmanship standards; the sample need not be a working model if the
nonworking condition is not misleading to employees being guided by the sample; and
•
when appropriate, contain or be tagged with a drawing number, revision level, and control
number (lot, serial, batch).
A card or tag as shown in the exhibits or an equivalent card may be used to identify and help
control the use of samples of assemblies or finished devices. Such tags are usually covered by a clear
plastic pouch and attached to the model or sample.
8−5
Samples and other aids such as photographs are subject to normal wear and tear in a production
environment. Therefore, such aids should be adequately protected by a suitable means such as being
located in a protected area, or covered by a protective pouch or container. Production aids should be
periodically audited to make sure they continue to be suitable for the intended use. Section 820.100
contains requirements for corrective action. Corrective action may involve the use of samples,
changes to the samples, or changes in the control of the samples.
Adequate Information
Although a manufacturer tries to document for the intended employees, there is a need to audit
periodically to see how well the goal is being met. There are various means of determining if
information in the device master record, production tools, and other production elements are
adequate for a given operation and associated employees. These include analyzing the:
•
•
•
•
•
•
•
•
•
assistance required by new employees;
assistance required when a new device is introduced into production;
confusion and hesitation;
information exchanged among employees;
"homemade" documentation drafted by the line employees;
rework;
products produced (productivity);
complaints from departments that subsequently process the device; and
customer complaints.
If any of these factors persist and are out of line with industry norms or with the previous
production experience, then the manufacturer should take corrective action. Management shall
review the quality system as directed by 820.20 and, thus, be aware of device quality problems or
quality system problems such as listed above. The corrective action may include changes in
supervision or documentation, adding new documentation, modifying the design, using different
tools, modifying the environment, etc.
Preparation and Signatures
A separate device master record is required for each type or family of devices. Also, a separate
device master record may be needed for accessories to devices when these are distributed separately
for health care purposes. Such accessories are considered to be finished devices. In practice, if the
device and accessories are made by the same manufacturer, the device master record for the
accessory may be incorporated into the device master record for the primary device.
Within a family of devices, variations in the family may be handled by dash number extensions on
drawing and procedure numbers. Usually, a top assembly or other major drawing contains a
table/list of the devices in the family and lists the variable parameters for each member of the family.
Section 820.40 of the QS regulation requires that an individual(s) be designated to: review, date,
and approve all documents required by the QS regulation including the device master record and
authorize changes. An individual(s) with the necessary technical training and experience shall be
designated to prepare and control device master records. In addition to requiring approval
signatures on device master records, the QS regulation requires individual identification for a few
other activities. For convenience, these activities along with the section numbers that require them
are listed in Table 8.1.
Table 8.1 GMP ACTIVITIES REQUIRING INDIVIDUAL IDENTIFICATION
820.30(b)
Approval of Design Plans
8−6
820.30(c)
820.30(d)
820.30(e)
820.30(f)
820.30(g)
820.40
820.70(g)
820.72(b)
820.75(a)
820.75(1)(2)
820.80(d)
820.80(e)
820.90(b)
820.120(b)
820.180(c)
820.198(b)
Approval of Design Input
Approval of Design Output
Results of Design Review
Results of Design Verification
Results of Design Validation
Approval of in Device Master Record or Changes
Equipment Maintenance and Inspection Activities Performed
Calibration Performed
Approval of Process Validation
Performance of Validated Process
Release of Finished Devices
Acceptance of Activities Conducted
Authorization to Use Non-Conforming Product
Labeling Inspection
Audit Certification
Decisions Not to Investigate Complaints
The list is self-explanatory except for audit certification. When a manufacturer certifies in writing
to FDA that quality system audits have been performed, the certification letter is signed by
management having responsibility for the matters audited. Also note that the records in 820.70,
820.72, 820.80, 820.90(b), 820.120(b) and 820.160 are not part of the device master record but,
instead, are part of the device history record (DHR). Records in 820.198(b) are part of the complaint
files.
If a record that requires a signature is maintained on a computer, it is best if the designated
individual(s) maintains an up-to-date signed printout of the record. Where it is impracticable to
maintain current printouts, computer-compatible identifiers may be used in lieu of signatures as
long as there are adequate controls to prevent improper use, proper employee identification,
inaccurate data input, or other inappropriate activity. If identifiers such as coded badges and
equipment keys are not controlled (i.e., not restricted to designated employees), then these will not
meet applicable GMP “signature” requirements.
Location of Records
Device master records shall be stored at the manufacturing establishment or at other locations
(820.180) that are reasonably accessible to company employees responsible for the manufacturing
activities and accessible to FDA investigators. Appropriate records may be maintained in computer
data banks if the records are protected, change controlled, and readily accessible for use by
responsible employees at all relevant facilities. It is acceptable for a manufacturer to maintain
records on microfilm and discard the original hard copies. Microfiche and/or microfilm reductions
may be used in lieu of original record retention if the following conditions are met.
•
All reductions shall be readily available for review and copying by FDA investigators and
designated company personnel at any reasonable time.
•
•
All necessary equipment shall be provided for viewing and copying the records.
Reproductions shall be true and accurate copies of the original record.
If the reproduction process results in a copy that does not reveal changes or additions to the
original record, the original should be retained. In this situation, the reproduced copy and any image
shown on a viewing screen should note any alteration from the original and indicate that the original
record is available.
8−7
By maintaining the device master record, complaints and other records required by the QS
regulation at the manufacturing establishment or other reasonably accessible location, responsible
officials of a company can exercise control and accountability over the entire design, manufacturing,
and postmarketing activities and, thereby, maximize the probability that the finished device
conforms to its design specifications. This GMP requirement helps assure that responsible officials
at the manufacturing establishment have ready access to those documents essential for producing
devices and for conducting self-inspections, complaint investigations, failure analyses, audits, and
corrective action.
The device master record is a single source document or file. Portions of this file may be kept in
various locations. A device master record may exist as:
•
one or more files or volumes of the actual records containing the information required by the
QS regulation;
•
a reference list of such documents and their location; or
•
any combination of actual documents and/or reference lists.
These documents shall contain the latest DMR revisions, be signed, and be dated to show they
have been checked for adequacy and approved for use (820.30, 820.40 and 820.181).
The QS regulation allows use of reference lists as a means to reduce the duplication of records,
particularly duplication of general documents such as standard operating procedures (SOP's).
General SOP’s (not directly related to a product or process) however should be made a part of the
quality system record (QSR) (820.186).
Use of a reference list also allows filing of device master record documents at several convenient
locations. If the device master record contains a list of documentation, the actual documents shall be
available for employee use and FDA inspection at the manufacturing site or other reasonably
accessible locations. As noted above, this is a key and important GMP requirement. Typical
locations of various device master records are shown in Table 8.2.
When performing an inspection of a company, FDA investigators shall have access to actual
records for review and copying during reasonable business hours. FDA investigators review these
records to determine if a manufacturer is complying with the QS regulation and with the Food,
Drug, and Cosmetic Act.
Records deemed confidential by a manufacturer should be marked to aid FDA in determining
whether or not specific information may be disclosed under the Freedom of Information Act.
However, routinely stamping every document as “Confidential” defeats the purpose of requesting
extra care be taken to protect a specific document or set of documents.
Table 8.2 LOCATION OF DEVICE MASTER RECORDS
TYPE OF DMR ELEMENT
ORIGINALS
Typical Locations of Documents
WORKING COPIES
Reference list(s)
Engr. master file
Component drawings
Engr. or Manuf. Engr.
8−8
Manuf. or Procurement
master file
Component acceptance
procedures
SOP master file
Receiving department
Device Input specifications
(final version)
Engr. master file
Marketing or Engineering
Manufacturing procedures
Engr. or Manuf. Engr.
master file
Manufacturing
Test specifications
Engr. master file
Engr. or Manuf. Engr.
Test procedures
Engr. or Manuf. Engr.
master file
Manuf., QA, QC or
Final Test
Inspection procedures
Manuf., QC, or SOP
master file
Manufacturing or QC
Label drawings
Engr. master file
Engr., QA, or Manuf.
Label artwork
Artwork master file
Engr., Procurement
Label control procedures
Manuf., QC, or SOP
master file
Manufacturing
Specific cleaning procedures
SOP master file
Manufacturing
General cleaning procedures
QSR master file
System audit procedures
QSR master file
Employee training procedures
QSR master file
SOP = Standard Operating Procedure
QSR = Quality System Record
QA = Quality Assurance
QC = Quality Control
Record Retention
The QS regulation in section 820.180(b) requires that all records pertaining to a device shall be
retained for a period of time equivalent to the design and expected life of the device, but in no case
less than two years from the date of release for commercial distribution by the manufacturer.
Manufacturers of long-life products should make prudent decisions as to how long to keep records.
For example, there
may be no value in keeping records for long-life devices such as stretchers, surgical tools, containers,
etc., forever if the probability is low that any post-distribution remedial activity will occur. For
devices that require repair or capital equipment devices that probably will be updated, appropriate
records should be retained to support these repairs or modifications.
8−9
Device master record requirements apply to devices modified in the field by the manufacturer's
representatives after the devices are commercially distributed. Modification of a device is
manufacturing and the QS regulation covers all manufacturing of devices where the result is placed
into commercial distribution. In any case, a manufacturer should be prepared to provide a rationale
for its decision to discontinue record-keeping.
DEVICE MASTER RECORD CONTENTS
As discussed above, the device master record shows and/or tells employees how to perform
specific functions related to the production of a device. The QS regulation does not dictate how this
information is to be arranged or filed in the device master record and quality system record except
that it shall be readily accessible. Because each device master record and quality system record
contain many documents, an index of each is usually needed.
Device Specification
There may be many specifications in the device master record. One of these is the device
specification. A device or product specification is a specific document in the device master record
that briefly describes and gives all important details of the external characteristics of a device. The
product specification may also contain some internal characteristics of the device that are important
to the manufacturer and/or the users. The finished device specification is derived from the design
input specifications in 820.30. For some devices, many of the external characteristics such as
temperature tolerance are related to the environment in which the devices will function properly.
For some in vitro products, the package insert is used by some manufacturers as the product
specification for marketing purposes.
Generally a product specification will contain the device's:
•
•
•
•
•
•
•
•
product trade and common name(s);
intended use(s);
performance characteristics and theory of operation;
regulatory classification;
physical characteristics;
environmental limitations and product stability;
important components and formula (if applicable); and
user safety characteristics.
Table 8.3 contains a list of characteristics that often appear in product specifications; however,
note that not all of the listed items will appear in the product specification for a given device.
In addition to defining and describing a device, a product specification is a communication tool
which, if used in a timely manner, can help achieve some important results. First, it helps assure that
everyone is talking about the same device and working toward the same objectives with respect to
safety, effectiveness, human factors, configuration, labeling, packaging, processing, finished device
acceptance, etc.
Ultimately, the device specification or a condensed version of it should be used in catalogs, or
other product documentation, to aid communication between salespersons and customers. If the
marketing department uses the product specifications when preparing advertisements and catalog
sheets, public relations with users will be enhanced because the marketing documents are based on
proven scientific safety and performance claims for the actual device. The user has an opportunity to
read the technical specifications of the item actually being offered for sale.
Thus the use of device product specifications will result in:
8−10
•
basis;
•
•
•
•
improved communication between employees on a departmental and interdepartmental
less confusion and increased morale;
an improved state-of-control;
a higher probability of meeting cost, time, safety, effectiveness, and regulatory compliance
objectives; and
product literature that correctly describes the device for the prospective customer.
A sample product specification for a portable defibrillator is in the exhibits at the end of this
chapter. This specification is long and detailed because it is a combined product and test
specification, and because it is for a complex device.
Specific Documents
Specific documents are drawings, procedures, labels, data forms, etc., for a specific product or
family of products. Product specific documents are almost always part of the device master record.
The originals of specific documents are usually located in files in engineering or technical service
departments. In most manufacturers, specific documents contain no general information; however,
they often refer to general documents. (A list of specific and general documents is exhibited later in
this chapter.) The number of specific documents for a given product line may range from about 10
to several hundred. If large numbers of documents are needed, an index is usually needed to help
locate them, particularly for personnel that do not work in the drafting department or in technical
services.
Records for In Vitro Diagnostic Products
The main differences between device master records for chemical-based in vitro products and for
electromechanical products, such as instruments and artificial kidneys, is terminology and the
relatively extensive use of written processing procedures and status reports for in vitro diagnostic
products rather than a few assembly drawings and test/inspection reports. For example, device
master records for chemical-based devices would contain a manufacturing section dealing with areas
such as solution preparation and filling, whereas manufacturing sections for electromechanical
products would cover operations such as assembly. Status records for weighing, mixing, filling, etc.,
are used for general control of in vitro products. Status reports are also used because it is often
difficult to determine the status of in-process in vitro products by looking at them -- the opposite is
usually true for most hardware devices. Records for in vitro devices also shall contain control data
that allows components and kits to be traced [809.10(a)(9), etc.].
8−11
Table 8.3 ITEMS THAT MAY APPEAR IN A DEVICE SPECIFICATION
1. Name of Product
a. Trade name
b. Trademark
c. Generic name
d. Chemical name
e. Official name
f. Common name
2. Performance Characteristics
a. Description/Intended use
b. Accessories
c. Functional parameters
d. Limitations
e. Contraindications
f. Input/Output requirements
g. Human interface
h. Other
3. Classification
a. Regulatory
b. Commercial
c. Functional
d. Other
4. Physical Characteristics
a. Weight
b. Size f. Packaging
c. Color
d. Form/Shape
e. Consistency
g. Power requirements
h. Other
5. Environmental Limitations
a. Operating temperature range
b. Storage temperature range
c. Vibration and shock range
d. Voltage range
e. Humidity range
f. Moisture protection
g. Pressure, altitude limits
h. Electromagnetic interference
i. Electrical transients
j. Shelf life/Other
6. Important Components
a. Active ingredients
b. Major subsystems
c. Diagnostic kit materials
d. Accessories
e. Labeling
f. Service labeling
g. Components/items supplied by user
h. Software
i. Periodic Warranty/Other
7. User Safety and Performance Considerations
a. Chemical
b. Electrical
c. Thermal
d. Mechanical sharp, moving parts
e. Personnel training
f. Periodic testing
g. Maintenance
h. Other
8−12
QUALITY SYSTEM RECORD DOCUMENTS
Quality system record (QSR) (820.186) or general documents are used for many activities
that are essential to operating a manufacturing establishment -- these are not specific to any
given product even if the company produces only one product. Thus, the quality system record
includes general documents such as standard operating procedures (SOP's) and standard quality
assurance procedures (QAP's). If the company added another product line, the basic content of
these documents would undergo none or only minor changes.
In a typical manufacturing operation, general QSR, SOP, and QAP documents may include
the following:
Employee training procedures
Cleaning procedures
Insecticide use-removal procedures
Air conditioning/heating procedures
Tool kit policy
Safety procedures
Procurement procedures
Returned goods policies
Drawing numbering system
Change control procedure
Service policy
Supplier assessment policy
General design control procedures
Component inspection procedures
Workmanship standards
Design review policy/procedure
Label review policy/procedure
Sterile water system maintenance
Calibration policy
Complaint handling procedure
Recall procedure
Deviation review policy/procedure
The above list is not all inclusive. Medium-to-large companies tend to have many of these
general documents to guide management in maintaining consistent operations. A very small
company may have only the most essential and appropriate of these documents such as
procedures for design controls, drawing numbering system, change control, employee training,
use of hazardous materials, etc.
The original copy of each general procedure is filed in the department specified by
management as having responsibility for maintaining that procedure, or it is filed in an
automated system with access by the designated departments. The working copies of the above
procedures are usually located in SOP manuals and QA manuals. The procedures are usually
numbered and arranged in a logical order by topic. The QS regulation does not require
manufacturers to keep quality system record documents in SOP or QA manuals; however, the
experience of many industries has demonstrated that such manuals are worthwhile if they are
kept current and contain only the real working procedures.
WRITTEN PROCEDURES
Many sections of the QS regulation require written procedures for instructions in performing
various quality system, design product acceptance, QA, and manufacturing tasks. Certain
devices such as in vitro products, because of the nature of the manufacturing operations, tend to
have a relatively large number of written procedures.
Written procedures are used for quality system audits, product development, manufacturing,
post-marketing activities, etc., to:
•
•
•
improve communication and guidance;
assure consistent and complete performance of assigned tasks; and
promote management of operations.
8−13
In large manufacturing facilities involving many operations and people of various skill levels,
many written procedures are usually necessary. In a small manufacturer, communication lines
are usually short, few people are involved, and management is readily available to provide
guidance, so that the need for written procedures is usually less than for a larger manufacturer.
A manufacturer, particularly a small manufacturer, may conclude that GMP requirements
for written procedures are not applicable for a particular operation. Although the number of
written procedures may vary, all manufacturers are required to maintain a device master record
(820.181) for each type or family of devices they produce.
Often training and work experience alone or combined with drawings, photographs, and
models are valid substitutes for written procedures. For example, machinists are typically skilled
personnel who fabricate components and finished devices using dimensional drawings for
guidance instead of written procedures. The company and FDA investigator will evaluate each
situation based on the training and knowledge of the operators and the control needed to meet
device specifications. Typically, a written procedure is not necessary when:
•
the activity is very simple;
•
the activity is relatively simple and models are used as production aids;
•
and
straightforward quantitative rather than qualitative standards determine acceptability;
• the operation is performed by personnel highly skilled relative to the task being
performed.
Written procedures and associated history or status records, however, are often needed for
activities where there is no change, such as color, texture, or form, to indicate that the activity
has been performed correctly.
Manufacturers should determine that they meet all GMP requirements and, if necessary,
exceed them in order to produce finished devices that meet device master record specifications
because FDA insists that manufacturers meet their quality claims [FD&C Act, section 501(c)].
Achieving this required state-of-control may require fewer or more written procedures than
specifically required by the QS regulation. FDA does not insist that a manufacturer generate
records that do not contribute to assuring conformance to specifications.
Developing Procedures
Developing written procedures is relatively labor intensive and time consuming, which may
lead to use of "back-of-the-envelope" notes instead of formal procedures. Likewise, changing
these procedures is time consuming, which may lead to delays or forgetting to make the changes.
Drafting or changing written procedures is also prone to errors. Therefore, manufacturers are
encouraged to use computers and low-cost printers as word processors to aid in writing and
changing procedures. With the use of computers, these tasks become easier thereby increasing
the probability that they will be performed correctly and when needed. Computers can also be
used for generating and maintaining device master record indices and complaint files, and
performing a host of other GMP related activities.
There is a method for developing procedures that will result in short, clear procedures that
help
solve real problems. The first two steps are:
8−14
•
•
identify the problems to be solved; and
decide if new or modified procedures are needed to help solve or reduce the problems.
Events that point to a problem are excessive rework, employee confusion, customer
complaints, recalls, etc. These "pointers," however, may not be the real problem. The real
problem may be inadequate design, components, equipment, maintenance, operational
techniques, documentation, environment, etc. The real problem should be identified before it can
be solved. A written procedure may or may not be needed to help solve the problem.
The real problem can be identified by careful analysis of:
•
•
•
•
•
•
the "pointers" noted above,
device design,
process design,
process flow and employee work habits (operational analysis),
test and inspection data, and
any other activity related to the quality of the device.
Operational analysis is aided by flow-charting which is a step-by-step chart of the minute
details of the operation. Thus, a flow chart is much more detailed than a QA audit report and is
very helpful in determining what is actually happening in a particular manufacturing operation.
This knowledge may lead to a solution of manufacturing and quality problems. An example of a
flow chart appears in the exhibit section of chapter 10.
From a company quality system, interface, and personnel management viewpoint, the
problem, the reason for flow-charting the given activity, etc., should be discussed with affected
personnel. Their input should be requested with respect to identifying and solving the real
problem. By using the information presented by the flowchart and the experience gained while
producing the chart, the QA auditor is better able to:
•
analyze the particular operation with respect to process requirements;
•
determine what needs to be added, modified, or deleted to solve any problems or improve
performance; and
•
if needed, write or modify a procedure to cover the new way of performing the activity.
Content of Procedures
Written procedures are widely used and industry experience has shown that these should
contain the following items:
•
•
•
•
company identification and a procedure title;
an identification or control number with a revision level code;
an approval signature, and date the procedure becomes effective;
the number of pages (e.g., sheet 1 of 4) in the procedure or another means to indicate that
the employee has the complete document; and
• step-by-step instructions for performing the required activities
The effective date may be the same as the approval date. Also, the effective date may appear
on a separate document such as an engineering change order (ECO) form. The main body of the
procedure should cover, as appropriate:
•
subject, scope, and objectives;
8−15
•
•
•
•
who is assigned to perform the task;
what activity or task is to be performed;
when and where the task is to be performed; and,
how to perform the task including what tools, materials, etc., to use.
Particularly for the new employee, it is important for the procedure to state the reason for
performing a function and the reason it is to be performed in a certain way. Background
information such as this helps the employee to understand an assignment and remember how to
perform it. For example, when working on static sensitive integrated circuits that are easily
damaged by electrostatic potentials, unskilled employees need to understand why they have to be
grounded, work on grounded mats and, especially, why they are not allowed to wear certain
fabrics while at work. Likewise, employees working in environmentally controlled, clean
manufacturing areas need to be told about invisible microbes and particulates, and that humans
are the major source of these unwelcome contaminates. If so informed, employees are more
likely to follow the operational procedures for working in controlled areas.
The task description in each procedure should cover appropriate details such as:
•
the expected and actual results from performing the tasks, such as what data to collect and
how to analyze, file, and report it;
•
and
what to do with the component, in-process device, or finished device if such is involved;
•
any related activities that need to be performed in order for the overall operation to
remain in a state-of-control or for the device to meet the company device master record
specifications.
If the procedure being developed, for example, covers change control, the procedure should
also cover related activities such as changes to labeling. Consider a change to a device where an
analog meter is replaced with a digital meter -- obviously the instruction manual (labeling) and
service manual also need to be modified. Otherwise the finished device:
•
may not meet company labeling policies;
•
is misbranded because it does not meet the labeling requirements of the FD&C Act; and,
•
is adulterated because the change does not meet the change control requirements of the
QS regulation.
After the procedure is drafted, if appropriate, it should be reviewed with the affected
personnel before it is approved and implemented. During the initial implementation, the use of
the procedure should be monitored. Then, based on actual experience in using the procedure, if
necessary, it should be modified to more exactly meet the need of the operation or process.
CHANGE CONTROL
The QS regulation in section 820.181 by reference to 820.40 requires that any changes to the
device master record be authorized by the signature of a designated individual(s). Change
control requirements also appear throughout the QS regulation. The control of changes to
devices, processes, and the associated device master records is one of the most important
8−16
elements of a quality assurance system. The requirements for a successful change control system
are so extensive that the entire next chapter of this manual is devoted to changes and associated
procedures.
8−17
EXHIBITS
Reprinted on the next pages are typical documents (records) that appear in device master
records. Manufacturers may use these as guides in developing their device master records.
Documents That May Appear in a Device Master Record
The first exhibit is a list of documents that might appear in device master records. Each
device master record would contain only those documents that are applicable for a specific
device. Some of the listed documents are general rather than product specific. General
documents are usually called standard operating procedures (SOP's) and, if necessary, are
referenced in the device master record rather than actually being included. The general
documents are usually part of the quality system record (QSR).
Device Master Record Index
This exhibit is a policy/procedure for drafting a device master record index. An index is also
known as a document plan, table of contents, etc. An example of a device master record index
follows immediately after the policy/procedure. Note that this particular policy/procedure
contains definitions. It is important that procedures contain definitions, in a case like a complex
device master record index where employees may not be familiar with the terminology.
Product Specification for a Portable Defibrillator
Finished device or product specifications are the backbone of any device master record. The
one illustrated as the third exhibit is for a complicated piece of equipment and is, therefore,
extensive. For long documents it is recommended that a table of contents be incorporated as was
done in this specification. Appendix A and B of this specification are not exhibited.
Zener Diode Specification
This specification for a non-complicated part contains the necessary information to describe
the item in sufficient detail for the correct part to be procured per the 820.50 Purchasing
Controls.
Label Example
A sample label is exhibited. Labels and labeling are components and their specifications, art
work, etc., are part of the device master record. As for any component, labeling shall be specified
(documented). The resulting device master record document shall be reviewed, approved,
change controlled, and stored such that it may be readily accessed. Such records are used to
meet requirements such as those in 820.50, 820.80(b), 820.80(d), 820.120(b), 820.120(e), etc.
Handle Assembly and Parts List
This exhibit is an engineering drawing and parts list for a handle assembly. Engineering
drawings, parts lists, or formulations are a vital part of many device master records. In this case,
the engineering drawing not only details how this assembly is to be made, but there is also
important information in the notes on the drawing. If properly trained and with sufficient
experience, employees are able to use this drawing as the instructions for assembly of this
handle. A written assembly procedure is not necessary.
Cable Assembly and Parts List
8−18
This exhibit is similar to the handle assembly mentioned above. The type of drawing used and
information on a drawing can aid a manufacturer in reducing paperwork needed to
manufacture a specific product.
Device Master Record Index for Amylase
This document is a device master record index for an in-vitro diagnostic product. Proprietary
information in this index is replaced by X's. The company that prepared this index uses
purchase specifications and raw material specifications. Some manufacturers, particularly small
companies, specify and purchase standard, routine items such as bottles and caps by using
catalog numbers. Component specification drawings are not always used for routine items such
as standard bottles.
Product Description
This exhibit is a product description for an in vitro diagnostic product. The standard
operating procedures, quality control procedures, manufacturing flow sheets, and notes
mentioned in this product description are not reprinted herein.
Amylase Diluent Solution
This exhibit is the procedure for making a batch of amylase solution. In this procedure, note
that for each step the company requires the initials or signature of the person actually
performing the operation and of the individual who checked that person’s performance of the
operation.
Filling Record - Liquid, Non Freeze Dried
This is an exhibit of a filling record used for liquid products to document the steps in a filling
operation. The completed filling record becomes a part of the device history record (DHR) for
the batch being filled.
Finished Product Release Form
This form is used to record that the device history record is complete for a lot of product, the
product meets specifications, and the lot may be approved for release.
Production Sample Card
This exhibit shows both sides of a card or tag used to identify and help control the use of
manufacturing aids such as samples of assemblies or finished devices. The use of a sample
identification card is described in the main text of this chapter.
Shop Order Traveler
The last exhibit is two job travelers or job followers. These cards, forms, tags, etc., are used to
identify a batch or sub-batch of in-process assemblies as they are passed from one department to
another. Where needed, travelers are used to reduce mixups and confusion and, in general
increase the state-of-control of an overall manufacturing operation. Travelers help meet the
general requirements of 820.60, Identification, and the specific requirements of 820.86,
Acceptance Status.
DOCUMENTS THAT MAY APPEAR IN A DEVICE MASTER RECORD
8−19
1.0 Device Master Record Index
The device master record Index is a table of contents which is used for convenience. It may
be known as a:
Device Master Record Index
Documentation or Device Master Record Unit;
Documentation Plan;
Product Tree;
Documentation Index;
Product Structure; or
Bill of Materials (if it also lists the device master record documents).
2.0 Device Specifications
(Device specifications are described in the chapter text.)
3.0 Manufacturing Information
3.1 Index
(Optional. See 1.0 above for total table of contents.)
3.2 Formulation or top assembly drawing
3.3 List of components
1. List of ingredients (including grade or type)
2. Bill of materials (i.e., component list usually arranged by subassembly or other
sub-product level or by process steps)
3. Formula
3.4 Procurement documentation
1.
2.
3.
4.
Specifications
Drawings
Certificate of compliance requirements
Supplier Assessment procedures
8−20
3.5 Device documentation
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Fabrication drawings
Surface finish procedures
Subassembly drawings
Wiring and piping diagrams
Assembly procedures
Assembly drawings
Reference documentation
a. Wiring and piping schematics
b. Test specifications
Sub-batch procedures
Blending or mixing procedures
Solution procedures
Final formulation procedures
Software packages
3.6 Precautions and special notations
1.
2.
3.
4.
5.
Apparel
Cleaning
Storage conditions
Filling, mixing conditions
Hazards and safety precautions
3.7 Equipment, lines, and procedures
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Process lines
Assembly lines
Vessels
Mixers, tools
Molds
Machine maintenance procedures
Calibration procedures
Setup procedures
Operating procedures
Process flow charts
3.8 Sterilization procedures
1.
2.
3.
4.
Procedures for ethylene oxide, radiation, filtration, steam, etc.
Handling and flow procedures
Cycle parameter specifications
Diagrams for loading products in the chamber
8−21
3.9 Production control documentation
1.
2.
3.
4.
5.
6.
7.
Inspection procedures
Test procedures
Blank job travelers
Blank inspection/test forms
Instrument charts
Reporting forms
Approved deviations
4.0 Labeling and Packaging
4.1 Index (Optional. see 1.0 above.)
4.2 Labeling
1.
2.
3.
4.
5.
6.
7.
8.
Label drawings
Labeling drawings
Label/labeling review procedures and forms
Production control procedures and history record forms
Instruction manuals
Service manuals
Customer software
Customer feedback forms
4.3 Packaging
1.
2.
3.
4.
5.
Package drawings (usually includes labeling information)
Closure drawings
Filling and/or packaging procedures
Packing procedures
Special shipment procedures
4.4 Storage requirements
1. Temperature
2. Humidity
3. Shelf-life
5.0 Control Procedures and Activities
5.1 Index (optional. see 1.0 above.)
5.2 Inspection procedures
1.
2.
3.
4.
5.
Incoming
In-process
Finished devices
Process control charts
Blank data reporting forms
5.3 Test procedures
1. Incoming
8−22
2.
3.
4.
5.
6.
7.
In-process
Pretest conditioning
Finished device
Process control charts
Blank device history record forms
Automated test programs and/or software
6.0 Final Release
6.1 Release document review list
6.2 Distribution procedures
6.3 Blank device history record forms
8−23
Title:
DEVICE MASTER RECORD INDEX
Policy No.
Rev.
Date
Approval
1.0 Purpose and Scope: To prescribe the responsibilities for preparing device master record
(DMR) Indices and content of DMR Indices (lists).
2.0 Policy: A DMR Index shall be prepared and maintained for all devices being developed or
manufactured.
3.0 Definition: A DMR Index is a table of contents for the device master record of a device. It
also contains information on the breakdown of the device into assemblies and/or
manufacturing steps. It is called a document plan during planning and early development of
a new product. A DMR is:
3.1 An aid in proposing, planning, tasking, and reviewing projects;
3.2 A framework for preparing drawings, parts lists, and test equipment lists;
3.3 A means of familiarizing personnel with the device configuration;
3.4 A current record and status of the physical configuration of the device and a list of all
reference documentation required; and
3.5 An index to the product-specific documentation required for procurement of components,
manufacture, and evaluation of a device.
4.0 Procedure:
4.1 Preliminary document plans may be generated for the convenience of Engineering. Upon
completion of the design when formal records are needed, a formal document plan will be
initiated.
4.2 The configuration and structure of the document plan is set by the Engineering,
Manufacturing Engineering, and Drafting Supervisors.
4.3 After agreements, the plan will be drawn, document numbers assigned, status of drawings
indicated, and the plan approved by Engineering and Manufacturing. All non-product
specific documents such as standard operating procedures that are used during production
of the device will be listed on the plan. (Because the plan is now complete, it is a DMR
Index.)
5.0 Example: Part of an index in "tree" form is on the following pages. A "tree" form allows a
large amount of information to be displayed in a small area. Each column covers a major
section of the documentation such as the battery charger. The index contains codes to
convey additional information such as a rectangle with a dark triangle in a top corner or a
mark such as "#" to indicate a parts list is included with a particular drawing.
8−24
8−25
8−26
(Sample for training purposes only. Do not use for technical parameters.)
PRODUCT SPECIFICATION PORTABLE DEFIBRILLATORS
CONTENTS
PRODUCT SPECIFICATION
1.0 Reference Documents
2.0 Overall Description
3.0 Configurations
4.0 Functional Characteristics
5.0 Performance Characteristics
APPENDIX A (not reprinted in this manual)
TEST RECOMMENDATIONS
APPENDIX B (not reprinted in this manual)
TEST POINT AND BOARD INTERCONNECT SIGNAL
DEFINITIONS
Throughout this Product Specification * indicates need for test.
NOTE: Values not in parentheses refer to Models D320 and D320W. Values in parentheses refer
to Models D400 and D400W.
LTR
1
2
3
4
A
DESCRIPTION
Pilot released per ER - 3556
Revised and Retyped per ECO - 3968
Revised and Retyped per ECO - 4225
Revised per ECO - 4636
Released to Production per ERN - 4645
Title:
PRODUCT SPECIFICATION PORTABLE DEFIBRILLATORS
DR BY: A J Lucas
APP’D:
DATE: 4/15/75
DATE
04/23/75
01/27/76
05/28/76
12/28/76
03/10/77
APPROVED
DWG NO. 04300538
Sheet 1 of 14
REVISION:
Date: 3/10/77
A
DATE:
PRODUCT SPECIFICATION PORTABLE DEFIBRILLATORS
8−27
D320, D320W, D400, & D400W
1.0
REFERENCE DOCUMENTS
1.1
Portable Defibrillators D320/400 and D320W/400W 23990081-XX
1.2
Adult Anterior Paddles 24990082-01 450 AA
1.3
Adult Anterior-Posterior Paddles 24990113-01 450 APA
1.4
Adult Anterior Paddles 24990114-03 450 AI
1.5
Pediatric Anterior Paddles 24990082-02 450 PA
1.6
Pediatric Internal Paddles 24990114-02 450 PI
1.7
Infant Internal Paddles 24990114-01 450 II
1.8
Adult Anterior Paddles with Remote Charge 24990082-03 450 AAR
1.9
Patient Cable Assy. 3 Electrode -21 D24990118-01
1.10 Tube XXXXXX (712) 1042507001
1.11 D320/400 Shipping List
1.12 D320/400 Operators Manual
1.13 D320/400 Maintenance Manual
2.0
OVERALL DESCRIPTION
The D320/400 (Ref. 1.1) is a portable defibrillator with integral isolated input, solid trace,
ECG monitor scope. The D320/400W contains in addition a 40 mm strip chart recorder. They
may be used for non-synchronous ventricular defibrillation or synchronous conversion of
arrhythmias. Power is derived from internal rechargeable batteries or from the AC power line
whenever the unit is connected to the AC power line via the internal charger.
Standard accessories included in the D320 Shipping List (Ref. 1.11) are:
1 - Adult Anterior Paddle Set (Ref. 1.2)
1 - Patient Cable-21(Ref. 1.8)
1 - Tube XXXXXX Electrode Paste (Ref. 1.9)
1 - Operator's Manual (Ref. 1.11)
1 - Shipping Carton
Optional Accessories are alternate paddles described in section 4.
8−28
3.0 CONFIGURATIONS
23990081-01
Battery Operated Defibrillator - D320 (120V)
23990081-02
Battery Operated Defibrillator - D320 (220V)
23990081-03
Battery Operated Defibrillator with Writer - D320W (120V)
23990081-04
Battery Operated Defibrillator with Writer - D320W (220V)
2399
Battery Operated Defibrillator - D400 (120V)
2399
Battery Operated Defibrillator - D400 (220V)
2399
Battery Operated Defibrillator with Writer - D400 (120V)
2399
Battery Operated Defibrillator with Writer - D400W (220V)
4.0
FUNCTIONAL CHARACTERISTICS
4.1
DEFIBRILLATOR FUNCTIONAL CHARACTERISTICS
The defibrillator becomes operational in the non-synchronous mode when the power
switch is turned ON and the paddle connector is attached. A charge cycle is initiated by
depressing and holding the MANUAL CHARGE button until the desired charge is
reached. Automatic charge to 160 (200) or 320 (400) joules is accomplished by depressing
the AUTO CHARGE 160 (200) or AUTO CHARGE 320 (400) buttons respectively. An
audible tone and a DELIVERED ENERGY bar display on the scope indicate when a
charge is in process. When the charge cycle is complete, the audible tone stops and the
DELIVERED ENERGY meter indicates the amount of energy to be delivered. The stored
energy is delivered in the form of an Edmark waveform by pressing the buttons located on
the anterior paddles or, if interior paddles are used, pressing the INTERNAL PADDLE
switch located on the control panel.
For safety and equipment protection, a charge cycle is followed by an automatic time
out that dumps the stored energy (disarms) after 45 seconds if energy is not delivered or
the charge button pressed again within the time out period. The stored energy is also
automatically dumped when the power switch is turned OFF. The operator may disarm
the unit by depressing the DISARM button.
4.1.1
Delivered Energy Indicator
The DELIVERED ENERGY INDICATOR displays the energy to be delivered into
a 50 ohm load as a horizontal line at the top of the CRT screen. When a charge is
initiated, the end of a solid bar will follow the amount of energy to be delivered.
4.1.2
Paddle and Accessory Storage
A molded paddle holder is in the defibrillator front panel cover for one set of
anterior-anterior adult defibrillator paddles. One (D320W/400W) or two
(D320/400) accessory holders are located below the front panel to hold cables,
electrodes, and paste. Under normal usage, the defibrillator is stored or
transported with defibrillator cables connected. This approach minimizes the
number of steps needed to bring the defibrillator from an idle state to the
emergency non-synchronous mode.
4.1.3
Anterior-Anterior paddles
Anterior-anterior paddle assemblies are available with two electrode sizes: adult
8.5 cm (Ref. 1.2) and pediatric 5.0 cm (Ref. 1.7). Each assembly consists of a
8−29
connector, two paddles with discharge buttons, and a dual coiled cord extendable to
10 feet.
Ethylene oxide sterilization is the only permissible sterilization technique for all of
these paddles.
4.1.4
Anterior-Anterior Paddles with Remote Charge (Optional)
Same as 4.1.3 except one paddle will have a charge button that functions identically
to MANUAL CHARGE button on the front panel (Ref. 1.8).
4.1.5
Anterior-Posterior Paddles
An anterior-posterior paddle assembly (Ref. 1.4) is available for use only on adults.
It consists of an anterior paddle identical to the 8.5 cm paddle in a 4.1.3, a posterior
12 cm paddle, a dual 10ft. coiled cord, and connector.
4.1.6
Internal Paddles
Internal paddle assemblies are available with three electrode sizes: adult 8.5 cm
(Ref. 1.4), pediatric 5.0 cm (Ref. 1.5), and infant 2.5 cm (Ref. 1.6). Each assembly
consists of a connector, 2 paddles, and a dual coiled cord extendable to 10 ft.
4.2
ECG AMPLIFIER AND SOLID TRACE SCOPE FUNCTIONAL CHARACTERISTICS
4.2.1
ECG Amplifier
The ECG amplifier is an isolated, variable gain amplifier which feeds the display,
QRS detector, and output jack. Input to the amplifier is through the defibrillator
paddle connector or through the patient cable. A lead selector switch selects the
paddles, or leads I, II, or III for input. The amplifier incorporates the following
features:
1. Slew Rate Limit - Limits the slew rate and, therefore, the amplitude of the pacer
pulses so that they can be seen on the display and will not trigger the QRS
detector in most lead configurations.
2. Fast Recovery Circuit - Returns the signal to on screen limits within 0.5 seconds
after defibrillation or other overload.
4.2.2
Solid Trace Display
The solid trace display shows the last 4 seconds of ECG waveform on the screen.
The waveform appears as if a strip chart recorder were writing the ECG at the
right hand edge of the screen and the paper was being pulled from right to left.
Current information is displayed at the right of the screen with information
becoming increasingly older towards the left. When operating the defibrillator in
the synchronous mode, sync pulses appear showing where the energy would have
been delivered had the discharge buttons been pushed. The waveform may be
stopped or "frozen" for review by pushing the latching FREEZE button.
4.3
HEART RATE METER FUNCTIONAL CHARACTERISTICS
8−30
The heart rate meter displays heart rate as a bar at the screen bottom. The heart rate is
also compared to alarm limits that are displayed on the same bar. When a limit is
exceeded for longer than three seconds, the red alarm led blinks, an audible alarm sounds,
and the hard copy writer runs (D320W/400W only). Alarms are disabled or reset by
putting the LOW LIMIT knob fully counter-clockwise and the HIGH LIMIT fully
clockwise. In this position the limit indications are not displayed on the screen.
The threshold for QRS detection is automatically adjusted depending on the amplitude of
the QRS complex. The minimum threshold is equivalent to 0.6 cm on the scope display. At
maximum gain, a 0.3 mv QRS complex will be detected. Detection of a complex will cause
an audible beep if the BEEP push-button is depressed. Proper adjustment of the gain
control will result in an R-wave amplitude on the screen of one to two cm.
*4.4 SYNCHRONIZED CARDIOVERTER FUNCTIONAL CHARACTERISTICS
The synchronizer detects the peak of the R wave and, after the discharge buttons on both
defibrillator paddles have been pushed, delivers the stored energy. The QRS amplitude
must be set to at least 0.6 cm on the scope display using the SIZE control. QRS detection
is verified by an audible QRS beep and by a SYNC pulse displayed on the scope at the
time relative to each QRS complex that the energy would have been delivered.
4.5
WRITER FUNCTIONAL CHARACTERISTICS ( D320W/400W only)
The D320/400W is equipped with a 40 mm direct hard copy writer. The writer is started
manually by the RECORD push-button on the front panel or automatically on alarm. No
other controls are provided. Gain of the writer is equal to the gain of the scope. Therefore,
setting the QRS size control to a convenient point for the scope will produce a reasonable
gain for the writer. Centering of the writer is automatic to within approximately .25 cm.
An internal stylus heat adjustment is provided. An external control is not needed due to
the regulation of the stylus power supply.
4.6
MODES OF OPERATION
The defibrillator has two modes of operation: non-synchronous defibrillation and
synchronous defibrillation. The defibrillator is always in the non-synchronous
defibrillation mode when power is turned on. It can be switched from the
non-synchronous mode to the synchronous mode by pressing the SYNC ON push-button.
It can be returned to the non-synchronous mode by pressing the SYNC OFF push-button.
Synchronous mode is indicated by a SYNC light on the front panel and by sync pulses
appearing on the scope coincident with QRS detection.
*4.7 OPERATOR CONTROLS
4.7.1
ON/OFF
A two push-button switch turns on the ECG amplifier and Solid TraceScope and
puts the unit in the non-synchronous mode when ON is depressed.
When OFF is depressed it dumps (disarms) the defibrillator capacitor and switches
off all power to the unit. Closing the front cover automatically depresses OFF.
4.7.2 MANUAL CHARGE
8−31
A momentary push-button that causes the capacitor to be charged while depressed.
4.7.3 AUTO CHARGE 160 (AUTO CHARGE 200)
A momentary push-button which initiates an automatic charge to 160 joules
delivered.
4.7.4 AUTO CHARGE 320 (AUTO CHARGE 400)
A momentary push-button which initiates an automatic charge to 320 joules
delivered.
4.7.5 PADDLE CHARGE (Optional)
A momentary push-button located on the right paddle which functions identically
to the MANUAL CHARGE push-button.
4.7.6 SYNC ON/SYNC OFF (Labeled SYNC/DEFIB ON D400/400W)
Two momentary push-buttons used to select synchronous or non-synchronous
mode of operation. Pressing SYNC ON after the power is turned on puts the unit in
the synchronous mode and illuminates the SYNC light. The unit is put in the
non-synchronous mode when power is turned on or by pressing SYNC OFF when
operating in the synchronous mode.
4.7.7 DISARM
A momentary push-button that is used to dump the internal stored charge. It is
used if a lower energy than the one already selected is desired, or if no more
countershocks are to be delivered.
4.7.8 QRS SIZE
A potentiometer used for setting the gain of the ECG amplifier. Gain may be varied
from X300 at fully CCW to X3000 at fully CW. At center position, the gain is
X1000.
4.7.9 FREEZE
A latching push-button that causes the scope to cease updating.
4.7.10 1MV
A momentary push-button that injects a 1 mv +/- 2.5% signal.
4.7.11 BEEP
A latching push-button that activates the QRS beep when depressed.
4.7.12 HIGH LIMIT
A potentiometer used for setting the alarm high rate limit over a range of at least
100 to 250 BPM. It is set to 120 BPM with knob pointer is straight up.
8−32
4.7.13 LOW LIMIT
A potentiometer used for setting the alarm low rate limit over a range of at least 0
to 150 BPM. It is set to 60 BPM with knob pointer is straight up.
4.7.14 RECORD
A latching push-button that starts the writer when depressed. The writer is always
started on alarm.
4.7.15 LEAD SELECT
Four interlocking push-buttons labeled PADDLES, I, II, III that select paddles or
standard leads I, II, III respectively as input to the ECG amplifier. A three-lead
cable with RA, LA, and LL (which may be labeled R) can be used.
*4.8 INDICATORS
4.8.1 BATTERY LOW
A red lamp that begins flashing when the battery has a minimum of ½ hour of
continuous monitoring capacity left or 2 charges to 320 joules (1 charge to 400
joules). The lamp flashes to indicate circuit operation when power is turned on.
4.8.2 SYNC
An amber LED that illuminates when the unit is operating in the synchronous
mode.
4.8.3 DELIVERED ENERGY, JOULES
An illuminated bar that indicates the energy in joules to be delivered into a 50 ohm
load.
4.8.4 TEST
A light located on the defibrillator paddle holder that illuminates when a counter
shock of at least 300 joules is discharged into the paddle holders.
4.8.5 ALARM
A red light that flashes during an alarm.
4.8.6 LINE
Two red lights that illuminate when AC power is being received by the unit.
4.8.7 QRS Beep
An audible tone that is produced every time a QRS complex is detected when the
BEEP push-button is depressed.
8−33
4.8.8 Charging
A audible tone that increases in pitch as the capacitor charges.
4.8.9
Sync Pulse
A negative pulse displayed on the ECG trace with its center within 20 ms of where
the energy should have been delivered if the DISCHARGE BUTTON(S) had been
pushed.
4.8.10 Heart Rate Bar
An illuminated bar graph showing Heart Rate and alarm limit settings.
*4.9 CONNECTORS
4.9.1
Defibrillator Paddle Connector
G pin High Voltage Connector
Pin D -High Voltage Paddle Lead
Pin A +High Voltage Paddle Lead
Pin F Ground
Pin C INTPDL - (Internal Paddle Jumper)
Pin B FDLSW - (Paddle Switch)
Pin E RMTCHG - (Remote Charge Switch)
4.9.2
Isolated Input Connector
5 pins MS series Connector - Located on front panel.
Pin A Right Arm
Pin B Left Arm
Pin C Left Leg
Pin D Left Leg
Pin E Left Leg
4.9.3
ECG/Output Connector
3-wire phone jack on front panel
Tip
ECG Output
Ring Signal Ground
Sleeve Chassis Ground
5.0
PERFORMANCE CHARACTERISTICS
5.1
DEFIBRILLATOR OUTPUT
5.1.1
*5.1.2
Waveform:
Monophasic pulse (Edmark Waveform)
Energy Range:
D320/320W
10-320 joules delivered into a 50 ohm load.
8−34
Energy Range:
D400/400W
10-400 joules delivered into a 50 ohm load.
*5.1.3
Energy Accuracy:
DELIVERED ENERGY INDICATOR OR AUTO 320 (400)
and AUTO 160 (200) pushbuttons
recommendations.
5.1.4
Pulse Width:
95% of the energy delivered in <5 ms
into 50 ohm load.
Charge Time:
(D320/320W)
Charge Time:
(D400/400W)
Charges to 320 joules in 10 sec. max.
8.5 sec. typical.
Charge to 400 joules in 12 sec. max.
10.5 sec. typical.
5.1.6
Pulse Rate:
<5
Deliver 15 400-joule counter shocks in
minutes.
5.1.7
Energy Loss Rate:
<15% in 30 seconds.
5.1.8
Charge Dump Time
<25 volts left in 4 seconds and <2 joules
in 3 minutes after activation of
capacitor dump circuit.
Isolation
Withstands 8 KV DC from either
paddle to chassis with relay in fire
position.
*5.1.5
*5.1.9
5.2
Error less than 10% or 4 joules, whichever is greater, into 50 ohms and 25%
or 4 joules, whichever is greater, into
a 25 to 100 ohm load when measured in
accordance with XXX
ECG AMPLIFIER
*Frequency Response:
.5 to 40 Hz. +0, -3 db max. from isolated
input connector to ECG output on front
connector or scope display at 1 cm scope
deflection.
*Risk Current:
<10 ua at 120 v 60 Hz without patient
cable.
<20 ua with 120 VAC applied to electrode end of ECG patient cable.
* Gain:
adjustable x300 to x3000. x1000 at
nominal gain position.
Input Impedance:
>1 megohm differential, DC to 60 Hz
through patient cable.
Input Offset Tolerance:
>1 volt
Input Dynamic Range:
+/- 3.5 mv at nominal gain setting.
8−35
*Isolation Voltage:
2500 volts RMS at 60 Hz from any
patient lead or combination of patient
leads to AC line for one minute.
Defibrillator Protection:
Will withstand 5 pulses at 20 second
intervals from defibrillator set to 400 ws
delivered energy and delivered across a
100 ohm load in parallel with any two
patient cable leads.
*Reset Recovery
Automatic return to on screen within .5
seconds after an electrosurgical or
defibrillator overload.
Slew Rate:
Internally limited at .2 to .25 mv/ms
referred to input at nominal gain.
*Calibration Signal:
1 mv +/-2.5% referred to input.
Output:
High-level single-ended output on front
panel. Output level dependent on gain
setting.
Output Impedance:
<100 ohms
Output Dynamic Range:
3.5 volts +/-10%
*Output Offset
<50 mv for DC input @ 25°C
<200 mv @ nom gain over full temp
range
Output Current
>+/-5 ma
*Noise:
<5 uv RMS referred to input at ECG
output with RA and LA connected to
RL by shielded 25 Kohm resistors.
<50 uv RMS referred to input at scope
display at nominal Gain setting.
Common Mode Input
5.3
>12 megohms from patient leads to
Impedance: chassis ground, from DC to
50 Hz.
SOLID TRACE SCOPE
Viewing Area:
3.94" wide x 3.15 high (8x10 cm)
*Gain
.33 mv/cm to 3.3 mv/cm from patient
leads to scope display depending on
ECG amplifier gain setting.
8−36
5.4
Brightness:
Internal adjustment.
Sweep Speed:
25 mm/sec. +/-5%
Warm-up:
Visible in 15 seconds.
Memory Time:
4 seconds visible
Sample Rate:
240/sec.
Resolution:
8 bits
Phosphor:
P31
Refresh Rate:
60 Hz
*Transient Response:
<5 percent overshoot to step input of
any magnitude up to full scale.
*Frequency Response:
.5 to 40Hz +0-3db max. from isolated
input to scope display @ 1 cm
deflection.
Horizontal Sweep Linearity:
Better than 5% over full viewing area.
Vertical Linearity:
Better than 5% over 6 cm central
viewing area from isolated input to
scope display.
Drift:
Baseline will not drift more than .5 cm
with 5 minutes after power turn on.
Sampling Noise:
SYNCHRONIZED CARDIOVERTER
<.3 mm at any gain setting.
QRS Detector:
Automatic threshold greater than .6 cm
either polarity QRS complex.
*Sensitivity:
<.3 mv at maximum gain setting
Range:
0-250 beats per minute.
QRS Tone:
1 KHz tone
Marker Pulse:
Shown on scope +/-20 ms from
beginning of counter shock.
*Discharge Delay:
5.5
Energy is delivered within 40 ms of the
R wave peak with proper gain setting.
HEART RATE METER
*Range
0-250 BPM
8−37
*Accuracy
3 BPM or 5% of reading whichever is
greater.
Response Time:
<5 seconds for rates greater than 50 and
an input step change of 70 BPM
Alarm Setting Accuracy:
Better than +/-5 BPM
Alarm Delay:
3 Seconds +/-1 second
*Pacer Artifact Rejection:
5.6
Will not respond to pacer spikes <= 4
ms with proper lead placement.
WRITER ( D320W/400W only)
Linearity:
1% of full scale
*Frequency Response:
5.7
.5 to 40 Hz +0, -3db maximum from
isolated input connector at 1 cm
deflection.
Chart Width:
40 mm
Chart Speed:
25 mm/sec +/-3%
DEFIBRILLATOR BATTERY SUPPLY
*Battery Life:
Minimum of 5 hours of monitoring, 1.7
hr
( D320/320W)
of
monitoring with writer running, or 50
defibrillator charges at 320 joules, or
any proportional combination at 25°C. 6
hours of monitoring or 60 shots typical.
*Battery Life
(D400/400W)
Minimum of 5 hours of monitoring, 1.7
hrs of monitoring with writer running,
or 40 defibrillator charges at 400 joules
or any proportional combination at
25°C. 6 hours of monitoring or 50 shots
typical.
Battery Type: NiCad 12 volt battery
pack located inside unit.
5.8
*Battery Charge Time:
14 hours to full charge
*Low Battery Indicator:
Comes on when minimum of 1/2 hour of
monitoring or 2 charges to 320 joules of
battery capacity left.
AC LINE REQUIREMENTS
8−38
5.9
Input Requirements
97/127 VAC 48-65 Hz. -01,-03,-05, -07
194/254 VAC 48-65 Hz. -02, -04,-06,-08
Power Requirements:
55 watts max, with fully discharged
battery in charge mode.
*Green Wire Leakage:
<50 ua RMS at 120 VAC 60 Hz
measured with AAMI load.
*Hipot:
2500 VAC RMS 60 Hz between AC hot
and neutral and green wire ground.
PADDLES
Electrode Finish:
<250 micro inches RMS surface
roughness.
Electrode Material
400 series stainless steel.
Handle Material:
Flame resistant plastic
5.10 PHYSICAL CHARACTERISTICS
5.10.1
Size:
17.81" x 15.10" x 8.94"
45.24 cm x 38.35 cm x 22.54 cm
Weight: 33 lbs. (-01,-03,-05,-07)
37 lbs. (-02,-04,-06,-08)
8−39
5.11 ENVIRONMENTAL CHARACTERISTICS
5.11.1
5.11.2
5.11.3
Temperature
Operating:
-10°C to 55°C (14°F to 131°F)
Storage:
-25°C to 55°C (-13°F to 158°F)
Notes:
Continuous battery charge over 40°C ambient reduces battery
life. Long term storage over 50°C reduces battery life.
Humidity
Operating:
5% to 96% relative humidity
Storage:
5% to 80% relative humidity
Atmospheric Pressure
70 kPA to 103 kPA
5.11.4
Shock and Vibration
Shall comply with the shock and vibration requirements of section 3.2.3 of the
XXX Cardiac Defibrillator Standard, document number XXX-XXX-021-0001.
8−40
Sheet 1 of 1
TITLE: IN4278 ZENER DIODE SPECIFICATION NUMBER
Drafted by
REV.
ECN History Notes
App.
Date
Date
1.
SCOPE: This specification describes a one-watt zener diode used for voltage reference in
the XYZ Stimulator.
2.
ELECTRONIC CHARACTERISTICS
2.1
Zener Voltage: 3.1 vdc @ 76 madc
2.2
Maximum Zener Impedance: 10 ohms @ 76 madc
2.3
Reverse Leakage Current: (25%) 100 microamps (max) @ l vdc
3.
TESTING: All diodes shall meet the requirements of JANTX IN4278 as specified in
MIL-S-19500/127G.
4.
PHYSICAL CHARACTERISTICS
5.
6.
7.
4.1
Diodes shall be packaged in a void-free silicone case.
4.2
Leads shall be readily solderable.
MARKING
5.1
The cathode shall be identified by a color band.
5.2
An identification number and lot number or date code shall represent a specific
manufacturing period.
5.3
All markings shall be permanent such that cleaning solutions will not remove the
markings.
CERTIFICATION
6.1
A certification of compliance with this specification and a test data sheet must
accompany each lot shipped.
6.2
Certification must include a statement that no changes have been made in materials or
physical or electrical characteristics.
APPROVED SUPPLIERS
7.1 XXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXX
8−41
OPEN HERE
HAND-SWITCHING PENCIL
STERILE REUSABLE
Catalog No. E2502B
STERILITY GUARANTEED UNLESS PACKAGE HAS BEEN DAMAGED OR OPENED:
CONTENTS:
One sterile reusable Hand-switching Pencil with 10 follt cord and plug and disposable blade
electrode. Accepts all standard 3/32" shaft electrodes.
DIRECTIONS:
1)
Open package by peeling apart at arrow.
2)
Remove LectroSwitch®Pencil from sterile package using aseptic technique. Do not
perrmit LectroSwitch®Pencil to contact unsterile end of package or any object outside the
sterile field.
3)
Check blade electrode connection for secure fit prior to use
4)
Insert plug connection into active hand-switching receptacle on generator. An adapter
may be required for generators not manufactured by Valleylab, Inc.
5)
Remove protective sleeve from blade electrode.
CAUTION:
NOTE:
AFTER USE THE LECTROSWITCH®PENCIL MUST BE STERILIZED. DISCARD
THE DISPOSABLE BLADE ELECTRODE BEFORE REPROCESSING.
RECOMMENDED STERILIZATION TECHNIQUE IS SHOWN ON PACKAGE
INSERT IN BOX CONTAINING LECTROSWITCH®PENCILS.
GOOD OPEATING ROOM PRACTICE SUGGESTS THAT ACTIVE ACCESSORIES
BE PLACED AWAY FROM THE PATIENT WHEN NOT IN USE.
8−42
8−43
COMPANY LOGO
PARTS LIST
USED ON 29330080
DRAWN
ITEM
NO.
TITLE
DATE
SIZ
E
24990672
Handle Assemby
CHECKED
PART NO.
PL
DATE
DESCRIPTION
SHEET
1 OF 1
APPROVED DATE
REF.DES.
QTY.PER.TAB NO.
.01
1
2
3
4
5
6
7
8
9
10
11
12
NOTES:
8−44
REV
C
.02
8−45
COMPANY LOGO
PARTS LIST
USED ON Port Scope
DRAWN
ITEM
NO.
TITLE
PART NO.
20500681
Cable Interconnecting &
Point to Point Wiring
DATE CHECKED
SIZ
E
PL
DATE
DESCRIPTION
SHEET
1 OF 1
APPROVEDDATE
REF.DES
.
QTY.PER.TAB
NO.
.01
1
2
3
4
5
6
7
Notes:
8−46
REV
B
.02
1.0
PRODUCT DESCRIPTION
1.0
Number XXXXXXX, Product specification
2.0
PREPARATION Manufacturing
2.1
Purchase Specifications
2.101
2.102
2.103
2.104
2.105
2.106
2.107
2.108
2.109
PS 01-0003
PS 01-0008
PS 01-0017
PS 01-0002
PS 01-0005
PS 01-0012
PS 01-0004
PS 01-0007
PS 01-0001
XXXXXXX Starch
Sodium Hydroxide
Hydrochloric XXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXX
Sodium Chloride
XXXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXXX
#1076
#1079,1080
#1078 XXXX
#1082 XXXX
Starch pretreatment
XXXXXX Diluent solution
Iodine solution
Substrate
2.2 Preparation
2.201
2.202
2.203
2.204
3.0 FILLING, LABELING AND PACKAGING
3.1
Purchase Specifications
3.101
3.102
PS 02-0201
PS 02-0103
Tube
Cap
PS 02-0001
PS 02-0101
PS 05-0006
PS 02-0701A
PS 03-0701
PS 03-0320
PS 03-0001
Bottle
Cap
Teflon liner
Label
Instruction sheet
Platforms
Boxes
Cat. XXXXXXX
3.103
3.104
3.105
3.106
3.107
3.108
3.109
TITLE: DEVICE MASTER RECORD FOR AMAYLASE
Dr By:
Date
Dwg No:
Sheet 1 of 2
App'd:
Date:
Revision A
Date
ECN
8−47
Cat. XXXXXXX
3.110
3.111
3.112
3.113
3.114
3.115
3.116
3.2
PS 02-0002
PS 02-0102
PS 05-0007
PS 02-0701B
PS 03-0707
PS 03-0301
PS 03-0002
Bottle
Cap
Teflon liner
Label
Instruction sheet
Boxes
Platforms
XXXXXXX Production
3.201
SOP-XXXXX
Filling, labeling and packaging
4.
Quality Control Specifications
4.1
Raw Material Specification (RM)
4.101
4.102
4.103
4.104
4.105
4.106
4.107
4.108
4.109
4.110
4.111
4.112
4.113
4.114
4.115
4.116
4.117
4.118
4.119
4.120
4.121
4.122
4.123
4.2
XXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXXXXXX
Sodium Hydroxide
XXXXXXXXXXXXXXXXXXXXXXX
Hydrochloric XXXXXXXXXX
Sodium Chloride
Bottle (3200-01)
Bottle (3200-10)
Cap (3200-01)
Cap (3200-10)
Label (3200-01)
Label (3200-10)
Boxes (3200-01)
Platform (3200-10)
Boxes (3200-01)
Boxes (3200-10)
Instruction sheet (3200-01)
Instruction sheet (3200-10)
Teflon liner (3200-01)
Teflon liner (3200-10)
XXXXXXXXXXXXXXXXXXXXXXX
In-process Specifications
4.201
4.3
RM 01-0002
RM 01-0003
RM 01-0005
RM 01-0007
RM 01-0008
RM 01-0012
RM 01-0017
RM 01-0004
RM 01-0001
RM 01-0002
RM 01-0101
RM 01-0102
RM 02-0701A
RM 02-0701B
RM 03-0001
RM 03-0002
RM 03-0301
RM 03-0320
RM 03-0701
RM 03-0707
RM 05-0006
RM 05-0007
RM 01-0001
SOP-58200B-0
0ptical Density of XXXXXXX substrate
Final specifications
4.301
QC-PB-007
5.
Final Release
5.1
Final Release Specification
5.101
#1087
Finished goods quality control-XXXXXXX set
Final Product Release Form
Device Master Record For Amaylase
Dwg No
8−48
Sheet 2 Of 2
Sheet 1 of 3
1.
PRODUCT SPECIFICATION FOR AMYLASE, CATALOG NO. 3200
1.1
Product name: Amylase Set
1.2
Description of product
This Amylase Set is used for the quantitative determination of amylase in biological fluids.
The principle of the procedure is as follows:
Starch + H20 amylase > colorless starch fragments
Unhydrolyzed Starch + I2 ----> colored starch-iodine complex
The color produced by the starch-iodine complex after 7.5 minutes incubation of substrate with
specimen and 15 minutes color development is compared with a reagent blank. The decrease in
absorbanceoptical density (OD) at 660 nm is proportional to amylase activity in the specimen
because the enzyme hydrolyzes starch to fragments that do not react with the iodine reagent.
1.3
Product availability
Catalog No.: 3200-01
Catalog No.: 3200-10
1.4
Components of product
Catalog No. 3200-01
15 Tubes of lyophilized substrate
1 Bottle (10 ml) Iodine (.OIN)
1 Instruction sheet
Catalog No. 3200-10
100 tubes lyophilized substrate
2 Bottles (30 ml ea.) Iodine (.OIN)
1 Instruction sheet
1.5
Storage of reagent
Store at room temperature. Do not refrigerate.
Minimum shelf life is one year.
Do not use any substrate tube in which moisture is observed.
1.6
Stability of specimen
Amylase activity in serum is stable up to one week at room temperature and for one to two
months if refrigerated at 2 to 8°C.
8−49
TITLE: SPECIFICATION FOR AMYLASE CATALOG NO: 3200
Dr By:
Date
Dwg No: 62-3200
Sheet 2 of 3
App'd:
Date:
Revision A
Date
ECN
1.7 Procedure for urine amylase
Collect a timed (minimum of 2 hours) sample of urine and measure the volume. Follow the
same procedure as used for serum amylase. Calculate the amylase activity excreted in the
urine per hour as follows:
Urine amylase (unit/hour) =
= OD Reagent blank - OD Specimen X IOV/H X Tf
OD Reagent blank
V = total volume of timed urine specimen in milliliters;
H = total collection time in hours;
Tf = temperature correction factor.
Example:
2 hour volume of urine = 130 ml;
OD blank= 0.57;
OD Specimen = 0.48;
Temperature = 37°C;
Urine amylase (unit/hour) =
= 0.57 - 0.48 X 10 x 130 X 1 = 103
0.572
2
Caution: Some urine specimens may contain reducing substances which could exhaust the
iodine reagent.
1.8
Units
One amylase unit is defined as that amount of enzyme activity which, under the conditions
of this procedure, will hydrolyze 10 mg of starch in 30 minutes to a stage at which no color
is generated with iodine.
1.9
Normal Range
Normal range for serum is 50 to 200 units at 37°C. Infants below two months have no
measurable serum amylase. Adult level is reached by the age of one year. The above normal
range includes an average serum blank of 25 amylase units. Normal values for urine is less
than 375 units per hour at 37°C.
8−50
Amylase Description
DWG NO: XX-3200
Sheet 3 of 3
1.10 Precision
Coefficient of variation of 5 to 6 percent at a level of 120 units and 3 to 5 percent at a level
of 250 units are obtained with good laboratory technique.
1.11 Performance characteristics
This assay measures amylase levels up to 500 units per 100ml specimen in a linear manner.
Specimens with higher activity must be diluted by the procedure given in Note 2 [not
reprinted in this manual]. The calculated value includes a serum blank, which averages
about 25 units in human sera. Control sera may have larger serum blanks, often up to 100
units. Values obtained on patient sera when corrected for the serum blank activity of
approximately 25 units are very close to the values obtained by the Somogyi Saccharogenic
method.
1.12 Cautions
This product must be protected from contamination by amylase. Saliva is a very potent
source of amylase. Perspiration contains some amylase as do other body fluids. Insensible
droplets of saliva are projected during speech, sneezing, etc.
Face masks and hair covering must be worn during solution and diluent preparation,
solution filling, tube racking and capping, and when handling any raw material defined for
use with this diagnostic test.
Equipment used in the procedure should be designed "For Amylase Only". Glassware and
other equipment suspected of amylase contamination must be rinsed with XXXXXXX.
Avoid contamination with detergents or soap. (See SOP #G021). Observe safety precautions
when handling acids (SOP #G022).
1.13 Manufacturing Flow Sheet.
See Form No. 9926. [Not reprinted in this Manual].
8−51
Page 1 of 2
FOR USE IN CATALOG Numbers: XXXX-01 15 tests and XXXX-10 100 tests
Batch No.
Code No.
Date
Checked by
Prepared by
MASKS MUST BE WORN THROUGHOUT THIS PROCEDURE TO PREVENT SALIVA
CONTAMINATION.
FOR 50 LITERS OF AMYLASE DILUENT SOLUTION:
1. Weigh the following chemicals and place them in 43 liters of deionized water in a calibrated
clean container.
DEIONIZED WATER: Source
Conductivity Light: On
VENDER
CODE
RM. NO.
Vol.
Off
LOT
NO.
ml Done By
Checked By
AMOUNT
REQ’D
WEIGHT
WEIGHED
BY
BY
CHEMICAL
01-0004
Sodium Chloride
425.0 g
±0.1
G
T
N
01-000X
XXXXXX
Basic
523.25
±0.1
G
T
N
01-000X
XXXXXX
Basic
1275.0 g G
±0.1
T
N
Note: Slowly add the sodium XXXXXXXX to prevent caking.
Procedure Amylase Diluent Solution
Completed by
Checked by
No.
Date
Date
Rev.
Date Eff.
App’d
8−52
Batch no.
2.
Page 2 of 2
Stir the diluent until all of the salts go into solution.
Done by
3.
Check the pH of the solution against 7.00 pH reference buffer.
Initial pH
4.
Checked by
Adjust the solution to a pH of 7.00 + 0.05 @ 25°C using 2N NaOH
mls of
used.
Lot No.
pH
@ 25°C
Checked by
5.
Add 125 mls of 1%
No. of mls added
6.
XXXXXX solution & mix well. Done by
. Supplier
Lot No.
Bring the volume to 50 liters with deionized water and mix well. Re-check the pH. It should
still be 7.00 + 0.05 @ 25°. Adjust, if necessary, with 2N NaOH or 6N HCl.
DEIONIZED WATER:
Source
Final Vol.
Conductivity Light: On
mls of
mls.
Off
Checked by
used to adjust. Lot No.
Final pH @ 25°C
Done by
Done by
Checked by
7.
Solution must be approved by the Solutions Supervisor(s) or their designee before it can be
Date
used. Approved by:
8.
The Solution is now ready to be used in the preparation of Amylase.
It will be filtered as it is during that preparation.
9.
Label the Diluent Solution with the Product Name, Batch Number, and Date of
Manufacturing.
PROCEDURE Amylase Diluent Solution
No.
8−53
Rev.
Form No. 1084
Sheet 1 of 1
FILLING RECORD - Liquid, Non Freeze Dried
Product Name
Distributor
Theoretical Tube & Vial Yield
Kit Cat. #
Kit Lot #
Kit Exp. Date
SPECIAL INFORMATION
IODINE
Batch #
Date Received
Date Manuf.
Time Received
TUBE AND VIAL
INFORMATION
Code #
# Lost
# Racked
Total # Used
FILLING DATA
Machine(s)
Before Filling - Signed
Cleaned:
After Filling - Signed
Fill Vol.
ml
Limits ±
ml Filling
Batch Vol.
ml
Leftover
ml Method
# Tubes or Vials Filled
#Bad Fills
APU
ml
TPU ml
Filling Operators 1)
Volumetric Fill Checks: 1)
4)
5)
Cap Code #
Cap Code #
Label Code #
Date
[ ] Refilled
[ ] Not Refilled
TPR ml
2)
3)
2)
6)
4)
3)
7)
Checks done by
CAP AND LABEL INFORMATION
1.
2.
Date
8)
Date
# Used
# Used
# Used
Signed
# Lost
# Lost
# Lost
Date
Date
Checked by
ATTACH SAMPLES OF LABELS
8−54
FINISHED PRODUCT
RELEASE
Form No.
Rev.
Form Approved by:
Sheet 1 of
1
Date
ECN notes:
Title: AMYLASE SET
Packaging lot number
Circle one CATALOG Number →
The device history documents below were reviewed by →
Circle one form number in 2, 5 & 7 below.
1. Form # 9926
Product flow sheet
2. Form # 1077 or 1078
Iodine solution
3. Form # 1082
Substrate solution
4. Form # 1083
Substrate tube filling sheet
5. Form # 1084 or 1085
Iodine filling sheet
6. Form # 1086
Packaging record
7. Form # QC-PP-07 or QC-PP-01
Finished device specification
AM-389-01
MFG
"
QC
"
Comments
Sign. MFG Designee
No→
APP. Yes or
Comments
Signature QC Designee
No
Approved Yes or
Production Workmanship and Configuration Sample Tag
8−55
xxxxxxxxx
A
PRODUCTION SAMPLE NAME
INSTRUMENT/PART NUMBER
REV
OPTION CODES
SAMPLE NUMBER
ECN HISTORY ON BACK
NOTES:
APPROVED FOR USE BY:
Form Number 6-53
PROJECT ENGINEER
DATE
Signature Master Sample Only
LEAD ASSEMBLER
DATE
Signature all samples
LEAD TECHNICIAN
DATE
signature all samples
PRODUCTION MANAGER
DATE
signature master sample only
Back of Sample Control Tag (the above tag)
SAMPLE MODIFICATION HISTORY
Modification
Number
ENG (MASTER ONLY)
LEAD ASSEMBLER
SIGNATURE
SIGNATURE
SHOP ORDER TRAVELER
DATE
LEAD TECHNICIAN
DATE
S.O.T. NUMBER
DATE
8−56
SIGNATURE
DATE
Form 058-SOT
Description
Part No.
FROM Department
TO Department
Quantity Delivered
Quantity Accepted
Supervisor
Supervisor
Remarks
Lot No. Complete Thru OPN
FOLLOWER TAG
Form 092-FT
Instrument Name
Line Voltage
S/N
Model No.
Record discrepancies & nature of rework on back
PROCESS
BY EMPLOYEE
Assembled
In-process Check
Chassis Check
Test & Calibration
Burn-in
Audio Calibration
Final In-process Inspect.
Seal Card Cage
Pre-Cover Inspection
Final Assembly
Final Test
Final Inspection
Packing/Shiping Inspect.
8−57
DATE
9
DOCUMENT AND CHANGE CONTROL
INTRODUCTION ................................................................................................................ 9-1
CHANGE CONTROL PROCEDURE ................................................................................. 9-2
Identification ................................................................................................................... 9-3
Effective Date ................................................................................................................. 9-3
Responsibility ................................................................................................................. 9-4
Revision Level ................................................................................................................ 9-4
Validation ........................................................................................................................ 9-4
Communication .............................................................................................................. 9-4
Updating Documentation ................................................................................................ 9-4
Documentation Distribution ........................................................................................... 9-5
Remedial Actions ............................................................................................................ 9-5
Regulatory Submissions ................................................................................................. 9-5
Business Factors ............................................................................................................. 9-5
QUALITY ASSURANCE REVIEW .................................................................................... 9-5
CHANGES UNDER PREMARKET NOTIFICATION ....................................................... 9-6
Regulatory Background .................................................................................................. 9-6
Premarket Notification Decisions ................................................................................... 9-6
Quality System Control Always Required ...................................................................... 9-7
EXHIBITS ............................................................................................................................ 9-8
Engineering Change Policy/Procedure ........................................................................... 9-8
Change Control Forms .................................................................................................... 9-8
INTRODUCTION
There is no easy way to properly control changes to devices, processes, device master records, etc.
Change control is a complex process. Failure to have an adequate change control system can cause equally
"complex" results. Inadequate change control exposes a company to product liability actions, results in
product recalls, causes internal confusion, and is a serious violation of the Quality System (QS) regulation.
Change control activities and procedures apply to: design; components, including software; labeling and
packaging; device manufacturing processes; production equipment; manufacturing materials; and all
associated documentation such as quality system procedures, standard operating procedures, quality
acceptance procedures and data forms, and product-specific documentation. Change control should also be
applied to any production aids such as labeled photographs and models or samples of assemblies and
finished devices.
The device master record (DMR) is a compilation of records containing the procedures and
specifications for a finished device [820.3(j)]. This record contains the manufacturer’s documentation for
the device specifications and all other documentation required to procure components and produce, label,
test, package, install, and service a finished device. Manufacturers are to prepare, control changes to, and
maintain a device master record using the document controls procedures outlined in 820.30 and 820.40.
CHANGE CONTROL PROCEDURE
9−1
Changes to DMR documents shall be reviewed and approved by an individual(s) in the same function or
organization that performed the original review and approval unless there is a specific designation that
states otherwise. These approved changes shall be communicated to the appropriate personnel in a timely
manner. Each manufacturer shall maintain records of changes to documents. Change records shall include:
•
•
•
•
•
a description of the change,
identification of the affected documents,
the signature of the approving individual(s),
the approval date, and
when the change becomes effective [820.40(b)].
For the medium to large company, a change control procedure is one of a family of standard operating
procedures (SOP's) used to produce and control documentation or control activities that result in
documentation. The sample engineering change policy/procedure exhibited at the end of this chapter lists a
group of six such procedures. However, this chapter concentrates on only one of these -- the change
control procedure -- because of the specific requirements for change control in the QS regulation. It is a
traditional and current practice for change control procedures to include change control forms. Some
manufacturers also use change request forms for suggested changes.
The written change control procedure should describe the company-approved procedures to be followed
from the time parts of the device master record are first released for production through examination of a
change in relation to other appropriate documents, activities, and implementation. The company procedure
should have an appropriate degree of flexibility integrated into it. That is, all changes do not need the same
degree of evaluation and approval. Consider manufacturers such as repackers/relabelers that may have to
make simple changes such as the size of a container or arrangement of the items in a kit. Also, production
runs for some kits may last only a few hours. Obviously, these manufacturers should develop and use a
change control procedure that allows rapid changes, approvals, and implementation. The QS regulation is a
flexible regulation which allows manufacturers to develop and use procedures that meet their specific
needs.
The important point to consider is that all changes are made according to the approved company policy
and procedure. A trap that is easy to wander into is the situation where a company, knowingly or
unknowingly, allows research and development personnel or other appropriate technical personnel to make
changes to a device that is already in production or make changes to an ongoing process without following
the approved procedure. Such changes generally do not receive the necessary evaluation and review and,
therefore, they may and in many instances have resulted in hazardous or ineffective devices. Making
uncontrolled changes is a violation of several sections of the QS regulation, including sections 820.30,
820.40, 820.70, 820.75, and 820.181. Also companies making uncontrolled changes are not operating in a
state-of-control. It bears repeating: all changes Should be made according to the approved company policy
and procedure.
A change control procedure may be long when a large number of activities are covered. However, a
very small manufacturer may have only a few activities. For very small manufacturers, the following are
some examples of how to word simple procedures for changing and approving the device master record:
• Draw a line through but do not black out the old information.
•
Ink in the new information.
9−2
•
Date and sign at the change or place a mark at the change which refers the user to the date and
signature.
•
Ascertain that the modified documents are placed into use and the old documents are removed from
production.
•
Ascertain that in-process and old finished devices are reprocessed or discarded.
•
Record the effective date for these procedures.
The above procedure obviously depends on the devoted attention and knowledge of the person
responsible for the change. It is obvious that for a large manufacturer or for complex operations, the person
responsible for the change would not or could not “pass the word” to everyone that has a need to know.
Hence, the need for written procedures. Small manufacturers, with short communication lines, usually
need a less extensive procedure than a large manufacturer; however, the use of a change control form, as
described below, by small manufacturers is highly recommended. As the manufacturer grows, all
procedures, particularly the change control procedure, should be analyzed and modified to meet current
needs. Such a review should be part of the quality system audit.
Change control records for documents should cover:
•
•
•
•
•
•
identification of the entity being changed,
a description of the change,
identification of the affected documents,
signature of the approving individual(s),
the approval date, and
when the change becomes effective.
These elements of a typical change control system are explained below. These controls extend to
installation and service when a manufacturer is performing, or contracting these activities.
Identification
The written procedure should cover the identification of the changed device, assembly, component,
labeling, packaging, software, process, procedure, manufacturing material and any other related item or
document. The change control form should have blanks for recording this data and other data discussed
below.
Effective Date
The procedure shall cover the effective date of the change which is usually a completion date, or an
action to be performed when a specific event occurs, such as "implement the change when the new mixer
is installed, validated, and operational." The blank on the change control form for recording the effective
date should not be left empty.
Responsibility
9−3
The change control procedure should state which department or designee is responsible for each
function to be performed. One of these is the issuance, use, and control of blank and completed change
control forms. Another is the extra level of management oversight during the phase-in of a change. (Also
see Document Distribution below.)
Revision Level
The way the revision level is to be incremented and which code should be used need to be covered by
the change procedure for: components including software, assemblies, and devices; and associated
documentation such as labeling, process procedures, and assembly drawings. It is common practice to use
numerical revision levels during pilot production and letters during full scale production.
Validation
Each changed device, accessory, labeling, packaging, and process should be thoroughly verified and/or
validated by the appropriate department. Then the test results and all information related to the change
should be reviewed by the change control board or other designated review group. This procedure is the
same as needed for designing and introducing a new product or process into production and is detailed in
section 820.30, Design Controls. Changes that only modify documents and do not change any design
aspect of a device or process are performed according to 820.40 Document Controls. The change control
procedure should state the details of the evaluation and review process or, as appropriate, refer to the
company control procedures. The change control procedure should define the responsibilities of the
various departments and members of the review board.
Communication
The change procedure should cover the communication of changes to all affected parties such as
production, purchasing, contractors, suppliers, etc. As appropriate, activities that apply to internal
operations are also applicable to suppliers. Examples are employee training, rework, or disposition of
in-process assemblies, use of revised drawings and/or procedures, and disposition of old documents.
Updating Documentation
The change procedure should cover updating of primary and secondary documentation such as
instruction manuals. Usually there are no problems with updating or revising primary documentation -- in
fact, that is a major reason the given change order is being processed. In contrast, it is rather easy to forget
that related secondary documents such as component drawings, instruction manuals or packaging require
revision if affected by a given change. The use of a good change control form can alleviate this problem.
Documentation Distribution
Revised documentation should be distributed to persons responsible for the operations affected by the
change and old documents removed and filed or discarded, as appropriate. After a document has been
approved, these documents shall be available at all locations for which they are designated, used, or
otherwise necessary, and all obsolete documents shall be promptly removed from all points of use or
otherwise prevented from unintended use. This means current documentation shall be accessible to
9−4
company employees [820.40(a)]. Supervisors should be vigilant in overseeing the flow and use of
documentation, especially if a change is being phased in, because both the old and revised documentation
may exist in a given department during the transition period.
Remedial Actions
Certain changes may affect installation or servicing, or require remedial action in the field or rework of
warehouse stock. Changes of this nature should be addressed in the change control procedure. The change
control procedure should outline the documentation and activities required for changes involving
installation, servicing, or field remedial actions or rework of warehouse stock. (Note that field remedial
actions may be classified as recalls depending on the nature of the change. Generally, rework of warehouse
stock which is under a manufacturer's control is not classified as a recall.)
Regulatory Submissions
Modifications to devices or manufacturing processes should be made and covered under the quality
system change control procedure as described herein. Such changes may also require a premarket
notification [807.87(g)] or premarket approval (PMA) supplement (814.20) depending on the classification
of the device. The change order or control form is a convenient document for reminding employees that
regulatory submissions should be considered when making a change.
Business Factors
In order for the change procedure to be complete, it should also cover other factors such as financial
impact, modification of sales literature, update of products in commercial distribution, etc.
QUALITY ASSURANCE REVIEW
Identifying the need for change; making, evaluating, and reviewing the change in the product or
process; and revising and distributing the documentation is about half of the change control process--the
change also needs to be correctly implemented. Quality assurance and other designated personnel should
make certain that the change is fully implemented during routine production, as shown by data and
activities that meet GMP requirements for:
•
review of production records [820.80(d)(2)];
•
acceptance of components, labels, materials, etc. [820.80];
•
assuring that quality assurance checks are appropriate and adequate for their purpose and are
performed correctly [820.30(d)], [820.181(c)] and [820.80(d)(1)];
•
finished device evaluation [820.80(d)];
•
collection of device history record data to demonstrate that the device is manufactured in
accordance with the updated device master record [820.184]; and
•
making certain that only accepted product is distributed, used, or installed [820.80(d) and 820.86].
9−5
The change procedure should cover these activities and specify that they are accomplished before the
first lot of the changed devices is released for distribution. After the change is implemented, resulting
components, in-process items and finished devices should meet the new specifications established in the
revised DMR as shown by the data in the Device History Record. This agreement, of course, is assured by
the change control procedure as well as the remainder of a manufacturer's quality system.
CHANGES UNDER PREMARKET NOTIFICATION
When making changes to devices and associated manufacturing processes for substantially equivalent
devices, manufacturers should consider both Subpart E of Part 807, and Part 820 of Title 21, Code of
Federal Regulations, which address Premarket Notification Procedures and Good Manufacturing Practices
for Medical Devices, respectively. By considering these simultaneously, labor costs can be reduced and
compliance enhanced.
Regulatory Background
Under the Act, the burden is on the manufacturer to determine whether a premarket notification should
be submitted for a change or modification in a device. It is not intended that the owner should submit a
premarket notification for every change in design, material, chemical composition, energy source, or
manufacturing process. Rather it is the manufacturer's responsibility to determine if a proposed change
could significantly affect safety or effectiveness. If this change will affect safety or effectiveness, another
Premarket Notification submission [510(k)] shall be submitted to FDA. (Please see Premarket Notification
510(k): Regulatory Requirements for Medical Devices, FDA 95-4158 and Deciding When to Submit
510(k) for a Change to an Existing Device.)
Changes in manufacturing processes, labels, packaging, device master record, design, etc., of a device
are also subject to GMP requirements in sections 820.30, 820.40, 820..70, 820.75, 820.90, and 820.181.
Compliance of manufacturers with these change-control requirements is checked during comprehensive
inspections by FDA investigators. Manufacturers may consider their degree of compliance with the QS
regulation as one factor, but not the sole factor, when making decisions about premarket notification
submissions for modified devices or processes.
Premarket Notification Decisions
Premarket notification submissions are required for changes that could significantly affect safety or
effectiveness and for new or modified intended uses. Additional submissions are not required for
marketing or convenience changes where safety or effectiveness could not be significantly affected.
Management should decide whether or not a change meets the threshold requirements for submitting a new
premarket notification. While waiting for an FDA review of the submission, a manufacturer may continue
to distribute the unchanged device for its original intended use.
Some manufacturers with highly qualified personnel and substantial experience may feel confident in
performing various technical operations and analyzing results to determine that a particular change in a
device, component, or manufacturing process will not significantly affect safety or effectiveness of the
device. After technical activities are completed and documented, the results should be reviewed by a
design-review panel, change control board, or equivalent group. Reviewing changes should include design
verification/validation, change control procedures, equipment qualification, equipment calibration, process
validation, personnel training, and routine manufacturing procedures. If it is determined that the change(s)
9−6
to a previously FDA cleared device could not significantly affect safety or effectiveness of the device, then
the intent of the regulation has been addressed and there is no need to submit an additional premarket
notification. If this thorough review of proposed changes indicates that a change will significantly affect
safety and effectiveness, either positively or negatively then another premarket notification shall be
submitted.
Quality System Control Always Required
Section 807.87(g) requires that a premarket notification submission "include appropriate supporting
data to show that the manufacturer has considered what consequences and effects the change or
modification or new use might have on the safety and effectiveness of the device." Regardless of whether
a change is submitted under the 510(k) process, the change should be evaluated under the QS regulation
and the associated data filed for an appropriate period of time (820.180) because demonstration of process
effectiveness and use of adequate quality assurance acceptance criteria for finished device release are GMP
requirements. Change control is also necessary to assure that a modified device or process results in a
device that meets company quality claims. Otherwise, the device is adulterated according to Section 501(c)
of the FD&C Act.
The above information applies to changes contemplated for devices and associated processes that are
subject to premarket notification requirements. If proposed device and process changes are for devices
subject to Investigational Device Exemption (IDE) requirements or Premarket Approval (PMA)
requirements, then FDA approval should be obtained, in advance, by submitting a supplemental IDE or
PMA.
9−7
EXHIBITS
An example of a detailed change control procedure and several change control forms are described
below and exhibited.
Engineering Change Policy/Procedure
This example of a change control procedure is typical of those used by many manufacturers of
electromechanical products. It includes all of the elements described in this chapter and may be used as a
guide in developing a change control procedure for medical devices.
Change Control Forms
To aid in the daily use of a change control system, manufacturers often use two forms in conjunction
with the change control procedure. Examples of these forms are printed after the sample change control
policy/procedures. The first form is called a request for engineering action (REA) or a similar title -- it is a
"technical suggestion box." The use of this form encourages all personnel to be involved in product and
process improvement, allows management to assign priorities to various tasks, and tends to prevent lack of
action. The second form is called an engineering change order (ECO), engineering change notice (ECN),
or a similar title. For most manufacturers, the use of ECO paper or computer forms is essential for the
implementation and control of all the many elements in a change control system. A log of changes is
usually maintained for fast reference to old ECO's and for controlling the issuance of sequential numbers
for new ECO's. Also, if used, the completed REA and ECO forms need to be filed as required by the QS
regulation in 820.180.
One of the example forms, Engineering Change Package (ECP), is simply an ECO cover sheet for a
group of ECO's. An example of a filled-in group change is included. It includes the completed ECP cover
sheet and two completed ECO forms. The other three completed ECO forms noted on the example ECP are
not reprinted.
The contents of any forms selected for use by a manufacturer and how to use them should be discussed
with all affected departments. Manufacturers may use, if appropriate, the example forms as exhibited or
modify them to meet their specific needs. In either case, after using an ECO procedure and forms for a few
changes to products, processes, and associated documentation, improvements to the form or procedure will
become obvious if needed to meet the needs of a specific operation of a company.
9−8
--------------------------------------------------------------------------------------------------------------------COMPANY LOGO
No: __________
Rev: ____________
DATE: ___________
Sheet 1 of 8
--------------------------------------------------------------------------------------------------------------------SUBJECT: ENGINEERING CHANGE POLICY/PROCEDURE APPROVED:
____________________________,
President
---------------------------------------------------------------------------------------------------------------------1.0 PURPOSE: The intent of this policy is to assure that our products are, and remain, what we
intended in our product specifications; are safe, efficacious and reliable; meet the needs of the
marketplace; and are cost effective to manufacture and test on a continuing basis.
2.0 SCOPE: This policy establishes the procedures to be followed for engineering changes to devices or
manufacturing processes.
3.0 APPLICABILITY: The responsibilities and procedures established by this policy shall apply to all
released documents. The policy becomes effective immediately upon approval by the President.
4.0 APPLICABLE DOCUMENTS: The latest revision of the following documents form a part of this
policy to the extent specified herein:
No. xxx
No. xxx
No. xxx
No. xxx
No. xxx
No. xxx
Document Control Policy/Procedure
Document Part Number Policy/Procedure
Interchangeability/Compatibility Policy/Procedure
Obsolescence Policy/Procedure
Change Request Policy/Procedure
Design Review Policy/Procedure
(Copies of these procedures and the ECO form discussed below are not included in this Manual. The
REA form is reprinted at the end of this procedure.)
5.0 DEFINITIONS
5.1 Engineering Change Board: Each Engineering Change Board Member will represent a major area
of activity. The Board will be under the direction of a moderator appointed by the President. The Change
Board will meet to review the technical content of all proposed changes to released documentation for
accuracy and impact on safety, efficacy, reliability, product cost, parts and finished goods inventory,
work-in-process, instruction and service manuals, data sheets, test procedures, product specifications,
compatibility with existing products, and other factors listed in ________section of Design Review
Procedure No._____________.
Sheet 2 of 8
9−9
5.2 Change Request: A request for engineering action (REA) may start the change activities. The next
stage is the completion of an engineering change request. An engineering change request (ECR) is a
completed engineering change order form filled out as described in this policy but unsigned by the Change
Board (i.e., is, it is an unsigned ECO form -- there is no ECR form in our company). To merit
consideration by the Board, the change request must be complete. Unless the change is so simple that it
can be readily understood from the Engineering Change "Request" form, the formmustbe accompanied by
a reproducible copy of the last released revision of each sheet of documentation from the device master
record that will be affected by the ECR if it is accepted. The reproducible copy must be marked with all
proposed changes.
5.3 Engineering Change Order (ECO): An ECO is an ECR (that is, the completed ECO form and
associated documents) which has been approved by the Engineering Change Board. An ECOmustpresent a
statement of the problem, a solution, updated documentation, an effective date, and a statement that the
device and proposed changes meet regulatory requirements.
5.4 Regulatory Compliance: The review by the Change Board includes an analysis of the change with
respect to regulatory requirements. For example, the following questions should be answered.
1. Is the change significant enough to require a 510(k) submission?
2. Is there a major change in the intended use? [Requires a 510(k).]
3. Does the change affect our quality system? (A new use such as infusion pumping by an existing
precision metering pump means additional GMP requirements may apply.)
4. Do we need to change the labeling in order not to be misbranded?
5.5 Disposition: This action statement defines the updating or disposition of nonconforming materials,
components, labeling, software, in-process assemblies, and finished devices at all applicable locations
such as suppliers, stockroom, production lines, final test area, finished goods storage, and in field service.
5.6 Effective Date: The effective date will be expressed in terms of shipment date. That is, every change
shall be applicable to all units shipped after a specific date. If shipment does not occur by the date
specified, an amendment must be issued. The amendment will be presented to the Change Board and upon
approval, the ECO cover sheet will be reissued. Quality Assurance has responsibility for verifying that the
effective date is met as specified and for maintaining records showing the actual effective date of each
change. If a change is not effective by the date specified, Quality Assurance shall be responsible for
requesting an amendment to change the effective date.
5.7 Cost: At the Change Board meeting, each department shall be prepared to give the cost impact on its
area for implementing each change order. Finance shall assure that all financial implications are
considered because the cost analysis must include engineering time, manufacturing time and material, and
field service material and labor. The following cost data is to be available at the meeting.
9 − 10
Sheet 3 of 8
1. Amount of increase or decrease in per unit unburdened material and labor cost. This cost change is
not to include extraordinary costs of rework and scrap which are incurred only when the change is
first phased in.
2. Total unburdened cost of material to be scrapped in each location indicated on the ECO form.
3. Total unburdened rework cost for all items requiring rework.
4. Total unburdened engineering manpower and material required to design, test and document the
change.
5. Where rework or replacement of units in the field is involved, Field Service must indicate the
proportion of costs to be charged to warranty expense.
5.8 Amendment: An amendment may be issued only to change the effective date or correct drafting
errors in implementing the change order. Any Board Member may request that an amendment be issued.
5.9 Board Member: An Engineering Change Board Member shall be a person appointed by the area
manager to represent a particular functional area. A Board Member may represent more than one
functional area. For changes to a process, or design of a device, labeling, or packaging, board members
must at least include a design review to meet the following GMP requirements:
• Each manufacturer shall establish and maintain procedures to ensure that formal documented reviews
of the design results are planned and conducted at appropriate stages of the device’s design
development.
• The procedures shall ensure that participants at each design review include representatives of all
functions concerned with the design stage being reviewed, as well as any specialists needed.
• The results of a design review, including identification of the design, the date, and the individual(s)
performing the review, shall be documented in the design history file [820.30(e)].
5.10 Alternate: Each functional area shall also designate an Alternate who shall be available to attend
Change Board meetings in the event that the Board Member is not available. Each functional area is to
notify the Change Board Moderator of the names of its Board Member and Alternate.
6.0 RESPONSIBILITIES
6.1 Engineering Change Board Moderator: The Engineering Change Board will meet at the discretion
of the Moderator. The Engineering Change Board Moderator is responsible for the conduct of the Change
Board meetings. This person is appointed by the President for an indefinite term. At least one full working
day before each meeting of the Change Board, the Board Moderator shall distribute to all Board Members
a copy of all ECR's to be discussed at the next meeting of the Board.
Sheet 4 of 8
6.2 Engineering Change Board Members: Engineering Change Board Members shall be responsible
9 − 11
for the functional areas they represent in all matters relating to engineering changes and shall be
empowered to act on behalf of their areas in Board actions. The Board Members or Alternates shall come
to each
meeting thoroughly prepared to discuss each Engineering Change Request (ECR) to be discussed. Specific
Board Member responsibilities are listed below.
Product Management - Product Management shall determine the effect of changes on marketability,
field information, catalogs, price lists, data sheets, and gross profit margin. Product Management must
verify the suitability of each design (not documentation only) change in the international as well as the
domestic marketplace.
Field Service - Field Service has responsibility for determining the: time required to implement the
change in the field; availability of components and assemblies for retrofit; impact of the change on service
manuals; and adjustments to service stock. Field Service will make the changes in the areas under their
jurisdiction and pass other defined tasks to appropriate departments.
Quality Assurance - Based on verification data, analysis and design reviews, Quality Assurance and
manufacturing engineering shall be aware of the effect of all changes on test requirements and on overall
quality of our products and assure that product specifications are met. Quality Assurance shall assure that
there is compliance with customer, corporate and regulatory agency requirements.
Manufacturing - Manufacturing shall determine component and raw material availability, break-in
point, effect on material-on-order, material-in-process and material-in-stock. Manufacturing engineering
shall assure that manufacturing and test procedures are adequate. Manufacturing shall determine total cost
to the Manufacturing Department of implementing each change.
Engineering - Engineering is responsible for making certain that the change is technically feasible and
complies with appropriate company and customer specifications and with accepted standards. Every major
change must be fully analyzed and tested (verified) and the results documented by Engineering before it
becomes a change order. Any Change Board Member may request that Engineering furnish evidence of
technical viability of a change. If the Board so decides, a change may be tried in Manufacturing on a
limited pilot production basis before final approval and implementation in full-scale production. None of
the trial units may be shipped until the change has been verified; validated, if appropriate; subject to design
review; and received final approval. If, as the result of such trial production, the change is altered or
modified before final approval, all of the trial units must be changed to the final form before shipment.
Engineering shall supply QA and Manufacturing Engineering with copies of verification protocols, if
any, to be used to update production test methods. The updated production documents are part of the
change.
Finance - Finance shall make certain that all financial aspects have been considered.
6.3 Engineering Documentation Section (Engineering Services): Engineering Documentation Section
shall have overall responsibility for coordinating, scheduling, and executing documentation changes.
Sheet 5 of 8
7.0 PROCEDURE: The procedure followed for a given change depends upon whether the change is
only to documentation or is a change that affects design, the manufacturing processes or just
9 − 12
documentation.
7.1 Procedure for Design and Process Changes
1. A request for engineering action (REA) is completed and forwarded to the Manager of
Engineering Services. (The REA form is reprinted at the end of this procedure.)
2. A number is assigned and appropriate audit controls are established. Engineering Services then
sends a copy of the REA to the cognizant device or process design section for recommended
solutions, evaluation of impact on specifications, and a recommended effective date. As
appropriate, the changes must be supported by device verification data and/or process evaluation
data or validation data. The REA is then forwarded to the Engineering Documentation Section.
3. Upon evaluation for adequacy of data, where-used considerations for the items being changed are
made. Engineering Services makes certain that the latest revision of all affected documentation is
included. If not already done, an "ECR" (unsigned ECO) form is completed at this stage.
4. Sepias (or separate computer versions in a computerized system) are made of all affected
documents. The ECR number and proposed changes are marked on the sepias. These sepias are
included as part of the ECR. The only exception from this procedure is where the change is
basically self-explanatory, i.e., where all necessary information can be discerned from the section
on the ECR form indicating "change from" and "change to."
5. The Engineering Documentation Section will then duplicate and distribute copies of the ECR to
each Change Board Member. Upon receipt of the ECR, each Member shall review the proposed
change and determine the impact on their area.
6. The Change Board Moderator then calls a Change Board Meeting.
7. All aspects of the change request are reviewed at the meeting including the following: Is the ECR
presented so that anyone may understand the problem and the solution? Does the verification data
show that the device meets the device product specification? Does the device continue to meet
the intended use and the needs of the user/patient? Has all documentation including manuals and
data sheets been updated?
The Board will then establish a reasonable effective date. Finance will make certain that all costs of this
change have been considered. After agreeing upon an effective date, each Board Member signs the change
request. Each signature implies concurrence with the method of solution, effective date, and costs. If the
Board Members are unable to reach a unanimous decision, the issue is submitted to the President for
resolution.
9 − 13
Sheet 6 of 8
After all Board Members in attendance have signed, the ECR becomes an engineering change order
(ECO). Copies of the cover sheet may be issued by Technical Services upon request of the Board
Members if the effective date is very near and the Change Board has not modified the ECR before
approval. This action permits Manufacturing to use the previously distributed marked-up sepias or
"from-to" information on the ECR as operating documentation until copies of the updated original
documents are available for distribution.
It is the responsibility of Manufacturing to indicate the earliest permissible effective date in all areas,
i.e., supplier, stockroom, raw material, and work-in-process. It is the responsibility of Field Service to
indicate an effective date for any field activities.
8. The change order is then sent back to Technical Services where copies are made for the Board
Members, who requested them. Upon completion of this task, the master documentation is
withdrawn from the print file, updated to the new revision, and copies are distributed and obsolete
documents are collected. During the updating process, a copy of the marked-up sepia (if any)
replaces the master in the print file.
9. After all documents are updated, the change order is filed permanently in the design history file for
the device. The verification protocol and data and design review documents and minutes are also
placed in the design history file.
7.2 Procedure for Minor Changes and Changes in Documentation Only.
This procedure is the same as that for design changes except that the second and third steps read as
follows:
2. A number is assigned and appropriate audit controls are established. Upon evaluation for adequacy
of data, where-used considerations are made. Technical Services assures that all affected
documentation is included and that it is the latest revision.
3. Technical Services then sends a copy of the ECR to the Design Section for evaluation of the effect
of the changes on the device and for recommendations on the effective date to be suggested to the
Change Board. The ECR is then returned to Technical Services.
8.0 ENGINEERING CHANGE ORDER FORM (ECO): A definition of the various items on the form
and instructions on completing each item follows.
1. Status: At the top of the form are the words "Engineering Change" followed by two words,
REQUEST and ORDER. When the mark appears in the request area or the form is not signed by the
Board Moderator, it shall be considered a request or preliminary copy -- not an action copy. The
change order is an action copy which must bear the signature of all Board Members or their
Alternates. (The Moderator is empowered to sign for any function not represented at a meeting.)
2. Amendments: Amendments shall be designated by an alpha suffix, e.g., A, B, C, etc.
Sheet 7 of 8
9 − 14
3. Originator: The individual who initiated the REA that resulted in the ECR or ECO.
4. Interchangeability/Compatibility: This area is made up of two blocks. First block is "Yes",
second block is "No". Interchangeability/Compatibility is expected to be checked off as "Yes" when
it affects form, fit, or function of any numbered part. (The design, design verification and design
review must always consider interchangeability and compatibility.)
5.
Change Complete Block: The drafting supervisor shall sign this block when the documentation is
updated.
6.
Prerequisite: Is there another ECO or new Product Release Notice which must be effective
before this change can be implemented? If so, what are the numbers?
7.
Reference: In this block will be listed any references such as REA's, etc.
8.
Device Affected: This block is used to indicate which device(s) or device line is affected by this
particular change notice.
9.
Description of the Problem: The description must be presented so it can be fully understood by
the technical personnel involved.
10. Solution: The solution is what has to be done to correct the problem. It must be explained in terms
that can be fully understood by our technical staff
11. Item Number: A sequential number beginning with 1.
12. Size: The size of the sheets of the drawing or procedure.
13. Revision: From what revision level the document is leaving and to what revision level it will go.
14. Description: This section must contain a general description of the drawing, not necessarily its
title.
15. Where Used: To which device(s) or processes do the changes apply? This information is
especially important if a component is used on several devices.
16. Disposition:
1. Engineering Cost: List engineering cost of design and documentation change.
2. Supplier: What needs to be done to update in-process assemblies at a supplier, i.e., rework, use
as is, or scrap?
9 − 15
Sheet 8 of 8
3. Stock Room: What should be done with non-conforming purchased components in our stock
room? By what date should the above action be complete?
4. Work-in-Process: What do we wish to do with the material on the floor?
5. Finished Goods: What do we do with the material in finished goods?
6. Field Service: What should be done to devices in the field?
7. Cost: Each department is responsible for reporting the cost of the change with respect to its
area.
17. Effective Date: Each change shall be applicable to all units shipped after a particular date where
the date is relatively unimportant because the change is a minor documentation change. In all other
changes, an effective date must be assigned by the Board. If it is important to a particular
functional area that a change be implemented by a date or not sooner than a date, it is the
responsibility of the appropriate Board Member to assure that an acceptable effective date is
designated.
The change notice is broken into Parts 1 and 2. Part 1 shows how to update the documentation. Part 2 is
the special rework instructions required by Manufacturing or Field Service Operations on how to update a
component or assembly that does not conform to the new revision.
(Note: The specific ECO form for this procedure is not included in this manual. However, several ECO
forms follow. One of the example forms, Engineering Change Package (ECP), is simply an ECO cover
sheet for a group of ECO's. An example of a filled-in group change is included. It includes the completed
ECP cover sheet and two completed ECO forms. The other three completed ECO forms noted on the
example ECP are not reprinted.)
9 − 16
REQUEST FOR ENGINEERING ACTION
Originator
Dept
REA No.
Date
Component, subassembly, or device:
Drawing(s)
Problem (in detail)
Solution recommended, if known
Date action required by
Comments
Dept Manager approval
Date
Assigned to
Date forwarded for solution
SOLUTION
Charge No.
Priority
App. By
ECO Number
Date
Not
Sheets attached? YES
es on back? YES
PROCEDURE
1. Originator: Complete top of this form except for REA number.
2. Obtain your Department Manager's approval.
3. Forward original to Technical Services Manager who will assign the REA number.
Note: One copy will be returned to originator with REA number assigned.
If problem involves safety, effectiveness, or reliability, Technical Services will forward to the QA Manager
a copy with the REA number assigned.
4. Technical Services takes appropriate action and also executes an ECO.
5. Technical Services returns a copy to Originator after resolution of problem.
Form No.
Rev.
App. By
Date
9 − 17
COMPANY LOGO
Engineering Change
Order (ECO)
Signatures
Date
Date
Originator
Approvals
Type A
ECO #
Reason for Change
[ ] Improve process
[ ] Biocompatibility
[ ] Design improvement
Project
Engr.
Type B
[ ] Correct error
[ ] Cost reduction
[ ] Customer request
TYPE
[ ] Labeling or packaging
Type C
A[ ] B[
] C[ ]
[ ] Regulatory
DESCRIPTION OF CHANGE
Change action
required
Purchasin
g
and
Production
codes
Action
Code
Drawings
Affected
REVISED
From To
Change action required
codes
Rework
compon
ents in
stock
1
Rework
part inprocess
2
9
Scrap
inprocess
items
3
10
Make
new
4
Service
and
Repair
Other
For reference only
Labeling Change Parts in
Field
9 − 18
8
11
parts
Action
Rework
finished
goods
5
Packaging Notify User of
Part
12
Notify
supplier
6
Employee training
13
See old
parts
for
spares
7
510(k) required for
Change
14
9 − 19
10
PURCHASING AND ACCEPTANCE ACTIVITIES
INTRODUCTION ................................................................................................................. 10-2
Components ....................................................................................................................... 10-2
Accessory Devices .............................................................................................................. 10-3
Contractors and Consultants ........................................................................................... 10-3
COMPONENT SELECTION AND VERIFICATION ...................................................... 10-3
PURCHASING AND RECEIVING OF PRODUCT ......................................................... 10-4
Specifications ..................................................................................................................... 10-4
Supplier Qualifications ..................................................................................................... 10-5
Acceptance Procedures ..................................................................................................... 10-5
Acceptance Criteria .......................................................................................................... 10-6
Testing and Inspection of Product .................................................................................. 10-6
Acceptance and Rejection Records ................................................................................. 10-7
Obsolete, Deteriorated, and Rejected Components ....................................................... 10-8
Component Storage .......................................................................................................... 10-8
Component Traceability ................................................................................................... 10-9
Written Test Procedures ................................................................................................ 10-10
Sampling Plans ................................................................................................................ 10-10
Control Numbers ............................................................................................................ 10-11
CONTRACTOR AND CONSULTANT ASSESSMENTS .............................................. 10-11
Interface Requirements .................................................................................................. 10-12
Process Validation Requirements .................................................................................. 10-12
Device Servicing Requirements ..................................................................................... 10-12
CONTRACT STERILIZATION ........................................................................................ 10-13
Labeling Requirements .................................................................................................. 10-13
Quality System Requirements for Contract Sterilization ........................................... 10-14
Information Transfer ..................................................................................................... 10-14
Record Keeping ............................................................................................................... 10-15
Process Validation ........................................................................................................... 10-15
Bioindicators and Dosimeters ........................................................................................ 10-15
Loading Configuration ................................................................................................... 10-15
Preconditioning ............................................................................................................... 10-15
Cycle Parameters and Process Control ........................................................................ 10-15
Post-sterilization Handling and Aeration ..................................................................... 10-16
History Records and Review .......................................................................................... 10-16
Finished Device Release .................................................................................................. 10-16
Audits of Both Facilities ................................................................................................. 10-16
Training ........................................................................................................................... 10-17
Nonconformance ............................................................................................................. 10-17
FINISHED DEVICE EVALUATION ............................................................................... 10-17
Sampling Plans ................................................................................................................ 10-17
Labeling and Packaging Inspection .............................................................................. 10-19
Records ............................................................................................................................. 10-19
Product Release ............................................................................................................... 10-20
10 − 1
EXHIBITS ............................................................................................................................. 10-21
Purchase of Components................................................................................................. 10-21
Acceptance of Components ............................................................................................ 10-21
Material Receiving and Inspection Procedure ............................................................. 10-21
Identification Decals and Forms .................................................................................... 10-21
Receiving Rejection Notice ............................................................................................. 10-22
INTRODUCTION
This chapter covers component specifications, supplier assessment, receiving components and the
services rendered in manufacturing medical devices. Manufacturers of medical devices should
maintain a consistent, systematic quality system which, along with other quality assurance activities,
should assure that all components, materials, and services involved with the manufacture of medical
devices are acceptable for their intended use. This control is a combination of: component and
supplier selection and verification; data collection, analysis and corrective action; supplier,
contractor, and consultant assessment; identification and status of product including labeling and/or
quarantine; and operational procedures.
The establishment and maintenance of requirements, including quality requirements, is essential
for the manufacturer when dealing with component suppliers, consultants, and contractors
[820.50(a)]. The ability to meet specified requirements is important when evaluating the suppliers
and service providers. Assessments of these providers shall be maintained and documented. Possible
appropriate methods of accomplishing these goals include audits, checking with other clients, and
previous performance data. If prior assessment is not possible, then the manufacturer should assess
the service as it is being performed. Assessment shall be documented. Procedures for accepting
incoming product shall also be established and maintained. Various acceptance activities may
include inspections, tests, and other forms of verification. Acceptance or rejection of components
and services shall be documented (820.80).
Components
"Component" is defined in 820.3(c) of the Quality System (QS) regulation as any material,
substance, piece, part, software, firmware, labeling, or assembly, which is intended to be included in
the finished, packaged, and labeled device. For example, fasteners, blood tubing assemblies and
labels are components. This definition excludes "manufacturing materials," which by definition, are
not intended to be included as part of the finished, packaged, and labeled device.
According to 820.3(p), "manufacturing material" is any material or substance used in or used to
facilitate the manufacturing process, a concomitant constituent, or a byproduct constituent
produced during the manufacturing process, which is present in or on the finished device as a
residue or impurity not by design or intent of the manufacturer. Examples of manufacturing
materials include: cleaning agents, mold-release agents, lubricating oil, or other substance used to
facilitate a manufacturing process which is not intended by the manufacturer to be included in the
finished device.
Manufacturers of components sold only for further manufacturing of a medical device are not
required to comply with the GMP requirements for finished devices. Many components of devices,
such as transistors, containers, hardware, etc., are readily available in the marketplace and are not
10 − 2
manufactured exclusively for use in devices. Many of these manufacturers supply only a small
fraction of their production to finished device manufacturers. However, section 820.1 of the Quality
System regulation encourages component manufacturers to use applicable GMP elements as
guidance.
If a component is manufactured in the same or proximal facility, and produced for use in finished
medical devices, then the component is considered part of the production of the finished devices and
is subject to the applicable requirements of the GMP requirements. If the component is
manufactured in a separate plant owned by the finished device manufacturer, then the
manufacturer has flexibility in handling the quality assurance activities related to the control of
components. One satisfactory approach is to have the plant that builds the components operate in
full GMP compliance. Under this arrangement, the plant which does the final device assembly would
still be responsible for ascertaining that the quality and integrity of incoming components have not
been damaged during shipment. Alternately, the component manufacturing plant may not fully
comply with Quality System regulation. Then the plant that does final assembly should handle the
acceptance of these components with the same degree of control as if the components were
purchased from an outside supplier.
For components such as labels, package inserts, packaging, etc., there is additional information in
chapter 11, Labeling; and chapter 13, Packaging.
Accessory Devices
The Quality System regulation applies to manufacturers who produce finished accessories to
devices intended to be used for health-related purposes. An accessory is any finished unit
distributed separately but intended to be attached to or used in conjunction with another finished
device. Therefore, any manufacturer of accessory devices should meet all FDA regulations for a
finished device. These regulations include 21 CFR Part 807 Subpart E, Premarket Notification; 21
CFR Part 807 Subparts B, C., and D, Registration and Listing; 21 CFR Part 820, Good
Manufacturing Practices (GMP); 21 CFR Part 801, General Device Labeling; 21 CFR Part 809, In
Vitro Diagnostic Labeling (if applicable); etc.
Contractors and Consultants
Contractors and consultants generally provide a service rather than a physical component. This
service should be treated in basically the same manner as physical components because these
services affect the quality of the finished device. The combination of both services and physical
components determines the quality of the finished device. Services should be obtained per 820.50,
Purchasing Controls, and be controlled upon receipt using the applicable requirements in 820.30,
Design Controls, 820.70, Production and Process Controls; 820.80, Receiving, In-Process, and
Finished Device Acceptance, etc., depending on the nature of the service.
COMPONENT SELECTION AND VERIFICATION
Verification of physical components is a very important step toward producing a high quality
product. Verification of components consists of determining through documented testing that a
component will perform its function reliably in the intended application and under the most adverse
environmental conditions in which the device is expected to be used. These conditions shall consider
10 − 3
the needs of the user and patient [820.30(c)] and shall encompass the manufacturer's labeling claims
for the device.
Components have to be carefully selected, using the requirements of the device as a guide.
Components should be chosen so that they will not be over-stressed and will be compatible with the
internal device environment, as well as the external environment that the device is expected to
encounter during manufacture, distribution, and use. The components should then be appropriately
tested, alone, and as part of the device, utilizing the specifications established for the component and
the device. New components or components used in an unusual application will usually need
extensive evaluation. This evaluation should include parameter and life testing as well as
compatibility testing for both the internal and external environment. Well known industry standard
components that are used in their normal application and that are not over-stressed will need only
minor testing, which is usually an integral part of the verification of the device design. A record of
any component verification testing should be maintained. This record should include the component
identity and the testing methods that were used, as well as the actual test data and results.
PURCHASING AND RECEIVING OF PRODUCT
Component quality is maintained through correct specifications, procurement, incoming
acceptance, storage, handling, installation, and change control. To monitor the adequacy of these
activities and procedures, feedback from the quality system is needed. Corrections are made if
necessary. In addition to maintaining quality, the manufacturer shall also establish and maintain
procedures for identifying product during all manufacturing stages from receipt through
installation (820.60 and 820.86). Product includes components, manufacturing materials, in-process
devices, finished devices, and returned devices.
Specifications
Component specifications are required as part of the device master record. Components are
selected and their specifications are documented during the design of the device. The specifications
should be well designed, achievable, and acceptable to suppliers. They should adequately describe
the quality characteristics, dimensions, design, materials, performance, and any other features
necessary to assure receipt of the item desired. For unusual, vital, new or key components the
specification data is derived primarily from the verification data with minor details from the catalog
data. For routine components, such as those that have been used for a long time or have a known
performance history, a catalog designation may be adequate to describe a component and assure its
purchase. For some components such as transistors, the catalog number also may be used to obtain
complete specifications from a reference manual. Specifications should reflect both design
requirements and quality/reliability needs. The quality level for each component should be specified.
Components usually are available in several quality levels such as reagent grade, commercial grade,
military grade, etc. In some cases, a significant increase in component quality can be obtained for a
modest increase in cost by specifying a higher grade, thus reducing the probability of future quality
problems and the possibility of significant associated costs.
Supplier Qualifications
10 − 4
A major factor in obtaining high quality components is the selection of suppliers. Although a
manufacturer's knowledge of supplier operations may be limited and information about the
operations difficult to obtain, the GMP requirement that a manufacturer is responsible for quality
remains undiminished. To the maximum extent feasible, selection and qualification of suppliers by
audits, performance analysis, etc., should be part of a quality system. If the manufacturer does not
have the capability to test components for conformance to specifications, then supplier test data or
outside lab results are acceptable provided that components are tested and inspected in a statistically
valid manner to show their acceptability for use in the finished device. Any outside test results
should be accompanied by relevant raw data used for the test so that judgments of authenticity may
be made by the finished device manufacturer. Excluding a supplier whose components are
unreliable from supplying components may help prevent problems with the final device and is
certainly worthwhile as a cost reduction effort.
It is important to remember that raw components acquire cumulative value as they are processed
through receiving, assembly, test, inspection, and as they ultimately become part of the finished
device. If a component fails during assembly, or as part of the device, additional costs will be
incurred for fault isolation, removal, replacement, inspection, testing, etc. When field failures occur,
the ultimate cost of the component becomes even higher because its replacement requires travel,
trouble-shooting, and retrofit. In addition, customer dissatisfaction, user injury, product liability
action, medical device reporting, or regulatory action may result. Usually, the initial cost of a
component is relatively insignificant compared to the later cost should the component prove to be
defective or improper for the selected use. Many recalls occur because manufacturers fail to qualify
components properly or to assure that a supplier's manufacturing methods and quality system are
adequate.
Acceptance Procedures
Written instructions are necessary to assure that components, manufacturing materials, etc. are
properly identified, processed, and stored when received. Written inspection and test procedures are
necessary to prescribe the:
•
•
•
•
•
acceptance activities performed;
dates acceptance activities are performed;
the results;
signature of the individual(s) conducting acceptance activities; and
where appropriate, the equipment used.
Before acceptance, all components should be either physically separated (quarantined) or clearly
identified as not yet accepted. The decision to separate or tag not-yet-accepted product should be
made based on the characteristics of the device, the potential for mixups, plant conditions, and
manufacturing practices.
Although 820.80 requires a written procedure for accepting components, the Quality System
regulation in 820.5 allows discretion in the quality system. Thus a very small manufacturer, usually
10 or fewer employees, may only need very brief written acceptance procedures referencing the
purchase orders and receiving tickets. As the size of the operation, the numbers of activities, and
number of people involved increase, the need for comprehensive written instructions generally
increases.
10 − 5
Acceptance Criteria
Manufacturers should have specific acceptance criteria for components. Acceptance criteria are
the attributes of a component that determine its acceptability, such as appearance, dimension,
purity, performance characteristics, etc. Typically, acceptance criteria are made a part of the
inspection/test procedure. For example, if component specifications or a drawing adequately
describe the attributes needed in order for the component to perform in its intended manner, these
may be used as the acceptance criteria. If components or the suppliers of the components have a
history of good performance, the components may be accepted for use after a visual check to assure
they are the items intended and that they are not damaged or contaminated. Components, which
need only a visual inspection, may be accepted using the purchase order data as acceptance criteria.
The purchase order and/or receiving ticket should at a minimum contain the following information:
•
•
•
name of supplier;
description of the component or other product; and
quantity shipped.
For a standard component, the catalog number may be used as a description. QA personnel
should determine whether the use of any "abbreviated" criteria are adequate during their audit of
production rework, history records, complaint files, and service records.
Testing and Inspection of Product
The minimum acceptance activity per current practice requires that all incoming components
and other product receive at least a visual inspection for contamination and/or damage and be
identified as the component specified on the purchase order. A manufacturer accepting the product
has the discretion to determine when and where product should be inspected, sampled, and tested
for conformance to specifications depending upon the risk that failure of that component may pose.
As appropriate, product may be tested and/or inspected by:
•
•
•
•
the supplier;
when received;
during manufacture of the device; or
as part of the finished device.
If components are tested as part of the finished device, the testing should be able to reveal failed
and "out-of-spec" components and not just that the finished device does not meet specifications.
This determination, of course, may be performed after removing the component from the device.
The rejection shall be documented [820.80(b)].
Manufacturers who decide not to sample or test specific components should be able to justify that
decision based on such factors as knowledge of the supplier's previous performance in providing
high quality components, the component performance history, and application of the components in
the device. Manufacturers may rely on component suppliers to conduct testing if the manufacturer
specifies or is knowledgeable about the supplier's quality system, particularly the inspection and test
programs and the supplier has specifications that properly define the manufacturer's acceptable
limits for the component or material parameters. These specifications may be used to meet the
10 − 6
device master record requirements for component specifications, if these accurately reflect the
parameters, composition, and configuration required for the component to perform the function for
which it was selected. Supplier specifications are usually adequate for standard components.
However, a manufacturer who relies on supplier specifications usually has no control over changes
in these and, therefore, should assure at an appropriate point in the manufacturing process that the
components received meet the desired specifications.
If components are tested by the supplier, acceptance of components can be based on certification
and review of test data submitted by the supplier for the specific components provided. Certification
should accompany each lot of components. When certification is used, the manufacturer should
periodically verify the validity of the certification through an assessment of the supplier.
Where historical data shows that certain components or other product have been substandard
and resulted in a device failing to meet specifications, or where performance history has not been
established, specific steps should be taken to assure components meet specifications. Typically, this
task is accomplished by sampling and testing each lot of components to assure that the components
meet specifications. Where appropriate, all significant or high risk components should be sampled
and tested.
Manufacturers may test entire assemblies of components rather than individual components. If,
however, testing an assembly cannot assure fitness-for-use of the components, then components
should be tested on an individual or lot basis, whichever is appropriate. For example, assemblies
with an internal feedback circuit could have a very marginal component. Because of the circuit
design, the condition of the marginal component might not be detected by testing the entire
assembly. Therefore, the feedback loop in the assembly should be opened during one of the tests, or
the individual components should be tested.
When using a contract laboratory to test production components, the laboratory becomes an
extension of the device manufacturer's quality system. The device manufacturer is responsible for
assuring that the contractor's test and inspection procedures are acceptable. This assurance maybe
obtained by audits of the laboratory, by the lab staff, and by the finished device manufacturer.
Inspection and testing will not improve the quality of components or other product; however, if
the inspection and testing is appropriate and performed adequately, these activities can be used to
prevent or significantly reduce the use of low-quality or defective product. Through feedback into
the overall quality system, data on products will help identify basic causes of problems and lead to
solutions (820.100). If problems are found, actions such as design changes, tighter acceptance
criteria, supplier assessments, or change of suppliers may be appropriate.
Acceptance and Rejection Records
Adequate records shall be maintained to provide objective evidence that components were
inspected and accepted, or rejected. These records are a part of the device history record and should
be maintained in a format that facilitates review. The records, however, are not required to be
maintained in a single file with other production history records, and are typically filed in the
receiving or quality control area according to part number or component nomenclature. Small
manufacturers may use purchase orders or packing slips to record acceptance and rejection if they
contain adequate information.
10 − 7
The Quality System regulation specifies in 820.80(b) that a record of component acceptance and
rejection be maintained. Typically, acceptance/rejection records should contain:
•
•
•
•
•
acceptance or rejection documentation;
number and type of deficiencies;
quantity approved;
quantity rejected; and
nature of corrective action taken.
Obsolete, Deteriorated, and Rejected Components
Obsolete, deteriorated and rejected components shall be identified (820.60, 820.86, and 820.150)
as such and be placed in a separate quarantine area or specially identified area to prevent mixups. If
practical, components should be individually identified as rejects. Where it is not feasible to tag each
rejected component, as in the case of transistors, bolts, bottles, etc., containers or packages of
rejected lots should be clearly marked and otherwise appropriately segregated from accepted
components. See 820.86 for clarification. Manufacturers should determine the need for a separate
written procedure for handling these components based on the size of the manufacturer and
complexity of their devices and operations. Disposition of nonconforming product shall be
documented [820.90(b)].
Records for rejected components should state whether the components were returned, scraped,
reworked, etc. In very small manufacturers, disposition can be recorded directly onto the purchase
order, receiving ticket, or other associated document. Small-to-medium sized manufacturers
generally record disposition on the form used to receive components. Most large manufacturers
record disposition of rejected components on standard forms such as a Nonconforming Material
Report (NMR).
When components, materials, etc., become obsolete, many manufacturers assign new
identification numbers to the new version of these components etc. The obsolete items are retained
for other uses, such as repair parts, engineering projects, etc. In these cases, the old and new items
should be adequately segregated and/or identified to prevent inadvertent use of obsolete components
in production.
Component Storage
Each manufacturer shall establish and maintain procedures for control of storage areas and stock
rooms for product to prevent mixups, damage, deterioration, contamination, or other adverse effects
pending use or distribution and to ensure that no obsolete, rejected, or deteriorated product is used
or distributed. When the quality of product deteriorates over time, it shall be stored in a manner to
facilitate proper stock rotation, its condition shall be assessed as appropriate. 820.150 procedures
shall be established and maintained that describe methods for authorizing receipt from, and
dispatch to, storage areas and stock rooms.
Although not a direct requirement, all raw materials and components used in the finished device
should be received through a central control point. Centralized receiving leads to orderly storage,
limits access to stored material, and aids a manufacturer in meeting other GMP requirements.
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Components and other product should be identified or stored so that it is obvious at all times that
product has been accepted, rejected, or is awaiting a disposition decision. A quarantine area can be
either a physically secure area or simply limited access area identified as a quarantine area. If
special environmental storage conditions are required such as for many biologically derived
components, these conditions should be controlled and monitored and the associated specifications
included in the device master record.
When the device is to be sterilized, storage conditions should be selected, as appropriate, to
prevent contamination of components and packaging by bacteria or filth. Also, temperatures should
be controlled as necessary to prevent or reduce the growth of bacteria. The higher bioburden
(bacteria, etc.) levels may challenge the sterilization cycle to an extent greater than the capability
established during process validation and, thereby, result in a sterility assurance level that may not
meet the finished device specification. Some components, particularly those used in the manufacture
of in vitro diagnostic devices, if not stored properly, may support growth of bacteria.
Component Traceability
The criteria as stated in 820.65 for determining the need to have traceability via a unit, lot, or
batch control number of a device specifies devices intended for surgical implant into the body or
those that support or sustain life and whose failure to perform, when properly used in accordance
with instructions for use provided in the labeling, can be reasonably expected to result in a
significant injury to the user. Identification of traceable devices should be based on the health
hazard presented if a device fails to meet its performance specifications when operated as intended.
Because of the design control requirements (820.30), user error and the environment are not
considered by FDA as a means for excusing the lack of device performance. User error is not a
performance failure, although it could be considered a result of inadequate directions for use, other
inadequate labeling, or poor human factors design. The environment could result in failure of a
device but it should not effect the result of the device failure.
FDA is concerned about the failure of components that would result in sudden or catastrophic
device failure, which can reasonably be expected to result in significant injury to the user, such as:
•
•
•
•
no output from an implantable cardiac pacemaker;
fracture of an implanted orthopedic implant;
runaway in an implanted cardiac pacemaker;
misfiring of a synchronized defibrillator; etc.
A manufacturer should know in detail how the device functions and the purpose of each
component in the finished device. If as a result of a failure, the performance, lack of performance, or
effect on safety or effectiveness of the finished device could result in significant injury to the user
when the device is properly used in accordance with instructions in the labeling, the component
under consideration may require increased control and traceability. The effect that each component
will have on finished device performance, should the component fail to perform as intended, should
be determined. Thus, manufacturers should carefully study the possible failure modes of their
devices and decide which components are truly critical under the various modes. This determination
may be time-consuming with respect to some devices, but it is necessary. It will, in the long run, save
manufacturers liability, repair, and replacement costs. To make such a determination,
10 − 9
manufacturers should conduct reliability tests and failure effects analyses during the design phase in
order to accurately identify critical components.
The number of components that need to be considered as potentially needing to be handled as
traceable components can be reduced by considering the reliability of components and whether they
"reasonably" can be expected to fail. For example, power cords, clamps, plugs, etc. seldom fail.
Therefore, manufacturers may not need to consider extensive tracing requirement of these
components. Also, manufacturers can consider a subassembly as a component and, thereby, reduce
the number of identification and record keeping activities, but all rationale and justification should
be documented.
Written Test Procedures
A device manufacturer shall establish and maintain procedures to ensure that all purchased and
otherwise received product conforms to specified requirements (820.50) and establish and maintain
procedures for acceptance activities [820.80(a)]. The manufacturer shall assure that all lots of
components or other products are accepted, sampled, tested and/or inspected using written
procedures. The inspection/test procedure for each component shall be correct [820.30(d), Design
Output and 820.30(h) Design Transfer], dated, and approved. The design verification procedures
usually may be used to develop production test procedures. The procedure should specify, as
appropriate,:
•
•
•
•
•
•
•
items to which it applies,
product characteristics to be inspected/tested,
acceptance/rejection criteria,
test method(s),
data forms,
sampling plans, and
necessary test inspection equipment and tools.
Sampling Plans
When assuring that components and other products meet acceptance criteria, manufacturers may
test either all components or may test a portion of the components using a sampling plan based upon
an acceptable statistical rationale (820.250). A manufacturer shall be prepared to demonstrate the
statistical rationale for any sampling plan used. Plans should be developed by qualified mathematicians or statisticians, or be taken from established standards such as ANSI Z1.4. It should be
recognized that all sampling plans have a built-in risk of accepting a bad lot.
This sampling risk is typically determined in quantitative terms by deriving the "operating
characteristic curve" for the selected plan. Each sampling plan has a characteristic curve. ANSI
Z1.4 contains operating characteristic curves for sampling plans presented in the standards, and it
can be used to determine the risk a sampling plan presents. A manufacturer should be aware of the
risks the chosen plan presents. Operating characteristic curves are a means of graphically showing
the relationship between the:
•
quality of lots submitted for sampling inspection, usually expressed in percent defective, but
may be expressed in defect per hundred units; and
10 − 10
•
the probability that the sampling plan will yield a decision to accept the lot, described as the
"probability of acceptance."
Control Numbers
Manufacturers of surgically implantable or life sustaining devices whose failure to perform when
properly used can be reasonable expected to result in a significant injury shall establish and
maintain procedures for identifying with a control number each unit, lot, or batch of finished devices
and when appropriate components. Control numbers should be assigned to each unit, lot or batch of
components that were manufactured under similar conditions over the same time period so that
defects can be traced to the component manufacturer and the cause of the defects determined and
corrected. If a subassembly is regarded as a traceable component by the manufacturer, a control
number for that traceable subassembly shall be recorded in the device history record.
CONTRACTOR AND CONSULTANT ASSESSMENTS
Manufacturers shall establish and maintain the requirements, including quality requirements,
that will be met by contractors/consultants that perform a service for them. To aid in accomplishing
this task each manufacturer shall:
•
evaluate and select contractors/consultants based on their ability to meet specified
requirements, including quality requirements. This evaluation shall be documented.
•
define the type and extent of control to be exercised over the contractors/consultants based on
the evaluation results.
•
establish and maintain records of acceptable contractors/consultants.
Contractors and consultants often provide information or a service rather than a physical
component. However, the thought and control processes are similar whether one is working with
services or with physical product. The input from contractors and consultants have a definite
impact on the finished device. Services may include: design activities, various product
verification/validation activities, sterilization, routine maintenance, and calibration of equipment.
Each manufacturer shall provide adequate resources and trained personnel to properly assess the
activities of their contractors and make adjustments as necessary. Contractors and consultants
maybe assessed based on their applicable education, experience, ability, resources such as facilities
and equipment, list of clients, patents, technical reports, etc. Assessment may include conducting
internal quality audits [820.20(b)(2)]. Therefore, each manufacturer that is having important work
done by a contractor should inform the contractor that their quality system and activities may be
audited. These services may include janitorial, consultants, design work, calibration, sterilization,
laboratory, and maintenance.
Interface Requirements
At various stages of product development the manufacturer may need to interface with different
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groups. If a need for this interface relationship arises during the design phase, a plan shall be
developed describing the interface with different groups or activities during the design process
[820.30(b)]. By planning for outside services, and including these providers in selected design review
meetings, a manufacturer increases the probability of receiving a service that meets requirements.
Also the manufacturer is held responsible for work done by outside contractors or consultants.
Thus, it is in the manufacturer’s best interest to keep providers adequately informed and to monitor
contractors to ensure that the correct design, production, or process controls are applied to
contractor services to ensure the service or finished product conforms to its specifications (820.30,
820.50, 820.70, and 820.80).
Process Validation Requirements
Regardless of whether a manufacturer or a contractor performs the actual work, the
manufacturer is responsible for establishing and maintaining control of the process parameters for
the validated process (820.75). Established procedures for validation and the validation results
should offer a high degree of assurance that the process consistently produces an output that meets
pre-established specifications. Validated processes shall be performed by a qualified person(s) and
be documented regardless of whether the manufacturer or an outside contractor performs the
validation activities. For more information see Process Validation, chapter 4.
Device Servicing Requirements
If a manufacturer contracts for device service with another party, the assessment and selection of
such contractors shall be done according to 820.50 Purchasing Controls. Such service activities and
reports should be periodically reviewed to assure that the service activities meet GMP servicing
requirements as briefly described below.
Device servicing performed by contractors and/or consultants shall be conducted using
established procedures for performing and verifying that the service meets specified requirements
(820.50 and 820.200). A written report on the servicing shall include:
1.
2.
3.
4.
5.
6.
the name of the medical device serviced;
any device identification(s) and control number(s) used;
the date of service;
the individual(s) servicing the device;
the service performed; and
the test and inspection data.
Each manufacturer should analyze the service reports they receive directly, as well as the ones
they receive from contractors, using the appropriate statistical methodology referenced in 820.100.
It is important that this service data be collected and organized such that it can be analyzed to
determine if quality problems exist. See Chapter 15, Complaints, for more details. If the report
represents an event which is reportable to FDA under medical device reporting (MDR)
requirements in 21 CFR part 803 or 804, these reports shall be handled as complaints using 820.198.
Contract agreements between the manufacturer and contractors and/or consultants will vary in
their degree of complexity. The most comprehensive is probably the agreement between the
manufacturer and the contract sterilizer. Thus, the contract sterilization agreement is an excellent
10 − 12
example of what is involved in setting up a contract between the device manufacturer and a
contractor. The steps necessary for an agreement may be less extensive with other contracts than it
is with the sterilization contract; however, the sterilization contract does provide a good basis for
understanding this contractual agreement.
CONTRACT STERILIZATION
Manufacturers of medical devices frequently use contract sterilizers to provide sterilization
processing for their devices prior to distribution. Contract sterilization of medical devices shall be
performed so that the device manufacturer and the contract sterilizer meet the applicable parts of
both the QS regulation and the labeling requirements of 21 CFR 801.
Labeling Requirements
Manufacturers of sterile devices commonly label devices as sterile at one establishment and ship
them to another facility or to a contract sterilizer for sterilization. Shipments of nonsterile devices
labeled as sterile are clearly misbranded and adulterated, and they may be diverted into consumer
channels, thus creating a health hazard. FDA recognizes that this longstanding practice is an
economic necessity for many manufacturers. Therefore, to meet the needs of these manufacturers in
a way that will also assure the protection of the public health, FDA added Part 801.150(e) to the
Code of Federal Regulations (CFR). This part identifies the necessary markings for such shipments
and requires a written agreement which specifies the sterilization process. Part 801.150(e) It is
reprinted below:
(e) As it is a common industry practice to manufacture and/or assemble, package, and fully label
a device as sterile at one establishment and then ship such device in interstate commerce
to another establishment or to a contract sterilizer for sterilization, the Food and Drug
Administration will initiate no regulatory action against the device as misbranded or
adulterated when the nonsterile device is labeled sterile, provided all the following
conditions are met:
(1) There is in effect a written agreement which:
(i)
Contains the names and post office addresses of the manufacturers involved and
is signed by the person authorizing such shipment and the operator or person in
charge of the establishment receiving the devices for sterilization.
(ii)
Provides instructions for maintaining proper records or otherwise accounting
for the number of units in each shipment to insure that the number of units
shipped is the same as the number received and sterilized.
(iii)
Acknowledges that the device is nonsterile and is being shipped for further
processing, and
States in detail the sterilization process, the gaseous mixture or other media, the
equipment, and the testing method or quality controls to be used by the contract
sterilizer to assure that the device will be brought into full compliance with the
Federal Food, Drug and Cosmetic Act.
(iv)
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(2)
Each pallet, carton, or other designated unit is conspicuously marked to show its
nonsterile nature when it is introduced into and is moving in interstate commerce, and
while it is being held prior to sterilization. Following sterilization, and until such time as
it is established that the device is sterile and can be released from quarantine, each pallet,
carton, or other designated unit is conspicuously marked to show that it has not been
released from quarantine, e.g., "sterilized awaiting test results" or an equivalent
designation.
Quality System Requirements for Contract Sterilization
The sterilization process are performed in compliance with applicable parts of the Quality
System regulation for medical devices because sterilization is a manufacturing process. Thus, the
contract sterilizer is a manufacturer [(820.3(o)] and the device master record (DMR) shall contain,
or refer to, the location of sterilization process specifications. Process specifications may be
generated by either the manufacturer, contract sterilizer, or by both parties, although overall
responsibility rests with the finished device manufacturer. The device manufacturer is ultimately
responsible for assuring that its devices are sterile. The responsibility for specific tasks may be
delegated to a contract sterilizer, but the device manufacturer retains the ultimate responsibility.
The contract sterilizer is subject to those parts of the QS regulations that apply to the operations
that it performs for the finished device manufacturers, e.g., equipment maintenance and calibration,
in-process controls, and associated record keeping, etc. Thus, both the manufacturer and the
contract sterilizer share the responsibility to comply with the QS regulation in assuring effective
sterilization.
Because the responsibility for effective sterilization is shared between the device manufacturer
and the contract sterilizer, it is essential that the two parties clearly define in writing the division of
responsibility for every aspect of the sterilization process. The QS arrangements between the
manufacturer and the contract sterilizer may be in the same written agreement used to cover the
801.150(e) labeling requirements. It is the manufacturer's and contractor's responsibility to assure
the agreement is a workable practical document and is followed by both parties. FDA inspects
finished device manufacturers and contract sterilizers to determine compliance. The following is QS
related information that should be in the written agreement for contract sterilization and
implemented during production, sterilization, and release.
Information Transfer
The manufacturer and contract sterilizer should designate the individual(s) at each facility
responsible for coordinating the flow of information between establishments and for approving
changes in procedures. All technical, procedural, and other information that pertains to the
sterilization process and associated activities should pass through these designees. The manufacturer
and the contractor shall agree to inform one another of any device or process changes, especially
those that may require cycle requalification.
Record Keeping
Documentation such as device master record procedures, device history records, etc., to be used
and maintained should be specified. If changes are made to the documentation, both parties should
10 − 14
agree on the manner in which the changes are to be made. These documentation changes shall
comply with QS requirements in 820.70(b) and .75(c) for manufacturing and process specification
changes, and with 820.40(b) for changes in device master records.
Process Validation
The device manufacturer has primary responsibility for the validation of the process used to
sterilize its devices. Commonly, responsibility for portions of the validation study are delegated to
the contract sterilizer in the written agreement. The manufacturer should work with the contract
sterilizer to assure that the facilities, equipment and processing parameters (including
preconditioning and aeration steps) will provide for effective sterilization and will not adversely
affect the devices or their packaging. Validation is required for every device or device family. The
written agreement should identify responsibility for all aspects of validation and define the criteria,
frequency, and responsibility for requalification. Likewise, the agreement should identify the
documentation that is maintained for validation studies.
Bioindicators and Dosimeters
The agreement should specify responsibility for placement, retrieval, handling, and processing of
product samples and any biological, chemical, or physical indicators. The agreement should include
instructions for packaging and shipment of indicators and samples to test laboratories for analysis.
Loading Configuration
The loading parameters for each lot of device(s) or device family should be specified. The routine
product load configuration should conform to the validated load configuration. It is not
recommended that a contract sterilizer mix products from different manufacturers in processing
cycles unless validation studies have proven the effectiveness of the cycle for those mixes or worst
case mixes, and the customers are informed about the practice.
Preconditioning
The agreement should address preconditioning requirements for external preconditioning and/or
in-chamber conditioning if required by the sterilization process.
Cycle Parameters and Process Control
The written agreement should specify the cycle parameters to be achieved during processing. After
the process is qualified, the contract sterilizer is responsible for maintaining control over the
process to make certain that process specifications are routinely achieved. Cycle parameters should
be clearly defined in written specifications, accurately monitored, and the actual parameter values
achieved during each run should be recorded.
The primary manufacturer should produce the product under a quality system, which includes
appropriate environmental control procedures such as bioburden control. Thus, the product is the
“same” product as that for which the original process was developed or specified.
Post-sterilization Handling and Aeration
10 − 15
The agreement should address procedures for post-sterilization quarantine of the product before
release for distribution. While waiting for release, the pallets, cartons, or designated unit shall be
marked to indicate the status of the product; for example, "sterilized: awaiting test results," or an
equivalent statement. If an aeration period is required, it should be specified. Both parties should
acknowledge that the product is not to be shipped for commercial distribution until it is properly
approved for distribution in accordance with procedures in the agreement.
If correctly labeled, a device that has been sterilized may be shipped to a controlled distribution
point before final release by the manufacturer. Routine distributors are NOT considered to be
"controlled distribution points." Shipments to a company warehouse or to another finished device
manufacturer may be acceptable as long as the manufacturers are able to show that they have
control of the product until final release and could recall it if necessary. See CFR 801 Subparts A &
E and QS sections 820.160, Distribution, and 820.80(d), Final Acceptance Activities.
History Records and Review
Both the manufacturer and contractor should agree on the procedures and responsibility for
reviewing and approving the device history records.
Finished Device Release
The agreement should include device release procedures. Individuals responsible for approving
device release for distribution should be identified. A contract sterilizer may handle the final release
of a batch of sterilized devices. The manufacturer should make sure, however, that this agreement is
part of a written contract. In addition, the manufacturer should: audit or have a consultant audit the
contract sterilizer; review the contractor's own QA audit report; or obtain written certification of
compliance to assure that personnel and procedures are adequate to meet the requirements of
820.160, Distribution, and, 820.80(d), Final Acceptance Activities.
Audits of Both Facilities
The device manufacturer should audit his quality system and assure by audits or other means
such as a review of the contractor's own QA audit that the contractor has adequate control over the
sterilization process. The agreement should cover the extent and frequency of the audit, corrective
actions, records, confidentiality, and the auditor(s).
Training
The manufacturer should assure that the entire sterilization process is performed and controlled
by properly trained operators. The agreement should provide the manufacturer access to applicable
training
records during agreed upon audits.
Nonconformance
10 − 16
Both parties should mutually agree to inform one another if the device or process deviates from
the agreed upon specifications. As appropriate, the nonconformance should be investigated,
evaluated, and, if necessary, corrective actions should be instituted. The parties should consider and
agree on conditions requiring corrective action and document all reprocessing. The agreement
should specify the individuals that should be contracted regarding any changes or deviations in the
manufacturing or sterilization process. It should also specify the individual at the manufacturer that
should be contacted when product is damaged to determine how the product should be handled at
the contract sterilizer.
It is highly recommended that manufacturers of sterile medical devices read Sterile Medical
Devices-A GMP Workshop Manual. This publication may be obtained from National Technical
Information Services (NTIS), phone: 703-487-4650. The ordering number is: PB84188713. As of 7/96
the price is $71.50 for a paper copy and $12.50 for a microfiche copy.
FINISHED DEVICE EVALUATION
Finished device inspection is typically a final test and review of safety, performance, labeling,
appearance, and configuration characteristics to assure the device meets the acceptance criteria
established in the DMR. For many medical devices this assurance requires an analysis, electrical
test, mechanical test, or other technical tests. For some simple devices, however, such as eyeglass
frames, a visual or dimensional check may be sufficient to prove acceptability. For both simple and
complex devices the manufacturer shall have written specifications or criteria for determining the
acceptability of the finished device. It is important that the device characteristics to be evaluated are
defined and also, where applicable, the equipment, environment, and handling procedure should be
defined and established.
Sampling Plans
To show the manufacturing process is operating in a state-of-control, the process may need to be
validated as explained in chapter 4, Process Validation. Testing product by using a sampling plan
based upon an acceptable statistical rationale may demonstrate that the process continues to operate
in a state of control. A manufacturer should be prepared to demonstrate the statistical rationale for
any sampling plan used. Plans should be developed by qualified mathematicians or be selected from
established standards such as ANSI Z1.4. Copies of this standard may be obtained by writing to:
American National Standards Institute, 11 West 42nd Street, 13th Floor, New York City, NY 10036,
or phone 212-642-4900.
All sampling plans have a built-in sampling risk of shipping devices that do not meet product
specifications. Each sampling plan can be graphically illustrated to show the relationship between:
the quality of lots submitted for sampling inspection and the probability that the sampling plan will
yield a decision to ship the lot. ANSI Z1.4 contains operating characteristic curves for sampling
plans presented in them. These curves can be used to determine the risk each sampling plan
presents.
When sampling plans are used, there exists the possibility that a few defective devices will be
shipped to the user. Thus, manufacturers should be aware of the risks a particular plan presents to
the manufacturer and to the user. Questions such as those listed below should be considered before
selecting a sampling plan.
10 − 17
•
Will the defect be obvious to the user? If not, what are the consequences of using the
defective device?
•
What is the state-of-the-art technology for 100% valid testing of this device?
•
Is the testing destructive?
•
Does the competition use sampling?
•
What is the probability of a product liability suit?
•
What are the regulatory consequences?
•
Does the marketplace expect or accept devices that have been sample tested and/or
inspected?
Manufacturers should recognize that straightforward logical answers to these questions may not
always be suitable. Acceptance status for devices may be influenced by the price the user is willing to
pay -- 100 percent testing usually costs more than sampling. Destructive testing makes 100 percent
testing impossible. Whether sample testing and inspection of a particular family of devices is
acceptable to the user also changes with technology. Where 100% valid automatic testing is not
feasible, validation of the process and the product with a follow up sampling plan is usually the
preferred method of establishing and maintaining a quality system, which can continuously produce
a device that meets specifications.
Each manufacturer shall establish and maintain procedures for rework, to include retesting and
reevaluation of the nonconforming product after rework, to ensure that it meets its current
approved specifications. Rework and reevaluation activities, including a determination of any
adverse effect from the rework upon the product, shall be documented in the device history record
(DHR) [820.90(b)(2)].
When a device fails testing, it should not be repeatedly retested until it passes. The problem
should be corrected. If a manufacturer's acceptance procedures allow acceptance after repeated
testing and rework, there should be a valid basis for such an acceptance procedure. Failed devices
shall be identified and segregated from acceptable devices and from the flow of the production
process.
Labeling and Packaging Inspection
The manufacturer shall establish and maintain procedures to control labeling. This control
includes the label’s integrity, inspection, storage, control numbers, and labeling related operations
(820.120).
The manufacturer shall control labeling and packaging operations to prevent labeling mixups.
The label and labeling used for each production unit, lot, or batch shall be documented in the DHR
[820.120(d)]. Where a control number is required by 820.65, that control number shall be on, or
10 − 18
shall accompany, the device through distribution [820.120(e)]. The DHR shall include or refer to the
location of the primary identification label and labeling used for each production unit [820.184(e)].
The manufacturer shall ensure that the device packaging and shipping containers are designed
and constructed to protect the device from alteration or damage during the customary conditions of
processing, storage, handling, and distribution (820.130, Device Packaging). This may include
containers and packaging examination as applicable to assure they are not damaged or misbranded.
All devices shall have the correct labels, package inserts, and/or manuals as specified in the DMR.
Records
A DHR is a compilation of records containing the production history of a finished device
[820.3(i)]. However, procedures for establishing and maintaining DHR shall be developed. These
records demonstrate the device is manufactured in accordance with the DMR. The DHR shall
include or note the location [820.80(e), 820.184] of:
•
dates of manufacture;
•
quantity manufactured;
•
quantity released for distribution;
•
acceptance records demonstrating the device is manufactured in accordance with the
DMR;
- date of acceptance
- results of acceptance activities
- signature of person(s) performing acceptance activities
- where appropriate, equipment used
•
primary identification label and labeling used for each production unit; and
•
any device identification(s) and control number(s) used.
The DHR should be reviewed before distribution because these records are used to show that
finished devices are manufactured in accordance with, and meet, the specifications in the DMR.
Beside these requirements, some device manufacturers should fulfill an additional traceability
requirement if their device is intended for surgical implant into the body or to support or sustain life
and whose failure to perform when properly used in accordance with the label instructions for use
can be reasonably expected to result in a significant injury to the user. For these devices procedures
shall be established and maintained to identify a control number for each unit, lot, or batch of
finished devices and, where appropriate, components. The control number is used to trace a
defective lot and facilitate corrective action. Identification of devices shall be documented in the
DHR (820.65).
Product Release
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Finished device manufacturers shall have sufficient controls to assure that only devices that have
passed test and inspection are released as discussed in chapter 14, Storage, Distribution and
Installation. The manufacturer shall establish and maintain procedures for identifying product
during all stages of receipt, production, distribution, and installation to prevent mixups (820.60).
Each manufacturer shall establish and maintain procedures for finished device acceptance to ensure
that each production run, lot, or batch of finished devices meets acceptance criteria. To prevent
mixups, not-yet-accepted and rejected devices shall be controlled to prevent mix up with devices that
have been through final evaluation and accepted for release [820.80(d)]. Methods of controlling nonreleasable product include storage location, boxing, or manifest tagging. The desired end result is to
assure operations are in a state-of-control. Finished devices should not be released for distribution
until:
•
•
•
•
the activities required in the manufacturers DMR are completed;
the associated data and documentation are reviewed;
the release is authorized by the signature of a designated individual(s); and
the authorization is dated.
10 − 20
EXHIBITS
Examples of forms that may be used for purchasing, accepting, receiving, and inspecting
components are exhibited at the end of this chapter. These examples show the types of information
required by the Quality System regulation. Procedures and forms for a particular situation may be
more or less comprehensive than these, and may assume other formats or arrangements according
to need.
Purchase of Components
This exhibit is a specification for purchasing a zener diode and is typical of device master record
documents that are used to purchase components. This spec describes the diode in sufficient detail
for the correct part to be procured.
Acceptance of Components
This example is intended as an acceptance procedure that may be followed by a small to medium
size manufacturer. The procedure has space for the number, revision level, and a blank for "ECN
History.” The history blank is for adding brief notes about changes that have been made to this
procedure. Included as part of this procedure is a "Receiving History Log" which immediately
follows the procedure. The other forms mentioned in the procedure are not reprinted; however,
similar forms are included with the "Procedure for Receiving and Inspection of Material" described
below with the example located immediately following the "Receiving History Log.”
Material Receiving and Inspection Procedure
This document is a more extensive receiving procedure than the one discussed above and it can
be used by a medium to large manufacturer. As part of this procedure you will note an extensive
revision record section. Also, part of the procedure is a flow chart which outlines the steps in the
procedure and the branches for each step. Next is a "Daily Report of Goods Received" which
includes the supplier name, quantity received, lot number or item number, purchase order or
requisition number, and information on where the item was sent. The next item in the procedure is a
"Receiving and Inspection Report" which contains information about the item and the sampling and
testing performed on the item. The report includes an acceptance or rejection slot along with a space
for the cause for rejection. The procedure continues with a "Daily Inspection Log" which is a
summary of the items received and their disposition, either accepted or rejected. Finally, as part of
the procedure, we find examples of the decals to be used to accept, reject, or quarantine the
incoming items.
Identification Decals and Forms
Examples of decals and travelers used to identify materials, components and in-process
assemblies are exhibited. Two of the decals deal with components and can be used as a means of
assuring proper disposition of these items. A "Material Lot Identification" is exhibited which is used
to identify components in a container. This form has space for, among other information, lot
number, expiration date, quantity in the subject container, date it was issued to stock, and the
person who received the container. The final example in this group is a "Stock Requisition" form,
10 − 21
used whenever items are being released from stock to production. This form contains information
such as, part number, quantity ordered and issued, and lot number. Note that part of this form is
used to indicate if the issued item is to replace a defective item.
Receiving Rejection Notice
This form is used when incoming components and materials are rejected and includes sections
for the inspector’s report listing the sampling plan, specification tested for, number of defects, and a
description of the defects. There is a section for a preliminary review, if necessary, and finally a
section for the Material Review Board (MRB) decision on the disposition of the rejected lot. A MRB
may accept temporary deviations that do not affect safety and effectiveness. These deviations or
changes should be approved by the MRB or other designee. MRB activities should be performed per
a written procedure and otherwise meet GMP requirements. The MRB should not change a device
master record (DMR) drawing or be used as a substitute for the primary change control system of a
manufacturer.
10 − 22
Sheet 1 of 1
TITLE: IN4278 ZENER DIODE SPECIFICATION NUMBER
Drafted by
REV.
ECN History
App.
Date
Date
1.
SCOPE: This specification describes a one-watt zener diode used for voltage reference in the
XYZ Stimulator.
2.
ELECTRONIC CHARACTERISTICS
2.1
Zener Voltage: 3.1 vdc @ 76 madc
2.2
Maximum Zener Impedance: 10 ohms @ 76 madc
2.3
Reverse Leakage Current: (25%) 100 microamps (max) @ l vdc
3.
TESTING: All diodes shall meet the requirements of JANTX IN4278 as specified in
MIL-S-19500/127G.
4.
PHYSICAL CHARACTERISTICS
5.
6.
7.
4.1
Diodes shall be packaged in a void-free silicone case.
4.2
Leads shall be readily solder able.
MARKING
5.1
The cathode shall be identified by a color band.
5.2
An identification number and lot number or date code shall represent a specific
manufacturing period.
5.3
All markings shall be permanent such that cleaning solutions will not remove the
markings.
CERTIFICATION
6.1
A certification of compliance with this specification and a test data sheet must accompany
each lot shipped.
6.2
Certification must include a statement that no changes have been made in materials or
physical or electrical characteristics.
APPROVED SUPPLIERS
7.1 XXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXX
XXXXXXXXXXXXXXXXXXX
10 − 23
TITLE: ACCEPTANCE OF COMPONENTS
Sheet 1 of 3
No. Rev. ECN History
_______________________________________________________________________________
Drafted by App. by Date
1.0 SCOPE
These procedures are to be followed in the receipt, inspection, and storage of product such as
raw materials, components, parts, manufacturing materials, etc., used in the manufacture of the
XYZ Stimulator, a device that does not require traceability per 820.65.
2.0 RECEIVING
2.1 All incoming shipments must be examined for external signs of damage. If the shipment is
damaged, immediately notify Purchasing and move the shipment to the unloading Hold area
until disposition is decided by Purchasing.
2.2 Upon receipt, check each shipment against the corresponding purchase order and verify
identity and quantity. The purchase order may include, reference, or have attached purchase
specifications.
2.3 Enter the appropriate data into the Received Goods Log for each shipment received.
2.4 After completing the data entry, attach a yellow "HOLD" tag to the product and immediately
move the products to the receiving quarantine area. The pink copy of the purchase order must
accompany the product.
2.5 Notify Quality Control when materials requiring inspection are received in the quarantine area.
This information is obtained from the device master record specification for the item ordered.
2.6 Quality control shall, after examining the product for damage and identity, move the
product, etc., to be inspected to the Receiving Inspection area.
3.0 INSPECTION
3.1 Pull the inspection history file for the product to be inspected. This file contains the Receiving
History form and inspection procedure. Enter the appropriate data from the purchase order
onto the Receiving History form and perform the inspection per the procedure.
10 − 24
Sheet 2 of 3
3.2 The QC manager shall assign a five digit lot number to each supplier lot received and enter the
number on the Receiving History form.
3.3 After the inspection is completed, enter on the Receiving History form:
a. the quantity accepted and sent to stock;
b. the quantity rejected; and
c. your signature and the date.
4.0 DISPOSITION
4.1 Receiving and test data for each shipment are sent to the designated individual for review and
the decision regarding the acceptability of the lot.
4.2 For accepted product, enter the quantity accepted, date accepted, and lot number on a green
"ACCEPTED" tag, attach the tag to the product, etc., and move it the stockroom.
4.3 For rejected product attach a red "REJECTED" tag to the rejected product and complete a
Rejected Material form. Place all rejected product in the rejected quarantine area and forward
the Rejected Material form to Quality Engineering for disposition.
5.0 STOCKROOM
5.1 All items entering the stockroom must be accompanied by a green "ACCEPTED" tag.
5.2 Components and other materials shall be stored and issued per SOP 17320.
5.3 Components and other materials will be issued from the stockroom on a first-in, first-out basis.
All materials with a limited shelf life or requiring controlled storage conditions will be stored
appropriately per SOP 17321.
Note: Sheet 3 is the Receiving History log for this procedure. The other forms mentioned in this
procedure are not reprinted. However, similar forms are included with another procedure located
later in this chapter.
Sheet 3 of 3
RECEIVING HISTORY RECORD
10 − 25
Description
Purchase
Order #
Lot
#
Date
Rec'd
Supplier
Lot
Size
Quantity
Accepted
10 − 26
Quantit
y
Rejecte
d
Inspec
t
Date
Comments
DRAFT BY ________________________________________
NUMBER PA-1004
SHEET 1 OF 9
APPROVED
TITLE
PROCEDURES FOR RECEIVING AND INSPECTION OF MATERIALS
(Receiving and Inspection Report Procedures (R.I.R)
PURPOSE This procedure outlines the activities and responsibilities involved in the receipt and inspecti
purchased product.
SCOPE
This procedure applies to the receipt and initial evaluation of incoming components, materials
other product; preparation of the receiving and inspection report; quarantining of received item
the inspection and accept/rejection of items.
CONTENTS
1. Procedure
2. Flow Chart
3. Sample Forms
REVISION RECORD
REV.
DESCRIPTION
A
ORIGINAL ISSUE
B
REVISED
ORIGINATOR
10 − 27
Q.A
OPER.
MANAGER
SHEET 2 OF 9
1.0 PROCEDURES FOR RECEIVING AND INSPECTION
1.1
Responsibilities of Receiving Clerk.
1.1.1
Sign for items received.
1.1.2
Verify numbers of packages, check for obvious shipping damage and
verify identification of packages to bill of lading.
1.1.3
Record information in receiving log and assign sequential receiving
number.
1.1.4
Obtain packing slip from container of items.
A. Attach to bill of lading, if available.
B. Stamp receiving date on package slip.
C. Obtain receiving copy of purchase order from file.
D. Verify count, hidden damage and identification of items to packing
slip.
If there is a problem, refer information to supervisor for resolution.
E. Circle quantity on packing slip.
F. Record receiving number on packing slip.
1.1.5
Production items.
A. Prepare part 1 of the receiving and inspection report (RIR). Use
receiving number as RIR number.
B. Record receiving number on yellow quarantined tag and attach to
item.
C. Move parts to quarantine area.
D. Send RIR to inspection.
E. Send packing slip to purchasing.
10 − 28
SHEET 3 OF 9
1.1.6
Non production items.
A. Send packing slip to purchasing.
B. Move material as per purchase order.
1.2
RESPONSIBILITIES OF RECEIVING INSPECTION
1.2.1
Receive RIR.
1.2.2
Obtain parts from quarantine area.
1.2.3
Obtain necessary instruction documents, such as specification sheets and
purchase orders from Q.C. files and uncontrolled drawings from engineering
files.
1.2.4
Perform inspection in accordance with instructions.
1.2.5
Record results of inspection on part II of RIR, sign, and date.
1.2.6
Fill out inspection log.
1.2.7
File original of RIR by receiving number.
1.2.8
If incoming materials are accepted:
A. Prepare green approval tag and attach tag to container, or item as
appropriate.
B. Destroy yellow quarantine tag.
C. Return parts to quarantine area.
D. Discard pink copy of RIR.
E. Send yellow copy of RIR to material handler.
1.2.9
If incoming materials are non-conforming:
A. Prepare red rejection tag and attach to container, or item, as appropriate.
B. Destroy yellow quarantine tag
C. Return parts to quarantine area.
D. Send pink and yellow copies of RIR to purchasing.
10 − 29
Sheet 4 of 9
Shipment arrives
Receiving clerk:
1. Sign for items received
2. Verify no. of packages,
check for damage,
check identity against bill of lading
3. Record information in receiving log &
assign sequential receiving number
4. Attach packing slip to bill of lading
5. Stamp receiving date on packing slip
OK?
No
Receiving Dept. copy of P.O.
Yes
Receiving clerk:
1. Open pkg., verify count, identity to
packing slip and P.O. and check for
hidden damage
2. Circle quantity on packing slip
3. Record receiving no. on packing slip
OK?
No
Contact supervisor
to resolve
No
Dispose of material
as per P.O.
Yes
Production
item?
Yes
Receiving clerk:
1. Prepare part 1 of RIR
2. Record receiving no. on yellow
quarantine tag and attach to item
RIR
Goods
A
B
10 − 30
Packing
Slip
C
Sheet 5 of 9
A
B
C
Goods
Quarantine
RIR
Instruction manuals, etc.
Receiving inspector:
1. Perform inspection in accordance with
instructions
2. Record results on part 2 of RIR; sign &
date RIR
3. Fill out inspection log
1.
OK?
No
2.
Prepare &
attach red
rejected tag
Remove
yellow tag
Pink &
Yellow
RIR
Packing
slip
Yes
Receiving inspector:
1. Prepare green approved tag & attach
to container, item, etc.
2. Remove & destroy yellow tag
Yellow
tag
Goods
Yellow
tag
Yellow
RIR
Material handler
Pink
RIR
Trash
Goods
Quarantine
10 − 31
Purchasing
Receiving Clerk
Received From
Date
Via
No.
Pkgs.
Weight
Quantit
y
Remarks:
10 − 32
Description of Goods
Sheet No. 6 of 9
P.O. OR
Req. No.
Charge
Paid
Delivered to
RECEIVING & INSPECTION REPORT
Sheet 7 of 9
No. A
PART I - RECEIVING
SUPPLIER:
P.O. NO:
Date:
Qty. Rec’d.
Part No.
Spec. No.
Description
Remarks
PART II - INSPECTION
Inspected by
Sample Lot
Conformance to Specifications
YES
NO
YES
Lot Size
Physical Damage
Electrical
Sample Qty.
Markings
Dimensions
Accepted
Date
Place in Stock
Rejected
NO
Date
Cause for Rejection
Forward to Next Operation
_____________________________________________
_____________________________________________
PART III PURCHASING
Rejected Parts Disposition
Conditional Acceptance Approvals
Return to Supplier______________________ Remarks: Mfg.
Eng.
Q.C.
Comments:____________________________________________________________________________
______________________________________________________________________________________
_
DAILY INSPECTION LOG
10 − 33
Sheet 8 of 9
DAT
E
RIR
NUMBE
R
ACCREJ
REJ/AC
C
S/D
DATE
RIR
NUMBE
R
10 − 34
ACC-REJ
REG/ACC
S/D
COMMENTS
SPECIAL DISPOSITION
Sheet 9 of 9
QUARANTINED
APPROVED
RIR
RIR
Product or Material
Part or
Spec #
Quantity
Author
Date
Remarks
REJECTED
By Quality Control
Product or Material
Part or
Spec #
Quantity
Author
Date
Remarks
10 − 35
MATERIAL LOT IDENTIFICATION
PART
NO.
REV.
DESC.
LOT CONTROL NO.
EXPIRATION DATE
QTY. THIS CONTAINER
DATE TO STOCK
RECEIVED BY
CAUTION
CAUTION
TRACEABLE COMPONENT
TRACEABLE COMPONENT
MUST BE ISSUED
BY LOT NUMBER !
RECORD LOT NUMBERS ON
ISSUING DOCUMENT !
Part No.
Desc.
Lot Control #
Quantity
STOCK REQUISITION
For Dept.
Date
Is this material for: [ ] Replacement of Defective Mat’l
N.O.D. #
[ ] Kit Error
PART
NUMBER
[ ] Bulk Issue
[ ] Sales Order No.
[ ] Test Inv.
[ ] Other
[ ] ECN No.
BIN
CTRL
Posted
ORDER
QTY.
ISSUED
QTY.
IF STOCK-OUT ITEMS TO BE BACK ORDERED CHECK BOX [ ]
FILLED BY
REQUISITIONER
PRODUCTION CONTROL
APPR’L
10 − 36
DATE
BACK
ORDER
QTY.
LOT
CONTROL
NUMBER
No
RECEIVING REJECTION NOTICE
VENDER NAME
PART NUMBER
PART NAME
DATE RECEIVED
RECEIVING NUMBER
DATE INSPECTED
P.O. NUMBER
QUANTITY RECEIVED
INSPECTOR
CROSS/REF.
INSPECTOR’S REPORT
NUMBER OF
DEFECTS
FOUND
SAMPLE PLAN
SPECIFICATION
ITEM
AQL
SAMPLE
SIZE
DESCRIPTION OF DEFECTS
ALLOW
DEF
PRELIMINARY REVIEW
CHECK
DISPOSITION
EXPLANATION
RETURN TO SUPPLIER
USE AS IS
MATERIAL REVIEW BOARD
OTHER
Q.C.
DATE
M.C.
DATE
PURCHASING
DATE
MRB DISPOSITION
CHECK
DISPOSITION OF LOT
ITEMS
INVOLVED
AMOUNTS
INVOLVED
MRB AUTHORIZATION
MRB
REJECTED RETURN TO SUPPLIER
FOR REPAIR OR REPLACEMENT
Q.C.
USE AS RECEIVED PER LIMITATIONS
LISTED ON D.E.O
ENG.
USE AS RECEIVED. SEE LIMITATIONS
LISTED UNDER COMMENTS
OTHE
R
SIGNATURE
ACCEPT PENDING SPECIFICATION
CHANGE PER E.O.
SCREEN AND/OR REWORK BY
PURCHASING NOTIFY SUPPLIER OF COST
OTHER (SPECIFY BELOW UNDER
COMMENTS)
COMMENTS
Acceptance for future shipments will depend on proper completion and return of this report by supplier within 14 days to
CAUSE OF DISCREPANCY
CORRECTIVE ACTION TAKEN
10-37
DATE
EFFECTIVE DATE
SIGNATURE & TITLE
10-38
DATE
11
LABELING
LABELING REGULATIONS ......................................................................................... 11-1
Misbranding ................................................................................................................ 11-2
False or Misleading Labeling ..................................................................................... 11-3
Adequate Directions for Use ...................................................................................... 11-4
Prescription Devices ................................................................................................... 11-4
Sterile Devices ............................................................................................................. 11-5
DESIGN OF LABELING ................................................................................................. 11-7
Write to the Reader .................................................................................................... 11-7
Refer to Actual Device ................................................................................................ 11-8
Obvious Identification of Controls ............................................................................ 11-8
Don't Distract Reader ................................................................................................. 11-8
Short and to the Point ................................................................................................. 11-9
Gobbledygook .............................................................................................................. 11-9
Introduce Each Item ................................................................................................. 11-10
Accentuate Key Terms ............................................................................................. 11-10
Select Words Wisely ................................................................................................. 11-10
Test Labeling ............................................................................................................. 11-11
Label Integrity ........................................................................................................... 11-11
Approval Policy and Procedure ............................................................................... 11-11
Design Transfer ......................................................................................................... 11-11
Production Controls ................................................................................................. 11-13
Receipt and Inspection ............................................................................................. 11-13
Area Separation and Inspection .............................................................................. 11-13
STORAGE ....................................................................................................................... 11-14
Label Check and Record .......................................................................................... 11-14
Control Numbers ...................................................................................................... 11-15
Access Restriction ..................................................................................................... 11-15
CHANGES ....................................................................................................................... 11-15
SHIPPING FOR PROCESSING ................................................................................... 11-15
OVER-LABELING ......................................................................................................... 11-17
EXHIBITS ....................................................................................................................... 11-18
Drafting and Approval of Labeling ......................................................................... 11-18
Approval Form for Labeling, Advertising, Literature, etc. .................................. 11-18
Administration Set Label ......................................................................................... 11-18
Labeling Control Record ......................................................................................... 11-18
Device History Record: OB/GYN (Plate) ............................................................... 11-18
User/Reader Comments ........................................................................................... 11-18
LABELING REGULATIONS
Medical devices in commercial distribution in the U.S. shall be properly labeled according to laws
and regulations enforced by the Food and Drug Administration (FDA). Specific labeling
requirements for medical devices are contained in:
•
•
The Federal Food, Drug, and Cosmetic (FD&C) Act;
The Fair Packaging and Labeling Act;
11-1
•
The Radiation Control for Health and Safety Act;
•
Title 21 of the U.S. Code of Federal Regulations, Part 801 for general devices, and Part 809
for in vitro diagnostic products;
•
Title 21 of the U.S. Code of Federal Regulations, Part 812.5 for investigational devices;
•
Title 21 of the U.S. Code of Federal Regulations, Part 820 for design and manufacturing
controls for labeling; and
•
Title 21 of the U.S. Code of Federal Regulations, Part 1010 - Performance standards for
electronic products. Also see Parts 1020 and 1040.
Section 201(k) of the FD&C Act defines the term "label" as "a display of written, printed, or
graphic matter upon the immediate container of any article . . . ." Under Section 201(l) of the FD
and C Act, the term "immediate container" does not include a package liner. Any word, statement,
or other information appearing on the immediate container should also appear on the outside
container or wrapper, if any, of the retail package or be easily legible through the outside container
or wrapper. The label is not required to appear on the shipping carton.
Section 201(m) of the FD&C Act defines the term "labeling" as all labels and other written,
printed, or graphic matter: (1) on the device or any of its containers or wrappers, or (2)
accompanying the device. The term applies any time while the article is in interstate commerce, or
being held for sale after shipment or delivery in interstate commerce. The term "accompanied" is
interpreted liberally. It extends to posters, tags, pamphlets, circulars, booklets, direction sheets,
fillers, etc., that may be displayed in proximity to the article or shipped to the user before or after
shipment of the device.
The distinction between labeling and advertising, while both draw attention to the article to be
sold, is often nebulous or superficial. Both are forms of publicity and are used for an identical
purpose. An appellate court described the relationship between the two as follows: "Most, if not all,
labeling is advertising. The term 'labeling' is defined in the Act [section 201(m)] as including all
printed matter accompanying any article. Congress did not, and we cannot, exclude from this
definition printed matter which constitutes advertising."
Section 502(f)(1) and (2) of the FD&C Act requires that device labeling bear adequate directions
for use, operating and servicing instructions, and either adequate warnings against uses dangerous
to health, or information necessary for the protection of users. All devices require directions for use
unless specifically exempted by regulation. Conditions for exemption from this requirement are in
21 CFR 801, Subpart D.
Misbranding
Section 502 of the FD&C Act contains the misbranding provisions for drugs and devices. It states
a device is misbranded under a number of different circumstances, including:
•
Its labeling is false or misleading.
•
Its packaging does not bear a label containing the name and place of business of the manufacturer, packer, or distributor, and an accurate statement of the quantity of contents.
11-2
•
Words, statements, or other required information are not prominent on the labeling or are
not stated clearly.
•
It is intended for human use, and the label fails to bear the name and quantity or proportion
of any narcotic or habit-forming substance contained in the product, and fails to display the
statement, "Warning: may be habit forming."
•
Its label does not contain adequate directions for use. These include warnings against use in
certain pathological conditions; against use by children where its use may be dangerous to
health; and against unsafe dosage, methods, duration of administration or application unless
exempt as unnecessary to protect the public health.
•
It is dangerous to health when used in the dosage or manner, or with the frequency or
duration prescribed, recommended, or suggested in the labeling.
•
It does not comply with the color additive provisions listed under Section 706 of the FD&C
Act.
The Medical Device Amendments expanded the authority of the FD&C Act over misbranded
medical devices. These amendments contain further circumstances under which a device is
misbranded:
•
The device's established name (if it has one), name in an official compendium, or including
common or usual name, is not printed prominently in type at least half as large as used for
any proprietary name.
•
The device is subject to a performance standard and it does not bear the labeling
requirements prescribed in that standard.
•
There is a failure or refusal to comply with any requirement prescribed under Section 518 on
notification and other remedies; failure to furnish material or information requested by or
under Section 518; or failure to furnish any materials or information requested by or under
Section 519 on records and reports.
•
The device is commercially distributed without FDA concurrence on a 510(k) premarket
notification submission.
False or Misleading Labeling
Section 502(a) states that a drug or device is misbranded if its labeling proves false or misleading
in any particular. It is not a necessary condition that the labeling should be flatly and blatantly false
for the FDA to take action. The word "misleading" in the FD&C Act means that labeling is
deceptive if it creates or leads to a false impression in the mind of a reader. A "false impression"
may result not only from a false or deceptive statement, but may be instilled in the mind of the
purchaser by ambiguity and indirection. It might be caused by failure to inform the consumer of
facts that are relevant to those statements actually made. In other words, the label that remains
silent as to certain consequences may be as deceptive as the label that contains extravagant claims.
Examples of misleading labeling include: ambiguity; half truths; trade puffery; expressions of
opinion or subjective statements; and failure to reveal material facts, consequences that may result
from use, or the existence of difference of opinion.
11-3
In the past, labeling found by the agency to be objectionable has featured such practices as:
deceptive pictorial matter; misleading testimonials; misleading lists of parts or components; and
brand or trade names instead of "established names" (see Sections 201(h), 502(e)(2), and 508 of the
FD&C Act). Examples of false representations are:
•
incorrect, inadequate or incomplete identification;
•
unsubstantiated claims of therapeutic value;
•
inaccuracies concerning condition, state, treatment, size, shape, or style;
•
substitution of parts or material;
•
subjective or unsubstantiated quality or performance claims; and,
•
use of the prefix U.S. or other similar indication suggesting government or agency approval or
endorsement of the product.
Adequate Directions for Use
Title 21, CFR Part 801.5, defines "adequate directions for use" as "directions under which the
layman can use a device safely and for the purpose for which it is intended." See Part 801.4 for a
definition of "intended use."
Among other reasons, directions for use may be inadequate because there is partial or total
omission or incorrect specification of one or more of the following items:
•
Statement of all conditions, purposes, or uses for which the device is intended. This includes
conditions, purposes, or uses for which it is prescribed, recommended, or suggested in its oral,
written, printed, or graphic advertising. This statement also includes conditions, purposes, or
uses for which the drug or device is commonly used. These statements should not refer to
conditions, uses, or purposes for which the drug or device can be used safely only under the
supervision of a practitioner licensed by law; those conditions, uses, and purposes may only be
referred to in advertisements directed to a licensed practitioner.
•
Quantity of dose including usual quantities for each intended use and usual quantities for
persons of different ages and physical conditions.
•
Frequency of administration or application.
•
Duration of administration or application.
•
Time of administration or application in relation to meals, onset of symptoms, or other time
factors.
•
Preparation for use, adjustment of temperature, or other manipulation or process.
Prescription Devices
Labeling exemptions for prescription devices are in 21 CFR Part 801.109. These are devices
which
11-4
because of a potential for harmful effect, potential for misuse, or the collateral measures necessary
to use, are not safe except under the supervision of a practitioner licensed by law. Hence "adequate
directions for use" cannot be prepared for these devices. They are exempt from Section 502(f)(1) of
the FD&C Act provided that all conditions specified in the labeling regulation are met.
These conditions state that the device shall be in the possession of a person, or his or her agents,
or employees regularly and lawfully engaged in the manufacture, transportation, storage, or
wholesale distribution of prescription devices; or in the possession of a practitioner such as a
physician, dentist, or veterinarian licensed by law to use or order the use of these devices. These
devices can be sold only to, on the prescription of, or by order of such practitioner for use in the
course of their professional practice.
The label of the prescription device, other than surgical instruments, is required to bear:
•
the statement "Caution: Federal law restricts this device to sale by or on the order of a
_____", the blank to be filled with the word "physician", "dentist", "veterinarian", or with
the descriptive designation of any other practitioner licensed by the law of the State in which
he or she practices to use or order the use of the device; and
•
the method for its application or use.
Labeling on or within the package from which the device is to be dispensed shall also bear
information for use under which practitioners licensed by law to administer the device can use the
device safely and for the purposes for which it is advertised or represented. This labeling
information includes indications, effects, dosages, routes, methods, frequency, and duration. Safety
labeling includes relevant information on hazards, contraindications, side effects, and precautions.
When a device is capable of producing serious injury, even when used by a person thoroughly
familiar with its operation, the directions for use shall provide detailed information. FDA has
specific regulations on the labeling of intrauterine contraceptive devices, 21 CFR 801.427, and for
diagnostic x-ray devices, 21 CFR 1020.30(h). In addition, FDA has issued general guidances for
labeling certain devices, i.e., transcutaneous electrical nerve stimulators and electronic muscle
simulators.
Where appropriate, directions for use should be supplemented with adequate warnings against
the use of the drug or device under certain conditions. Any caution statement, similar to the
directions statement, may appear in the labeling of the product; it is not necessary that it be printed
on the label. In each instance, the responsibility for the adequacy of the warning statement
appearing on the labeling rests with the manufacturer or distributor. For some devices, there are
national consensus standards that specify that certain caution statements be on the device. There is
no list of prescription devices in the CFR.
Sterile Devices
Special attention should be given to the labeling of sterile devices. For example, sterility may be
needed only for a portion of certain devices and this condition should clearly be identified in the
labeling. Devices that are not sterile in their entirety should be labeled to properly inform users what
is actually intended to be "sterile" in the package. For example, a possible limiting statement might
be:
11-5
"Caution: Only the fluid path of this set is sterile and nonpyrogenic. Do not use in a sterile or aseptic
area without proper precautions."
The label of multi-device kits or packages containing a combination of sterile and nonsterile
products will be considered to be false or misleading if it implies that all contents are sterile.
Some devices are intended to be sterilized by the user before use. In this situation, the labeling
should provide adequate information about a suitable method of sterilization and any precautions or
safeguards to be followed. For example, the labeling should describe any:
•
special cleaning methods required;
•
changes in the physical characteristics of the device that may result from reprocessing which
affect its safety, effectiveness, or performance; and
•
limit on the number of times resterilization and reuse can be done without affecting the safety
or effectiveness of the device.
In the case of single-use sterile devices, many manufacturers include labeling to advise against
resterilization and reuse. Some devices are not designed or constructed to be recleaned, and may not
be capable of withstanding the necessary recleaning and resterilization procedures. Where reuse is
common practice, manufacturers are encouraged to provide the information described in the above
list.
The need for users to have instructions on how to open a sterile device package to avoid
contamination of the device also needs to be evaluated. When necessary, such instructions should be
included in the labeling.
If a manufacturer modifies a device, the manufacturer should also review the labeling to ensure
that it reflects current revisions and specifications. Thus, change control forms should contain a
check off box for labeling and packaging. Some manufacturers identify labeling with a drawing
number plus a revision code or date as an aid in identifying current labeling. The package insert or
other labeling for in vitro diagnostic products is required to contain the revision date [21 CFR
809.10(b)(15)].
Shelf-life dating solely for package integrity and sterility is not usually required for general
medical devices. There may be a need for expiration dating when a particular component of a
device, such as a battery or diagnostic reagent, has a finite useful life. Labeling for in vitro diagnostic
devices [809.10 (a) and (b)] requires an expiration date or some other means by which users may be
assured of quality at the time of use. This requirement applies to both sterile and nonsterile in vitro
diagnostic devices.
Although not required by regulation, most manufacturers of complex devices and sterile devices
voluntarily use lot or serial numbers for production control and, if the need arises, to expedite
failure investigations, repairs, modifications, or recalls. Lot, batch, or other control numbers are
required for:
•
implantable and life sustaining devices [820.65, Traceability];
•
some products subject to radiological health standards [1002.30(b)(1), Records to be
maintained by manufacturers]; and
11-6
•
in vitro diagnostic devices [809.10(a)(9), Labeling for in vitro diagnostic products].
DESIGN OF LABELING
Various sections of the Quality System (QS) regulation have an impact on labeling including:
section 820.30, Design controls; section 820.80, Receiving, in-process, and finished device acceptance;
and section 820.70(f), Production and Process controls, which requires buildings to be of suitable
design and have sufficient space for packaging and labeling operations. Section 820.120 deals with
specific requirements for device labeling. These sections apply controls to the labeling content to
meet the needs of the user and patient, as well as to meet the labeling specifications contained in the
device master record. Applying the regulations to the physical design applications of labeling assures
legibility under normal conditions of use over the expected life of the device. It also helps assure the
proper inspection, handling, storage, and distribution of labeling. The requirements in 820.30(c),
Design input, address the intended use of the device, and the needs of the user and patient.
Labeling includes equipment labels, control labels, package labels, directions for use,
maintenance manuals, etc. The displays on CRTs and other electronic message panels are considered
labeling if instructions, prompts, cautions, or parameter identification information are given.
Adequate labeling for a medical device requires proper design and procurement of the labels and
labeling. Design includes generating the content of labels and labeling and making sure the content
meets FDA requirements as well as the needs of the customer. To achieve these goals a number of
concepts must be kept in mind such as: writing to the reader, referring to the actual device in
labeling, obvious identification of the controls used, etc. Design controls for label integrity are
discussed later.
There are some basic guidances, rules, and practices that can be used to immediately improve
writing. The following paragraphs will discuss them, with emphasis on how they can be used to make
labeling clear and comprehensible.
As an essential aid, writers are encouraged to obtain a copy of 40,000 Words published by
Webster’s New World Dictionary or a similarly titled book by any of the reference-book publishing
companies. Most of these reference books have about four pages of punctuation rules. Using these
pages of rules can immediately improve not only the style and clarity but also the accuracy of your
writing. Writers are also encouraged to obtain and use a standard college-level text on technical
writing.
Write to the Reader
The most serious problem is that writers tend to write to themselves. Their material is clear to
them so they mistakenly think it is as clear to others. For example, the sensitivity control on an
instrument is called "gain" control on page one of the instruction manual, "amplitude" control on
page two, and "level" control in the next section. Further, the photograph in the introduction shows
the same control with a call-out identification note labeled "Signal Adjust." No wonder readers get
confused! Yet the author of the example knew what he was trying to write about and, most certainly,
he was writing to himself.
11-7
When writing labeling, especially for an over-the-counter (OTC) device, the author must know
the reading level of the target audience. If data on reading levels is not available, this may necessitate
reader interviews to establish a reading level for the target audience. If the device is designed for
home use, a useful guide is Write It Right available through DSMA.
Refer to Actual Device
One simple way to reduce control identity confusion as described above, reduce other types of
labeling errors, and increase clarity is for authors to keep a labeled instrument, kit, or photograph(s)
nearby and refer to it as they write. It is easier to write the truth when you know the truth. Make
sure the terminology and descriptions in the labeling match that on the actual device. It is best to
always use the same title for each given item or control throughout the manual, insert, label, and
advertisement. Likewise, the same title should be used in charts, figures, or screen displays such as
cathode-ray tubes, LCD panels, etc. Remember to write to your intended readers, write with a
labeled device or photographs in sight, and use consistent titles.
Obvious Identification of Controls
Because the title of controls or other items in screen displays and other labeling should be exactly
the same as in the labels on equipment, reagents, accessories, etc., authors may need to develop and
use an appropriate correlation technique for corresponding titles in instruction manuals, package
inserts, etc. One common and simple technique is to use all capitals for the titles of controls in
labeling. For example:
OFF ⇐=#
ON
POWER SWITCH
╔════╗
║░░░░║
╚════╝
╔═══╗
║ ¤ ║
╚═══╝
PRESS FOR HEAT
READY LAMP
The associated text, for example, might state:
Flip the POWER SWITCH to ON.
In about three seconds, the READY LAMP will illuminate.
Now press the HEAT button to switch the heater on.
With this correlation technique, the words "on" and "off" are capitalized in the labeling only
when they actually appear on the instrument control panel. Note that "ON" is capitalized in
"POWER switch to ON" as the actual switch has "POWER," "ON," and "OFF" printed by it. In
contrast, note that "on" is not capitalized in the statement "to switch the heater on" as it is not a
label of a control on the device. Also, be careful to use a simple correlation system that is readily
apparent to the intended audience.
Don't Distract Reader
Readers are very busy trying to learn how to use a new device. They should not be annoyed by
any unnecessary distractions such as:
•
•
•
changes in format,
unusual typeface,
incorrect page numbers, and
11-8
•
incorrect figure numbers.
For a person trying to read in a hurry, a font such as script can be a major distraction; therefore,
it is best not to use script, italics, or any other unusual or hard-to-read type-faces. Remember, you
have decided to write for the benefit of the intended audience. Forget about your personal
preferences and use only the most common fonts. Also, select a type size that is readable at the
intended distance. For example, labeling displayed on the screen of a wall-mounted heart monitor
should be readable from several feet away. Also, use a consistent format throughout the document.
Check the format and section titles against information on the contents page. In some cases, such as
for in vitro diagnostic products, the arrangement of information in the labeling may be dictated by a
regulation. Page numbers should not be referenced in instruction or service manuals. It is too easy
for the actual page numbers to be changed during the original writing or when the manual is
updated. It is much better to refer to paragraph titles or numbers as these are less likely to change;
and, if changed, titles are more noticeable by writers and typists than are page numbers. The use of
correct figure numbers is easy -- just check them.
Short and to the Point
It is important to use sentence structure that will convey the intended message with a minimum of
misinterpretation or need to reread. Tests have been conducted to determine the ability of readers to
follow instructions in a sentence based on the number of activities to be performed. The average
person's ability to follow instructions decreases rapidly when a sentence contains more than two
facts. (Keep in mind your own experiences in reading instructions.) Therefore, sentences in labeling
need to be short and to the point. Avoid long strings of adjectives and be specific. Try to be as
specific as possible with your instructions. For example, "ambient" or "room temperature"
generally should not be used. Instead specify the desired or necessary range of operating conditions.
In many cases a list of activities to be performed is better than burying the facts in long sentences. A
numbered list is better if the user may have to repeat any part of the procedure. If it takes lots of
words to get to the point, the reader will probably miss the point! Short, choppy sentences are
acceptable in instruction manuals and other labeling. You are not trying to entertain readers with
beautiful, flowing prose -- rather, you want to catch their attention with key facts so they correctly
perform the specified instructions. Thus, use short sentences, get to the point, be specific, and keep
graphics and pictures near the corresponding text.
Gobbledygook
Another way to be more specific and shorten sentences is to avoid "gobbledygook." The
following terms were collected from actual instruction manuals:
ORIGINAL
Makes provisions for
Serves to
At the time of
In conjunction with
Carried out in
Comes up to
Will also serve as a chance to
Will be sure that will
Available through the use of
Care should be used so as not to
PREFERRED EQUIVALENT
*
*
When
And
Perform
Reaches
May
Ensure
*
Be careful
11-9
Be provided for positive determination
Causes power to be applied to
Due to the fact that
Take the form of
*
Switches power to
Because
Be
In most cases, the equivalent term in the list can replace the original term. For the asterisked
items, the equivalent is simply a direct statement of what is intended. Of the terms listed, the
combination most often used is "makes provision for." Simply eliminating "makes provision for"
and "be provided for" from labeling will result in an immediate improvement for readers.
Introduce Each Item
Always introduce each control, indicator, device, or subject before it is discussed in the text. The
introductions should be brief and may be very brief. Keep in mind the items will be described in
more detail later. Abbreviations and new or uncommon terms should be defined. The introductions
and definitions prevent readers from going into mental shock, breaking their train of thought, and
asking: What is this? By then readers have probably forgotten the last two or three facts read. Also,
readers may wonder about any "cliff-hanging" item when they resume reading. This disturbance
may detract readers from fully assimilating the next instructions being read. To avoid distractions
and confusion, a writer of labeling should always:
•
•
introduce each item, and
define new or uncommon terms.
With respect to definitions, a writer should never give a new meaning to an existing common term
in the language. To avoid this disservice, coin a special term or code number such as Class Q, Code
1, or Level 2.
Accentuate Key Terms
Whenever it is stated in instructions that something shall be done, then "shall" should be set in
bold type, or otherwise delineated. Likewise, caution and warning statements should be emphasized
by boxing, bold type, etc. Underlining should not be used as it makes the descending part of a letter
hard to read and appears to be top lining on some printers. Refer to any regulations or standards for
a specific product and use the recommended or required caution statements. When standard
terminology exists in a consensus standard, creating new caution statements is not advisable.
Confusion is less likely to occur when one stays with the commonly understood terminology.
Select Words Wisely
When large print is needed for reading at a distance or to attract attention to signs, caution labels,
and screen prompts, words generally should be short in order to fit the available space. This rule
also applies to the wording on control labels. This situation places a burden on the writer to select
terms that convey the desired message. Consider the following wording from two actual highway
signs:
PLANT TRAFFIC
ENTERING HIGHWAY
NO FISHING
OFF BRIDGE
11-10
Have you ever been run over by a pachysandra? If you can't fish off the bridge, does that mean
you are allowed to fish only on or from the bridge? Better choices for the intended messages are:
"Traffic entering highway" and "No fishing from bridge".
Test Labeling
Finally, always have someone not familiar with the product operate it exactly according to the
draft instructions, labels, screen displays, etc. You should not do any coaching because coaching
destroys the validity of the trial. By coaching you transfer your “memory” to the user. Therefore, no
coaching -- this is the "acid" test -- good luck! During the trials, note any significant problems and
make appropriate corrections to the instructions, prompts, or other labeling.
Label Integrity
All labels shall be designed and applied to devices and containers so that the labels will remain in
place and legible during the customary conditions of distribution, storage, and use [820.120(a)].
Likewise, other labeling such as user instructions should remain legible during customary storage
and use. For example, labeling printed by machines onto plastic in vitro diagnostic media plates is
often smeared and thus is inadequate [FD&C 502(f)]. The manufacturers of such devices should
assure that the print is legible and will remain legible until used.
Many magazines use "wet" ink which smears when touched by sweaty or oily fingers. Obviously,
this type of ink will not meet the design requirements for package inserts, instruction manuals, and
the like.
Labels may be mounted by adhesives, screws, rivets, drive screws, etc., or printed or etched onto
panels and/or onto controls. The labels should be located so that they will be seen but not be abraded
during use. (Many of us have seen the unbelievable cases where safety labels on ladders and riding
lawnmowers were placed in the foot rest areas. Of course, they were worn off after a few uses!)
Approval Policy and Procedure
The review of labeling from the design stage through to the finished device should be documented
like the review of other significant components. This includes the labeling development, any changes,
and final approval. Documentation should be included in the design history file of the procedures
used, signature of the responsible person, and date. Because several activities are performed and
controlled during the development and use of labeling, Table 11.1, “Drafting and Approval of
Labeling” and “Final Approval of Labeling, Advertising, Etc.” are presented as guidances. This
table contains a typical sequence of events required to develop and control labeling. Other controls
are discussed below.
Before release for use, labeling should be reviewed and approved by product development,
service, marketing, quality assurance, and other appropriate managers (820.30). Manufacturers
need to have a policy/procedure which covers the drafting, review, and approval of labeling.
Approval forms are generally used in conjunction with such a policy/procedure. A sample approval
form and procedure are presented at the end of this chapter. Other procedures and forms such as
11-11
"Change Control" are referenced in this procedure. Note that this procedure also covers other
elements such as a correct device master record, correct transfer of labels into production, lot
control, change control, etc. Samples of various procedures appear at the end of chapters throughout
this manual.
Design Transfer
Specifications are required in the device master record for the content and physical design
parameters
of labels. (see Chapter 8). Labeling specifications include the engineering drawing and/or artwork
for each label, appropriate inspection or control procedures, and appropriate procedures for
attaching the labels. All procedures, drawings and artwork should have the name of the preparer, an
approval signature, and a date. The approval signature, date, etc., may be on the back side of
artwork or on a label approval form. Further, artwork may contain only an identification code or
title if the "content" of the artwork is duplicated on approved engineering drawings, adequately
identified, or cross-referenced with respect to the label approval form. That is, a manufacturer
should be able to identify isolated artwork.
Hardcopy labels, package inserts, and similar labeling are also specified and purchased as
components (see Chapter 8). For correct purchase and use of labeling, specifications are usually
stated on engineering drawings and/or purchase specifications. Thus, artwork or "copy" alone will
not fulfill the device master record and purchasing control requirements for labeling except for the
most simplistic labeling such as brief errata sheets.
The engineering drawings or purchase specifications should specify, as appropriate, the label
substrate, dimensions, ink, finish, mounting method, etc., so that the purchased label will remain
attached and legible during the customary conditions of processing, storage, handling, distribution,
and use.
Table 11.1 TYPICAL SEQUENCE OF THE CONTROL OF LABELS
PHASE
SECTION
CONTROL ACTIVITY
1. Design
820.30, 820.120
& 820.130
Meets needs of user and intended use.
Text review. Quality of mounting such as rivets, adhesives, etc. Quality of
ink, anodize, etc. Content per 21 CFR 801 and 809 company claims and
standards.
2. Verification/
Validation
820.120, 820.75
& 820.30
Simulated or actual processing such as sterilization, shipping tests, label
affixing, etc. Saline, alcohol, and coffee spill tests?
3. Changes
820.30 & 820.75
Establish and maintain approval procedures.
4.
Documentation
820.30,
820.181 &
820.120(e)
Approve, date and change control label drawings.
A key label shall contain the control number of the finished device either
on or accompanying device.
5. Procurement
820.120(b)
820.180
Proofread before release to inventory stock.
Record signature of proofreader and date.
6. Storage
820.120(c) & (d)
Store labels to prevent mix-ups.
Restrict access to authorized persons.
7. Separate
operations
820.120(d)
Separate multiple operations to prevent mix-ups.
8. Area
820.120(d)
Before beginning labeling operations, designee to inspect area and remove
11-12
inspection
extraneous devices and labels.
9. Issuance
820.120(b),
820.120(e) &
820.65
Examine for identity and, where appropriate, expiration date and control
number. Record date and person examining labels.
10. File Sample
820.184(e)
Copy of primary identification label shall be in the device history record.
11. Inspection
820.80(d), 820.86
& 820.80(e)
Inspect finished device per written procedure.
Designee shall check all acceptance records and test results and see that
requirements are met and records are present and complete.
Front panels, other instrument panels, meters, fuses, pushbuttons, and the like often are either
labels or contain labels and thus should, as appropriate, meet device master record and control
requirements. Component specifications, assembly drawings, and test/inspection procedures are
appropriate controls to prevent mixup of meters, push buttons, and other labeled instrument
controls.
Whether a manufacturer considers a software driven display to be labeling or data makes little
difference under the QS regulation because, either way, the finished device labeling or data should
meet the device master record specifications. When manufacturers develop and validate software,
they should also review any electronic displays to see that the "labeling" meets all applicable
requirements, such as adherence to specifications in the device master record, correct parameter
identification, agreement with the instruction manual, and, of course, correct display of performance
data.
Production Controls
When reviewing or auditing labeling operations, it is wise to keep in mind that the GMP
requirements are flexible. The degree of labeling control needed to satisfy the QS regulation varies
considerably for different devices and operations. In order to avoid wasting money and increasing
the cost of health care, manufacturers need to give considerable and prudent thought to the
appropriate level of control needed for their operations as allowed by 820.5. Information and
guidances presented in this manual should aid manufacturers in making these decisions. The level of
control needed should be reconsidered when products are changed. Likewise, the controls needed,
and the success of the existing control program, should be reviewed during quality system audits (see
Chapter 17).
Medical device manufacturers should incorporate in their quality system several elements that
relate to labeling in order to meet the GMP requirements. The quality system should be adequate to
assure that labeling reflects user needs, meets the device master record requirements with respect to
legibility, adhesion, etc., and assure that labeling operations are controlled so that the correct
labeling is always issued and used.
Receipt and Inspection
Upon receipt, all packaging and labeling materials, including preprinted containers, inserts, and
preprinted packaging materials, should be examined and, if deemed necessary by the company,
tested to assure conformance with specifications as discussed in Chapter 10, Purchasing and
Acceptance Activities. Also, samples of labels, including labeled panels, meters, etc., shall be
proofread by a designated individual(s). After being accepted by a responsible individual, these
components may be placed into inventory or into production. These inspections shall be recorded in
11-13
the device history record as required by 820.80(e) and 820.120(b) to show that inspection and
proofreading were performed. The inspection record for device labeling should be kept simple.
Area Separation and Inspection
All labeling and packaging operations should be separated to the degree necessary [820.120(d)] to
assure there are no mixups between similar products or labels. Separation may be either a physical
or spatial separation or by performing the labeling and packaging at different times for different
devices. Separation is not required when mixups are impossible, such as the case of labeled front
panels that only fit the intended family of devices.
The likelihood of a labeling mixup determines how stringent production area controls should be.
For example, label control need not be stringent if only one product or dissimilar products and
labeling that are unlikely to create confusion are processed. Before beginning any packaging and
labeling operation in which mixups could occur, the production area and equipment for the
operation should be thoroughly examined to ensure that any devices and labeling materials
remaining from previous operations have been removed. It is important to make certain that the
surrounding area, tables, packaging lines, printing machines, and other equipment are cleared of
labels and other materials used in the previous operation.
Unused labeling that contains pre-coded serial numbers, manufacturing dates, expiration dates,
control numbers, etc., should be destroyed and not returned to the label storage area. The GMP
requirements do not include reconciliation of the number of labels used with the number issued,
although, this control is recommended for some devices, such as when different sizes of the same
product are being packaged or otherwise labeled.
STORAGE
Where feasible, labels for similar devices should be designed with different shapes and colors to
reduce the probability of mixups. Thereafter, all printed packaging and labeling materials, including
preprinted containers, inserts, and preprinted packaging materials shall be stored in an area and
manner suitable to prevent mixups [820.120(c)]. For example, if labels from one container are
accidentally dropped, they should be stored so they will not fall into another container of similar
labels. Labeling should be identified and segregated to the degree necessary to prevent mixing of
similar labeling. Access to labeling should be limited to authorized personnel.
Storage control should be appropriate for the number and kind of devices. For example a
manufacturer that has only one product with one label does not need an elaborately controlled
storage area. Similarly, a manufacturer with only a few types of devices having dissimilar labeling
would not normally require stringent control.
One case that requires dedicated attention to storage and control is prelabeled "sterile" but
not-yet-sterilized devices. Manufacturers should make absolutely certain that mixups cannot occur.
Also, they should make certain that all samples used for market promotion are sterile or labeled
with a manifest caution statement, because a packaged and labeled market-promotion sample might
be used by the recipient. One approach is to sell sterile samples at zero cost so that such samples are
subjected to all of the company product release and distribution controls. Quality awareness
training is required by section 820.25. Marketing personnel should be informed of labeling control
requirements and the consequences of a violation.
Label Check and Record
11-14
In summary labeling should be carefully examined to assure that the contents of the labeling
comply with the labeling specifications in the device master record. This examination should include
any control numbers or expiration dates used on the labels. A record of this check, including the
date and name of the person performing the examination, should be made in the device history
record.
If expiration dates are used, they should reflect the time limitations within which the device is fit
for its intended use when stored and used per its labeling. The manufacturer should have stability
test data establishing how long the device will remain fit for use to support expiration dates.
If label mixups cannot occur -- for example, a manufacturer makes only one device or uses only
one label -- and there are no control numbers or expiration dates, the original inspection when the
labeling was placed into inventory is an adequate check for compliance with the device master
record specifications. A second check need not be performed because it serves no purpose (820.5). If,
however, there is any possibility that incorrect labeling can be used, a second check should be made
when the labeling is issued for application, packaging, or shipping.
Control Numbers
Devices intended for surgical implant, and devices intended to support or sustain life and whose
failure to perform properly can be expected to result in significant injury, shall contain a control
number, serial number, letters, etc., for traceability (820.65). Procedures for establishing and
maintaining control numbers shall be documented in the DHR. This means a control number for
the finished device, and not the label itself. Although this control number may be on a label, most
labeling also contains another number, such as a drawing number, for control of labeling
configuration and procurement.
The control number for traceability need not be on every label on the device; however, the control
number should appear on the primary label that goes to the ultimate user. The label on a shipping
carton does not meet this requirement because bulk items may go to a central distribution point in
the user-facility and the shipping carton will most likely be disregarded.
Access Restriction
Access to labeling should be restricted to authorized personnel. Labeling also should be stored in
an adequately segregated area to minimize the chance of mixups. Segregation is recommended
because it increases the control over the label storage area with no significant increase in cost.
CHANGES
Labeling is a component of the device and part of the device design output; therefore, all changes
to labeling should be made under a formal change control system. Design changes shall meet
820.30(i); and other changes are made according to 820.40. Any changes to labeling should be
formally reviewed and authorized before implementation. That is, follow the guidance in this
chapter as if new labeling is under development.
When making changes to primary aspects of a device and to primary documentation, the review
group should determine if any secondary items such as labels or instructions are affected and also
need changing. There should be a check-off block on change-order forms, or any other change
control mechanism, for recording that the effect of the primary change on labeling was considered
11-15
and appropriate action was taken. The failure of a change control system to alert employees of basic
requirements is considered to be a serious deficiency in a quality system.
SHIPPING FOR PROCESSING
Devices that are prelabeled “sterile,” but are not yet sterilized, require be controlled at the
manufacturer and during shipment for further processing. Likewise, devices that have been
sterilized and shipped to the manufacturer's warehouse or other controlled distribution point before
final release should be properly labeled. The pallets, or designated unit, should be marked to
indicate the status of the device, such as "non-sterile," "sterilized: awaiting test results," or an
equivalent statement (820.86). The company should be able to show that it has control of the devices
until final release and, could have them destroyed or returned for reprocessing if necessary. Unless
so qualified, a distributor's warehouse or facility is not considered a controlled distribution point.
The QS regulation states that each manufacturer shall establish and maintain procedures to
ensure that mixups, damage, deterioration, contamination, or other adverse effects to product do not
occur during handling (820.140).
The storage regulation at 820.150 states, “(a) Each manufacturer shall establish and maintain
procedures for the control of storage areas and stock rooms for product to prevent mixups, damage,
deterioration, contamination, or other adverse effects pending use or distribution and to ensure that
no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product
deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its
condition shall be assessed as appropriate. (b) Each manufacturer shall establish and maintain
procedures that describe the methods for authorizing receipt from and dispatch to storage areas and
stock rooms.”
Manufacturers of sterile devices commonly label devices as sterile at one establishment and ship
them to another facility or a contract sterilizer for sterilization. Shipments of nonsterile devices
labeled as sterile are clearly misbranded and adulterated, and if diverted into consumer channels,
could create a potential health hazard. FDA recognizes that this longstanding practice is an
economic necessity for many manufacturers. Therefore, to meet the needs of these manufacturers in
a way that will also assure the protection of the public health, FDA added Part 801.150(e) to the
Code of Federal Regulations (CFR). It is reprinted below.
(e) As it is a common industry practice to manufacture and/or assemble, package, and fully
label a device as sterile at one establishment and then ship such device in interstate commerce
to another establishment or to a contract sterilizer for sterilization, the Food and Drug
Administration will initiate no regulatory action against the device as misbranded or
adulterated when the nonsterile device is labeled sterile, provided all the following conditions
are met:
(1)
There is in effect a written agreement which:
(i)
Contains the names and post office addresses of the firms involved and is signed by the
person authorizing such shipment and the operator or person in charge of the establishment
receiving the devices for sterilization,
(ii)
Provides instructions for maintaining proper records or otherwise accounting for the number
of units in each shipment to insure that the number of units shipped is the same as the
number received and sterilized,
11-16
(iii)
Acknowledges that the device is nonsterile and is being shipped for further processing, and
(iv)
States in detail the sterilization process, the gaseous mixture or other media, the equipment,
and the testing method or quality controls to be used by the contract sterilizer to assure that
the device will be brought into full compliance with the Federal Food, Drug and Cosmetic
Act.
(2)
Each pallet, carton, or other designated unit is conspicuously marked to show its nonsterile
nature when it is introduced into and is moving in interstate commerce, and while it is being held
prior to sterilization. Following sterilization, and until such time as it is established that the device is
sterile and can be released from quarantine, each pallet, carton, or other designated unit is
conspicuously marked to show that it has not been released from quarantine, e.g., “sterilized -awaiting test results” or an equivalent designation.
OVER-LABELING
Over-labeling by placing a new label over an old label is discouraged by FDA but is acceptable as
long as the new label and its use meet GMP requirements [(820.30, 820.120, 820.90(b)(2)] for user
needs, attachment, legibility, reprocessing, and change control. Over-labeling is also discouraged in
some foreign countries.
11-17
EXHIBITS
Exhibits that cover labeling design and labeling control are presented on the following pages.
These exhibits show how some GMP requirements for label control may be met. These procedures
and forms may need to be modified to meet the needs of a specific operation.
Drafting and Approval of Labeling
This drafting and approval procedure is used to establish a uniform system for controlling the
content of labeling and for approving labeling. This procedure is adaptable for use by any size
manufacturer. The approval form which follows may be used with this procedure.
Approval Form for Labeling, Advertising, Literature, etc.
This form is intended for use by a medium to large manufacturer, however, the checklist style can
be adapted even to a small manufacturer. The areas of concern are listed under the group that is
responsible for that concern. Thus, every department has input into the acceptability of the labeling.
Administration Set Label
This example of a label for an administration set begins with a complete description of the device
inside the package. The directions for use section is arranged so that each point in the directions for
use is numbered and only one point is made for each step. The various points in the directions are
short and to the point. Where emphasis is needed, as in the case of air bubbles, the information is
bolded for further emphasis.
Labeling Control Record
This blank copy of a labeling control record shows what a sample form looks like. At the bottom
of the form, there is space to attach the actual labeling used so that a comparison of the actual
labeling used versus that required can be made during product release review.
Device History Record: OB/GYN (Plate)
The history record exhibited here is limited to the filling operation for a media product. The form
has space to print the same label as printed on the plates during the filling operation for label
control and release review. This technique eliminates human copying errors.
User/Reader Comments
Feedback is an important element in any QA system. Whenever manuals or instructions form
part of the labeling for a product, it is wise to solicit review from persons not familiar with the use of
the product. These people can be employees of the manufacturer or, as in this exhibit, actual users of
the product. The information received will reflect the problems encountered by persons trying to
follow the instructions without any preconceived knowledge of the actual operation of the product.
11-18
PAGE 1 OF 3
Procedure Policy Title: DRAFTING AND APPROVAL OF LABELING SOP#:_______
Prepared by:
App:
Date:__________________
Prep. Date:
Rev:
Date:
ECN History:
1.0 PURPOSE
To establish a uniform procedure for controlling the content of labels and labeling and obtaining
approval within our company.
To assure compliance with GMP requirements and with company policy directives.
2.0 SCOPE
Applies to all devices including those used for market research or clinical investigations.
Advertising material is excluded from this SOP. It is covered by our SOP #____, "Advertising
Material Control and Approval."
3.0 REFERENCE DOCUMENTS
3.1 Food and Drug Administration LABELING, GMP, etc. requirements in 21 CFR Parts 800-1299.
3.2 SOP #_____, Advertising Material Control and Approval
3.3 SOP #_____, Change Control System
4.0 FORMS
4.1 Form SOP #_____, Labeling Development and Verification Checklist
4.2 Form SOP #_____, Labeling Approval Form
4.3 Form SOP #_____, Engineering Change Order Form
5.0 DEFINITIONS
5.1
Labeling is all labels and other written, printed or graphic matter accompanying or attached to
the device or its container.
6.0 PROCEDURE
6.1 Preparation and Approval
PAGE 2 OF 3
11-19
The Labeling Development and Verification Checklist should be used as a guidance for all
activities because the finished labeling must be evaluated versus this checklist.
6.1.1 The need for a label or labeling is determined by an operating department such as Engineering,
Marketing, Manufacturing, or Quality Assurance. Marketing, as appropriate, will conduct
and document literature searches and perform design input market research to determine
any special needs of the users. Design input, regulatory, safety, and other appropriate
information shall be used to create a labeling specification.
6.1.2 The Engineering Department prepares a manuscript complete with illustrations or prepares a
drawing(s) of the label showing the wording, label use, and/or location. The label may be on
a front panel drawing or other engineering drawing.
6.1.3 When final prototypes and/or pilot production models are available, the labeling shall be
verified and the results recorded on the Labeling Development and Verification checklist. If
needed, appropriate corrective action shall be taken by the appropriate department. The
completed checklist shall be filed with the device design verification records.
6.1.4 Before final approval, labeling will be discussed at appropriate design review meetings. The
minimum attendees are the originator, Engineering, and QA.
6.1.5 The Engineering Services Department then prepares form SOP #_____, Labeling Approval
Form, and circulates it to the originating department, Training and Education, Marketing,
and Quality Assurance for approval. (See the following sample approval form.)
6.1.6 Engineering Services will coordinate and file all labeling verification checklists, notes, approvals
and approval forms in the design history file.
6.1.7 When approval is received from all parties, the label or manuscript is assigned a drawing
number and is released and added to the product structure (DMR Index) following the
Change Control System (SOP #_____) procedure.
6.2
Implementation and Control
6.2.1 When labels or labeling are produced, Quality Control must proofread the material and verify
that it is correct by first article inspection and so indicate by signing an appropriate
document.
6.2.2 All labels and labeling will be reviewed by QA for lot control requirements. Each original
document will be marked by Engineering Services to indicate the level of control required.
At least one label on each device intended for surgical implant into the body or to support or
sustain life must have a lot, serial, or other control number. See 820.65, Traceability.
PAGE 3 OF 3
7.0 EXPERIMENTAL DEVICES
11-20
7.1
Labels and labeling for experimental or investigational devices are required.
7.2 The documentation need not be as complete as for production labels and labeling; but, it must be
adequate to allow procurement of the labels or labeling and adequate for the intended use. If
appropriate, such labeling must meet 21 CFR 812.5.
8.0 CHANGES
8.1 Any changes to released labels or labeling are accomplished according to SOP #_____, "Change
Control System".
9.0 SCHEDULES
(Design QA requirements are presented below. There are also related production requirements.)
9.1
Drafts must be generated according to a schedule that allows a normal approval procedure.
While urgent copy approval is occasionally necessary, it should not become standard operating
procedure.
9.2
All labels must be approved according to the routine engineering schedule for components.
9.3
Labeling must be approved before or when the device is released for full-scale production.
HOWEVER, any pilot units placed in commercial distribution must be labeled with approved
pilot or final labeling.
9.4
The design review for any pilot lots and the design review of initial full-scale production lots
shall include a design review of labeling.
9.5 The design review records for labeling shall be identified for easy recall. These records shall be a
part of the design history file.
11-21
FINAL APPROVAL OF LABELING, ADVERTISING, Etc.
Return to Approval Coordinator after each signature or after checking any "no" box.
Doc. No.
Dwg. No.__________
Title
Intended use/distribution
Project Leader
Approval Coordinator
Yes
[]
[]
[]
[]
[]
[]
[]
[]
[]
No
[]
[]
[]
[]
[]
[]
[]
[]
[]
N/Applicable
[]
[]
[]
[]
[]
[]
[]
[]
[]
ENGINEERING
Tech. specs., installation data, & part numbers correct.
Procedural information is accurate and complete.
Standards imposed by CSA, UL, IEC, etc. are met.
Illustrations are technically accurate.
Equipment protection cautions included where necessary.
Procedures verified on final prototype or prod. model.
Changes requested in draft have been made or negotiated.
Procedures are safe and effective.
Final draft has been proofread.
Project Engineer:
Date: __/__/__
[]Approved
[]Approved with noted changes []Not approved
Engineering Services Mgr:
Date: __/__/__
[]Approved
[]Approved with noted changes []Not approved
Yes No
[]
[]
[]
[]
N/A
[]
[]
SERVICE
Maintenance information is written for intended user.
Lists part numbers needed for maintenance and repairs.
Service Manager:
Date: __/__/__
[]Approved
[]Approved with noted changes []Not approved
Yes No
[]
[]
[]
[]
N/A
[]
[]
TRAINING AND EDUCATION
Document is adequate for training purposes.
Document agrees with experience of training specialists, if experienced
with this or similar products.
Training Manager:
Date: __/__/__
[]Approved
[]Approved with noted changes []Not approved
Yes No
[]
[]
[]
[]
[]
[]
[]
[]
N/A
[]
[]
[]
[]
MARKETING
Material is effective and complete for intended use.
Material meets the needs of the international market.
Material is professional and projects the company image.
All claims supported by verification data.
Date: __/__/__
Project Manager:
[]Approved
[]Approved with noted changes []Not approved
Director Marketing:
Date: __/__/__
[]Approved
[]Approved with noted changes []Not approved
Yes No
[]
[]
[]
[]
N/A
[]
[]
QUALITY ASSURANCE
Hazards situations are highlighted with adequate warnings.
All FDA labeling and GMP requirements, are met.
Date: __/__/__
Quality Engineer:
[]Approved
[]Approved with noted changes []Not approved
Form #
Approval Coordinator
signature
Approved
11-22
Date: / /
Date: / /
MAJOR MEDICAL, INC.
ADMINISTRATION SET
Catalog Number 1403
With macro non-vented drip chamber, 80 inch length and "Y" site.
INSTRUCTIONS FOR USE
1. Prepare solution container.
2. Close side clamp and open
device.
3. Remove protector cap from drip chamber piercing spike.
4. Aseptically insert spike through set port of solution containers.
5. Squeeze and release drip chamber until solution half fills the drip chamber.
6. Open slide clamp and allow the tubing to fill with solution, thus eliminating all air
bubbles. DO NOT ALLOW AIR TO BE TRAPPED IN SET.
7. Close slide clamp.
8. Make venipuncture with I.V. device of choice.
9. Open slide clamp.
10. Regulate rate of infusion with
device.
Micro Set: 60 drops delivers about 1 ml; Macro Set: 15 drops delivers about 1 ml.
11. To stop flow without disturbing valve adjustment, use slide clamp.
PRECAUTIONS:
•
Supplementary medication may be injected with 20 or 22 gauge needle into
injection site.
•
If fluid path is interrupted, take special care to ensure fluid path has not been
contaminated.
•
Do not use to administer blood, blood products, suspensions, emulsions or any
medication not totally soluble in the solution being administered. These
medications may be administered through the distal Y-injection site with slide
clamp closed.
•
Puncturing drip chamber or tubing can cause air contamination and leaking.
FOR SINGLE USE ONLY
CAUTION: Puncturing tubing can cause air embolism.
NONPYROGENIC
STERILE: Unless Package has been opened or damaged.
CAUTION: U.S.A. Federal law restricts this device to sale by or on the order of a
physician.
STORE AT ROOM TEMPERATURE
Sterilized by E.T.O.
Date of Sterilization:
Lot No.
11-23
Manufactured for:
Major Medical, Inc.
Debbiville, Maryland 20906
Printed in U.S.A.
LABEL CONTROL RECORD
Sheet 1 of 1
1. Labeling area was inspected and no labels from previous operations were present.
Initials:
2. Just before starting the labeling operation, labels were examined for correct:
[ ] Identity
[ ] Expiration date on label
Name:
[ ] Control number
Date:
3. REAGENT INFORMATION
3.1. CONTAINER INFORMATION
Description
Size
Catalog Number
Type
Stability
Quantity
Lot Number
Other
Reagent Expiration Date
Initials
Date Recorded
4. [ ] Labels were correctly applied.
5. [ ] Unused labels with filled-in expiration date were destroyed.
6. [ ] Remaining labels, if any, were returned to proper storage area.
7. Place sample(s) of labels here:
8. Inspector
Completion date
Comments:
9. [ ] Place completed form in the device history record for this lot.
Form No. LC-11-21
Rev. A Approved
Date
DEVICE HISTORY RECORD
11-24
I. INITIATION
DEVICE NAME:
OB/GYN
THEORETICAL YIELD:
2500
EXPIRATION:
DEVICE LOT NO.:
INITIATED BY:
DATE INITIATED:
II. FILLING OPERATIONS
A. CONTAINER:
MFG:
LOT NO.
B. LABELING
..........................
.
.
Paste Label Here
.
or
.
Run This Sheet Through
.
Labeling Machine
..........................
LABEL PREPARED BY:
LABEL APPROVED BY:
C. MEDIA
SECTION
MEDIA
BATCH NO.
TEMP.
DEPTH OF
RANGE FILL (mm)
1
Levine EMB
41-52 C
3.5 - 4
2
BiGGY
41-52 C
3.5 - 4
3
Mannitol Salt Agar
41-52 C
3.5 - 4
4
TSA w/5% Human Blood
44-52 C
3 - 3.5
5
Mod. Thayer Martin
44-52 C
2.5 - 3.5
FILLING ROOM PERSONNEL:
DATE DEVICES FILLED:
11-25
.
.
.
.
.
USER OR READER COMMENTS
In order to improve the quality and utility of our manuals and inserts, our company
needs the active cooperation and participation of its user readership. Your comments as
a user or reader will be greatly appreciated and reviewed for information in the next
revision of this document.
Please comment on the completeness, accuracy, organization, usability, and readability
of this manual or insert.
Did you find errors in this document? If so, specify by page.
How can this document be improved?
Other Comments:
User's Name:
Position:
Employer:
Department:
Address:
City:
State:
Zip:
Date:
Country:
Form Number: MKT-139 Rev. 1
Revised: J. Strojny, 2-96
Edited: J. Puleo, 3-1
Revised: A. Lowery, 3-4
11−26
Edited: J. Strojny 3-4 and 3-12
Reviewed: J. Puleo, 3-14
Edited: J. Strojny, 3-15
Revised: A. Lowery, 3-20
Revised: J. Strojny, 4-16
Revised: A. Lowery, 4-16
Edited: J. Strojny, 4-18
Edited: T. Cardamone, 4-22
Edited: N. Freeman, 5-3
Edited: J. Strojny, 5-9
Reviewed: T. Cardamone, 5-9
Revised: K. Trautman, 7/96
Edited: J. Strojny, 8-9
Word Searches: GMP, QS, firm, guideline, U.S. Designated Agent, chapter
Edited: T. Cardamone, 8-13
Edited: J. Strojny, 9-9 word search: Quality System = QS after initial reference
Edited: J Strojny, 9-10 chapter
Edited: C. Nelson, 10-24 chapter
Edited: J. Puleo, 11-6 word search
Edited: C. Nelson, 10/96
11−27
12
PRODUCT EVALUATION
INTRODUCTION ................................................................................................................. 12-1
Evaluation Specifications ................................................................................................. 12-2
CORRECTIVE AND PREVENTIVE ACTION ................................................................ 12-3
REPACKER/RELABELER DEVICE EVALUATION ..................................................... 12-4
NONCONFORMING PRODUCT ....................................................................................... 12-4
FAILURE INVESTIGATION .............................................................................................. 12-5
EXHIBITS ............................................................................................................................ 12-7
Portable Defibrillator Test Procedure ................................................................................. 12-7
Test DHR of a Printed Circuit Board Assembly ............................................................ 12-7
Device History Record (urine plate)................................................................................. 12-7
Batch Production Record (XLD) ..................................................................................... 12-7
Batch Production Record (Thayer Martin)..................................................................... 12-7
Batch Production Record (Blank form)........................................................................... 12-7
INTRODUCTION
Product evaluation is performed to show with documented evidence that a component, in-process
unit, or finished device was manufactured according to the device master record (DMR) and meets
all of the acceptance criteria/acceptance specifications in the DMR. The blank forms for recording
the data become a part of the DMR. The emphasis in this chapter is on finished device evaluation;
however, evaluation of incoming product and in-process units is conducted according to the same
type of controls [820.80(a), 820.80(b), 820.80(c)].
The GMP requirements for finished device evaluation are covered in section 820.80, which
requires that the manufacturer establish and maintain procedures for finished device acceptance, to
ensure that each production run, lot, or batch of finished devices meets acceptance criteria. Finished
devices shall be held in quarantine or otherwise adequately controlled until released. Finished
devices shall not be released for distribution until:
•
•
•
•
the activities required in the DMR are completed;
the associated data and documentation is reviewed;
the release is authorized by the signature of a designated individual(s); and
the authorization is dated.
Manufacturers shall also identify by suitable means the acceptance status of product, to indicate
the conformance or nonconformance of these items with acceptance criteria. The identification of
acceptance status shall be maintained throughout manufacturing, packaging, labeling, installation,
and servicing of the product to ensure that only products which have passed the required acceptance
activities are distributed, used, or installed (820.86).
If a manufacturer has adequate test and inspection procedures and these are used correctly by
appropriately trained personnel, then there is a high probability that devices released for
distribution will meet the company device specifications for acceptable product. Further, the data
collected during in-process or finished device evaluation should be appropriate, complete, and
12−1
correct. This data shows the good and bad points about the product and specific production
activities. The data may be fed back into the quality system to identify and solve real problems as
well as to help maintain and improve the quality system.
Evaluation Specifications
In order to be assured that a device is fit for the intended use, a manufacturer should decide
which characteristics of a device to test and/or inspect and to what detail or extent to test and/or
inspect for conformance with the device specifications.
Decisions on what to test and how to test are made during the product and process development
phase. For example, this decision is typically based on the:
•
•
•
•
•
•
•
•
intended use;
intended user;
nature of the device and its components;
intrinsic safety of the device;
reliability of the device;
overall process capability of the manufacturing operation;
characteristics of test and inspection equipment and procedures; and
performance margin of the device compared to the device specification.
Device test and/or inspection specifications, and test and/or inspection procedures, shall be
carefully written and shall cover all appropriate points in the device acceptance specifications, in
order to improve communication and reduce errors.
Design controls in 820.30(f) require device developers to verify the device design. Verification
requires each manufacturer to write a test protocol and test, to the maximum feasible extent, all
parameters of each device design against the design input specification. (The design input
requirements become the input specifications at the verification stage of the development.) The
verification test protocol includes the tests that will be performed on production units. Therefore,
the production test procedures and some aspects of the inspection procedures are easily derived
from the verification protocol.
Before the manufacturer is ready for full scale production, the test and inspection decisions shall
be completed, documented as test/inspection or acceptance procedures, and approved for use. It is a
violation of the FD&C Act to place inadequately evaluated devices into commercial distribution. It is
also a violation of the quality system regulation to allow test and inspection procedures to evolve
during production, except during a highly controlled pilot-production phase. Further, devices that
are not adequately evaluated may not meet company written or unwritten quality claims -manufacturers cannot bypass their responsibility by simply not writing quality claims. Under
Section 501(c) of the FD&C Act, a device is adulterated if its purity or quality falls below that which
it purports or is represented to possess.
By the time the manufacturer is ready for production, the device specifications shall be supported
by one or more test and inspection procedures documentation. These procedures are part of the
DMR. To reduce drafting, filing, retrieval, and copying costs, test and inspection procedures may
appear on process and assembly documents. Combination documents are commonly used for the
fabrication and inspection/testing of subassemblies. There may be several test and inspection
12−2
documents because evaluation may be performed at several in-process stages and at the finished
device stage.
Although the manufacturer shall establish and maintain procedures for finished device
acceptance, there are situations where a simple data sheet or blueprint may be referred to as the
written acceptance criteria. For example, the acceptance of a simple molded or machined component
or device may be determined by using a checklist, blueprint, or specification which specifies finished
article dimensions, flash removal, etc. In machine-shop operations, a blueprint or engineering
drawing may be used as acceptance criteria and used to meet the quality system written procedure
requirements.
CORRECTIVE AND PREVENTIVE ACTION
GMP section 820.100 requires an analysis of problem data, returned product, and an
investigation of non-conforming product. Also 820.198 requires an investigation of complaints that
allege a device does not meet specifications. Section 820.100 refers to analysis of processes, work
operations, concessions, quality audit reports, quality records, service records, complaints, returned
product, and other sources of quality data to identify existing and potential causes of nonconforming
or other quality problems. Section 820.198 also involves reviewing and evaluating complaints to
determine whether or not an investigation is necessary. All these activities and their results shall be
documented.
Some devices have a specified requirement for servicing. If this is the case, the manufacturer shall
establish and maintain instructions and procedures for performing and verifying this servicing
(820.200). The servicing reports shall also be analyzed using 820.100, Corrective and Preventive
Action; if the servicing involves a death or serious injury, the service report is considered to be a
complaint per section 820.198, Complaint Files, and is reported to FDA per parts 803 and 804,
Medical Device Reporting.
The significance of the device and any hazard the defective device presents should be taken into
consideration when determining compliance with corrective and preventive action requirements.
Analysis shall be taken to the level necessary to determine the actual failure mechanism, e.g.,
defective component, incorrect raw material, erosion, composition, etc. The cause of failure is
obvious in some cases and a formal investigation may not be needed. A record of the investigation,
follow up, and conclusions shall be made in accordance with section 820.100.
When a systematic failure has been diagnosed, manufacturers need not analyze every device with
the same diagnosed symptoms. However, enough devices should be analyzed to clearly establish
symptoms before any assumptions are made about the cause of failure or about corrective actions.
When an investigation results in identification of a deficiency, such as a failed component or a design
flaw, and this deficiency may exist in other product lines, the investigation will not be effective
unless it extends to determining the effect on other product lines.
If the failure is design related, the design shall be corrected per the design control requirements in
820.30 in order for the devices to meet company quality claims and not be adulterated under the
FD&C Act section 501(c). When a failure is determined to be related to documentation, assembly,
processing, labeling, testing, packaging, or other manufacturing operations, the manufacturing
deficiency shall be identified, corrected, and documented.
12−3
REPACKER/RELABELER DEVICE EVALUATION
Finished devices received by a repacker/relabeler typically have been inspected and conform to
specifications determined by the original manufacturer except for the final packaging and/or
labeling. In most cases a repacker/relabeler would not have to assure that the finished device as
received meets performance and configuration specifications. Finished bulk materials, such as
dental resins, in vitro diagnostics, etc. may be accepted on the basis of a certificate of analysis for
each batch.
Before releasing devices for distribution, repackers/relabelers should assure that devices are
properly labeled (see chapter 11) and packaged (integrity, contents, etc., also see chapter 13). Often
this can be accomplished using a list, illustration, or a model. When the packaged product will be
sterilized or aseptically filled, written instructions and inspection/testing are necessary. Final
acceptance of repacked/relabeled devices shall be recorded in accordance with 820.80(e). As noted,
the final acceptance data is primarily related to correct labeling, correct packaging, and sealing of
the packaging. In the case of aseptic filling operations, validation of the filling operations and
finished device sterility testing are required.
NONCONFORMING PRODUCT
The manufacturer shall establish and maintain procedures to control product that does not
conform to specified requirements. These established procedures shall include identification,
documentation, evaluation, segregation, and disposition of nonconforming product. The evaluation
of product non-conformance shall include a determination of the need for an investigation and
notification of the persons or organizations responsible for the nonconformance. This evaluation and
any investigation shall be documented (820.90). The manufacturer shall establish procedures for
identifying the training needs of personnel who handle nonconforming products in the course of
their work. These people should be trained to recognize product noncomformance and take
appropriate action to control nonconforming products including identifying product as
nonconforming, documenting and evaluating the nonconformance, and segregating and disposing of
nonconforming product. This training should be documented (820.25).
To facilitate detection of failure or defect trends, internal problem data, including service reports,
and complaints should be arranged in a way that permits correlating present and past data for a
particular product or product line. This can usually be achieved by organizing files according to
product or product lines. Such data may be maintained in a computer file for quick accessibility and
analysis.
The manufacturer shall establish and maintain procedures that define the responsibility for
review and the authority for the disposition of nonconforming product. Nonconformance may occur
in-house, as well as before product is distributed, along with nonconformances of distributed
product. Procedures shall set forth the review and disposition process. Disposition of nonconforming
product shall be documented. This documentation shall include the justification for any use of
nonconforming product and the signature of individual(s) authorizing this use [820.90(b)(1)]. The
decision to use a nonconforming product is usually done by a material review board (MRB). MRB
boards should operate according to a written procedure and be comprised of individuals having the
knowledge to determine suitability for use of nonconforming product.
12−4
Each manufacturer shall establish and maintain procedures for rework, including retesting and
reevaluation of the nonconforming product after rework, to ensure that the product meets its
current approved specifications. Rework and reevaluation activities, including the determination of
any adverse effects from the product rework, shall be documented in the DHR [820.90(b)(2)].
FAILURE INVESTIGATION
In order for a quality system to be self correcting, data on quality problems from all sources
should be fed back into the system. For example, complaints, service reports, and nonconforming
products can provide valuable information that can point toward possible corrective actions. The
more comprehensive a quality system is in taking preventive action, the lower the probability of
customer dissatisfaction and the resulting need for corrective action. A true quality system has many
preventive safeguards including GMP requirements for design, packaging, labeling, manufacturing
control, installation, repairs, and complaint and failure analysis. A quality system that also covers
the customer needs generally results in increased overall quality and greater customer satisfaction.
Service requests resulting from long use, misuse or accidental damage usually do not require
corrective and/or preventive action. However, if service requests or other customer concerns are the
result of rapid wear, unusual problems, unusual maintenance, or development of hazardous
conditions, action may be necessary.
The manufacturer shall establish and maintain procedures for implementing corrective and
preventive action. The procedures shall include the following [820.100(a)]:
•
Analyzing processes, work operations, concessions, quality audit reports, quality records,
service records, complaints, returned product, and other sources of quality data. The purpose
of the analysis is to identify existing and potential causes of nonconforming product, or other
quality problems. Appropriate statistical methodology shall be employed where necessary to
detect recurring quality problems.
•
Investigating the cause(s) of nonconformities relating to product, processes, and the quality
system.
•
Identifying the action(s) needed to correct and prevent recurrence of nonconforming product
and other quality problems.
•
Verifying or validating the corrective and preventive action to ensure that such action is
effective and does not adversely affect the finished device.
•
Implementing and recording changes in methods and procedures needed to correct and
prevent identified quality problems.
•
Ensuring that information related to quality problems or nonconforming product is
disseminated to those directly responsible for assuring the quality of such product or the
prevention of such problems.
•
Submitting relevant information on identified quality problems, as well as corrective and
preventive actions, for management review.
12−5
All these activities and their results shall be documented [820.100(b)].
12−6
EXHIBITS
Several forms for recording device production and evaluation data are briefly described below
and then exhibited.
Portable Defibrillator Test Procedure
Ten pages extracted from a 31-page test specification for a family of portable defibrillators are
reprinted below. This test procedure is long and detailed because a defibrillator is a complex device
with a benefit to risk ratio that approaches infinity. This sample evaluation procedure covers final
manufacturing, testing, and data collection performed by the production department to make
absolutely certain that finished defibrillators comply with DMR specifications. This test procedure
was developed based on the company approved device specifications.
To reduce errors and increase clarity, the test number column on the data sheet contains the
paragraph number of the detailed requirements in the specifications section of the procedure. The
test equipment and schematics are not reprinted here.
Test DHR of a Printed Circuit Board Assembly
A data or "device history record" card for a printed circuit board is exhibited. The test
procedure for the board is not reprinted. This data card is not the complete device history record for
the finished device. When the finished device is tested, this board is tested again as an integral part
of it.
Device History Record (urine plate)
A record sheet of the filling, labeling sample, inspection, and sample testing of a five-media urine
plate is exhibited. Each activity is performed per procedure -- these procedures are not exhibited.
The label record is an actual label as printed on the urine plates -- the record sheet is passed through
the printing machine. This technique reduces costs and eliminates human copying errors.
Batch Production Record (XLD)
This exhibit is the batch production record of the XLD component used to fill one section of the
five-part urine plate discussed above.
Batch Production Record (Thayer Martin)
This exhibit is a blank copy of the form used to record the batch production record for the
Thayer Martin component used in the urine plate.
Batch Production Record (Blank form)
This exhibit is a form used to record the batch production record of various growth media. It
could be used to record the production of XLD as mentioned above.
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13
PACKAGING
INTRODUCTION ....................................................................................................... 13-1
PACKAGING DESIGN CONTROLS ...................................................................... 13-2
User Preference ..................................................................................................... 13-4
PACKAGING MATERIALS .................................................................................... 13-4
PACKAGE VALIDATION ........................................................................................ 13-5
PROCUREMENT, ACCEPTANCE, AND STORAGE .......................................... 13-7
PACKAGING PROCESS .......................................................................................... 13-7
EXHIBITS ................................................................................................................... 13-9
Product Specification: Pouch ............................................................................... 13-9
Header Bag (Specification Form) ........................................................................ 13-9
INTRODUCTION
The packaging industry is continuously evolving as medical product companies institute changes
in the design, development, and manufacture of packaging systems. Thus, this chapter is not aimed
at providing an all-inclusive list of packaging procedures and/or materials. Rather the goal is to
instill an awareness of important packaging issues involving both design and manufacture. This
chapter will also provide a basic understanding of the importance of validating processes and
equipment, and the continuing need to maintain control of established packaging processes. The
result should be a package that protects the device during handling and shipping, and from the
environment and microorganisms until the package is opened. This includes allowing for any
necessary sterilization. Packaging contains the product identification and other information as
described in Chapter 11, Labeling. Packaging may also contain integral labeling and instructions for
use or these instructions may be in a manual or package insert. Finally, when the consumer is ready
to use this product, the package should be easy to open without compromising the quality of the
device. In the end, a well designed package facilitates use of the device and contributes substantially
to the overall appeal of the product. It makes sense for the manufacturer to invest in the
development of a safe, user friendly package.
The design of the device, the labeling, the packaging and the manufacturing processes form the
design output [820.3(g)]. These should be integrated. Manufacturers should consider the needs of the
user as required by 820.30, Design Controls. Manufacturers should document these design outputs
in the device master record then, procure, handle, store, and use the specified materials according to
the device master record. FDA regulations are compatible with this total systems approach to device
process design, production, packaging, and labeling.
Finally, manufacturers should perform quality assurance tests or acceptance tests on samples of
the finished packages and, if sterilized, repeat the tests after sterilization. These tests should be based
on a statistically valid sample to insure confidence that the packaging is capable of maintaining the
integrity of the finished product. Where the device is very expensive, or only available in small
quantities, the packaging tests may be performed on labeled, controlled packages that contain
identified, rejected or simulated devices, as appropriate. The results of testing and/or inspection
13−1
should be recorded in the device history record. Correctly performing these activities can reduce or
prevent customer complaints, recalls, and product liability actions.
PACKAGING DESIGN CONTROLS
Package design should be an integral part of the product development program. Waiting until the
end of the development process to design packaging can result in severe delays in getting the product
into distribution. The whole idea is to “build quality in.” The total device and package system
should be considered with respect to: device characteristics, sterilization process if any, sealing,
labeling, secondary packaging, handling, shipping, environment, storage, federal regulations, and
end use.
Defective packaging and seals have been a major cause of medical device recalls. This type of
recall can often be avoided by correct package design including validation of the packaging and
sealing processes. Packaging and sealing machines should be set up according to written procedures
that are based on the known capability of the manufacturing system. It is important to be aware of
the state-of-the-art in sealing methods and packaging materials, including their physical, chemical,
biological, and compatibility characteristics and, of course, cost. "Wet" devices require high-barrier
package materials and sealants with impermeability; resistance to solvents, grease, chemicals, and
heat; and the ability to contain wetting agents, reagents, oils, or fragrances. Thus, the ability to seal
in the presence of liquid components, if spillage occurs in the seal area, is important. Some peelable
adhesives are highly solvent-resistant and also remain intact during radiation sterilization. If
necessary, obtain guidance from suppliers, technical literature, and consultants. After the process
has been developed and validated, the packaging aspect of production should be performed
according to GMP requirements in order to maintain a state of control.
The design controls established by 21 CFR 820.30 and, particularly 820.3(g), define packaging as
part of the device design output. This means the design phase of packaging shall include the
application of quality systems requirements and the documentation of these applications. Control
over package design shall be performed according to 820.30 for any Class II or Class III devices,
devices automated with computer software, and the following Class I devices:
Device
Section
Catheter, Tracheobronchial Suction
Glove, surgeon’s
Restraint, Protective
System, Applicator, Radionuclide, Manual
Source, Radionuclide Teletherapy
868.6810
878.4460
880.6760
892.5650
892.5740
Manufacturers of other Class I devices should establish and maintain procedures for ensuring
that their device design is correctly translated into production specifications. They may use
820.30(h) as guidance. For these Class I devices that require design controls, packaging design is
performed according to 820.130. The nature of the device as well as the sterilization method(s),
intended use, shelf life, transport, and storage all affect package design.
The following activities are important to maintain control of package design:
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1. Planning for the design and development of packaging; and defining responsibility for
implementation of design activities and controls. These plans should identify the different
groups and activities providing input into the design process. Periodic review and approval is
necessary as the package design evolves.
2. Establishing design input and output procedures, including review, documentation,
signature, and date, that are appropriate for the intended use and the needs of the user and
the patient. The procedures shall include safeguards for addressing concerns about the
proposed designs.
3. Ensuring that design review procedures for all appropriate stages of the design development
are conducted by qualified individual(s) and include an individual not directly responsible
(NDR) for the design stage under review. This NDR person could be one of several people on
the design review committee. The design identification, review results, reviewers, and date
shall be documented in the design history file [820.30(j)].
4. Documenting design verification/validation to confirm that the design output meets the
design input requirements in the design history file. This documentation must include the
reviewers and date of review.
5. Establishing and maintaining design transfer procedures that insure that the package design
is correctly translated into production specifications. The correct translation, of course, may
be directly done as part of the design output.
6. After the package design is accepted, controlling changes according to company change
control procedures. The manufacturer shall establish and maintain procedures for the
identification, documentation, validation or where appropriate verification, review, and
approval of design changes before their implementation. A significant part of this control is
achieved when design controls are followed.
7. Establishing a design history file to demonstrate the design was developed and approved
according to plan. This, of course, should show that the design output meets the design input
-- a fact which should be obvious from data presented during the final design reviews.
Design controls require that a packaging design undergo considerable validation, review, and
documentation. However, the end result is a smooth transfer into production with increased package
safety and efficacy, resulting in greater customer satisfaction and cost savings and reduced liability.
In addition to the GMP requirements, manufacturers should always study current packaging
practices for products similar to theirs to determine current favorable practices and to prevent user
packaging problems. For example, customary use may dictate the use of double primary packaging
for some sterile devices. Finally, any packaging used for medical devices should satisfy the end user
or customer requirements, which automatically satisfies one of the design GMP requirements. This
is a key point to be considered during the design phase.
User Preference
In the Medical Device and Diagnostic Industry magazine, the article, "Hospital-User Preference
in Sterile Device Packaging,” reports the results of a survey of nurses from operating room and
13−3
central services areas of hospitals. Several conclusions from the test results are listed below that
should be of interest to sterile device manufacturers.
•
96 percent of the nurses had become "increasingly aware of the importance of quality
packaging to infection control."
•
90 percent said that packaging quality could influence their selection of a sterile medical
device.
•
87 percent wanted at least one package side to be transparent.
•
95 percent preferred the adhesive to transfer from the lid to the lip of a tray when opened to
indicate a broken seal.
•
89 percent wanted sterilization process indicators printed on packages for sterile devices.
•
99 percent said fiber-free opening of a sterile device package is important or very important.
•
55 percent believed larger, high-profile devices would be best packaged in a tray with a
peelable lid.
•
55 percent preferred black printing on the package for easy reading.
Package features that might favorably influence practitioners in the selection of a sterile medical
device include:
•
•
•
•
•
clean, fiber-free opening,
double packaging,
printed process indicator,
easy-open notches on chevron peel pouches, and
lids with adhesive transfer.
The nurses believe that being able to see and clearly identify a device is a "very important
criterion of user preference.” Also, as stated above, double primary packaging is preferred for some
sterile devices.
PACKAGING MATERIALS
Fulfilling the design control procedures discussed above should include using the most
appropriate packaging materials available for the device. Although requirements for components,
device master records, environmental control, etc., that affect the selection and use of packaging
appear throughout the Quality System (QS) regulation, the specific requirements for packaging are
in section 820.130. Also the design requirements for Class II, Class III, and the few Class I devices
that require design control extend to the broad requirements in 820.30. Device packaging and
shipping containers should be designed and constructed to protect the device from adulteration or
damage during the customary conditions of processing, storage, handling, and distribution. Closely
related label integrity requirements are in section 820.120. Also, the quality of packaging should be
considered in relation to the 21 CFR Part 812, Investigational Device Exemptions (IDE's) for clinical
evaluations; Part 814, Premarket Approval (PMA) applications; Part 807, Premarket Notification
13−4
[510(k)] submissions and, of course, customer requirements. Failure to meet these packaging
requirements renders a device adulterated and has resulted in recalls of sterile devices.
The package and device should be designed together so that all factors in the product and
package system can be considered, such as device sharp edges and severe vacuum stresses. Some
other factors to consider are:
End use
Temperature
Moisture resistance
Thermal capacity
Device composition
Device size and shape
Sterilization process
Adhesives
Package porosity
Cling resistance
Pressure
Vacuum
It is important that sterile devices and their packaging material meet the requirements of the
sterilization process, package sealing method, and intended use. For example, radiation sterilization
may discolor packaging and sealing materials, or reduce their functional capabilities. All plastics are
somewhat affected by radiation sterilization, occasionally positively, frequently negatively.
Consideration should be given to the effect produced and the radiation dose needed to produce an
effect. Complete storage and stability data should be compiled for sterile device packaging subjected
to radiation or should be obtained from the supplier.
Ethylene oxide (EO) sterilization requires packaging material of sufficient porosity to allow air
to leave the package and the gas to rapidly permeate the package, sterilize the product, and then
leave the package. Adverse levels of EO residues left on the device harm the patient. Air washing at
the end of the cycle reduces residues. Evacuation of the sterilization chamber for air removal, gas
fill, and air washing can induce package stress, particularly when the cycle calls for high
temperature, pressure, and rapid pressure changes before and after the gas exposure (dwell) period.
PACKAGE VALIDATION
Package validation involves two separate validations: 1) the design validation of the package as a
component of the device and 2) the process validation of the packaging process. Design validation
uses evidence to establish what design specifications will conform with the user needs and the
intended use(s) [830.3(z)(2)]. Process validation establishes by objective evidence that a process
consistently produces a result or product that meets predetermined specifications [820.3(z)(1)].
The regulation, of course, refers to establishing evidence that the manufacturing steps involved
in packaging the device will consistently produce packaging which meets specifications. For
example, the process capability of packaging and sealing equipment should be determined during
process validation and documented. Validation of the package design shall be performed under
actual or simulated use conditions that show the package conforms to its stated intended uses. Risk
analysis shall also be included where appropriate.
Design validation results shall include: the design identification, name of the individual(s)
performing the validation, method(s) used, and the date. All of this information should be recorded
in the design history file. If any significant change is made in the packaging or packaging operation
after validation, the new process will need to be revalidated.
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One of the most difficult aspects of package validation is determining how many samples to test.
The goal is not to over test because of cost considerations while still running sufficient tests to
provide statistically valid sampling. Statistical methods of analysis are important in process
validation. The following decision tree from Medical Device and Diagnostic Industry, “Streamlining
Package-Seal Validation,” October 1992, provides various methods of statistical analysis. The
manufacturer is challenged with determining which statistical method is most applicable to their
individual needs. See Chart 1 below for possible methods of analyzing data. The resulting validation
plan should identify, measure, and evaluate the key processes and variables that will require
assessment to complete a validation or revalidation of the packaging and the packaging process.
Chart 1 above shows various possible methods for analyzing data. Source: Medical Device and
Diagnostic Industry periodical, October 1992.
PROCUREMENT, ACCEPTANCE, AND STORAGE
The packaging associated labeling, sealing methods, acceptance tests, etc., are part of the design
output. These design output documents are part of the device master record. The device master
DATA
Test for normality
(Pearson or Shapiro-Wilk)
Normal (parametric)
distribution
Z test
One-sample
t test
Pooled
variance
t test
Paired
t test
F test for
equality of
variance
Not Normal (nonparametric)
distribution
One-sample
Wilcoxon
signed rank
Paired-sample
Wilcoxon
signed rank
Ansari-Bradley
test for
equality
of dispersions
Chebyshev's
theorem
Mann-Whitney
test for pooled
samples with
equal dispersions
Unpooled
variance
t test
record (820.181) should contain appropriate specifications so that the desired packaging components
may be purchased, properly stored, and properly used. Suppliers are selected according to 820.50,
Purchasing Controls. Manufacturers shall have adequate procedures for approval or rejection of all
incoming packaging components such as adhesives, wrapping materials, corner protectors, pouches,
cartons, etc. (820.80, discussed in Chapter 10). The supplier may test these components and provide
the manufacturer with a protocol for testing and the test results for each batch (i.e., certificate of
conformance to purchase specifications). The manufacturer could accept this specific data as
13−6
sufficient certification based on his assessment of the supplier along with the review of the certificate
or order his own testing.
Incoming components should be examined for damage and identity before being used. At a
minimum, this examination should include visual inspection. Thereafter, the packaging should be
handled and stored in such a way that it is kept clean and safe from damage. Packaging and devices
to be sterilized should, obviously, be kept clean before sterilization. For transfusion and infusion
assemblies, devices that come in contact with circulating blood or cerebrospinal fluid, intraocular
lenses and the surgical instruments used in their implantation, and any device labeled as “pyrogen
free” or “nonpyrogenic,” the manufacturer should carefully and appropriately control the
environment to which the associated packaging materials are exposed in order to minimize
bioburden and cellular debris from dead bacteria. Pyrogens primarily arise from cellular debris of
gram-negative bacteria.
PACKAGING PROCESS
The packaging operation is a manufacturing process as described in Section 820.70, Production
and Process Controls. Other GMP sections also apply to packaging including, but not limited to:
•
•
Receiving, In-Process and Finished Device Acceptance, section 820.80; and
Distribution, section 820.160.
These sections require adequate controls for components, processing, and test/inspection. The
controls necessary for all devices should assure that:
•
labeling, whether a separate label or printed on the package, properly reflects the package
contents and other labeling requirements;
•
the packaging materials meet the device master record specifications;
•
only devices approved for release are packaged and released; and
•
the packaging operations are performed according to established procedures.
The controls required will vary with the type of device packaged. For example, when a sterile
device is packaged, a manufacturer's considerations should include:
•
environmental and personnel hygiene control;
•
validated operating procedures for sealing equipment;
•
inspection to assure package integrity and sanitation; and,
•
stringent control of packaged devices marked "sterile" but not yet sterilized.
For a product to be sterilized in-house, either a physical quarantine area or label control should
be used to prevent shipment of devices marked sterile, but not yet sterilized. The required level of
control is very high. The stringent control also extends to give-away samples not intended for actual
use on patients -- samples should be sterile if so labeled because they might be used. One approach is
to sell samples at zero cost so that the samples are subjected to all of the company finished product
controls.
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A written procedure is required by 801.150(e) for interstate contract sterilization. The purpose
of this requirement is to help prevent the erroneous release of packaged and labeled “sterile” devices
that are not yet sterilized even though they appear to be sterile and ready for release. Regardless of
whether 801.150(e) applies, the QS regulation requires sufficient controls as necessary to prevent
mixups in complex situations such as contract sterilization. For consistency, a contract is commonly
used by manufacturers for interstate and intrastate shipments. Such a contract, and compliance with
it, satisfies the applicable GMP requirements.
Section 820.181(d) requires that the device master record include packaging methods and
processes. Written instructions should be provided to assure that the necessary controls are
understood and consistently implemented. The need for, and the extent of, written instructions
should be determined based on the complexity of the operation and the nature of the product. Some
products such as radioimmunoassay test kits can deteriorate during packaging if the process is not
timed properly. In such cases, written instructions should describe how the device(s) should be
handled and expedited during packaging in order to prevent delays, and thus deterioration.
The procedure for testing and/or inspection of finished packages shall be written [(820.80(d)]. To
the extent feasible, the testing of finished packages should be quantitative. The packaging of sterile
devices should be tested and/or inspected before and after sterilization. This testing is done on a
sampling basis. Sampling plans are valid only when a process is in a state-of-control; therefore, the
device must be manufactured and packaged using a quality system as described in this manual.
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EXHIBITS
The examples that follow will aid a company in preparing product packaging specifications
and/or in purchasing standard packaging.
Product Specification: Pouch
This form is used to purchase specific pouches from a standard family of pouches. The finished
device manufacturer completes the form with the desired size, material, style, etc. The form refers to
other documents which define the technical characteristics of the pouches.
Header Bag (Specification Form)
This specification for a header bag is set up as a checklist with the specifications on the righthand side and a drawing of the bag on the left. The finished device manufacturer completes the form
with the desired technical characteristics, assigns it a part number, and approves the finished
document. An interesting idea reflected in this form is the important information block at the
bottom of the form. This is a good way to remind personnel of pertinent information that is not
strictly a part of the specification yet is vital to the control of this particular item.
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14
STORAGE, DISTRIBUTION, AND INSTALLATION
INTRODUCTION ............................................................................................................. 14-1
Holding and Distribution Procedures ....................................................................... 14-1
Warehouse Storage ..................................................................................................... 14-2
Distribution Records ................................................................................................... 14-3
DEVICE INSTALLATION ............................................................................................. 14-4
EXHIBITS ......................................................................................................................... 14-5
Finished Product Release Form ................................................................................. 14-5
Release To Finished Goods/Shipping ........................................................................ 14-5
Product Shipping Hold ............................................................................................... 14-5
Release From Product Shipping Hold ...................................................................... 14-5
Partial List of Traceable Devices................................................................................ 14-5
INTRODUCTION
The device Quality System (QS) regulation covers the manufacture, storage (820.150),
distribution (820.160) and installation (820.170) of finished devices. For manufacturers and
importers, distribution is one of the most important steps in their quality system. After a product is
distributed, a manufacturer rarely has direct control over the product or how it is used. Thus, it is
important that controls be in place to assure that only correctly labeled, packaged and approved
finished devices are distributed and, if necessary, installed.
Holding and Distribution Procedures
Section 820.160 requires that the purchase order be reviewed to ensure that ambiguities and
errors are resolved before devices are released for distribution. Manufacturers should have a
program to reduce problems in this area. Marketing personnel should be adequately trained. Sales
specification flyers and catalogs should be carefully written and kept current to reduce ordering
problems. Incoming purchase orders should be checked and ambiguities and errors resolved. After
receipt by appropriately trained personnel, orders should be reviewed immediately. If purchase
orders are reviewed late in the manufacturing process or just before distribution, the value of the
review may be significantly reduced. Where the customer includes specifications, each specified
parameter should be checked against the corresponding parameter for the device. A checklist of
device parameters may be a helpful tool for this review and should be filed with, or keyed to, the
purchase order.
The QS regulation (820.60), Identification, requires manufacturers to set up and maintain
identity control of their products from component receipt, production, distribution and through
installation to prevent mixups. The regulation also requires that written procedures be provided for
control and distribution of finished devices (820.160). The purpose of this requirement is to assure
that only approved devices are distributed. Each manufacturer should determine what written
procedures are needed to assure that only "approved for release" devices are distributed from the
manufacturer. If a manufacturer believes written procedures will not contribute to assuring that
only “approved for release” devices are distributed by their manufacturer, they should be able to
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defend their decision. For example, the control is integrated into the activities required to package
the device or to complete the device history record. This flexibility is allowed by section 820.5,
Quality system, of the QS regulation.
Many manufacturers mark their released finished devices or identify them by location or
packaging so that a simple visual check is sufficient to indicate whether the product is acceptable to
release for distribution. For example, radiation-emitting electronic products are subject to a
performance standard. The application of the certification label is often the last step in approving
product release for distribution, and this label is used to distinguish such devices. After final release,
the crating of large equipment is a very distinguishing feature. These types of operations may
preclude the need for a separate written procedure.
For interstate contract sterilization, 21 C.F.R. section 801.150(e) requires a written agreement
between the parties which details the necessary procedures to help prevent the erroneous release of
packaged and labeled "sterile" but not yet sterilized devices that appear to be, but are not, ready for
release. Regardless of whether 801.150(e) applies, the QS regulation requires controls, as necessary,
to prevent mixups in complex situations such as contract sterilization. For consistency, a contract as
described by 801.150(e) is commonly used by manufacturers for interstate and intrastate shipments.
Compliance with such a contract satisfies the applicable GMP requirements. (See Chapter 10,
Purchasing and Acceptance Activities, and Compliance Policy Guide 7382.830B for details.)
Sometimes manufacturers need to ship "finished devices" that have not been officially released
because the final test data is not yet available. The critical factor is that the device still remains
under the manufacturer’s control. The most common example occurs when a manufacturer is
waiting for the results from biological indicator tests. FDA permits manufacturers to ship such
devices under quarantine to their own controlled warehouses where the devices may be readily
recalled prior to any use, if the need arises. Manufacturers should not ship non-released devices to
routine distributors or anyone outside of their direct control. Non-released products or products on
"hold" for any quality reason should be controlled to prevent release. A suitable control is
quarantine with a label on the units, pallets, etc., to indicate their status.
Warehouse Storage
Storage should always be done under systematic, orderly conditions (820.150). Manufacturers
should use a first-in, first-out (FIFO) distribution system when fitness for use of a device deteriorates
over time (820.150).
When a controlled environment is necessary to prevent abnormal deterioration, the environment
should be specified, controlled, and monitored according to sections 820.70(c) (see Chapter 6,
Buildings and Environment). Environmental specifications, such as storage temperature, should be
included in the device master record.
The storage and handling of devices to be distributed may involve extensive activities (820.140
and 820.150). For example, damaged, recalled or returned devices should be suitably marked and
segregated from devices acceptable for release (820.86). Returned devices should be handled and
stored such that the cause of failure or other useful information is not destroyed. Returned defective
devices should be formally investigated according to 820.100 Corrective and Preventive Action and
any associated complaints investigated according to 820.198. Therefore, manufacturers will need
14-2
controls to assure that returned defective devices do not dead-end in the warehouse, but are
expeditiously routed to the appropriate department for evaluation, investigation, conclusions and
follow-up (see Chapter 15, Complaint Files).
Distribution Records
Quality System section 820.184, Device History Record (DHR), requires manufacturers of
devices to maintain basic records for:
•
•
•
•
•
•
dates of manufacture,
the quantity manufactured,
quantity released for distribution,
acceptance records,
primary identification labels and labeling used, and
any device identification and control number used.
Section 820.160, Distribution, requires the following records:
•
•
•
•
name and address of the initial consignee,
identification and quantity of devices shipped,
date shipped, and
any control number used.
Some of the above information necessary for the distribution records is a duplicate of Device
History Record (DHR) requirements. These duplications may be copied or transferred electronically
from the DHR. If appropriate, a manufacturer may combine the records by adding the distribution
information to the DHR.
In addition to the above requirements, manufacturers of implantable devices and life sustaining
devices, the failure of which during use could result in significant injury to the user, are required to
establish and maintain procedures for identifying with a control number each unit, lot, or batch of
finished devices and, where appropriate, components (820.65). A partial list of traceable devices that
meet this definition is printed at the end of this chapter.
Distribution records may be the same as, or part of, the normal business records. Generation of a
separate record is not required unless the business records are not readily available, e.g., not
maintained at the same establishment as the device history record and not readily retrievable
electronically. Many manufacturers, also keep distribution records for billing and market survey
purposes.
Manufacturers of radiological electronic products listed in 21 CFR 1002.1, Record and Reporting
Requirements By Product, shall maintain distribution records that will enable them to trace specific
products or production lots to distributors, or to dealers in those instances in which the
manufacturer distributes directly to dealers (See 21 CFR 1002.30, Records to be Maintained by
Manufacturers).
Distribution records shall be kept for a period of time equivalent to the design life and expected
14-3
life of the device, but in no case less than two years from the date of release for commercial
distribution by the manufacturer [820.180(b)]. The intent of this requirement is support for
potential repairs, corrective actions and recalls. Each manufacturer should make a prudent decision
whether to discard records or keep all, or part, of them for a longer period. When requested,
distribution records shall be made available to FDA investigators for review and copying during
normal business hours.
DEVICE INSTALLATION
Section 820.170 on installation requires that each manufacturer establish and maintain adequate
installation and inspection instructions and, where appropriate, testing procedures. The purpose of
this requirement is to ensure that the device is properly installed and will perform as intended after
installation. This regulation applies to medical device systems and complex devices that require set
up and adjustment at the location where they are to be used. For example, before a diagnostic x-ray
machine can be used, it has to be installed and adjusted and the performance checked.
Cardiopulmonary bypass machines also require set up and adjustment at the user location.
Manufacturers of such devices shall:
•
•
•
install the device, or have it installed by a representative;
inspect and test, as appropriate, the device after installation to assure the device will perform
as intended; or
provide adequate instructions and procedures for proper installation by another party.
These instructions and procedures for proper installation by the manufacturer's representative,
user, or third party (820.170) shall include instructions on how to determine that the installed device
is safe, performing satisfactorily and ready for use. Safety checks at installation refer to safety
aspects directly related to the installation and setup activities and not to intrinsic safety features that
have already been checked during final acceptance testing at the factory.
The instructions and procedures shall be distributed with the device or otherwise made available
to the person installing the device. Such procedures and instructions are part of the device master
record and generally include a checklist for the installer to make certain that all necessary
installation and checkout activities have been performed correctly. The installer should complete the
checklist. If available to the manufacturer, the filled-in checklist or other installation records are
part of the device history record.
Installation and servicing are related activities. Therefore, see Chapter 16, Servicing, for more
information.
14-4
EXHIBITS
Various forms to show that devices are finished and may be released or stopped from release and
a list of some traceable devices are briefly described below and then exhibited.
Finished Product Release Form
This exhibit shows an example of a finished product release form which is actually a checklist for
the manufacturing and QC departments of an in vitro diagnostic manufacturer to show that all
required processes have been completed. The checklist acts as a reminder of the acceptance forms
that are needed for a product and has space for the manufacturing and QC people to indicate that
these forms have been completed and reviewed. Finally there is space for the designees to approve or
disapprove the lot for release and for comments, if needed.
Release To Finished Goods/Shipping
This exhibit is a release form as described above except that it is for various hardware products.
The employee writes in the specification for the product being released.
Product Shipping Hold
This exhibit is an example of a form used to stop the shipping of a finished device for reasons
related to safety, performance, reliability, regulatory compliance, or other quality requirements.
Release From Product Shipping Hold
This is a form used to release a finished device from a stop shipment order. Because stop orders
are always significant, this release form requires a signature by key management.
Partial List of Traceable Devices
This exhibit lists many of the devices for which a manufacturer must adopt a method of device
tracking and the citation to 21 C.F.R. for the device.
It is required that implantable devices and life sustaining devices, whose failure during use as
described on the label, could result in significant injury to the user, establish and maintain
procedures for identifying with a control number each unit, lot, or batch of finished devices. Where
appropriate, this traceability rule also applies to components. These procedures should facilitate
corrective action. This identification should be documented in the device history record. Many of
these devices were formerly called critical devices.
14-5
FINISHED PRODUCT RELEASE
Form No.
Rev.
Form Approved by:
Sheet 1 of 1
Date
ECN notes:
Title: AMYLASE SET
Packaging lot number
Circle one CATALOG Number AM-389-01
AM-389-02
The device history documents below were reviewed by →
Circle one form number in 2, 5 & 7 below.
MFG
"
1. Form # 9926
Product flow sheet
2. Form # 1077 or 1078
Iodine solution
3. Form # 1082
Substrate solution
4. Form # 1083
Substrate tube filling sheet
5. Form # 1084 or 1085
Iodine filling sheet
6. Form # 1086
Packaging record
7. Form # QC-PP-07 or QC-PP-01
Finished device specification
QC
"
Comments
Sign. MFG Designee
APP. Yes or No
Comments
Signature QC Designee
RELEASE TO FINISHED
GOODS/SHIPPING
Approved Yes or No
Form # Release-110
Form Approved by:
Rev. B
Sheet 1 of 1
Date 4-15-1974
14-6
ECN notes:
Type of Product: [ ] Cable [ ] Instrument [ ] Spare/Replacement part/assembly
PRODUCT NAME
Part Number
Serial / Lot Number
Inspection Specification Number
Revision
PRODUCT STATUS
Circle yes or no ↓
1. Final inspection complete per standards set forth in the QC manual
and device inspection specification ?
YES
NO
2. Device history record packet present ?
YES
NO
3. Has Final Inspection performed a simulated use test ?
YES
NO
4. An identified final test data sheet is with the unit ?
YES
NO
YES
NO
If the answer to 1 or 2 is NO, return lot to Production.
Comments
Signature QC Designee
Approved
Quantity Released
Date
14-7
HOLD NUMBER:
DATE:
PRODUCT SHIPPING HOLD
BY QUALITY ASSURANCE DEPARTMENT
The product listed below is on SHIPPING HOLD and under NO circumstances is to be shipped from
the factory or any field office without the written approval of the Director, Quality Assurance.
PRODUCT:
HOLD STARTING DATE:
CLASSIFICATION OF HOLD
[ ] EFFICACY
[ ] RELIABILITY
[ ] STERILITY
[ ] OTHER (describe)
[ ] SAFETY
[ ] REGULATORY COMPLIANCE
[ ] GOOF UP
REASON FOR HOLD:
ACTION REQUIRED BEFORE RELEASE:
MDR/RECALL NOTES:
Sign., DIRECTOR, QUALITY ASSURANCE
DISTRIBUTION:
[ ] Manager, Shipping Department
[ ] National Field Manager
[ ] General Manager
[ ] Controller
[ ] V.P. Corporate (if s/e problem)
[ ] Director, Manufacturing
[ ] Division President
[ ] Director, R & D
[ ] Director, Marketing
[ ] V.P. International (if int'l sales)
14-8
HOLD NUMBER:
DATE:
RELEASE FROM PRODUCT SHIPPING HOLD
BY QUALITY ASSURANCE DEPARTMENT
The product listed below is RELEASED from SHIPPING HOLD.
PRODUCT:
HOLD RELEASE DATE:
REASON FOR RELEASE:
MDR/RECALL NOTES:
Sign., DIRECTOR, QUALITY ASSURANCE
DISTRIBUTION:
[ ] Manager, Shipping Department
[ ] National Field Manager
[ ] General Manager
[ ] Controller
[ ] V.P. Corporate (if S/E)
[ ] Director, Manufacturing
[ ] Division President
[ ] Director, R & D
[ ] Director, Marketing
[ ] V.P. International (if Int'l sales)
Partial List of Traceable Devices
14-9
CFR
Cite
Classification
Name of Device
PART 868 -- ANESTHESIOLOGY DEVICES
868.1200
Indwelling blood oxygen partial pressure (PO2) analyzer
868.2375
Breathing frequency monitor
868.5090
Emergency airway needle
868.5160(a)
Gas machine for anesthesia
868.5240
Anesthesia breathing circuit
868.5400
Electroanesthesia apparatus
868.5440
Portable oxygen generator
868.5470
Hyperbaric chamber (Monoplace)
868.5610
Membrane lung for long term pulmonary support
868.5650
Esophageal obturator
868.5720
Bronchial tube
868.5730
Tracheal tube
868.5740
Tracheal/bronchial differential ventilation tube
868.5750
Inflatable tracheal tube cuff
868.5800
Tracheostomy tube and tube off
868.5810
Airway connector
868.5830
Autotransfusion apparatus
868.5895
Continuous ventilator
868.5905
Noncontinuous ventilator (IPPB)
868.5915
Manual emergency ventilator
868.5925
Powered emergency ventilator
868.5935
External negative pressure ventilator
PART 870 -- CARDIOVASCULAR DEVICES
870.1025
Arrhythmia detector and alarm
870.1330
Catheter guide wire
870.1360
Trace microsphere
870.1750
External programmable pacemaker pulse generator
14-10
CFR
Cite
Classification
Name of Device
870.1800
Withdrawal-infusion pump
870.3250
Vascular clip
870.3260
Vena cava clip
870.3300
Arterial embolization device
870.3375
Cardiovascular intravascular filter
870.3450
Vascular graft prosthesis of less than 6 millimeters diameter
870.3460
Vascular graft prosthesis of 6 millimeters and greater diameter
870.3470
Intracardiac patch or pledget made of polypropylene, polyethylene
terephthalate, or polytetrafluoro-ethylene
870.3535
Intra-aortic balloon and control system
870.3545
Ventricular bypass (assist) device
870.3600
External pacemaker pulse generator
870.3610
Implantable pacemaker pulse generator
870.3620
Pacemaker lead adaptor
870.3650
Pacemaker polymeric mesh bag
870.3670
Pacemaker charger
870.3680
Cardiovascular permanent or temporary pacemaker electrode
870.3700
Pacemaker programmers
870.3710
Pacemaker repair or replacement material
870.3800
Annuloplasty ring
870.3850
Carotid sinus nerve stimulator
870.3925
Replacement heart valve
870.4320
Cardiopulmonary bypass pulsatile flow generator
870.4350
Cardiopulmonary bypass oxygenator
870.4360
Nonroller-type cardiopulmonary bypass blood pump
870.4370
Roller-type cardiopulmonary bypass blood pump
870.5200
External cardiac compressor
870.5225
External counter-pulsating device
870.5300
DC-defibrillator (including paddles)
870.5550
External transcutaneious cardiac pacemaker (noninvasive)
---
Percutaneous transluminal coronary angioplasty (PTCA) balloon
14-11
CFR
Cite
Classification
Name of Device
dilation catheter
---
Automatic implanted cardioverter defibrillator system
PART 872 -- DENTAL DEVICES
872.3640
Endosseous implant
PART 874 -- EAR, NOSE, AND THROAT DEVICES
872.3620
Ear, nose and throat synthetic polymer material
874.3695
Mandibular implant facial prosthesis
874.3730
Laryngeal prosthesis (Taub design)
874.3820
Emdolmphatic shunt
874.3850
Endolymphaic shunt tube with valve
874.3930
Tympanotomy tube with semipermeable membrane
---
Ear, nose, throat natural polymer-collagen material
PART 876 -- GASTROENTEROLOGY-UROLOGY DEVICES
876.3350
Penile inflatable implant
876.5270
Implanted electrical urinary continence device
876.5540
A-V shunt cannula
876.5630
Peritoneal dialysis system and accessories
876.5820
Hemodialysis system and accessories, dialysate concentrate, hollow
fiber capillary dialyzers, disposable dialyzers, high permeability
dialyzers, parallel flow dialyzers, single coil dialyzers, twin coil
dialyzers, single needle dialysis set, dialysate delivery systems
876.5870
Sorbent hemoperfusion system
876.5880
Isolated kidney perfusion and transport system and accessories
876.5955
Peritoneo-venous shunt
46 FR 7566
Urethral sphincter prosthesis
(1/23/81)
46 FR 7566
Urethral replacement
(1/23/81)
14-12
CFR
Cite
Classification
Name of Device
PART 878 -- GENERAL AND PLASTIC SURGERY DEVICES
42 FR 63474
Absorbable surgical sutures
(12/16/77)
42 FR 63474
Nonabsorbable surgical sutures
(12/16/77)
879.4520
Polytetrafluoroethylene (Teflon) injectable
878.3300
Surgical mesh
878.3500
Polytetrafluoroethylene with carbon fibers composite implant
material
878.3530
Inflatable breast prosthesis
878.3540
Silicone gel-filled breast prosthesis
---
Implanted mammary prosthesis of composite saline and gel-filled
design
878.3610
Esophageal prosthesis
878.3720
Tracheal prosthesis
878.4300
Implantable clip
878.4750
Implantable staple
---
Maxillofacial prosthesis
PART 880 -- GENERAL HOSPITAL AND PERSONAL USE DEVICES
880.5130
Infant radiant warmer
880.5400
Neonatal incubator
880.5410
Neonatal transport incubator
880.5725
Infusion pump
---
Implanted infusion pump
PART 882 -- NEUROLOGICAL DEVICES
882.5030
Methyl methacrylate for aneurysmorrhaphy
882.5150
Intravascular occluding catheter
14-13
CFR
Cite
Classification
Name of Device
882.5200
Aneurysm clip
882.5225
Implanted malleable clip
882.5250
Burr hole cover
882.5300
Methyl methacrylate for cranioplasty
882.5320
Preformed alterable cranioplasty plate
882.5330
Preformed nonalterable cranioplasty plate
882.5360
Cranioplasty plate fastener
882.5550
Central nervous system fluid shunt and components
882.5820
Implanted cerebellar stimulator
882.5830
Implanted diaphragmatic/phrenic nerve stimulator
882.5840
Implanted intracerebral/subcortical stimulator for pain relief
882.5850
Implanted spinal cord stimulator for bladder evacuation
882.5860
Implanted neuromuscular stimulator
882.5870
Implanted peripheral nerve stimulator for pain relief
882.5880
Implanted spinal cord stimulator for pain relief
882.5880
Epidural spinal electrode
882.5900
Preformed craniosynostosis strip
882.5910
Dura substitute
882.5950
Artificial embolization device
---
Lyophilized human (cadaver) dura mater
---
Stabilized epidural spinal electrode
---
Implanted intracranial pressure monitor
---
Totally implanted spinal cord stimulator for pain relief
PART 884 -- OBSTETRICAL AND GYNECOLOGICAL DEVICES
884.5360
Contraceptive intrauterine device (IUD) and introducer
884.5380
Contraceptive tubal occlusion device (TOD) and introducer
PART 886 -- OPHTHALMIC DEVICES
886.3300
Absorbable implant (scleral buckling method)
886.3400
Keratoprosthesis
14-14
CFR
Cite
Classification
Name of Device
886.3600
Intraocular lens
886.3920
Eye valve implant
PART 888 -- ORTHOPEDIC DEVICES
888.3000
Bone Cap
888.3010
Bone fixation cerclage
888.3020
Intramedullary fixation rod
888.3025
Passive tendon prosthesis
888.3027
Polymethyllmethaccrylate (PMMA) bone cement
888.3030
Single/multiple component metallic bone fixation appliance and
accessories
888.3040
Smooth or threaded metallic bone fixation fastener
888.3050
Spinal interlaminal fixation orthosis
888.3060
Spinal intervertebral body fixation orthosis
888.3100
Ankle joint metal/composite semi-constrained cemented prosthesis
888.3110
Ankle joint metal/polymer semiconstrained cemented prosthesis
888.3120
Ankle joint metal/polymer non-constrained cemented prosthesis
888.3150
Elbow joint metal/metal or metal/polymer constrained cemented
prosthesis
888.3160
Elbow joint metal/polymer semi-constrained cemented prosthesis
888.3170
Elbow joint radial (hemi-elbow) polymer prosthesis
888.3180
Elbow joint humeral (hemi-elbow) metallic uncemented prosthesis
888.3200
Finger joint metal/metal constrained uncemented prothesis
888.3210
Finger joint metal/metal constrained cemented prosthesis
888.3220
Finger joint metal/polymer constrained cemented prosthesis
888.3230
Finger joint polymer constrained prosthesis
888.3300
Hip joint metal constrained cemented or uncemented prosthesis
888.3310
Hip joint metal/polymer constrained cemented or uncemented
prosthesis
888.3320
Hip joint metal/metal semi-constrained, with a cemented acetabular
component, prosthesis
14-15
CFR
Cite
Classification
Name of Device
888.3330
Hip joint metal/metal semi-constrained, with an uncemented
acetabular component, prosthesis
888.3340
Hip joint metal/composite semi-constrained cemented prosthesis
888.3350
Hip joint metal/polymer semi-constrained cemented prosthesis
888.3360
Hip joint femoral (hemi-hip) metallic cemented or uncemented
prosthesis
888.3370
Hip joint (hemi-hip) acetabular metal cemented prosthesis
888.3380
Hip joint femoral (hemi-hip) trunnion-bearing metal/polyacetal
cemented prosthesis
888.3390
Hip joint femoral (hemi-hip metal/polymer cemented or uncemented
prosthesis
888.3400
Hip joint femoral (hemi-hip) metallic resurfacing prosthesis
888.3410
Hip joint metal/polymer semi-constrained resurfacing cemented
prosthesis
888.3480
Knee joint femorotibial metallic constrained cemented prosthesis
888.3490
Knee joint femorotibial metal/composite non-constrained cemented
prosthesis
888.3500
Knee joint femorotibial metal/composite semi-constrained cemented
prosthesis
888.3510
Knee joint femorotibial metal/polymer constrained cemented
prosthesis
888.3520
Knee joint femorotibial metal/polymer non-constrained cemented
prosthesis
888.3530
Knee joint femorotibial metal/polymer semi-constrained
cemented prosthesis
888.3540
Knee joint patellofemoral polymer/metal semi-constrained
cemented prosthesis
888.3550
Knee
joint
patellofemorotibial
polymer/metal/metal
constrained cemented prosthesis
888.3560
Knee joint patellofemorotibial polymer/metal/polymer semiconstrained cemented prosthesis
14-16
CFR
Cite
Classification
Name of Device
888.3570
Knee joint femoral (hemi-knee) metallic uncemented
prosthesis
888.3580
Knee joint patellar (hemi-knee) metallic resurfacing
uncemented prosthesis
888.3590
Knee joint tibial (hemi-knee) metallic resurfacing uncemented
prosthesis
888.3640
Shoulder joint metal/metal or metal/polymer constrained
cemented prosthesis
888.3650
Shoulder joint metal/polymer non-constrained cemented
prosthesis
888.3660
Shoulder joint metal/polymer semi-constrained cemented
prosthesis
888.3680
Shoulder joint glenoid (hemi-shoulder) metallic cemented
prosthesis
888.3690
Shoulder joint humeral (hemi-shoulder) metallic uncemented
prosthesis
888.3720
Toe joint polymer constrained prosthesis
888.3730
Toe joint phalangeal (hemi-toe) polymer prosthesis
888.3750
Wrist joint carpal lunate polymer prosthesis
888.3760
Wrist joint carpal scaphoid polymer prosthesis
888.3770
Wrist joint carpal trapezium polymer prosthesis
888.3780
Wrist joint polymer constrained prosthesis
888.3790
Wrist joint metal constrained cemented prosthesis
888.3800
Wrist joint metal/polymer semi-constrained cemented
prosthesis
888.3810
Wrist
joint
ulna
14-17
(hemi-wrist)
polymer
prosthesis
15
COMPLAINT FILES
INTRODUCTION.............................................................................................................. 15-1
Complaint Handling System ....................................................................................... 15-3
Complaint Responsibility ............................................................................................ 15-3
MDR Reportable Complaints ..................................................................................... 15-4
Complaint Records ...................................................................................................... 15-4
Investigation Records .................................................................................................. 15-5
File Accessibility and Location ................................................................................... 15-5
Non-medical Complaints ............................................................................................. 15-6
Complaint Analysis...................................................................................................... 15-6
DEVICE FAILURE ANALYSIS...................................................................................... 15-6
FEEDBACK FOR QA SYSTEM ..................................................................................... 15-7
COMPLAINT SOURCES................................................................................................. 15-7
MEDICAL DEVICE REPORTING ................................................................................ 15-8
Who Must Report ........................................................................................................ 15-8
When to Report ............................................................................................................ 15-8
Individual Adverse Event Reports ............................................................................. 15-8
Written MDR Procedures ......................................................................................... 15-10
MDR Event Files ........................................................................................................ 15-11
How to Maintain MDR Event Files.......................................................................... 15-11
ADDITIONAL MDR GUIDANCE ................................................................................ 15-12
Reports of Removals and Corections ............................................................................ 15-12
EXHIBITS ........................................................................................................................ 15-13
Complaint Processing Procedure and Forms.......................................................... 15-13
MedWatch Forms ...................................................................................................... 15-13
INTRODUCTION
Section 820.3(b) of the Quality Systems regulation defines a complaint as “any written, electronic,
or oral communication that alleges deficiencies related to the identity, quality, durability, reliability,
safety, effectiveness, or performance of a device after it is released for distribution.” All medical
device manufacturers are subject to the complaint requirements in 21 CFR Part 820, Quality
System regulation and to the reporting requirements in 21 CFR Part 803, Medical Device Reporting
(MDR) regulation. A complaint is any indication of the failure of a device to meet customer or user
expectations for quality or to meet performance specifications. A complaint may be lodged against
any finished device that had been released for distribution. Any complaint involving the possible
failure of a device, labeling, or packaging to meet any of its specifications is subject to the provisions
of 21 CFR 820.198, Complaint Files.
The sources of oral and written complaints are numerous. A manufacturer can receive this
information via telephone, facsimile, written correspondence, sales representatives, service
representatives, scientific articles, and FDA or internal analyses. Information will also be submitted
by health care professionals, lay users, consumers, user facilities and distributors on the MedWatch
Forms FDA 3500 and FDA 3500A.
15−18
Manufacturers are required to review, evaluate, and, when appropriate, investigate complaints,
establish and maintain written procedures describing the process used to perform these activities,
and designate a responsible individual or entity to perform these tasks. Complaints concerning
death, serious injury or malfunctions, as defined in the MDR regulation, shall be reported to FDA as
discussed later. Manufacturers of any class of medical devices are never exempted from the Quality
System regulation complaint requirements (820.198) nor the general record requirements (820.180)
which permit FDA review and copying of these records. Complaint file requirements are necessary
to make certain manufacturers have adequate quality systems for investigating complaints and
taking corrective action. Access to complaint files, device-related death and injury reports, and
complaints about device defects enables FDA to determine if a manufacturer's quality system and
corrective actions are adequate.
Manufacturers can identify problems with device component, labeling and packaging quality by
several methods. To meet all GMP requirements these identification methods should include a
review and evaluation of all complaints, failed devices, and service or repair requests. Complaints
and service or repair requests are important sources of feedback information for a quality system.
Finished devices that are returned for service or repair may meet the complaint requirements
identified in section 820.198; therefore, these service or repair requests shall be evaluated to
determine if they are complaints. Service or repair data shall be reviewed [820.200(b)&(e)] to
identify systematic problems and problems that may qualify as complaints. When these problems
are identified they should be processed as complaints according to the requirements in 820.198.
Complaint data, in conjunction with product audits, QA systems audits, operational analyses,
inspection and test data, etc., is used by the quality assurance organization to:
•
identify poor performance in the overall quality system, particularly faulty design of devices,
and faulty manufacturing processes;
•
aid in implementing solutions to these quality problems;
•
verify confidence in, and improve the performance of the quality system;
•
improve the safety and performance of devices;
•
reduce medical device reporting;
•
reduce costs and improve production schedules;
•
reduce employee confusion;
•
improve customer relations by reducing the frequency of problems, complaints, and recalls;
and,
•
assure compliance with device regulations and consensus standards.
Complaint Handling System
An effective complaint handling system is an extremely important part of any quality system.
Even manufacturers who have not received complaints should be prepared to receive and process
15−19
them. Manufacturers should understand that any complaint received on a product shall be
evaluated and, if necessary, thoroughly investigated and analyzed, and corrective actions shall be
taken. The results of this evaluation should lead to a conclusion regarding whether the complaint
was valid, what the cause of the complaint was, and what action is necessary to prevent further
occurrences. Complaints cannot be ignored. They are an excellent indicator of problems with the
use, design, and/or manufacture of a product. A single complaint that is thoroughly investigated may
lead a company to take remedial or corrective action. It may also take an ongoing analysis of
numerous complaints before a trend is spotted that causes a company to initiate changes in their
product, labeling, packaging or distribution.
Using written procedures for handling complaints increases confidence that all complaints will be
handled properly. Written procedures should be provided to employees to facilitate communication,
maintain consistency, and reduce quality problems. Written procedures for the receiving, reviewing
and evaluating of complaints by a formally designated unit shall be established and maintained in
accordance with 820.198, Complaint Files, and 820.40, Document Controls, respectively. The
procedures should include the need for complaints to be evaluated in accordance with 820.100,
Corrective and Preventive Action.
The complaint files shall be maintained in accordance with the general record keeping
requirements of 820.180. All complaint files are to be retained for a period of time equivalent to the
design and expected life of the device, but in no case less than 2 years from the date of release for
commercial distribution by the manufacturer. The written procedure should specify: authority;
responsibilities; and the process to follow in receiving, reviewing, and investigating complaints.
However, for very small manufacturers where division of work is minimal, and authorities and
responsibilities are obvious, the GMP requirements as detailed in 820.198 in conjunction with
appropriate forms may be sufficient as a protocol for handling complaints.
Although FDA does not specify a standard complaint handling system, the GMP requirements do
specify certain actions that shall be included in any system. Manufacturers shall:
•
•
•
•
•
•
document, review, evaluate, and file all complaints;
formally designate a unit or individual to perform these activities;
determine if an investigation is necessary;
record the reason if no investigation is made;
assign responsibility for deciding when not to investigate; and,
determine if the complaint requires an MDR report.
Complaint Responsibility
Manufacturers shall formally assign responsibility for maintaining complaint files and
conducting complaint investigations to individuals or an organizational unit. Under 820.25(b) it is
the manufacturer’s responsibility to ensure that personnel are properly trained to adequately
perform their duties. These employees shall have the proper education and training to process
complaints. Any difficulty noted in employees performing required tasks for proper complaint
handling may be an indication that additional training is needed. Training shall be documented.
The person(s) assigned to review complaints should have a thorough knowledge of the product
line in order to make an informed, reasonable decision as to the severity and significance of a
complaint and to decide whether an investigation is necessary. If it is decided that an investigation is
15−20
not necessary, a record shall be made of the rationale used to arrive at this decision. The record
must identify the individual responsible for making this decision.
Executive management should ensure that adequate resources are provided, including trained
personnel, to the designated complaint handling unit within the company. The activities of the unit
should be assessed on a regular basis, and corrections made if necessary.
MDR Reportable Complaints
Section 820.198(c) specifically requires that any complaint involving the possible failure of a
device, labeling, or packaging to meet its performance specifications shall be reviewed, evaluated,
and investigated unless such investigation has already been performed for a similar complaint and
another investigation is not necessary. Also, section 820.198(d) further specifies that any complaint
that requires an MDR report shall be promptly reviewed, evaluated, and investigated by a
designated individual(s), and shall be maintained in a separate portion of the complaint files or
clearly identified. However, if maintained separately a manufacturer should duplicate these serious
complaints in the regular complaint file to assure that any analysis performed by product is
inclusive of all complaints. Analysis by appropriate statistical methodology where necessary is a
means of identifying quality problems. A single event, of course, may also be an indicator of a
quality problem.
Complaint Records
FDA does not specify a standard method for recording or retrieving complaint information. Each
manufacturer should develop a method for maintaining records of complaints and investigations
that: is functional and economical, meets company needs, and meets requirements of the Quality
System regulation. A two sided form is suggested when using hard copy to record complaints. One
side may be used to record complaint information such as:
•
•
•
•
•
•
•
sequential number of the complaint;
origin of the complaint;
customer information;
product information;
any corrective actions already taken;
details of the complaint;
and dates, signatures, assignments, etc.
The other side may be used to record:
• instructions;
• investigations;
• analyses;
• conclusions;
• corrective action with respect to the product and to the customer;
• and dates, signatures, etc.
A typical form is exhibited at the end of this chapter. The completed form should be stored in the
complaint file which may be a physical or electronic file.
Investigation Records
15−21
The designated unit or person(s) responsible for maintaining the complaint file(s) shall prepare a
written record of any investigations. This record shall include [820.198(e)]:
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
The name of the device;
The date the complaint was received;
Any device identification(s) and control number(s) used;
The name, address, and phone number of the complainant;
The nature and details of the complaint;
The dates and results of the investigation;
Any corrective action taken; and
Any reply to the complainant.
Also, the investigation record of any complaint that is being reported to FDA in an MDR report
shall include a determination of [820.198(e)]:
(1) Whether the device failed to meet specifications;
(2) Whether the device was being used for treatment or diagnosis; and
(3) The relationship, if any, of the device to the reported incident or adverse event.
Section 820.198(e) requires the record of investigation to include any reply to the complainant.
Manufacturers should send a reply to each complainant as a courtesy, but more important to
prevent further misuse, injury or other adverse situations from recurring. However, because of the
nature of the complaint, there may be cases where a reply is not necessary. In such cases, the record
should state that no reply was made and the reason for not replying. When the problem was caused
by misuse, it is very important to advise the user to help prevent further misuse. Also, the
manufacturer should determine if inadequate labeling may have lead to misuse.
File Accessibility and Location
The GMP requirement states in 820.180 that "All records required by this part shall be
maintained at the manufacturing establishment or other location that is reasonably accessible to
responsible officials of the manufacturer and to employees of the Food and Drug Administration
designated to perform inspections." "All records" includes complaint files and records of
investigations. For complaint processing, responsible officials are general managers, complaint
processors, QA managers, R&D and process engineers, and others who receive, process, investigate,
and correct problems associated with complaints. Complaint files shall be reasonably accessible to
FDA for review and copying. FDA has clear authority under Section 704(e) of the Food, Drug, and
Cosmetic Act to inspect and copy all records required under section 519 of this Act.
The GMP requirement states that complaint files must be handled by a formally designated
complaint unit. If the unit or individual(s) designated as responsible for investigating complaints is
located away from the actual manufacturing site, the investigated complaint(s) and the record(s) of
investigation shall be reasonably accessible to the manufacturing site. If a manufacturer’s formally
designated complaint unit is located outside of the United States, records required by this section
shall be reasonably accessible in the United States at a location in the United States where the
manufacturer’s records are regularly kept or at the location of the original distributor.
When devices are produced for a manufacturer by a contract manufacturer, the manufacturer
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should forward to the contractor copies of complaints and investigations that pertain to operations
performed by the contractor. The contractor should maintain a complaint file and process
complaints as discussed herein for the primary manufacturer.
Relabelers, importers, and others who distribute under their own name should forward
complaints to the actual manufacturers, including foreign manufacturers, who are usually in the
best position to resolve complaints on their own products.
Non-medical Complaints
Certain manufacturers’ products may be used both as a medical device and for non-medical uses,
for example lasers and motors. The complaints received from non-medical users do not necessarily
have to be included in complaint files. However, if the non-medical product fails to meet
specifications, then that report should be in the manufacturer's complaint file. This action would
help assure compliance with 820.100, which requires identifying, recommending, or providing
solutions for quality problems and verifying implementation of such solutions. The person receiving
such complaints shall be trained [820.25(b)] to identify complaints that also affect those units used as
medical devices.
Complaint Analysis
To facilitate detection of failure or defect trends, complaint files should be arranged in a manner
that permits correlating present and past complaints for a particular product or product line. Thus,
files are usually organized according to product or product lines. Manufacturers who do not
organize complaint files by product or product line may have to search several files to find similar
complaints or indications to identify problem trends. Complaints may be maintained in a computer
file so that complaint data on a specific device or type of complaint can be readily accessed and
analyzed. As appropriate, complaint analysis or their summaries should be included in the
management review and the quality system [820.20(c)].
DEVICE FAILURE ANALYSIS
Manufacturers should process and analyze failed devices per 820.100. Section 820.100(a)(1) states
that returned product is subject to corrective action. Failure analysis must be conducted by
appropriately trained and experienced personnel [820.25(b)]. They should use a written procedure
to assure that the process of device handling and analysis will not compromise the determination of
the cause of the device failure. The failure investigation and analysis should determine the actual
failure mechanism to the objective level necessary to correct the problem. When systematic failure
has been diagnosed and corrective action established, a manufacturer need not analyze all additional
devices that are returned with the same symptoms.
If a failure is determined to be related to safety and effectiveness, the deficiency should be
determined, corrected and documented. If an investigation verifies a particular device deficiency
and that this deficiency may exist in other products, the investigation should extend to determining
its effect on other medical products.
Any corrective or preventive action taken shall be done following the requirements in 820.100.
FEEDBACK FOR QA SYSTEM
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The more comprehensive a quality system is, the lower the probability of complaints occurring.
However, in order for a quality assurance system to be dynamic or self correcting, data on quality
problems from all sources should be fed back into the system. Complaints are a valuable source of
data that can point to corrective actions.
Feedback data should flow into all operations that could be affected by the data and should be
used to aid in device and process design evaluation and/or redesign, and to aid in improving the
overall quality system program.
Regardless of the size of the formal quality system, the feedback data path in any company
should be the same, that is, the data should flow into all affected operations even if some of these are
not covered by the formal quality system or by FDA regulations.
COMPLAINT SOURCES
Complaints that shall be processed according to the GMP requirements may be received from:
•
•
•
•
•
•
customers by letter, credit memo, returned goods form, or phone;
a manufacturer's representative, or other employees;
the MedWatch voluntary reporting program;
a service or repair request;
journal articles; or
the FDA.
Complaints from any source shall be equally addressed by and be processed according to the
company complaint policy and procedure. The company should make certain that market, sales,
engineering, manufacturing, regulatory, installation, and service personnel are trained to properly
identify and report complaints. These employees shall be made aware of this requirement according
to section 820.25(b).
MEDICAL DEVICE REPORTING
In addition to the GMP requirements covering complaint handling and failure investigations,
device
manufacturers shall also comply with the Medical Device Reporting (MDR) regulation, 21 CFR Part
803.
Who Must Report
The MDR regulation requires that all manufacturers of medical devices notify FDA when they
become aware of a death or serious injury that may have been caused or contributed to by one of
their marketed devices and/or any malfunction of one of their devices which, if it were to recur,
would be likely to cause or contribute to a death or serious injury. These are the same complaints
that the Quality System regulation requires a manufacturer to place in a separate portion of the
complaint file or otherwise clearly identify [820.198(d)]. The MDR regulation is intended to
supplement the Quality System regulation -- it is not meant to replace the GMP complaint and
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failure investigation requirements.
When to Report
There are specific time limits within which the MDR reports shall be made. Any report of a
device-related death, serious injury and malfunction shall be submitted within 30 calendar days
from becoming aware of an MDR reportable event. To meet these requirements, manufacturers
shall have an information handling system to assure that data are screened to determine what shall
be reported to FDA. This system shall also be able to follow up this information quickly and
accurately in order to comply with the MDR regulation. Manufacturers which have a good system
for processing complaint and failure investigations such as described in this chapter will have the
organization and data processing capabilities to meet the MDR requirements.
Manufacturers of medical devices are required to report a device related death, serious injury or
malfunction to FDA using FDA Form 3500A, within 30 calendar days after becoming aware of the
event. However, if the event necessitates remedial action to prevent an unreasonable risk of
substantial harm to public health, then a report shall be submitted within 5 work days. Reports shall
also be submitted when FDA notifies a manufacturer that 5-day reports involving a particular type
of medical device or type of event are required.
The reporting process starts when an MDR reportable event is first recognized. Manufacturers
are responsible for making sure their employees know how to recognize what may be reportable.
Manufacturers should also emphasize that any employee may learn of an adverse event during a
phone call, a sales visit, a professional conference, from correspondence received or from
service/warranty orders.
Individual Adverse Event Reports
There are two types of individual adverse event reports that may be submitted by manufacturers.
The 5 work day and 30 calendar day reports.
The 5-day report (803.53) is for MDR reportable event(s) that require a remedial action to
prevent an unreasonable risk of substantial harm to the public health or where FDA has specified
that a 5-day report is needed. This situation may be identified by the manufacturer or FDA:
•
If the manufacturer identifies the event and initiates a remedial action to prevent an
unreasonable risk of substantial harm to the public health, a 5-day report is submitted instead
of the 30-day report. Information not available within the five days should be provided in a
supplemental report.
•
If FDA identifies the event, the manufacturer will receive a written request directing them to
file a 5-day report for all subsequent events of the same nature that involve similar devices for
a specified time period. The FDA identification may be a result of its review of 30-day reports,
inspection reports, user facility reports, etc.
The 5-day period of reporting starts the day after any employee, who is a person with
management or supervisory responsibilities over persons with regulatory, scientific, or technical
responsibilities, or a person whose duties relate to the collection and reporting of adverse events,
becomes aware that a reportable MDR event or events, from any information, including any
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analysis, necessitate remedial action to prevent an unreasonable risk of substantial harm to the
public health.
The MDR regulation defines remedial action as any action other than routine maintenance or
servicing of a device where such action is necessary to prevent recurrence of a reportable event.
Not all remedial actions need to be submitted as 5-day reports. Only remedial actions that are
necessary to prevent an unreasonable risk of substantial harm to the public health shall be
submitted. If a remedial action is taken, but it is not done to prevent an unreasonable risk of
substantial harm to the public health a 5-day report is not required. A 30-day report, however, may
be required.
The discovery that a remedial action is necessary may be a direct result of one or more MDR
reportable events occurring, or may be discovered through the performance of internal analyses
using appropriate statistical or other acceptable methodologies for processing data.
Actions taken to fix a single device involved in the MDR reportable event are not remedial
actions.
A 30-day report is required once a manufacturer receives or otherwise becomes aware of
information that reasonably suggests that a device they have marketed:
(1) has or may have caused or contributed to a death or serious injury; or
(2) has malfunctioned and such device or similar device marketed by the manufacturer would be
likely to cause or contribute to a death or serious injury, if the malfunction were to recur.
The 30-day period for reporting starts the day after receipt by any employee of information that
reasonably suggests that an MDR reportable event has occurred. FDA expects manufacturers to
train their employees to recognize that they have received information on an adverse event and to
know to whom in the company to forward this information for an MDR evaluation.
A manufacturer is NOT required to file an MDR report:
•
when it determines that a device related event did not occur, or
•
when it determines that the device was made by another manufacturer.
For the latter instance, the regulation requires the manufacturer to forward whatever
information they have to FDA with a cover letter explaining that they did not manufacture the
device so that FDA can send it on to the correct manufacturer. In this case, a 3500A should not be
completed. Manufacturers may also voluntarily send a copy of this information to the manufacturer
they identify as being the actual manufacturer.
Written MDR Procedures
In addition to having general complaint handling procedures, the MDR regulation (803.17)
requires manufacturers to develop, maintain and implement written MDR procedures that at a
minimum:
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A. Set up internal systems for:
•
timely and effective identification, communication, and evaluation of any events that may be MDR reportable;
•
a standardized review process/procedure for determining when an event meets the criteria for reporting under the
MDR regulation; and
•
timely transmission of a complete MDR report to FDA.
B. Set up documentation and recordkeeping for:
•
information that was evaluated to determine if an event was MDR reportable;
•
all MDR reports and information submitted to FDA;
•
any information that was evaluated when preparing the annual certification report; and
•
systems that ensure access to information that facilitates timely follow up and inspection by FDA.
The MDR procedures should be either incorporated in the overall complaint handling procedure or be a companion to it. In
either case these MDR procedures shall be clearly identified. If a companion procedure, it shall be incorporated by reference in
the overall procedure. This will assure that all complaints are properly evaluated for MDR reporting.
Each manufacturer has certain discretion to determine the level of detail and depth of information that their written MDR
procedures contain. FDA suggests that manufacturers provide policy and interpretation information regarding “typical” adverse
events or product problems that may be MDR reportable. FDA also suggests that the procedures describe the investigation
protocol that will be followed, e.g., two or three or four attempts will be made to contact the reporter either by phone, FAX or
letter before an investigation is closed; that the complaint records will contain a concise but thorough description of the adverse
event or product problem, that the complaint records will be legible, etc.
MDR Event Files
Each event that requires a determination regarding its MDR reportability shall be documented in an MDR event file (MEF)
(803.18). This MEF will be one of the bases for establishing compliance with the requirements of the MDR regulation. Files are
to be accessible to FDA personnel for review and evaluation, be as complete as possible, and are to clearly document MDR
related actions and decisions. The following information should be in the MEF to assure that it complies with the MDR
requirements:
a)
The original or a copy of the initial record complaint/event. This record should include the available information needed
to complete the Form FDA 3500A. The record may be documentation of a telephone call, a letter or facsimile, a service
report, documents related to a lawsuit, a voluntary FDA 3500 received from a health care professional or consumer, or
mandatory FDA 3500A received from a User Facility and/or a Distributor, etc.
b) Copies of any records documenting the manufacturer’s attempts to follow-up and obtain missing or additional
information about the event. When information cannot be obtained an explanation shall be made part of the file.
c)
Copies of any test reports, laboratory reports, service records and reports, records of investigation, etc.
d) Copies of all documentation involving the final assessment of the event, any deliberations and/or decision making
processes used to determine whether an MDR report was or was not needed. When applicable, the final assessment
should indicate what action, if any, the manufacturer has taken to assure that the cause of the event is corrected or
otherwise mitigated.
e)
Copies of all FDA 3500A forms submitted to FDA, when applicable. This includes a copy of any FDA 3500A forms
received from User Facilities and Distributors.
f)
Documents verifying that the event has been evaluated in accordance with the applicable requirements of the QS
regulation, sections 820.100 and 820.198.
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g) References to any other relevant documents or information used during assessment.
How To Maintain MDR Event Files
The MEF can be written or electronic files. They may make reference to other information that was used during the
investigational process, in lieu of copying and maintaining duplicates in the file. Any referenced material is to be made available
to FDA personnel for review, copying and verification.
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Each MEF shall be retained for a period of two (2) years from the date of the event or a period of time equivalent to the
expected life of the device, whichever is greater. Each MEF file shall be maintained for this period of time even if the device is
no longer sold/distributed by the manufacturer.
The MEF may be maintained as part of the complaint file required by 21 CFR Section 820.198, however, the MEF files shall
be prominently identified.
ADDITIONAL MDR GUIDANCE
Manufacturers should refer to the guidance document entitled, “Medical Device Reporting for
Manufacturers,” for further information on how to comply with this requirement.
REPORTS OF REMOVALS AND CORRECTIONS
At the time of completion of this manual, FDA has not published a final rule implementing its
authority under section 519(f) of the Act to require reports of removals and corrections. It is
important to note, however, that the agency published a proposal to implement this authority at 59
FR 13828 (March 23, 1994). A final rule based on the proposed rule may require reporting different
from or in addition to that required by the Quality System and MDR regulations.
EXHIBITS
Exhibits are described below which follow in the order described.
Complaint Processing Procedure and Forms
This sample procedure is used to establish and help implement a system for processing routine
complaints for devices. The customer complaint form mentioned in the sample procedure is
essentially the same as the form, "customer/device complaints," in the next exhibit. Nowadays the
complaint log shown on sheet 3 of 5 is easily maintained on a computer.
An example of a complaint recording form follows the complaint processing procedure.
The form titled "Customer Complaint" can be used to record most complaints.
If it matches a manufacturer's needs, the complaint form may be used as is. Also, it may be
modified to meet specific needs. If the form is modified or a new one is developed, a manufacturer
should make sure the resulting form is consistent with the GMP requirements and consistent with
any complaint handling policy and/or procedures being used at the manufacturer.
MedWatch Forms
A copy of the MedWatch 3500A is included at the end of this chapter. This form may be
photocopied for submitting reports.
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*** SAMPLE PROCEDURE ***
Sheet 1 of 5
COMPANY LOGO
Title Complaint Processing Procedure
SOP Number
Prepared by
Date Prepared
Approved by
Date
Rev
ECN Notes
PURPOSE: To establish and implement a procedure and forms for recording customer complaints,
analysis, response, and corrective action.
POLICY: It is the policy of our company that all complaints regarding safety, performance, or
quality of our products or services will be subject to management review and/or investigation and
will result in prompt response and corrective action where indicated.
SCOPE / DEFINITION: This policy is applicable to and must be complied with by all personnel
who receive a customer complaint, including personnel in Sales and other departments.
A "complaint" is any indication of the failure of a device to meet customer or user expectations
for quality or to meet performance specifications. Thus, any written, oral, or returned goods
expression of dissatisfaction relative to the identity, quality, durability, reliability, safety,
effectiveness, or performance of any device manufactured by this manufacturer would be considered
a complaint.
Types of complaints intended to be covered by this policy are as follows:
1. PRODUCT PERFORMANCE: the product in some way does not perform to user's expectation
or to any level of performance conveyed to the customer by printed labeling or verbally by
company employees.
2. PRODUCT SAFETY: all safety complaints are covered by this procedure.
3. PRODUCT RELIABILITY: failure rate or need for service adjustments greater than user
expectation, i.e. beyond the tolerable level of expected wear or malfunction.
4. PRODUCT APPEARANCE: visual defects inconsistent with the user's expectations for a
medical device.
5. GENERAL COMPLAINTS: order or shipping error, delayed or unacceptable response to
problems, unfulfilled promises, etc.
6. MDR REPORTABLE COMPLAINTS: all complaints involving device-related deaths, serious
injuries and malfunctions. (See Policy/Procedure No. XXX for handling of MDR reports.)
FORMS USED: Customer/Device Complaint and Analysis and Complaint Log
PROCEDURE: Upon receipt of a customer complaint, the recipient completes side one of a
CUSTOMER/DEVICE COMPLAINT form and, if the complaint is written, attaches the complaint
letter to the form. The recipient then gives the form, with any attachments, by the next day to the
Manager of Quality Assurance.
*** SAMPLE PROCEDURE
Sheet 2 of 5
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IMPORTANT COMPANY POLICY: Where a complaint requires immediate corrective action or
response to a customer, the complaint recipient must either take the required action or
communicate with the proper person to take the required action. It is the responsibility of the
recipient of any complaint to see that the customer receives a response -- nothing in the following
procedure relieves him or her of this responsibility.
Quality Assurance:
1. Assigns a sequential complaint number and enters the complaint into the Complaint Log.
2. Determines and notes on the complaint form the person to whom the complaint is to be assigned
for investigation and/or corrective action and the date a response is required from the assignee.
3. Notes any specific instructions to the assignee.
4. Distributes a copy to appropriate Department(s) as checked on side 1 of the complaint form.
5. Makes 2 copies of all sides of the in-process form and attachments, and distributes:
Original to the Assignee.
One copy to the "UNDER INVESTIGATION" complaint folder.
The Assignee:
1. Performs the investigation and/or corrective actions and records the results on the form; and
attaches any investigation records. If no investigation was done the reason why must be recorded
and the name of the approving official documented.
2. Returns the original of the in-process form to QA.
Quality Assurance:
1. Records on the Analysis side:
If no action is taken, the reason for inaction should be recorded on the analysis form.
Any additional corrective action taken or directed by QA.
Whether an MDR report was submitted to the FDA.
The nature and date of any response made to the originator or the customer. If this response is
written, a copy of the letter or FAX is attached to the analysis form.
The final disposition of the complaint.
QA signature and date.
2. Records the final disposition of the complaint on the complaint log.
3. Files the completed form in the appropriate complaint file for the type of device involved; and
discards the copy previously filed in the "UNDER INVESTIGATION" complaint folder.
4. Distributes the complaint log monthly to Staff and specifically involved departments. This log
should include a trend analysis of complaints for the month correlated with trends noted in
previous months.
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*** SAMPLE RECORD ***
COMPLAINT LOG
Sheet 3 of 5
MONTH
Seq.
No.
COMPLAINT
DISPOSITION
Date
Rec’d.
Type
Device
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, 19
*** SAMPLE RECORD***
Sheet 4 of 5 of Procedure No.
CUSTOMER COMPLAINT (Side 1)
SEQUENTIAL NO.
Device Name
Model Number
Catalog Number
Lot Number
Distributor
Name of Complainant
Phone No.
Complainant Address
Complaint Received by
Title
Date Received
By: ! Visit ! Phone ! Letter ! Sales ! Credit Memo ! Other
COMPLAINT ABOUT
! Sterility
! Particulate Matter Type
Location
! Defect
! Packaging
! Labeling
! Patient Death
! Patient Injury
! Product Malfunction
! Other (specify)
Comments/Description of Event
ATTACHMENTS ! Implicated Sample ! Associated Sample
Received By QA Mgr
Assigned To
! Letter
Date
Response Due
Instructions
Distribution: ! Quality Control ! Engineering ! Production ! QA ! Sales ! Service
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*** SAMPLE RECORD***
Sheet 5 of 5 of Procedure No.
CUSTOMER ANALYSIS (Side 2)
SEQUENTIAL NO.
Device Name
Model Number
Catalog Number
Lot Number
Date of Complaint Report
Name of Complainant
Nature of Complaint
ASSIGNEE EVALUATION
Date(s) Evaluation Performed
Evaluation Results
! Copy of evaluation attached
CONCLUSIONS
! Device Defective
! Shipping Damage
! Device Failed to Meet Specifications
! Repair Request
! Improper Use
! Other(specify)
ACTION/REPLY TO COMPLAINANT
! None. Reason for no action
! Recalled. FDA phoned on - Date
! Complaint Committee Informed on - Date
Spoke to
! MDR Filed on - Date
! Referred to
for Further Investigation or Correction
! Replaced ! Repaired ! Credited ! Letter Sent ! Sales Follow Up
! Reason for No Reply
NOTES:
FINAL DISPOSITION
Reviewed by: Quality Assurance
Date
If requested: Engineering
Date
Date
Production
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15−35
15−36
16−37
16
SERVICING
INTRODUCTION ................................................................................................................. 16-1
Interfaces ........................................................................................................................... 16-1
SERVICE PERSONNEL ...................................................................................................... 16-2
SERVICE REQUIREMENTS .............................................................................................. 16-3
INSTALLATION ................................................................................................................... 16-3
CONTRACT SERVICE ........................................................................................................ 16-4
SERVICE EQUIPMENT ...................................................................................................... 16-6
SERVICE PROCEDURES ................................................................................................... 16-6
ACCEPTANCE STATUS ..................................................................................................... 16-7
SERVICE REPORTS ............................................................................................................ 16-8
SERVICE REPORT ANALYSIS ......................................................................................... 16-8
Parts Shipping Trends ...................................................................................................... 16-9
COMPLAINTS ...................................................................................................................... 16-9
CORRECTIVE AND PREVENTIVE ACTION .............................................................. 16-10
EXHIBIT .............................................................................................................................. 16-11
INTRODUCTION
The requirements in the Quality System (QS) regulation govern the methods used in, and the
facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation,
and servicing of all finished devices intended for human use. Servicing covers the maintenance and
repair of finished, distributed devices.
The intent of the quality system regulation is to assure that servicing is correctly performed and
verified according to company specified requirements such that the serviced device is suitable for the
intended use and that service information is collected and analyzed to help correct any quality
system problems and device design, manufacturing, labeling, or packaging problems.
The basic servicing requirements are in 820.200, Servicing. However, there are related
requirements throughout the QS regulation. For example, service procedures are documented per
820.181, Device Master Record; and servicing activities and/or data may lead to complaint analysis
per 820.198, Complaint Files, or require corrective and preventive action per 820.100.
When a finished device manufacturer contracts with another supplier to perform their servicing,
such service (or service contractor) must meet the applicable purchasing and servicing requirements
in the QS regulation.
Interfaces
There are interface requirements in the QS regulation that apply to service functions. Section
820.30(b), Design and Development Planning, requires that each manufacturer shall establish and
maintain plans that describe or reference the design and development activities and define
responsibility for implementation. The plans shall identify and describe the interfaces with different
16−38
groups or activities that provide, or result in, input to the design and development process.
The preamble clarifies the fact that these requirements extend to service functions by stating: the
plan shall identify and describe the interfaces with different groups or activities that provide, or
result in, input to the design process. Many organization functions, both inside and outside the
design group, may contribute to the design process. For example, interfaces with marketing,
purchasing, regulatory affairs, manufacturing, service groups, or information systems may be
necessary during the design development phase. To function effectively, the design plan should
establish the roles of these groups in the design process and describe the information that should be
received and transmitted.
Therefore, for medical devices that require servicing, during appropriate activities such as design
input and design reviews, service requirements and ease of service should be considered; and service
managers, senior service technicians, etc., may need to participate in these design functions. Such
participation may reduce the:
•
•
•
•
need for maintenance and repairs;
time to perform repairs,
need for special tools; and
cost of repairs.
Reducing the time for repairs and the need for special tools usually reduces production assembly
time and manufacturing costs.
SERVICE PERSONNEL
Service shall be conducted by appropriately trained and experienced service personnel (820.25) in
order to:
•
•
•
•
assure, to the extent feasible, that the process of device handling, diagnosis, and repair will not
compromise the determination of the root cause of the device failure;
identify and correct the failure;
correctly report the service information; and
identify and report data related to a serious incident or adverse event.
The repair diagnosis should also try to determine, and/or provide adequate data to assist analysts
in determining, the actual failure mechanism to the objective level necessary to correct or reduce the
problem.
Thus, service personnel must be trained to adequately perform their assigned maintenance,
repair, and reporting responsibilities. Such training shall be documented (820.25). The training is
also performed in accordance with the instructions and procedures established under 820.200 for
performing and verifying that servicing meets the specified requirements. Because servicing must be
verified, service personnel must be made aware of defects and errors that may be encountered as
part of their job functions (820.25). This training requirement usually does not require separate or
additional training because basic training to perform repairs emphasizes the identification of defects
and errors.
SERVICE REQUIREMENTS
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The QS regulation does not require that a manufacturer service a device. The decision to service
or have their devices serviced is left to the manufacturer. When a manufacturer specifies that they
will perform service or contract to have service performed, such service must meet all of the
applicable QS regulation requirements. Such a manufacturer shall establish and maintain
instructions and procedures for performing and verifying that the servicing meets the
manufacturers specified requirements. Section 820.200, Servicing, states:
(a) Where servicing is a specified requirement, each manufacturer shall establish and maintain
instructions and procedures for performing and verifying that the servicing meets the specified
requirements.
(b) Each manufacturer shall analyze service reports with appropriate statistical methodology in
accordance with 820.100.
(c) Each manufacturer who receives a service report that represents an event which requires
reporting to FDA under part 803 or 804 of this chapter shall automatically consider the report a
complaint and shall process it in accordance with the requirements of 820.198.
(d) Service reports shall be documented and shall include:
(1)
(2)
(3)
(4)
(5)
(6)
The name of the device serviced;
Any device identification(s) and control number(s) used;
The date of service;
The individual(s) servicing the device;
The service performed; and
The test and inspection data.
INSTALLATION
Where service and installation are required by a manufacturer, both of these product activities
are related and so are the QS requirements for both. Section 820.170 Installation states:
(a) Each manufacturer of a device requiring installation shall establish and maintain adequate
installation and inspection instructions, and where appropriate test procedures. Instructions and
procedures shall include directions for ensuring proper installation so that the device will perform as
intended after installation. The manufacturer shall distribute the instructions and procedures with
the device or otherwise make them available to the person(s) installing the device.
(b) The person installing the device shall ensure that the installation, inspection, and any
required testing are performed in accordance with the manufacturer's instructions and procedures
and shall document the inspection and any test results to demonstrate proper installation.
Some manufacturers use their service department or a service contractor to install their medical
devices. Servicing may also include re-installing a device. As shown in Table 16.1, Comparison Of
Servicing And Installation Requirements, the QS requirements for installation in 820.170 essentially
parallel the requirements for service in section 820.200. For example, The QS regulation includes
detail of the reporting requirements for servicing; for installation, the manufacturer chooses the
information to document. However, from a practical viewpoint, each manufacturer would choose to
have the same information documented. Thus, as appropriate, a manufacturer may combine most of
16−40
their service and installation QS activities.
CONTRACT SERVICE
When a finished device manufacturer contracts with another supplier to perform their servicing,
such service (or service contractor) must be obtained per the applicable requirements in 820.50,
Purchasing. Each manufacturer shall establish and maintain procedures to ensure that all
purchased or otherwise received services conform to specified requirements. Each manufacturer
shall establish and maintain the requirements, including quality requirements, that are to be met by
contractors. Each manufacturer shall:
(1)
Evaluate and select potential contractors on the basis of their ability to meet specified
requirements, including quality requirements. The evaluation shall be documented.
(2)
Define the type and extent of control to be exercised over the contractors based on the
evaluation results.
(3)
Establish and maintain records of acceptable contractors.
Each manufacturer shall establish and maintain data that clearly describe or reference the
specified service requirements, including quality requirements. Purchasing data shall be approved
in accordance with 820.40.
A major portion of the purchasing requirements are met when the manufacturer meets the
servicing requirements in section 820.200(a) which states:
(a) Where servicing is a specified requirement, each manufacturer shall establish and maintain
instructions and procedures for performing and verifying that the servicing meets the specified
requirements....
That is, these specified requirements, service instructions and procedures, and device verification
procedures may be used together with other information such as the finished device description to
help show a prospective contractor the scope and expected quality of the servicing that is being
contracted.
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Table 16.1 COMPARISON OF SERVICING AND INSTALLATION REQUIREMENTS
SERVICING
INSTALLATION
(a) ... establish and maintain instructions and
procedures for performing and verifying that
the servicing meets the specified
requirements.
(a) ... establish and maintain adequate
installation and inspection instructions, and
where appropriate test procedures.
(a) .... and verifying that the servicing meets
the specified requirements.
(a) Instructions and procedures shall include
directions for ensuring proper installation so
that the device will perform as intended after
installation.
(b) The person installing the device shall
ensure that the installation, inspection, and
any required testing are performed in
accordance with the manufacturer's
instructions and procedures and ...
(b) Each manufacturer shall analyze service
reports with appropriate statistical
methodology in accordance with 820.100.
(a) ... establish and maintain instructions and
procedures for performing and verifying that
the servicing meets the specified
requirements.
(a) ... The manufacturer shall distribute the
instructions and procedures with the device
or otherwise make them available to the
person(s) installing the device.
(d) Service reports shall be documented and
shall include:
(b) The person installing the device shall
ensure that the installation, inspection, and
any required testing are performed in
accordance with the manufacturer's
instructions and procedures and shall
document the inspection and any test results
to demonstrate proper installation.
(1) The name of the device serviced;
(2) Any device identification(s) and control
number(s) used;
(3) The date of service;
(4) The individual(s) servicing the device;
(5) The service performed; and
(6) The test and inspection data.
(c) Each manufacturer who receives a
service report that represents an event which
requires reporting to FDA under part 803 or
804 of this chapter shall automatically
consider the report a complaint and shall
process it in accordance with the
requirements of 820.198.
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SERVICE EQUIPMENT
Section 820.20(b)(2) Resources requires each manufacturer to provide adequate resources,
including the assignment of trained personnel, for management, performance of work, and
assessment activities to meet the requirements of this part. As appropriate, adequate resources
include service instructions, service procedures, supporting DMR drawings, and service equipment.
Service equipment includes equipment to perform the repair and to verify the proper performance
of the serviced devices. Service equipment may include complex apparatus; however, it also includes
any simple jigs, test cables, special hand tools, etc., as needed to meet the service needs of specific
medical devices.
Servicing and Installation both require verifying that the device meets acceptance criteria.
Therefore, appropriate and calibrated test equipment should be used. Section 820.72, Inspection,
Measuring, and Test Equipment, requires that each manufacturer to ensure that all inspection,
measuring, and test equipment, including mechanical, automated, or electronic inspection and test
equipment, is suitable for its intended purposes and is capable of producing valid results. Each
manufacturer shall establish and maintain procedures to ensure that equipment is routinely
calibrated, inspected, checked, and maintained. The procedures shall include provisions for
handling, preservation, and storage of equipment, so that its accuracy and fitness for use are
maintained.
When establishing service and installation procedures, each manufacturer needs to comply with
the Inspection, Measuring, and Test Equipment requirements, as appropriate, in order to assure
that the serviced/installed device performs as intended. For example, a manufacturer may need to
determine which service equipment, if any, needs to be calibrated in a laboratory and which, if any,
may be calibrated using the self-contained internal calibrators. Also, the manufacturer may need to
select equipment that is capable of producing valid results after being subjected to repetitive and
demanding service.
SERVICE PROCEDURES
If any are required, maintenance needs, schedules, and procedures are developed as part of the
device design program. Some preventive maintenance tasks and their schedules may result from
reliability studies performed during design development.
Repair procedures are based in part on design verification and finished device test and inspection
procedures, production procedures, and rework procedures. Other aspects of repair procedures are
developed by qualified technical personnel and senior repair technicians. The development of
procedures may involve inserting failures or defects and having another person find and repair
them. The problems, discovery methods, and rework techniques are documented.
For redesigns, existing maintenance and/or repair procedures that are known to be current and
correct may be referenced in the new service procedures or these may be renumbered and copied
into the new procedures.
Identifying defective subassemblies or modules in the device and replacing them with good
modules is a common servicing practice. The defective assembly is discarded, sent to be investigated,
or is repaired at a designated facility with the necessary environmental conditions and facilities; test
equipment and tools; component availability; trained rework employees; etc. This approach should
16−43
also be covered by appropriate procedures.
The development of service procedures includes the development of appropriate service reporting
forms.
Service instructions and procedures must be documented per 820.40. They are part of the device
master record (DMR). Typical DMR documents (820.181) that are needed for service or that may be
modified for service include:
•
device specifications including appropriate drawings, component specifications, and software
specifications;
•
quality assurance procedures and specifications including acceptance criteria and the quality
assurance equipment to be used; and
•
installation, maintenance, and servicing procedures and methods.
These DMR documents usually cover:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
what the device does;
theory of operation;
operating instructions;
safety;
device specifications;
component specifications, identification, and nomenclature;
test apparatus, jigs, and special tools;
typical failure modes and conditions;
how to identify and isolate failures;
test points where specific parameters may be measured;
removal and replacement of parts;
testing and inspecting (verifying) the repaired device;
re-installation procedures, if applicable; and
reporting forms.
ACCEPTANCE STATUS
Each manufacturer shall identify by suitable means the acceptance status of devices to indicate
whether it has been service and whether it conforms with the acceptance criteria. The conformance
is determined by the procedures established inaccordance with 820.200(a).
The identification of acceptance status shall be maintained throughout servicing of the device to
ensure that only devices which have passed the required acceptance activities are distributed, used,
or installed (820.86). Identification is usually done by appropriate information on a decal, tag, or an
attached pouch that contains the service request and/or report.
If a decal is left on the serviced device, for the next request and service, the decal can provide
immediate information about the last service date, etc.
16−44
SERVICE REPORTS
Service activities shall be documented by service personnel and sent to the manufacturer
according to the manufacturer's established procedures. As mentioned, service reports shall include:
(1) the name of the device serviced;
(2) any device identification(s) and control number(s) used;
(3) the date of service;
(4) the individual(s) servicing the device;
(5) the service performed; and
(6) the test and inspection data.
The device identification should be specific regarding the revision level, modification version,
software version, etc., of the device in order to support analysis of the service data.
The test and inspection data should verify that the servicing meets the manufacturer’s specified
requirements. That is, the serviced device did, or did not, meet the acceptance criteria. (See
Acceptance Criteria below.)
The service reports should also include information such as:
•
•
•
•
•
•
•
•
device owner, address and phone number;
specific location of the device;
any unusual environmental conditions;
any evidence of damage or misuse;
if the device failed to meet specifications;
if the device was being used for treatment or diagnosis;
relationship, if any, of device to a death or serious injury; and
date of last service and service report number, if known.
SERVICE REPORT ANALYSIS
Each manufacturer that performs servicing shall analyze service reports with appropriate
statistical methodology in accordance with 820.100, Corrective and Preventive Action, which
requires manufacturers to establish and maintain procedures for implementing corrective and
preventive action. The procedures shall include requirements for analyzing service records and
other sources of quality data to identify existing and potential causes of nonconforming product or
other quality problems. The primary intent is to identify the action(s) needed to correct and prevent
recurrence of nonconforming product and other quality problems; and to verify or validate the
corrective and preventive action to ensure that such action is effective and does not adversely affect
the finished device.
Failure and service report analysis should be conducted by appropriately trained and experienced
personnel (820.25). Such personnel are also one of the resource requirements in 820.20(b)(2).
The analysis of service reports or subsequent analysis of the same or equivalent device(s) should
be designed to determine the actual failure mechanism or quality problem to the objective level
necessary to correct the problem.
When systematic failure has been diagnosed and corrective action established, a manufacturer
16−45
need not analyze all additional devices that are serviced or returned with the same symptoms.
The analysis of service reports is totally dependent on the quality of the data in the reports.
Therefore, it is very important that service training cover reporting so that the resulting reports are
correct, complete, understandable, and easy to analyze.
The service reports for routine service requests for maintenance, adjustment, or repair of damage
or failure resulting from long use, misuse or accident, usually do not need the same level of analysis
as for other failures. However, some requests for service may appear to be routine when, in fact,
they may be for unusual conditions that warrant attention. For example, service requests because of
rapid wear, unusual problems, unusual maintenance, or development of hazardous conditions
should receive a complete analysis in order to determine if corrective action is needed in the
preventive maintenance procedures, design, labeling, manufacturing processes, etc. Enough
information should be obtained from the customer to determine whether the request is for routine
maintenance or the device is to be serviced for other reasons.
Parts Shipping Trends
As appropriate manufacturers should periodically (e.g., monthly) examine shipping records for
repair parts. Any increases in shipment of specific parts due to unknown reasons should be analyzed
to determine if a significant failure problem exists. Manufacturers have identified quality problems
by this simple, low-cost technique.
COMPLAINTS
Service requests for repairing or investigating an event that allegedly resulted in a death or
serious injury shall also be investigated as a complaint. Section 820.200(c) requires that each
manufacturer who receives a service report that represents an event which requires reporting
[Medical Device Reporting (MDR)] to FDA under part 803 or 804 of this chapter shall automatically
consider the report a complaint and shall process it in accordance with the requirements of 820.198.
Section 820.198(d) requires that any complaint that represents an event which must be reported
to FDA under part 803 or 804 of this chapter shall be promptly reviewed, evaluated, and
investigated by a designated individual(s) and shall be maintained in a separate portion of the
complaint files or otherwise clearly identified. In addition to the information required by 820.198(e),
records of investigation under this paragraph shall include a determination of:
(1) whether the device failed to meet specifications;
(2) whether the device was being used for treatment or diagnosis; and
(3) the relationship, if any, of the device to the reported incident or adverse event.
Because of the MDR and complaint relationship, manufacturers should have the service
personnel collect as much as is possible of the information required to complete the records of
investigation, steps 1 - 3 listed above. Thus, the service form for some devices may need blanks/areas
to support the collection of the needed information.
The service requirements AND complaint requirements shall be met for such combination
service/MDR/complaint events. If the death or serious injury was caused by a design error, it may
not be possible to perform a repair.
16−46
CORRECTIVE AND PREVENTIVE ACTION
A major intent of the service requirements is to look for quality problems during servicing and
analysis of service data, and, if problems are found that affect or could affect safety or performance,
to mandate appropriate corrective action. Thus, the collection (820.200) and analysis (820.100) of
servicing data are required and these are part of the quality feedback system. Without the feedback
provided by the quality audit and other information sources, such as complaints and service records,
manufacturers operate in an open loop system with no assurance that the process used to design and
produce devices is operating in a state of control.
Section 820.100, Corrective and Preventive Action, requires the analysis of quality records,
service records, complaints, returned product, and other sources of quality data to identify existing
and potential causes of nonconforming product, or other quality problems. Appropriate statistical
methodology shall be employed where necessary to detect recurring quality problems.
In-warranty or out-of-warranty are not factors to be considered when collecting or analyzing data
regarding servicing.
When nonconformities are found they are to be investigated to determine the cause, such as an
inadequate quality system or a defect in the design, component(s), assembly, processing, labeling,
packaging, installation method, service technique, etc.
The collection and analysis of service data should be broad based because the root cause may be:
an inappropriate component; a bad component; early wear out; poor maintenance; compatibility;
human factors, and safety; misuse; misuse due to inadequate labeling; poor workmanship; incorrect
assembly; etc.
The investigation and corrective actions should continue until valid actions are identified and
implemented to correct and prevent recurrence of nonconforming product and other quality
problems.
If service instructions, techniques, equipment, etc., contribute to a quality problem, make a
quality problem worse, destroy valuable data, etc., then such items are also subject to investigation
and corrective action.
16−47
EXHIBIT
An example of a service request form is included in this chapter. This form may be modified to
match individual needs as appropriate.
16−48
*** SAMPLE ***
Page 1 of 2
CUSTOMER SERVICE REQUEST
Service Report No.:
Device Name:
ID/Cat. No.:
Lot Number:
Any Specific Rev/Mod. #:
Date placed in use:
Manufacturer/Distributor:
Account Name:
Account Address:
Phone Number:
Fax Number:
Last Service Report (optional):
Date Of Last Service:
Last service comments:
Technician:
Date:
Device Location:
Customer Description Of Device Problem:
Were you told that there was a serious injury or death associated with this problem?
YES
If yes, describe relationship to incident or event.
NO
Was device being used for treatment or diagnosis?
Describe any unusual environment:
Describe any evidence of misuse:
If a repair, device problem(s) you found:
Maintenance and/or repairs performed:
Service Completed:
Service not completed:
Reason Not Completed:
16−49
*** SAMPLE ***
Page 2 of 2
CUSTOMER SERVICE REQUEST
In charts below, write identification code of components replaced. Write in first letter of ID code
where necessary. Be SURE to put drawing number & rev. level in top row.
Drawing number that shows replaced components listed below: .....................................................rev.
CAP
CAP
CAP
CAP
RES
RES
RES
RES
IC
IC
IC
IC
TRANSISTOR
TRANSISTOR
TRANSISTOR
TRANSISTOR
DIODE
DIODE
DIODE
DIODE
BAT
LED
COIL
COIL
FUSE
FUSE
LAMP
LAMP
CABLE
CABLE
DET
DET
Drawing number that shows replaced components listed below: .....................................................rev.
CAP
CAP
CAP
CAP
RES
RES
RES
RES
IC
IC
IC
IC
TRANSISTOR
TRANSISTOR
TRANSISTOR
TRANSISTOR
DIODE
DIODE
DIODE
DIODE
BAT
LED
COIL
COIL
FUSE
FUSE
LAMP
LAMP
CABLE
CABLE
DET
DET
Drawing number that shows replaced components listed below: .....................................................rev.
CAP
CAP
CAP
CAP
RES
RES
RES
RES
IC
IC
IC
IC
TRANSISTOR
TRANSISTOR
TRANSISTOR
TRANSISTOR
DIODE
DIODE
DIODE
DIODE
BAT
LED
COIL
COIL
FUSE
FUSE
LAMP
LAMP
CABLE
CABLE
DET
DET
16−50
17
QUALITY SYSTEM AUDITS
INTRODUCTION ............................................................................................................. 17-1
AUDIT REQUIREMENTS .............................................................................................. 17-2
Procedure ..................................................................................................................... 17-2
Audit Schedule ............................................................................................................ 17-4
Independent Auditor .................................................................................................. 17-4
Employee Training ..................................................................................................... 17-4
Evaluation Criteria ..................................................................................................... 17-5
Results and Corrective Actions ................................................................................. 17-5
Audit Certification ...................................................................................................... 17-6
EXHIBITS ......................................................................................................................... 17-7
Policy/Procedure for Quality System Audit ............................................................. 17-8
Quality System Audit Procedure ............................................................................. 17-14
Vendor Survey Form ................................................................................................ 17-17
INTRODUCTION
Section 820.20 outlines the quality system requirements of the Quality System (QS) regulation. As
discussed in Chapter 2, every quality system should include: management policies; objectives; an
organization; documentation; performance of tasks according to policies; monitoring of the system
(feedback) and corrective action as indicated by the feedback. Section 820.22 requires that the
quality system be monitored through audits. The analysis and use of feedback data from product
acceptance, audits, complaints, repairs, and other sources are necessary parts of a self correcting
quality system. Thus, the audit of a quality system is one of the most important GMP requirements.
The quality system first implemented by a new manufacturer will change as the manufacturer grows
and as the company’s products, operations and employees change. Therefore, a quality system
should change with the company. Quality system audits are the primary tool for assuring that the
quality system changes are correct and are correctly implemented.
A quality audit is a documented independent inspection and review of a quality system. The audit
is performed on a periodic basis in accordance with written procedures. The objective is to verify, by
examination and evaluation of objective evidence, the actual degree of compliance with those
elements of the quality system under review. These audits are an essential part of every medical
device manufacturer's effort to assure safe and effective devices. Regardless of how well a quality
system is planned, monitoring of the system is required if the quality system program is to be
effective in assuring that finished devices meet specifications. FDA analysis of factory inspections has
shown that manufacturers who do not have an adequate quality audit system usually do not have an
adequate quality system. An evaluation of approximately 2400 manufacturers that had received
GMP inspections by FDA showed that manufacturers with an adequate quality audit system were in
compliance with approximately 96 percent of the GMP requirements, while those that did not have
an adequate audit system were in compliance with approximately 70 percent of the requirements.
If conducted properly, a quality audit can detect quality system defects. Isolation of
unsatisfactory trends and correction of factors that cause defective products prevent the production
of unsafe or nonconforming devices. Without an effective quality audit function, the quality system
program is incomplete -- there is no assurance that a manufacturer is consistently in a state-of17-51
control. In addition, the proper implementation of a quality audit system can result in cost savings
by identifying and correcting problem areas. Without an audit, the quality system becomes an open
loop without feedback to management and without corrective action. Without overt management
support, the quality system program will eventually become ineffective and, as history has shown,
ignored.
AUDIT REQUIREMENTS
The QS regulation requires that planned and periodic audits of the quality system shall be
performed to verify compliance with the quality system requirements. The audits are to be
performed in accordance with written procedures by appropriately trained individuals who do not
have direct responsibility for the matters being audited. Audit results shall be documented in written
audit reports, which shall be reviewed by management personnel, who have responsibility for the
matters audited, and by other involved parties. Follow-up corrective action, including re-audit of
deficient matters, shall be taken when indicated. Upon request of a designated FDA employee, an
employee in management with executive responsibility shall certify in writing that the audits have
been performed and documented, the dates on which they were performed, and that any required
corrective action has been undertaken.
To assure that company quality goals will be routinely met and to comply with the QS regulation,
quality system audits should:
•
•
•
measure the effectiveness of the quality system;
provide objective evidence that adequate controls are in place; and
assure that products and processes conform with specifications.
Where practical, manufacturers should include audits of their suppliers, calibration laboratories,
and contractors as part of a quality system audit. Manufacturers should audit suppliers where
needed, to assure that they have adequate quality system controls for raw materials and components
shipped to and received by the manufacturers under supplier certification or certificate of
compliance with specifications. An example of a detailed supplier (vendor) survey (audit checklist)
form is in the Exhibits.
Procedure
All manufacturers should have a written quality audit procedure, although the details will vary
with the manufacturer size and nature of the manufacturing operations. An audit procedure should
include:
•
•
•
•
•
•
•
an objective,
audit scope,
an audit schedule,
assignment of responsibilities,
evaluation criteria,
management review of results, and
corrective action policies, schedules, etc.
Before writing their audit procedure, some manufacturers may find it helpful to rearrange the
key GMP requirements for an audit in a structured format as shown below:
17-52
•
•
•
•
•
•
Who?
What?
When?
How?
Results?
Actions?
Designee(s)
Quality system
X months
Per checklist
Report/review
Corrective
This structured format helps lead auditors into covering key requirements in the audit
procedure and "getting straight to the point when writing procedures." Thus, this format tends to
reduce the length and increase the clarity of audit procedures.
Formal procedures should start with an objective. In this case, the audit objective was discussed
in the opening paragraphs of this chapter -- to monitor the quality system and take any needed
corrective action. The audit scope should include all functions that impact on whether devices will
meet specifications. These functions include personnel training, facilities, environment, design
controls, device master and history records, equipment calibration, suppliers, label control, process
controls and validation, complaint files, data feedback, preparation for FDA GMP inspections, etc.
Manufacturers that have a total quality system composed of a design quality system and a
manufacturing quality system should audit the entire system; otherwise, it is no longer a total
quality system! Audits should cover all buildings and operations as necessary to make certain that
the desired or required quality system is properly implemented.
The quality system audit required by the QS regulation is not intended to be a product audit.
However, the adequacy of procedures used to determine product acceptability should be audited
periodically. Product audits and review of the device master record are desirable as independent
evaluations of product quality to determine the product's fitness for use and conformance to
specification and, these may be acceptable in satisfying most quality audit requirements when
product and process are very simple and the operation is small. As products and processes become
more complex, evidence from inspection and testing of products no longer provides full assurance
that the manufacturing system will consistently produce quality products. Instead, full quality
system audits are required to make certain that:
•
the established quality system is adequate for producing devices that consistently meet the
device master record requirements,
•
all system requirements are being met, and
•
the system will continue to function when new products are introduced, changes are made,
the workforce is understaffed, and the manager is on vacation.
Audit Schedule
Manufacturers are responsible for deciding the frequency of audits. The frequency should
depend upon previous audit findings, any indications of problems, and known stability of the
manufacturing process. If an audit reveals no problems, the audit intervals could be lengthened -- if
problems are identified, audits may need to be conducted more often. Audits are usually conducted
every 6 to 12 months, but should not exceed 12 months. Some companies split their audit into parts,
and perform one or more parts per month or quarter, or audit one or more operations per month or
quarter. This approach is valuable because it tends to direct attention toward problems that can be
17-53
resolved within reasonable time limits and existing budgets. However, such segmented audits may
fail to identify company-wide problems. Thus, reviewers of segmented audit reports should look for
indications of company-wide problems.
Independent Auditor
The QS regulation (820.22) requires that quality system audits be conducted by individuals not
having direct responsibility for the matters being audited. This requirement may be satisfied by an
audit team consisting of persons representing product development and manufacturing. Then, when
the product development area is being audited, the manufacturing persons should have the lead
responsibility and vice versa. For any element of the quality system being audited, at least one
member of the team should not have direct responsibility for the element being audited.
Management should designate one member as the team leader for a given audit in order to support
consistency, timeliness, completeness, and uniform response. Of course, a consultant, corporate, or
other independent auditor may be used.
The requirement for an independent audit should generally be met; however, if a very small
manufacturer, particularly one in which everyone is directly involved in daily design and production
activities, concludes that independent audits would be unduly burdensome or impractical, the
requirement for independence may be waived. However, if FDA finds, as a result of inspection or
other means, this waiver has compromised the quality system, FDA may require an independent
audit, increase the frequency of FDA GMP inspections, or take other appropriate regulatory action.
Employee Training
Individual(s) responsible for conducting audits should be sufficiently trained and experienced to
detect variations and problems in the quality system [820.20(b), 820.22]. An auditor is expected to
objectively compare existing employee training, design controls, manufacturing processes, facilities,
environmental control, records, test/inspection activities, label control systems, feedback, etc.,
against what they should be. To do this, the individual(s) should have a working knowledge of:
•
•
•
•
•
•
how products are developed and validated,
how the device(s) is made,
the manufacturing processes and process controls,
how changes are controlled,
quality assurance principles that apply, and
the human relations aspect of auditing.
As with any GMP training, a record shall be maintained of the audit training given each
employee.
Because the quality system requires a written audit report, auditors should have sufficient
writing skills to effectively communicate findings and recommendations. The effectiveness of the
audit begins with the planning. The manufacturer should start by defining the purpose and scope of
their audit keeping in mind their quality systems requirements. An audit team leader and the other
members of this team should be identified early in the planning process. The members of this team
should possess skill and knowledge of quality system principles. Preparing an audit checklist will
enable the team to properly cover the quality system requirements. Review of previous audits and
their resulting reports is an excellent way for the audit team to correctly evaluate their quality
17-54
system audit program. The background preparation should also include becoming familiar with
company policies, operations, and products. The audit team should notify the parties they will audit
and also hold a pre-audit conference among the audit team members to clarify exactly what the
audit will include and what the objective(s) of their audit will be. Thus, preparing for an audit
should include elements such as:
•
•
•
•
•
selecting a knowledgeable audit team,
preparing an audit checklist,
developing a planned and systematic procedure,
structuring the audit to determine both positive and negative trends, and
structuring the audit and report to promote follow-up actions.
Evaluation Criteria
Each manufacturer shall determine the criteria to be used for conducting the audit. In general,
medium to large manufacturers will need extensive documentation outlining the areas to be audited
and the acceptable criteria for each of these areas. The GMP requirements are a baseline for the
evaluation criteria; however, because the QS regulation is broad, each manufacturer shall tailor the
criteria to the design and manufacturing operations they are actually performing. Small
manufacturers may need only minimal documentation, and this may consist of an audit checklist
with appropriate ancillary instructions to assure that all aspects of the quality system are covered.
An audit checklist may be a series of questions, phrases, trigger words, or any combination of
these that will prompt auditors to cover the entire quality system. Checklists should cover
requirements of the QS regulation applicable to company products, operations, and other areas
company management has decided are included in their total quality system. If operations or devices
change, evaluation criteria and checklists shall be appropriately updated.
Results and Corrective Actions
A quality system audit program that has been established in accordance with the QS regulation
and implemented in sufficient depth can detect undesirable variations and trends in operating
procedures. Management awareness of these undesirable variations should lead to corrections and
help prevent the design and production of unsafe, unreliable, or ineffective devices.
The QS regulation requires follow-up corrective action, including re-audit. When indicated,
audit results shall be given to individuals responsible for each of the operations audited, especially if
deficiencies are found. Audit results shall be reviewed by all key management personnel, especially
those responsible for the matters audited.
An audit should never be used as a disciplinary tool. This use will lead to ineffective audits
because employees may become reluctant to reveal any possible problems for fear of retribution.
Audit Certification
Under 704(e) of the FD and C Act FDA has authority to review and copy all records required by
the QS regulation; however, FDA has elected not to review audit reports. The exception [820.180(c)]
to FDA's policy of not seeking access to reports of audits of quality systems is that FDA may seek
production of these reports in litigation under applicable procedural rules, along with other
17-55
confidential documents. Thus, a copy of the current audit report should be maintained by the
manufacturer. FDA policy was established because the agency does not wish to prejudice audits by
having auditors concerned that their comments will be reviewed by FDA investigators. Although
FDA investigators do not have routine access to audit reports, they can request manufacturers to
certify that audits have been conducted and the results documented; however, investigators do not
routinely request certification. If requested, an employee in management with executive
responsibility should certify, in writing, that the manufacturer has complied with the audit
requirements of the QS regulation.
Investigators usually will ask questions regarding the audit report such as:
•
•
•
•
•
•
who prepared the report;
what does the quality system audit include;
when was the report written;
using the checklist how should the audit be conducted;
who reviewed the information and wrote the report; and
were corrective action and re-audit(s) taken based on the audit result.
If investigators suspect audits are not being conducted, questions to determine consistency in
answers may be addressed to those individuals who should have reviewed these reports. FDA
investigators will routinely review audit procedures and audit checklists.
17-56
EXHIBITS
Two examples of audit procedures with checklists are included in this chapter. These may be
modified to match individual operations as appropriate or used as guidances.
Policy/Procedure for Quality System Audit
In response to requests by small manufacturers, DSMA developed this procedure as an example
of a minimum procedure for quality system audits. Following the procedure are comments to aid
small manufacturers in completing the procedure and developing a checklist that should be used
with it.
No details are given for the format of the audit "report" because the format generally is not
important for the small manufacturer -- employees of small manufacturers communicate daily with
each other. In fact, the "report" may be the list of findings neatly noted on the audit checklist. As
noted in the procedure, however, summaries of the audit findings and corrective actions are
recommended. The format Who, When, etc. discussed in the text, was used to develop this example
procedure. The first three items in this format are reflected in item 1 of the example and the
remaining three are reflected in items 2, 3 and 4 of the example. The scope encompasses the entire
quality system.
Quality System Audit Procedure
Quality System Audit Procedure is an audit procedure that can be used by a medium to large
manufacturer. In comparison to the small company, there are more people on the audit team, more
audits per year, and the reports are distributed to more managers, some of which may be at
corporate headquarters. Therefore, this procedure contains more details than the one suggested for
the small company. For example, the procedure dictates the format of the audit report for the
benefit of the managers, who may review reports for many different operations per year.
Vendor Survey Form
The vendor survey form is applicable to a vendor or contractor or may be modified and used as
an internal audit checklist. This survey form is divided into areas of concern such as raw material
and component control, manufacturing, quality control/assurance, etc. Also, it is a more
conventional checklist with places to check off answers to the questions. This form includes a header
with space for manufacturer name, address, date prepared, etc., and general information about the
manufacturer such as, annual sales, years in business, other plant locations, etc. Your manufacturers
can look at these two styles of checklists and decide to use one or the other, a combination of both, or
a totally different format.
Sheet 1 of 6
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Title: POLICY/PROCEDURE FOR QUALITY SYSTEM AUDIT
No. _____ Rev. ______
Approved by_____________________________________Date______________________________
1. A general audit of the entire quality system shall be performed by________________________
every_______ months (an audit team may be used).
2. The latest company approved audit checklist (number) _________shall be used. The audit
checklist shall be updated as required and approved by __________________________to reflect
our current quality system needs.
3. The completed checklist and audit results summary report shall be reviewed with the following
managers, as appropriate, who are responsible for the matters audited: ____________________,
_______________________________________and____________________________________ .
Minutes of the review meeting, including a list of attendees and desired corrective actions, shall
be taken, distributed and filed by__________________________________ . This same procedure
shall be used when reviewing the findings of GMP inspections by FDA investigators. (820.20)
4. Corrective actions shall be taken by all affected persons as discussed in the review meeting.
____________________________ will coordinate the corrective actions, re-audits, and keep
management informed. A summary report of the status of the corrective actions, as determined
by a re-audit of the affected areas or other appropriate means, will be written by
_________________________ and filed with the original audit report. The status report shall be
updated at least bimonthly if there are any uncompleted corrective actions.
**********
Comments on the Policy/Procedure
A. ”Rev." is the revision level of the latest company approved procedure.
B. The above blanks should be completed with employee position titles and, if desired, employee
names.
C. An audit checklist may be a detailed series of questions, phrases, trigger words or any
combination of these to assure that the auditor covers the entire quality system. The checklist
should cover the requirements of the QS regulation applicable to each company's products and
operations plus other areas that company management had decided are included in the total
quality system. A suggested way to develop a question-type checklist is to refer to the table of
contents of the QS regulation and the chapters of this manual. Then generate questions for each
topic as applicable to specific products and operations of the manufacturer. If operations or
devices change, the checklist should be updated. A small portion of a quality audit checklist
follows.
Sheet 2 of 6
A few cites are given. There are more. For example most of the QS regulation applies to labeling -not just 820.120.
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SPECIFICATION CONTROLS (820.30, .40, and .181)
1. Is an adequate system in place to control
all engineering drawings, specifications
and other related documentation?
2. Does the system require adequate review,
and approval of all new documentation and
changes to documents?
3. Does the system require controlled,
timely distribution of new specifications
and specification changes?
4. Are procedures provided and adequately
implemented to assure collection of obsolete
documentation?
5. Are all specifications used in production
approved, dated, and current?
6. Etc.
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YES
NO
COMMENTS
Sheet 3 of 6
PROCESS CONTROLS (820.70, .40, .60 and .80, .86)
1. Are current, approved process specifications/procedures such as work instruction,
etc., used to define each process?
2. Are process changes made according to a
formal change system and documented?
3. Are process changes communicated in a
timely manner?
4. Do process specifications and procedures
properly reflect the work to be accomplished?
5. Are adequate acceptance and rejection criteria
provided for the output of each process?
6. Are in-process and rejected items adequately
identified and/or segregated to prevent mix-ups?
7. Etc.
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YES
NO
COMMENTS
Sheet 4 of 6
PERSONNEL 820.20(b)(2), 820.25, and 820.70(d)
1. Are there sufficient personnel having the
necessary education, background, training,
and experience to assure that all design and
manufacturing operations are correctly performed?
2. Are training programs conducted and documented?
Is the program proactive? Do design personnel
have basic training in safety, use of standards,
labeling, and applicable regulations?
3. Are all employees made aware of device
defects which may occur from the improper
performance of their specific jobs?
4. Are all employees including salespersons
made aware that they must report all
complaints received from any source to
the company complaint department?
5. Are quality system personnel made aware of defects
and errors likely to be encountered as
part of their individual quality system function?
6. Are verification/validation personnel made aware
of design errors that may be found?
7. Are personnel in contact with the device or its
environment appropriately:
a. clean?
b. healthy?
c. attired?
8. Etc.
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YES
NO
COMMENTS
Sheet 5 of 6
QUALITY ASSURANCE FUNCTIONS
YES
NO
COMMENTS
1. Does the quality assurance unit or qualified
designee do the following?
a. review customer purchase orders
b. approve or reject components
c. approve or reject manufacturing materials
d. approve or reject in-process materials
e. approve or reject packaging materials
f. approve or reject labeling
g. approve or reject finished devices
h. approve or reject devices manufactured by
another company
i. review production records
j. approve or reject devices processed by
another company
k. approve or reject devices packaged by
another company
l. approve or reject devices held under
contract by another company
m. help provide solutions for quality system problems
n. verify implementation of solutions for
quality system problems
o. assure that all quality system checks are appropriate
and adequate
p. assure that all quality system checks
are performed correctly
2. Are periodic audits of the quality system conducted
to verify compliance with quality system program
requirements?
3. Are audits of the quality system program:
a. performed in accordance with written
procedures?
b. conducted by appropriately trained
individuals?
c. conducted by individuals who do not have
direct responsibility for matters being audited?
4. Are audit results:
a. documented in written audit reports?
Sheet 6 of 6
QUALITY ASSURANCE FUNCTIONS
YES
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NO
COMMENTS
b. reviewed by management having
responsibility for the matters audited?
5. Does company have a copy of the last
audit report on file?
6. Is follow-up corrective action, including
re-audit of deficient areas, taken when
indicated?
7. Etc.
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QUALITY SYSTEM AUDIT PROCEDURE
Sheet 1 of 3
No._______ Rev._____ Approved___________________________________ Date _____________
ECN
History____________________________________________________________________
___________________________________________________________________________________
POLICY: Periodic and planned audits of systems, training documentation processes, product flow
and feedback shall be performed to assure compliance with regulatory and company requirements
for current Good Manufacturing Practices (quality system).
SCOPE: All facilities, design activities, manufacturing operations, and product lines.
PROCEDURAL GUIDE: An audit of design activities shall be done annually. Routine quality audits
of selected production areas shall be conducted each month. The entire operation shall be covered
during a 12-month cycle. An area may be audited more than once. An "Action Audit" for any area
or element may be initiated by the Manager of Quality Assurance at any time if a special problem
arises.
The teamwork approach shall be used to identify and correct deficiencies.
The audit team shall consist of the Senior Quality Auditor (team leader) plus one or more
individuals from other disciplines who have no direct responsibility for the area being audited. A
team auditing an Operations unit should include an R&D representative. A team auditing a quality
systems unit should include an Operations representative. An audit of design activities shall include
a representative from both the regulatory and the manufacturing divisions.
The Manager of Quality Assurance selects the team member in consultation with the Department
Managers.
A. AUDIT PREPARATION - The Quality Auditor (team leader) reviews applicable change
control records subsequent to a design transfer, any FDA clearance delay information, recall
records, standard manufacturing procedures, device histories, complaint history, device labels
and inserts, previous audits with results, follow-up audits, plus any other document relative to
the audit.
B. AUDIT INITIATION - The Quality Auditor prepares/updates an audit checklist for
systematic examination of the area to be audited, informs the Manager of the department being
audited at the start of the audit, and reviews observations with the Department Manager.
C. AUDIT ANALYSIS - The Quality Auditor reviews the data gathered, verifies important
details, and writes an audit report according to the format delineated in the attached audit
report outline.
Sheet 2 of 3
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D. ISSUANCE OF AUDIT REPORT - The Quality Auditor issues the written audit report to the
President and Department managers within three working days following completion of the
audit. If conditions are critical, the Director of Quality Assurance shall verbally brief
appropriate staff members within 12 hours following audit completion. Audit reports shall be
stamped "Confidential".
E. CORRECTIVE ACTION - The appropriate Management staff member shall be responsible
for developing a schedule for correcting deficiencies cited in the audit report and submitting
same within five working days to the Quality Assurance Manager. Included in the correction
schedule shall be the responsible individual, and the date when corrective action will be
completed. The Manager of Quality Assurance shall act as arbiter, if necessary, to judge validity
of the deficiency, responsible individual, and reasonable date to complete the corrective action.
F. AUDIT FOLLOW-UP - The Quality Auditor maintains a log listing deficiencies, responsible
individual, target date for corrective action, and actual date of correction. If the same deficiency
occurs on a second follow-up audit, the President shall be notified in writing by the Quality
Assurance Manager.
G. LOG OF AUDITS AND FOLLOW-UP AUDITS - The master log shall be maintained by the
Senior Quality Auditor. The audit log file shall include a copy of current audits, list of areas to be
audited during the 12-month period, and list of areas audited to date (i.e., part of the Master
Log).
H. REPORT NUMBERS - Audit numbers shall be composed of the date followed by the
sequential number of the audit being reported (e.g., 98-4 for the 4th audit during 1998).
AUDIT REPORT COVER DATA
Area Audited ____________________________ Audit No._____________ Date: ____________
Audit Team members________________________________________________________________
_________________________________________________________________________________
Sr. Auditor's Signature: ___________________________________________________ (Team Leader)
REPORT OUTLINE
1. PURPOSE AND AREA DESCRIPTION - Describe initiating factors for the audit, limitations
of audit, and area being audited.
2. MAJOR FACTS - Summarize for management review the most undesirable conditions and
practices in order of their relative importance.
Sheet 3 of 3
3. OBSERVATIONS AND FACTUAL DETAILS - Give a detailed account of the current
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practices and the deficiencies listed in four below.
4. DEFICIENCIES - List deficiencies in procedures, standards, documentation, safety, etc., along
with identity of relevant regulation, SMP, SOP, etc.
5. FOLLOW-UP - State plans for follow-up review to establish individual responsibilities and
completion dates.
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18
FACTORY INSPECTIONS
INTRODUCTION ............................................................................................................. 18-1
AUTHORITY AND COVERAGE .................................................................................. 18-2
Inspection Plan ............................................................................................................ 18-2
Inspection Refusals ..................................................................................................... 18-2
Inspection Preliminaries ............................................................................................. 18-3
Conduct During the Inspection .................................................................................. 18-3
Close-out Meeting ....................................................................................................... 18-5
After the Inspection .................................................................................................... 18-6
BASIC POINTS FOR AN INSPECTION PLAN ........................................................... 18-6
REGULATORY SANCTIONS ........................................................................................ 18-7
Adulteration ................................................................................................................ 18-8
Misbranding ................................................................................................................ 18-8
Management Letter .................................................................................................... 18-9
Warning Letter ........................................................................................................... 18-9
Seizure......................................................................................................................... 18-10
Detention .................................................................................................................... 18-10
Restraining Orders and Injunctions ....................................................................... 18-10
Recalls ........................................................................................................................ 18-10
Penalties ...................................................................................................................... 18-11
EXHIBITS ....................................................................................................................... 18-12
Notice of Inspection .................................................................................................. 18-12
Receipt for Samples .................................................................................................. 18-12
Affidavits .................................................................................................................... 18-12
List of Observations .................................................................................................. 18-12
Establishment Inspection Report ............................................................................. 18-12
Warning Letter .......................................................................................................... 18-12
INTRODUCTION
FDA determines compliance with the GMP requirements set forth in the Quality System (QS)
regulation primarily by factory inspections. An FDA inspection of an establishment, however, can be
initiated for a number of reasons. The reasons may be general, such as routine scheduling or a need
to obtain data on industries new to FDA or, the reasons may be specific, such as investigation of a
consumer or trade complaint, a product defect report, an adverse reaction, or a death. FDA also
conducts inspections under the Compliance Status Information Systems (Com STAT) on behalf of
the Veterans Administration (VA), Department of Defense (DOD), and Health Resources and
Services Administration (HRSA). Upon arrival, the investigator presents his/her credentials and
issues a Notice of Inspection form FDA 482. At the end of the inspection, observations are recorded
on form FDA 483, List of Observations, and discussed with the manufacturer’s management. Later
the investigator will write an Establishment Inspection Report (EIR), which is a detailed record of
the inspection and findings.
AUTHORITY AND COVERAGE
Section 704(a) of the Food, Drug, and Cosmetic (FD&C) Act gives FDA the authority to conduct
GMP inspections of medical device manufacturers. During these inspections, facilities,
manufacturing processes, records, and corrective action programs are examined by an FDA
investigator. The results provide information necessary to evaluate a manufacturer's compliance
with the device QS regulation (21 CFR 820).
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Anyone who manufactures or stores a medical device can be inspected. A manufacturer is any
person who designs, manufactures, fabricates, assembles, or processes a finished device.
Manufacturer includes but is not limited to those who perform the functions of contract sterilization,
installation, relabeling, remanufacturing, repacking, or specification development, and initial
distributor(s) of devices from foreign entities performing these functions.
Inspection Plan
This chapter offers ideas on ways that a manufacturer might prepare for, undergo, and respond
to an FDA inspection. First and foremost, it is important to plan ahead! Before being visited by an
FDA investigator, a manufacturer should have in place an inspection procedure which takes into
account, and prepares a manufacturer for, any eventuality. It should detail company policy
regarding an inspection and, very importantly, designate those individual(s) who will work with the
FDA investigator. Try to anticipate situations and have written procedures covering them. These
procedures will provide continuity from one inspection to another and help assure that corporate
policies are followed by employees receiving and accompanying the investigator.
Each person designated as an FDA contact should be chosen carefully and be thoroughly familiar
with the inspection procedure and company operations. An inspection will take longer if the contact
person cannot answer questions without continually referring to the written procedures. The contact
should be familiar with FDA regulations and practices and be able to anticipate problems or
requests. FDA contacts be should knowledgeable about plant operations, and able to answer or
obtain answers to the investigator's questions. Other individuals, with similar qualifications, should
be designated to fill in during absences of the primary contact. A manufacturer might want
secondary contacts to accompany the FDA investigator even when the primary contact is present in
order for the secondary contact to become familiar with FDA methods and procedures.
Along with the designated contact, the manufacturer may want operations managers to
accompany the investigator, such as the production manager, QA manager, etc. These individuals
should be familiar with the plant operations and company policy, and be able to answer questions
about procedures and processes. However, a manufacturer should keep the number of individuals
accompanying the investigator to a minimum to prevent problems such as contradictory statements.
Receptionists should be informed that FDA investigators will eventually visit and have procedures
to follow when they arrive. These procedures should include instructions to call the FDA contact
person and what to do or who to contact when that person is not available.
Inspection Refusals
As noted above, Section 704(a) of the FD&C Act gives FDA authority to conduct inspections.
Refusing an inspection may set up an adversarial situation and arouse an investigator's suspicion
regarding the manufacturer's compliance with the QS regulation. If a manufacturer refuses an
inspection without a valid reason, FDA may obtain a warrant which grants entry for an inspection.
Refusals to permit inspection are noted in the manufacturer's file maintained by FDA and may be
interpreted as a lack of cooperation. Moreover, refusal to permit an inspection is a prohibited act
under section 301(f) of the FD&C Act, which may result in sanctions that include criminal
prosecution and injunction.
There may be instances, however, when a manufacturer needs to ask the investigator to return at
a later time to conduct the inspection. Explain why it is best that an inspection be done at a later
time. For instance, if the FDA contact person(s) is not in the factory and no one knowledgeable about
the manufacturer's operations is available, it may be appropriate to ask the investigator to come
back. However, FDA investigators do expect to be admitted if a device factory is operating. The
rationale is that if a factory is operating, someone should be in charge and that individual should
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understand factory operations and procedures. If the factory is not in operation or not yet
manufacturing any medical devices, this should be explained to the investigator. The FDA
representative may still want to go through the factory to make sure it is not in operation -manufacturers should have a policy covering this situation. It is advisable, in this situation, to allow
the investigator to walk through the factory to verify that it is not in operation. If the factory is not
in operation, advise the investigator when operations will begin. The investigator will consider the
request and circumstances, then determine whether to proceed with the inspection.
Inspection Preliminaries
Before an inspection begins, an investigator is required to show his/her credentials. The
credentials have a picture of the investigator and identify him/her as a representative of FDA.
After presenting credentials, the investigator will issue form FDA 482, Notice of Inspection. This
form is issued to the owner, operator, or agent in charge of the factory or to the designated FDA
contact. The bottom portion of the Notice of Inspection contains excerpts from Section 704 of the
FD&C Act. The investigator will complete the top portion of the form by filling in the manufacturer
name, address, name of the individual given the signed form, date, and time of inspection. The
investigator then signs the form.
The FDA contact person should always be prompt. It is important not to keep the Investigator
waiting because misunderstandings can occur regarding the manufacturer’s intentions.
Conduct During the Inspection
Awareness of what is going on at all times by the contact person of the manufacturer during the
inspection is important. Therefore, once started, the inspection should be given priority. If the
contact person is distracted by other business, the inspection may be prolonged and the
investigator's questions concerning suspected deficiencies may be misunderstood or answered
inadequately. Familiarity with the circumstances surrounding any deficiencies listed on form FDA
483 (the list of deviations presented at the close of the inspection) is vital in discussion of these with
the investigator.
During inspections, the FDA contact person will deal with many issues such as viewing records,
copying, photos of the manufacturing site, tape recordings, differences of opinion, immediate
corrections, promises, samples, notes, etc. All of these issues should be addressed by a company
procedure.
There should be a procedure for responding to requests for design history records, device master
records, quality system records, device history records, change control records, complaint files, and
shipping records. All records required by the QS regulation shall be made available to the
investigator for review and copying (820.180). Therefore, records required by the QS regulation
shall be readily accessible. The procedures covering review of records by the investigator should
identify who will retrieve records, how many records can be reviewed at one time and, who should
be present to answer questions raised by the investigator.
Because all records required by the QS regulation shall be available for copying, management
should decide on a policy concerning record copying during inspections. In all situations, the contact
should make duplicate copies and keep these together as a record of the documents that the
investigator copied.
If any records copied by an investigator contain confidential information, they should be
identified, i.e., by a confidential stamp. This identification does not automatically prevent release of
these records under the Freedom of Information (FOI) Act; however, the FOI officer filling a
request is then made aware that the manufacturer considers the information confidential.
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Information deemed confidential by the FOI Act or 21 CFR part 20 shall not be released by the
agency. Reserve “confidential” marking to only those items that are genuinely confidential..
FDA investigators sometimes photograph equipment, conditions, and product at a facility. FDA
feels that picture taking is a normal inspection activity. Include this policy in the inspection
procedure.
If the manufacturer disagrees with any observation made by the investigator, be sure to discuss
with the investigator the reason for the observation. You may find that there was a
misunderstanding that can easily be corrected. When explaining situations or answering questions,
be honest. Don't make up answers, as this could lead to additional problems. If you don't know the
answer, say so. Personnel with responsibility for representing a manufacturer during an inspection
should refer to the FDA regulations and guidances, whenever possible, rather than base discussions
and disagreement on personal opinion.
If there are questions for which you don't have immediate answers, promise to research the
questions. A list of these unanswered questions is a reminder to get the answers and give them to the
investigator. The investigator usually records the questions, and resolving unanswered questions
may help avoid inaccuracies on the form FDA 483 and in the establishment inspection report
prepared by the investigator at the end of the inspection.
If possible, any GMP deficiencies that the investigator notes, and on which you agree, should be
corrected immediately. However, before implementing an immediate corrective action,
manufacturers should first evaluate their action to assure that is the best action to take to avoid
future quality problems. The investigator should be made aware of these corrections as this will
show intent to comply with the regulations and commitment to quality assurance. Corrective actions
that are verified by FDA during the inspection will be documented in the investigator's EIR.
If correction cannot be made during the inspection, management may want to consider providing
an estimated timetable for correction. However, the manufacturer should not present or commit to a
timetable that may be difficult or impossible to meet. If a timetable cannot be immediately
developed, try to get one to FDA as soon as possible.
As with any production change, it is a good idea to discuss possible corrective actions with
affected company personnel before promising correction to FDA. This concept was discussed in
Chapter 8, Device Master Record, and Chapter 9, Document and Change Control, and may prevent
promises that have adverse effects on other areas of production. Hastily conceived corrections can
cause greater problems in the long run.
Any commitments made to FDA should have top management concurrence. It can be detrimental
to the manufacturer to be committed to a course of action that cannot be completed or that
management refuses to pursue. Therefore, only persons with the authority to do so should make
commitments.
During an inspection, investigators may collect samples. These may be used for a variety of
investigational purposes including:
• to verify conditions in the factory;
• to establish interstate movement of finished devices and their components; or,
• to fulfill a request from FDA's Center for Devices and Radiological Health (CDRH).
CDRH may request samples for a number of reasons, such as surveys of device manufacturers
and investigation of user complaints. It is a wise policy for a manufacturer to collect and store
18−74
duplicate samples whenever an investigator collects samples. If problems are uncovered by FDA,
testing of these duplicate samples by the manufacturer may confirm FDA results or form a basis for
discussion of FDA findings.
When an FDA investigator collects samples he/she will issue a form FDA 484, Receipt for
Samples. Where indicated, interstate movement of the shipments from which these samples were
taken will be documented by the investigator with copies of shipping records. The investigator will
then prepare an affidavit (forms FDA 463a, 463, 1664a or 1664b) referencing these documents. A
responsible employee of the manufacturer will be asked to read the affidavit, identify inaccuracies
for correction, and to verify, by signature and/or initials, that the documents referenced in the
affidavit pertain to the shipment(s) in question. This action is to formally document interstate
receipt or distribution of medical devices. Therefore, the manufacturer should include in its
inspection procedure the company policy on the reading and signing of affidavits. Refusal to sign an
affidavit is usually noted on the affidavit and in the EIR.
Having accurate and complete knowledge of what an investigator has done is an important part
of handling an FDA inspection. Good notes record this information. Comments and suggestions
made by the investigator, unanswered questions, and promises should all be recorded. General
information on the areas of the plant the investigator visited, to whom he spoke, etc., can help when
commenting on form FDA 483 items, making corrections to the facilities or QA system, or advising
top management of the results of an inspection.
Notes will also be useful in fulfilling promises or obtaining answers to previously unanswered
questions. When the items on the FDA 483 are presented, accurate notes help to prevent surprises.
Good notes can also help to prepare well thought out and adequate answers to FDA 483 items even
before these items are presented at the close-out meeting.
Close-out Meeting
At the end of an FDA inspection, the investigator conducts a close-out meeting. It is usually held
immediately after the inspection, but may take place a day or so later, especially if it takes a long
time to prepare form FDA 483. During this meeting, the investigator discusses with company
management the observations recorded on form the FDA 483 and other observations not listed that
the Investigator wishes to bring to management’s attention. The manufacturer should compare the
form FDA 483 against notes taken during the inspection to confirm the accuracy and completeness
of the investigator’s recorded observations. Close-out meetings present an opportunity for all parties
to correct such misunderstandings. Inaccurate observations will be changed or deleted as
appropriate. Top management should be present at the close-out meeting to provide information
regarding any planned corrective actions to be taken and schedules for these actions.
The investigator should be reminded of any corrections that have been made. Corrections that
have been made during the inspection will be documented in the investigator's establishment
inspection report (EIR) if verified by the investigator if time allows, but these observations will still
appear on the FDA 483. Mention your plans to make corrections, and provide a timetable for these
future actions. Answers given at this meeting will be recorded by the investigator.
Again, it is important that the company individual promising corrections and setting timetables
have the authority to do so. Future inspections will cover those areas where correction was promised
as well as other appropriate areas.
After the Inspection
Completion of the inspection by FDA should signal the start of certain activities by the
manufacturer, if these activities have not already been initiated, such as discussion of deficiencies
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with appropriate department employees to advise them of corrections to be made and time frames
involved.
Unresolved form FDA 483 items should be reviewed by company technical and legal personnel. If
a decision is made that corrective action is not needed and there is disagreement with the
investigator's opinion regarding the deficiency, state this, along with the rationale and documentary
evidence, in a letter to the FDA District Office responsible for the inspection. Even if a manufacturer
agrees with all the items on the FDA 483, it is a good idea to respond to each item in a letter, along
with documentation showing how the corrections have been implemented, to the District Office. The
response to the FDA 483 observations should include system corrections and not just “band-aiding”
the specific observations. It is very important that the root cause is investigated, where it can be
determined, corrected and that appropriate preventive actions take place. This reply shows a
commitment to quality assurance and "officially" presents the company's case to FDA. This reply
should help resolve any doubts that the inspection report might raise about a manufacturer.
The final step for a manufacturer is to determine what can be learned from the inspection, so that
the business can operate in a better state of control, improve quality assurance, and assure future
QS compliance.
The following is a concise summary of the major points made in this chapter. This summary
should help the manufacturer formulate an inspection plan.
BASIC POINTS FOR AN INSPECTION PLAN
1. Be prepared for the eventual inspection by trying diligently to comply with applicable medical
device regulations and preparing an inspection plan. If needed, assistance is available from
DSMA, Phone 800-638-2041 and other offices of the Center for Devices and Radiological Health.
Note: DSMA and CDRH can not provide assistance during an FDA inspection by the District
office, nor can DSMA provide assistance during an ongoing FDA regulatory action.
2. Receptionists should know who to call when an FDA investigator visits.
3. Determine that an FDA investigator is calling by examining his/her credentials.
4. Receptionists or initial contact persons should inform all key employees that an FDA
investigator is present.
5. Someone, but not a large number of individuals, should accompany the investigator and be with
the investigator at all times.
6. If the investigator is not familiar with the manufacturer, describe the product line and
operations before entering the manufacturing area.
7. At the beginning, review with the investigator all company policies and programs.
8. Employees should be cooperative and seek to avoid conflict. Base discussions on the laws,
regulations, guidances, etc.
9. Don't start an argument with, get up-tight with, or lie to the FDA investigator.
10. Understand the investigator's questions before answering. If needed, ask for an explanation.
Refer each question to the most suitable employee.
11. Be sensitive to the compliance role of the FDA investigator; do not threaten to call his/her
supervisor when the investigator is doing his/her job.
12. Deviations noted by the investigator should be corrected as soon as possible.
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13. Keep duplicate copies or samples of material given to the FDA investigator.
14. During the exit interview, make sure that all deviations are adequately discussed. If there is
disagreement, present all of the company information and any regulations and official
interpretations that support the company’s viewpoint.
15. Immediately submit to the local FDA District office a written reply to the FDA 483. Make sure
you address all of the observations. State how and when you expect to make corrections. If you
disagree with an observation, give reasons and references to regulations, guidances, etc., for
your position.
16. Be reasonable in setting schedules for corrective actions -- don't state impossible deadlines or
drag out completion schedules.
17. A follow-up report covering findings and corrections should be distributed to appropriate
company employees.
REGULATORY SANCTIONS
Responsible officials, who are in positions of authority at regulated manufacturing sites, have a
primary legal duty to implement whatever measures are necessary to ensure that their products,
facilities, and operations are in compliance with the law. The law presumes these individuals are
fully aware of their responsibilities.
Whenever FDA determines, as a result of an inspection, investigation, complaint, or other source,
that a product is, or may become, adulterated or misbranded, several actions may be taken. These
actions may be in the form of a warning letter to the manufacturer; or result in the seizure or
detention of a product; or an injunction of the firm and/or responsible individuals; or result in
prosecution of the manufacturer and/or responsible individuals. The actions vary depending on the
degree of danger to the public or willingness of the manufacturer to correct violations. [Following
are several sections of the Food, Drug, and Cosmetic (FD&C) Act commonly used in misbranding or
adulteration charges. In this reprint, some key words are bolded for emphasis. Added notes are in
brackets.]
Adulteration
Section 501 (351). A drug or device shall be deemed to be adulterated -(a)(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or
(2)(A) If it has been prepared, packed, or held under insanitary conditions whereby it may have
been contaminated with filth, or whereby it may have been rendered injurious to health;
(c) If it is not subject to the provisions of paragraph 9(b) of this section* and its strength differs from,
or its purity or quality falls below, that which it purports or is represented to possess.
[* Paragraph 9(b) refers to drugs].
(h) If it is a device and the methods used in, or the facilities or controls used for its manufacture,
packing, storage, or installation are not in conformity with applicable requirements under Section
520(f)(l) or an applicable condition prescribed by an order under Section 520(f)(2).
Misbranding
Section 502 (352). A drug or device shall be deemed to be misbranded -18−77
(a) If its labeling is false or misleading in any particular.
If in a package form unless it bears a label containing (1) the name and place of business of the
manufacturer, packer, or distributor; and (2) an accurate statement of the quantity of the contents
in terms of weight, measure, or numerical count ...
(f) Unless its labeling bears (1) adequate direction for use; and (2) such adequate warnings against
use in those pathological conditions or by children where its use may be dangerous to health, or
against unsafe dosage or methods of duration of administration or application, in such manner and
form, as are necessary for the protection of users ...
(j) If it is dangerous to health when used in the dosage or manner, or with the frequency or duration
prescribed, recommended, or suggested in the labeling thereof.
A device may be considered misbranded for other administrative reasons such as failure of the
manufacturer to register, formally list the product, or failure to submit a premarket notification (21
CFR Part 807).
When it is consistent with the public interest, it is FDA's policy to: advise regulated
manufacturers of potentially violative products, practices, or conditions; advise manufacturers of
violations requiring correction; and, give manufacturers an opportunity to make corrections
voluntarily before initiating legal or administrative action.
Management Letter
When top management is not present during the issuance of the FDA 483 at the end of the
inspection,
FDA may send a Management Letter to top management such as the president, CEO, etc., to assure
that top management has a copy of the FDA 483. Because the Management Letter is only a brief
transmittal letter, it is not to be considered or confused with the Warning Letter described below.
It is imperative that the manufacturer respond to any recommendations or observations made by
the FDA investigator or other official. A written response to the FDA 483, along with documentation
to show how the manufacturer has or intends to remove or correct the objectionable conditions or
practices, can assure the FDA that the manufacturer has corrected or intends to correct listed
violations. The manufacturer should prepare such a response even if they do not hear from FDA in
writing. To repeat, a plan of corrective action is very important. Management should evaluate the
FDA 483 and their management letter. If they feel any misunderstanding can be resolved by
discussion, they may also request a meeting with district management to discuss violations and the
manufacturer's proposed courses of action. This approach gives a first hand opportunity to present
the case to FDA.
Warning Letter
A Warning Letter is a specifically worded and formatted enforcement letter written by top
management of an FDA field or headquarters unit to top management of a manufacturer. The letter
is sent by FDA primarily to draw the company's attention to violations and, thereby, obtain prompt
correction. A Warning Letter is intended to effect correction of deficiencies noted: during an
inspection; from an investigation of a product complaint; or from information received from other
sources. A purged Warning Letter is reprinted at the end of this chapter.
A Warning Letter may be issued by FDA instead of immediately seizing product or obtaining an
injunction against the manufacturer. The Warning Letter contains a formal warning to the
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manufacturer advising that specific sections of the law have been violated and, unless corrective
action is taken, the FDA is prepared to impose legal and/or administrative sanctions. Sanctions
include seizure, prosecution, injunction, and civil penalties. Unless otherwise indicated, within 15
working days after receiving a Warning Letter, a formal response should be made by the
manufacturer to FDA. The manufacturer should state the specific steps it has taken to correct noted
violations, including an explanation of each step taken to prevent the recurrence of similar
violations. If corrective action cannot be completed within 15 working days, state the reason for the
delay and the time within which the corrections will be completed.
A Warning Letter is also a prior warning and notification to responsible company officials of
possible civil or criminal action to be taken by FDA.
Responsible individuals should not assume they will always receive a Warning Letter before FDA
initiates administrative action or recommends an injunction, seizure, civil penalty, and/or criminal
proceeding. FDA is under no legal obligation to warn manufacturers or individuals that they or their
products are in violation of the law, before initiating formal regulatory action.
Remember, the issuance of a Warning Letter to the manufacturer by FDA does not preclude the
initiation of other concurrent action, such as seizure, as part of an overall enforcement strategy.
Seizure
A seizure is a civil court action against a specific quantity of goods whereby FDA seeks to remove
these goods from commercial channels. After seizure, no one may tamper with the seized goods
except by permission of the court. The claimant of the seized merchandise may file a claim and an
answer, or may take no action. If no action is taken,the government will move to have the goods
forfeited to the government by default. If a claimant decides to contest the Government's charges,
the case will be scheduled for trial. A third option allows the owner of the goods to request
permission of the court to bring the goods into compliance with the law. The owner of the goods is
required to provide a bond (money deposit) to assure that the orders of the Court will be performed
and the owner will be ordered to pay for FDA supervision of any activities by the company to bring
the goods into compliance.
Detention
An administrative detention prohibits the distribution or use of adulterated or misbranded
devices encountered during inspections. The detention usually lasts up to 30 days, and can last
longer, until FDA has considered what action it should take concerning the devices, or has initiated
legal action if appropriate. During the detention, detained devices may not be used, moved, altered,
or tampered with in any manner by any person.
Restraining Orders and Injunctions
A Temporary Restraining Order (TRO) is sought by FDA before an injunction and is designed to
stop the alleged violative practice until the court can hear evidence that may lead to an injunction. A
TRO imposes restraint upon a defendant for not more than 10 days; this period may be extended by
the courts.
An injunction is a court order that restrains a person or manufacturer from violating the law,
e.g., to prevent interstate distribution of violative products, and to correct conditions in the
establishment in which the violation occurred. FDA may also seek a preliminary injunction. To
obtain this preliminary form of relief, the government needs only to show that the law has been
violated, and that it will probably continue to be violated unless the court enjoins the violative
behavior.
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Recalls
The Food and Drug Administration prefers to promote compliance by means other than through
the courts. Recall by the manufacturer of violative products from the market is generally the fastest
and most effective way to protect the public. A recall may be initiated by the manufacturer or
shipper of the product, or initiated by FDA. The first step in a product recall is for the manufacturer
or distributor to contact the nearest FDA field office for guidance. FDA can provide technical
assistance to small and large manufacturers on how to conduct an effective recall.
It is recommended that manufacturers develop plans which can be put into effect immediately if a
recall emergency arises. Accurate and complete product and shipping records are vital to the success
of a product recall. Products should be labeled (direct or by code) to show date and place of
manufacture.
Recently, FDA has observed that when a manufacturer discovers a risk presented by a medical
device, it often voluntarily notifies appropriate persons of this risk in order to reduce or eliminate it.
In some cases these notifications meet the definition of recall in 21 CFR Part 7.3(g). There is a
proposed rule 21 CFR 810 issued on June 14, 1994, that would establish procedures to implement
the medical device recall authority provided in the SMDA. This authority will add to other remedies
already available to FDA including rectification, repair, replacement, and refund.
Because of concern that a notification might be classified as a recall, manufacturers have
sometimes delayed issuing a notification while discussions are held with FDA. To try to eliminate
delays in situations where public health might be at risk, FDA published, "Medical Device
Notification and Voluntary Safety Alert Guideline," in March 1984, which contains procedures that
manufacturers should use in notifying or alerting health professionals who prescribe or use a
medical device. These procedures also describe the steps used by FDA in the notification and safety
alert process.
Penalties
FDA has authority to impose civil penalties. Manufacturers are liable for a maximum of $15,000
per violation of the FD&C Act, with a cap of $1,000,000 per proceeding. See Section 303 of the
FD&C Act for details of additional penalties. Also, see the Safe Medical Devices Act of 1990 for more
details on FDA's authority to impose penalties.
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EXHIBITS
Associated with inspections are various FDA forms. Examples of forms are included at the end of
this chapter. The form (FDA) numbers are in the lower left corner of each sheet.
Notice of Inspection
The first form is the FDA 482 (Notice of Inspection) which is issued at the beginning of the
inspection. It includes blanks for basic information on the manufacturer, the investigator’s name,
and contains a reprint of applicable sections of the FD&C Act and Public Health Service Act. This
form is to be signed by the investigator and given to the individual noted on the form.
Receipt for Samples (page 18-14)
If an investigator collects samples, form FDA 484 (Receipt for Samples) is issued to the company
agent. A copy of the receipt needs to be submitted with the firm’s invoice or other billing documents
if payment has beed agreed to by the firm and the FDA Investigator. This form contains the name of
the individual given the form, manufacturer information, and sample description. The investigator
signs the form and issues it to the individual noted on the form.
Affidavits (pages 18-15 to 18-18)
The next four forms are used where interstate movement of devices is documented by collection of
shipping records. The investigator prepares an affidavit (forms FDA 463a, 1664a, or 1664b)
referencing these shipping records. A brief statement is included along with space for a description
of the documents that relate to the interstate movement of the sample in question. Each form is
signed by the investigator and the person giving the information. On one of the sample forms, FDA
463a, the individual giving the information refused to sign the affidavit; and in this case the
investigator added a statement to explain the lack of a signature.
List of Observations (page 18-19)
During an inspection, an investigator will note what is considered to be GMP deviations, or
deviations from a manufacturer's established procedures. These observations comprise the form
FDA 483 (List of Observations) which is issued to the company. The observations are listed in the
large blank area of the form, and the form is signed by the investigator. (Page 18-19)
Establishment Inspection Report (pages 18-20 to 18-34)
The final example is the "Establishment Inspection Report". After completion of an inspection,
an investigator prepares a comprehensive EIR covering a manufacturer's operations, items on the
FDA 483, plus the details that support the FDA 483, and any corrective actions taken by the
manufacturer. A manufacturer may receive an unpurged copy of their EIR report under the
Freedom of Information (FOI) Act by requesting it in writing from their local FDA District Office.
Copies of EIR's requested through FOI by other than the inspected manufacturer will be purged of
confidential or trade secret information. The fictitious sample EIR near the end of this chapter has
certain lines highlighted to simulate purging. The normally purged material is left in the simulated
EIR to show the type of information that would be purged.
Warning Letter (pages 18-35 & 18-36)
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18−82
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ESTABLISHMENT REPORT (EIR) PURGED
SUMMARY OF FINDINGS
This inspection was conducted in accordance with the NYK-DO June 1986 Workplan, under
CP 7378.830 Inspection of Medical Device Manufacturers, and under CP 7378.830A Sterilization of
Medical Devices. This inspections was also conducted to follow up medical device complaint M00210, dated 5/31/84, re: leaking of a Cardio-Minipor IV Filter (no specific lot number).
This firm produces various sterile disposable blood filters and cardiovascular catheters. This
inspection was limited to the firm’s sterile blood filter which is intended for extracorporeal use as
indicated during any cardiopulmonary bypass procedure (open heart surgery). This product is
currently classified as a noncritical device.
Previous inspection 6/82 was performed as a follow up to PHI-DO memo 4/2/82 (J.L. Smith)
requesting information on validation studies, and the firm’s controls for testing for sterility and
ETO residues. PHI-DO’s inspection of a contract sterilizer, Minix Lab, Erie, PA, revealed the firm
had no validation study and that the firm failed to follow its own established ETO process
parameters. NYK-DO’s 6/82 inspection revealed that sterility testing and controls were adequate,
that an ETO residue study had been conducted and that the firm was conducting a validation
study. No FD 483 was issued, and no samples were collected.
Next previous inspection, 12/20/81, was conducted as a follow up of two medical device problem
reports, M32012 and M32190, both concerning leakage during use of the firm’s IV filter.
Inspection revealed that the product probably failed due to its being used as pressures in excess of
600 mm Hg, as filters from the same lot passed this specification upon retesting. No FD 483 was
issued.
The current inspection revealed some deficiencies in the firm’s master device record for the
blood filters. No other deficiencies were noted. The deficiencies were listed on an FD 483, which
was presented to and discussed with management at the close of the inspection. Deficiencies noted
in the master device record are:
1. it does not list acceptance criteria for incoming components;
2. it does not list that components made of plastic are to receive an IR spectrographic analysis;
3. it does not list that the cellulose acetate filtering material is about 120 mesh, nor does it list the
quantity of this material that is used to manufacturer blood filters;
4. the operation sheets have not been signed by all approving officials;
5. the engineering diagrams for the housing, and top end cap do not bear the signature/initials of
an approving corporate official.
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Management promised correction of the noted deficiencies, and stated that they had already
attended to the first point (Ex. 8). No samples were collected during this inspection.
Investigation of complaint M-00210 revealed that the IV filter had probably been subjected to
pressures in excess of 600 mm mercury. The product is labeled for use below 600 mm mercury.
Current inspection also revealed that the firm intends to discontinue using Minix Lab as the
contract sterilizer. The firm intends to develop/perform its own ETO sterilization procedures
within the next year.
On 6/7 to 9/84, I was accompanied by John Goodguy. Mr. Goodguy represents the Center for
Devices and Radiological Health, Division of Small Manufacturers Assistance. Mr. Goodguy
wanted to become familiar with the way FDA field offices were conducting medical device
inspections. Mr. Goodguy’s tight schedule did not permit him to accompany me for the complete
inspection.
HISTORY OF BUSINESS
The firm is a New York State corporation with the following corporate officers:
Mrs. Alice B. Potts
Mr. John (NMI) Fogg
Mr. William L. Pearl
Mr. Walter Y. Ratkowski
-
Chairman of the Board
President
Senior Vice President
Vice President and General Manager
-
Cardio-Medical Products, Inc. is a wholly owned subsidiary of Medical Products USA, Inc. and
both firms occupy the same premises. The corporate officers of Medical Products USA, Inc. are:
Dr. Michael P. Heart
Mrs. Alice B. Potts
Dr. Mary L. Day
Mr. John (NMI) Fogg
-
Chairman of the Board
President
Executive Vice President
Senior Vice President
Filters are manufacturers under the Cardio Minipor trade name and in general are intended
for hospital use. The firm manufacturers four types of filters, as follows:
1.
2.
3.
4.
Blood Dialysis Filters
Cardiopulmonary Bypass Blood Filters
Infusion Line Filter
IV Filter
The firm operates 3 shifts (24 hours per day) Mon.-Fri., except for two weeks around
Christmas. The firm also closes for two weeks in July for major cleaning operations. The firm is
currently registered as a medical device establishment.
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PERSONS INTERVIEWED AND INDIVIDUAL RESPONSIBILITY
At the start of the inspection credentials were shown and an FD 482, Notice of Inspection, was
issued to Mr. John (NMI) Fogg, President. Credentials were also shown to Dr. Paul M. Turner,
Ph.D., Quality Assurance manager, and to Mr. Thomas (NMI) Romano, Quality Control Manager.
During this inspection, I was also introduced to: William L. Pearl, Senior Vice President;
Walter Y. Ratkowski, Vice President and General Manager; Charles Miller, Asst. QC Manager;
Alice Oprice, QA Technical Assistance; Joseph DiRisio, Metrologist; Harold Miller, Operations
Manager; and Katherine Anderson, Materials Manager. Mr. Fogg and/or Dr. Turner accompanied
me during most of the inspection and supplied most of the relevant information. Some relevant
information was also supplied by the above named individuals.
At the close of the inspection and FD 483, Inspectional Observations, was issued to and
discussed with Mr. Jonn (NMI) Fogg, President.
Key officers/plant personnel are as follows:
John (NMI) Fogg
William L. Pearl
Walter Y. Ratkowski
Dr. Paul M. Turner
Thomas (NMI) Romano Charles Miller
Harold Miller (brother)
Joseph DiRisio
John Dace
-
-
President
Senior Vice President
Vice President and General Manager
Quality Assurance Manager
Quality Control Manager
Asst. Quality Control Manager
Operations Manager
Metrologist
Vice President
Mr. John Fogg stated he was the firm’s president and chief executive officer, and bore overall
responsibility and authority for the firm’s activities (see Ex. 1, pg. 4). Mr. Fogg stated that he could
authorize capital expenditures on his own authority, and that he did not have to obtain
authorization from any official of the parent firm before making a capital expenditure. Mr. Fogg
stated he was responsible for authorizing research and development programs, marketing
programs, allocation of space, new construction, plant maintenance, acquisition of capital
equipment, labeling changes, and for authorizing any studies such as validation studies, bioburden
studies, and residue studies.
Mr. Fogg stated that William L. Pearl, Sr. VP, was responsible to him for engineering; that Dr.
Paul M. Turner, QA Manager, was responsible to him for the QA program; that Thomas Romano,
QC Manager, was responsible to him for the routine review and approval of device history records
and for the release of lots from quarantine; that Harold Miller, Operations Manager, was
responsible to him for production and warehouse activities; and that Walter Ratkowski, VP and
General Manager, was responsible to him for sales and marketing operations. Mr. Fogg stated he
has a BS in Chemistry from Furman University, Greenwich, South Carolina, has been with the
firm since 1962, and has been president for about the last eight years.
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During the inspection Mr. Fogg directed various employees, such as Dr. Turner, Mr. Romano,
Mr. Harold Miller, and Ms. Oprice to provide me with requested information. These requests for
information were honored by the various employees.
William L. Pearl, Sr. VP, stated he was responsible to John Fogg for engineering. These
responsibilities include reviewing and approving engineering diagrams, research and development
projects for new equipment and new products, and performing major equipment overhauls. Mr.
Pearl has been with the firm since 1969 and has a BS in Mechanical Engineering from Duke
University, Durham, North Carolina.
Walter Y. Ratkowski, VP and General manager, is responsible for sales and marketing
operations to John Fogg. As a follow up to a product occurrence report (complain) Mr. Ratkowski
is responsible for determining if and when complimentary replacement units are to be sent out.
Mr. Ratkowski has a BS in Chemical Engineering from the University of Toronto and has been
with the firm since 1968.
Paul M. Turner, QA manager, stated he was responsible to John Fogg for the quality assurance
program of Cardio-Medical Products, Inc. These responsibilities include the periodic auditing of
production, lab quality control, and metrology procedures, implementing studies authorized by
Mr. Fogg, and ensuring that the firm meets its regulatory responsibilities and complies with GMP
regulations. Dr. Turner stated that it was his responsibility to prepare and submit 510(k)s to the
FDA. Dr. Turner has his Ph.D. in Chemistry from Western Michigan University, Kalamazoo,
Michigan and has been with the firm since 1976.
Thomas Romano, QC Manager, stated he is responsible to Mr. Fogg for renewing and
approving device history records to determine if a lot of finished filters can be released from
quarantine and entered into inventory, for the inspection and approval of incoming components,
for the activities and records of the QC labs in performing tests on incoming components, in
process products, environmental plates, bioburden, and pyrogen.
Mr. Romano stated he coordinates complaint investigations by reviewing complaints and
deciding which department(s) will be responsible for investigating the complaint, and is responsible
for sending out responses to complaints when necessary. Mr. Romano stated that Mr. Charles
Miller, Asst. QC Manager, assists him in his duties. Mr. Miller is also responsible for maintaining
the firm’s reserve samples, which are used for stability study purposes only. Mr. Romano has his
BS in Chemistry from Wright State, Dayton, Ohio and has been with the firm since 1978. Mr.
Charles Miller has his BS in Biology from Yale University, New Haven, Connecticut and has been
with the firm since 1977.
Joseph DiRisio, QA Metrologist, stated he was responsible to Dr. Turner for all of the firm’s
metrology (measurement and calibration) functions, and that he originated the firm’s metrology
manual (Ex. 4). Mr. DiRisio stated he was formerly the metrologist for American Armature Co.,
Cleveland Ohio and that he has been with the firm since 1976.
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Harold Miller, Operations Manager, stated he was responsible to John Fogg for production and
warehouse operations. Mr. Miller is also responsible for ordering raw materials and for routine
maintenance and clean up operations. Mr. Miller has his BS in Mathematics from New York
University and has his MS in Industrial Engineering from Columbia University, New York, New
York and has been with the firm since 1979.
GUARANTEES AND LABELING AGREEMENTS
The firm does not offer and FD&C guarantees. Dr. Turner stated that the firm does have
agreements with some of their component suppliers whereby suppliers have agreed to notify
Cardio-Medical of any changes in components. testing or procedures related to the manufacture of
the components. Dr. Turner provided me with copies of these agreements (Ex. 10). These
agreements appear to satisfy the GMP regulation re: critical component supplier agreements,
although the firm is not required to have these agreements as the device is currently classified as a
non-critical device. The firm also ships some filters in bulk to overseas divisions/subsidiaries of
Cardio-Medical Products, Inc. without the need of a labeling agreement.
FIRM’S TRAINING PROGRAM
The firm’s training program for production employees consists of on-the-job training and
lectures. Mr. Fogg stated that any formal training given to employees is documented and recorded
in the employee’s personnel file. I requested Mr. Fogg to remove the documentation of Mr. Joseph
DiRisio’s training from hsi personnel file for my review. Training was adequately documented.
RAW MATERIALS
Raw materials and components used to manufacture the firm’s blood filters include:
Materials
Gellulose Acetate
Bonding epoxy
Polyprepylene end cape
Glycerine Lubricant
Ultrasonic cleaning solution
Polypropylene tubing
Suppliers
-
Macomb Laboratories, inc. (Bohemia, NY)
Ideal Materials Co. (Toledo, Ohio)
ABO Excruders Inc. (Los Angeles, CA)
Sigma Laboratories (Miami, Florida)
Ace Science Inc. (Kenilworth, NJ)
ABO Excruders Inc. (Los Angeles, CA)
Components used to manufacture the firm’s filters are listed in Ex. 6 Suppliers’ addresses are
listed in Ex. 7.
Components are stored in the firm’s warehouse, located down the block at 2700 Ogden Street.
Incoming components are stored in a chaged quarantine area in the warehouse. When components
are inspected and found to be acceptable, cartons containing the components are each ink stamped
“ACCEPTED.” The firm does not use the system of designating quarantined components with a
“QUARANTINE” stamp of sticker, and then subsequently identifying the component as
“ACCEPTED” or “REJECTED.”
Mr. Fogg stated that Quality Control inspectors inspect incoming components for
characteristics as specified in the master device record. Ex. 8 is an example of the characteristics
for some of the blood filter components listed in the master record. Though QC inspects
components for these characteristics, no pass-fail specifications were noted during the inspection.
This was pointed out to Mr. Fogg and Dr. Turner. By the conclusion of the inspection, Mr. Romano
had drafted up such a specification, as is shown on Page 1 of Ex. 8.
All incoming components are assigned a control number, which reflects the purchase order
number (P.O.#). For example, if P.O.#23466 is for 200 cartons of filtermesh and the order is
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received from the supplier in several shipments, then the cartons in the first shipment will be
identified with control number 23466-1, and the cartons in the second shipment will be identified
23466-2, and so on until all the cartons shipped under this purchase order are received. This
information is recorded manually as well as fed into the firm’s computer. The computer is used for
inventory control and facilitates the firm’s first-in, first-out policy.
Mr. Romano described the components inspection procedure. Components are inspected for
the characteristics specified in the deice master record (see Ex. 8) which requires that 10% of the
log, up to 1,000 units, be inspected. A QC inspector can accept the lot if he finds no defective units;
otherwise a deficient lot will have to be approved by the firm’s Materials Review Board (William
Pearl, John Fogg, and Thomas Romano).
During the inspection a QC Inspector was noted to be inspecting an incoming lot of housing
units for the blood filter. Upon questioning, the inspector stated that he checks the housing units
using a B&L 200X stereoscopic microscope and standardized micrometer. The inspector stated he
checked each sampled unit for burro and sharp edges using the microscope. The micrometer was
used to check the wall thickness of the housing. The tolerance spec for the wall thickness was 0.01
cm.
Using one of several microscopes, the firm’s QC lab checks the cellulose acetate filtering
material for mesh count of every lot of mesh received, and records the results of the inspection in a
log book. This log book cross-references the purchase order number of the lot.
OPERATIONS
The firm occupies a two story building in a light industrial area: the first floor is mainly for
plant operations and the second floor is mainly for office space. As previously stated, the premises
are shared between Cardio-Medical Products, Inc. and Medical Products USA. Cardio-Medical
Products has 65 employees, working three shifts Mon.-Fri. The firm is closed for two weeks around
Christmas and In July. The firm has a warehouse at 2700 Ogden Street which is used to store raw
materials and finished products. Finished products ready for ETO sterilization are shipped to the
contract sterilizer via company trucks. Finished products ready for distribution to consignees are
usually shipped via UPS.
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Mr. Fogg estimated that his firm manufactured about 10,000 blood filters last year, of which
about 3,000 were used for arterial use, and about 7,000 were used for cardionomy use. Blood filters
are manufactured to be compatible with either ½ inch or 1 inch connectors. The bulk of the firm’s
blood filters are manufactured with ½ inch connectors.
The manufacturing operations are listed and described in the master device record’s
“OPERATION SHEETS.” Ex. 11 is an example of some of the “OPERATION SHEETS.” In
essence, the manufacturing process consists of the following operations:
1.
Molding of plastic parts. Appropriate quantities of virgin resin (60%) and regrind resin
(20%) are selected and weighed. Red #12 is added and the material is mixed.
2.
The above mixture is dated and given a lot number and placed into a sized tumbling device
(Rich Hopper) for blending for 6 hours.
3.
Prior to using the molding, machine is purged of any previous materials. A mixture of mold
release agents is used. This is forced thru the system using air at 50 PSI.
4.
After flushing with mold release agents, the system is lubricated using a glycerin lubricant
manufactured by Sigma Labs, Miami, Florida.
5.
The molding machine is set up using the appropriate mold. The firm has 4 different molds.
Two molds are used for the arterial filter, one for 1 inch connectors and one for ½ inch
connectors. The other 2 are for cardionomy filters, again 1 for 1 inch and the other for ½
for ½ inch connectors.
6.
When the plastic parts have been molded, the cellulose acetate filtering material must be
inserted. This is done by a special machine which places one layer of material on top of
another. The completed filter has a total of 60 layers for the arterial model and 75 for the
cardionomy model.
7.
After the cellulose acetate has been inserted into the filter, the end cap is placed on the open
end and bonded using a bonding epoxy. This operation is performed using a specially
designed capping machine. Epoxy is applied to the cap at one state of the machine
operation, then the cap is inserted into the body of the filter. The machine then twists the
cap into place.
8.
Once the cap and body have been applied, the polyurethane tubing is attached to either end
of the filter. The tubing is received in a large spool and cut to the proper length using a
Ronfro tube cutter model 54.
9.
The finished filter is then placed into its metal housing and then into polypropalene bags
which are sealed using a Smith #2 heat sealing machine. The bags are then loaded into
cartons, 10 filters to a carton for shipment to the contract sterilizer. Each carton is labeled
as “caution, this product has not yet undergone sterilization”.
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10. When the sterilized product is returned, samples are removed and the cartons placed in a
quarantine area. When the results of the sterility test are received, the cartons are marked
“approved for packaging.” The final step in the process is the packaging of the filters into
labeled cardboard unit packages. This is accomplished using a Packo Packaging machine
model #8245. Once packaged, the product is stored in a quarantined area until released for
shipping.
Samples designated for testing are pulled by QC. The firm performs its own Bubble Point
SSP/NF testing of each lot of filters prior to ETO sterilization. See Ex. 16 for USP/NF Bubble Point
testing procedures and Ex. 17, pages 20-22, for some Bubble Point log book records. See Ex. 14 for
bioburden testing procedures and Ex. 17, pages 23 and 24, for LAL Pyrogen Testing log book
records.
Filters designated for sterility testing are held separate from the rest of the lot until the lot is
ready for shipment to the contract sterilizer. Samples designated for pyrogen and safety (toxicity)
testing, by outside labs, area also pulled at this time.
The firm’s QC lab was noted to have on hand the Jones Bubble Point Testing Apparatus to test
the filters prior to ETO sterilization. These were calibrated at 0.001 ml. of air per cubic inch.
The firm also performs its own LAL pyrogen testing. This pyrogen testing is performed on the
IV filter only, as only these filters have a Lewis Crenshaw filtering media. All other filters have
Wren media, which are not as likely to support bacterial growth as Lewis Crenshaw media. The
firm’s QC lab had Pyro Gen Lab test serum and testing apparatus. Review of LAL testing records
going back 6 months revealed no positive results. Charles Miller, Asst. QC Manager, stated that
QC lab uses a 40% alcohol solution as first a rinse on the filter, a 25% solution as a second rinse to
collect the solution used for pyrogen testing and a 10 unit sample for each testing run.
The rest of the cartons in the lot are pelletized and the pallets are completely wrapped with
large sheets of cardboard and banded with steel bands to discourage tampering. Each pallet is
identified with a Cardio-Medical sterilization lot number, which is a number that can be correlated
to the contract sterilizer’s sterilization lot number. Each pallet is also identified with a contents
statement, indicating the product numbers, day lot numbers, and the number of cartons of each lot
contained on the pallet. A Cardio-Medical truck will take up to 6 pallets of products to the contract
sterilizer, Minix Lab, Brie, PA about once a week. The filters designated for testing by outside labs
are shipped along with the pallets to the contract sterilizer. Through contractual agreements
Cardio-Medical has notified the contract sterilizer of the desired placement of the test samples
within the sterilizer, as shown in Ex. 20, Pg. 3. For each sterilization lot Cardio-Medical notifies the
contract sterilizer which samples are not to be sent to which outside labs. A Cardio-Medical truck
will pick up he lot after it has been sterilized, and return it to the Cardio-Medical warehouse at
2700 Ogden Street, where the lot is placed in quarantine until the test results are returned and
approved.
18 − 92
In the meantime, QC personnel will open up 6 cartons from each day lot of all the day lots in
each sterilization lot and inspect the plastic bags for any air leaks/burst bags. If any air leaks/burst
bags are found, then every carton in the day lot is opened to determine how extensive the problem
is. Leaks/burst bags indicate either the bags were not sealed properly and/or that the contract
sterilizer pulled a vacuum larger than they should have during the ETO sterilization cycle. Lots
found with the significant numbers of leaks/burst bags are re-bagged and subjected again to ETO.
Once the QC Manager approves of the QC inspection tests and approves of the outside testing
lab results (sterility, pyrogen, and safety), then he will sign the lot release report (Ex. 17, Pg. 1)
which permits the release of the lot from quarantine and entry into inventory.
Mr. Charles Miller stated that he maintains the firm’s reserve samples which are collected 10
times a year and are used for shelf life studies (see Ex. 22). No other reserve samples are taken.
Shelf life studies testing includes tests for Bubble Point, Porosity and Sterility.
Regarding components and products rejected during processing, Mr. Fogg stated that all
rejects are discarded, rather than shipped back to the supplier. Mr. Fogg stated that his firm
preferred to use only components made from polypropylene, and that to avoid any of the problems
associated with recycling, his firm did not ship rejected components (rejected during processing)
back to the suppliers. Rejects are taken to the Smith & Company incinerator about 5 times a year
for destruction. Mr. Fogg stated that his firm documented these destructions, and showed me the
records coving the most recent destruction.
METROLOGY
Mr. Joseph DiRisio, QA Metrologist, stated he was responsible to Dr. Paul Turner for all the
firm’s metrology (measurement and calibration) operations. Mr. DiRisio stated he maintains the
logs and records that show when equipment was last serviced, who serviced it, what the calibration
errors are, if any, and when the next service calibration is scheduled. Each piece of production and
testing equipment is assigned a unique number for calibration record purposes. As can be seen in
Ex. 4, the firm has primary standards, for which calibration is recorded traceable to the National
Bureau of Standards (NBS). Primary standards consist of transfer equipment such as weight sets,
lengths, thermocouples and digital multi meters. These standards are calibrated by Calibra
Metrologist, Inc. White Plains, New York. Mr. DiRisio showed me the metrology manual and some
of the records covering the servicing and calibration of equipment. Inspection revealed that the
firm’s laminar-flow hoods were serviced by Lami Flow, Ltd. New York, New York and that the
firm has records to show that the hoods were serviced about every 6 months going back to 12/76.
The most recent service was in 2/84.
18 − 93
POROSITY STUDIES
The firm has an ongoing porosity study program. Products from each day’s production are
tested for porosity by the firm’s QC lab. Ex. 17, pages 23 and 24, are examples of the records for
routine porosity testing. Mr. Fogg and Dr. Turner stated that routine porosity testing was a good
QA procedure to establish a long term history of their products, and was much more valid than a
one shot porosity study.
VALIDATION OF STERILIZATION
ETO sterilization has always been performed by an outside contracted firm, Minix Labs, Erie,
PA. Mr. Fogg stated that Minix has never disclosed its ETO sterilization cycle parameters, feeling
that such information was proprietary and that such information would not be released unless
Cardio-Medical agreed not to make use of this information for its own purposes and agreed to
release this information to any firm that might make use of this trade secret information. Mr. Fogg
stated that Cardio-Medical was not able to agree to such a proposal. As such, Cardio-Medical
asked Minix Labs, Erie, PA to conduct a validation study using Cardio-Medical’s parameters, on
Cardio-Medical’s newest product, the IV fluid filter/air eliminator. This study is attached as Ex.
20, and was conducted in 1978. Mr. Fogg stated that this study determined that ten to the minus 6
kill could be achieved in 14 hours using their parameters, and that, as a safety feature Minix Labs
has been asked to sterilize Cardio-Medical’s filters to the equivalence of 16 hours of CardioMedical’s ETO sterilization parameters.
The sterilization validation study (Ex. 20) lists the parameters of the sterilization cycle (Pg. 1),
the configuration of the test samples (Pg. 3), the protocol of the study (Pg. 1), the records and
results of the study (Pages 8-34) and other information.
Mr. Fogg stated that his firm intended to discontinue using this contract sterilizer, and start
using a sterilization procedure of their own, in about 6 months. Mr. Fogg stated that the proposed
sterilization procedures would involve placing cartons of filters into each 3x2x1 foot aluminum
orib. The orib would then be filled with 80% ETO, 20% mix. After 10 hours of exposure, the
cartons would be removed from the orib and routed to the holding room for 24 hours. Mr. Fogg
stated that his firm has been consulting with Steri Consultant, Inc and would be consulting with
FDA’s Dr. Bruch re this proposed ETO sterilization procedure, and methods to validate this
procedure.
DEVICE HISTORY RECORDS
Device history records are maintained by sequential Cardio-Medical sterilization lot numbers.
During this inspection, the most recently completed device history record available for review was
for sterilization lot #340, for which the lot release report was signed on 5/29/84. Sterilization lot
#340 contains the records for 26 lots (“day lots”) of blood filters (see Pg. 17 of Ex. 17). Day lot
#00441 was randomly picked as the device who’s record I would review. Ex. 17 consists of most of
the device history records relevant to sterilization lot #340, day lot #00441, which consists of
records as follows:
18 − 94
PAGE
1
2-4
SUBJECT
Lot release report
Component Materials Record - lists the lot numbers of the components used in day lot
#00441
5-13
Operation Cards - shows the who, what, when, and how many of each manufacturing
step; and that the lot was divided into 9 tote boxes for easy handling
14-15
Forms Traceability
16
Inspection of Vacuum Bag Integrity
17
Material Movement Report - shows which pallet day lot #00441 was placed on, out of 4
pallets
18-19
In Process Testing Report - shows that day lot #00441 was subject to porocity testing
and USP/NF Bubble testing as well as LAL Pyrogen testing. The firm’s LAL pyrogen
testing procedure is described in Ex. 16.
20-22
QC Lab Book - shows the results of Bubble Point testing
23-24
QC Lab Book - shows the results of LAL testing
25
Transfer Receiving Report - lists the products and quantities shipped to the contract
sterilizer
26
QC Lab Book - shows the day lots of quantities which were designated for sterility
testing by Steri Consult, Inc., Boston, MA and the day lots which were designated for
pyrogen and safety testing by Test All Ltd., Patterson, NJ
27
Letter, dated 5/1/84, directing Steri Consult, Inc. to test for pyrogens and safety
28
Letter, dated 5/1/84, directing Steri Consult, Inc. to test filters for sterility
29
Letter, dated 5/9/84, re: results of pyrogen testing
30
Letter, dated 5/12/84, re: results of safety and testing
31-32
Letter, dated 5/6/84, re: results of sterility testing
33
Final Inspection Record - inspection of lot after sterilization
18 − 95
DEVICE MASTER RECORD
During this inspection the firm’s device master record for their Minipor Blood Filter was
reviewed. Review of this record revealed that it contained, or referred to, almost all of the
information required by the device GMPs (device specifications, manufacturing processes, quality
assurance procedures, and packaging and labeling information). Only some minor deficiencies
were noted. These are discussed under Objectionable Conditions. Information relevant to the
device master record is contained in Exhibits 6 thru 16.
OBJECTIONABLE CONDITIONS
During this inspection the only objectionable conditions noted were some minor deficiencies in
the device master record for the Minipor Blood Filters. These deficiencies were listed on an FD
483, Inspectional Observations, which was presented to and discussed with management at the
close of the inspection.
Deficiencies noted were:
3. it does not list acceptance criteria for incoming components;
4. it does not list that components made of plastic are to receive an
I.R. spectrographic analysis;
5. it does not list that the cellulose acetate filtering material is
about 120 mesh, and it does not list the quantity of this material
used to manufacture the blood filters;
6. the Operation Sheets have not been signed by all approving officials
(Ex. II); and
7. the engineering diagrams for the housing, and top end caps do not
bear the signature or initials of an approving corporate official
(Ex. 12).
No other objectionable conditions were noted during this inspections.
MANUFACTURING CODES
The firm uses two manufacturing codes: a day lot code and a sterilization date code. The day lot code
is a code that represents the date the product was manufactured (assembled). For example: “00441"
means the 4th day of 1984, the 1st shift, where 004 if the fourth day, 4 is 1984, and 1 is the first shift.
The sterilization date code “Jan 30 1984" is self explanatory.
The day lot code is ink stamped on every box and every carton, prior to EtO sterilization. The
sterilization date code is ink stamped on every carton after the lot returns form Ethylene Oxide
sterilization. The firm does not have a policy of coding the actual filter nor of coding the stick-on label
applied to the filters.
CONSUMER COMPLAINTS
During this inspection the firm’s consumer complaint file was reviewed, and a follow up was made of
Medical Device Complaint M-00210 dated 5/31/84, which concerned leaking of Cardio Minipor IV Filter
(no lot number given). Mr. Fogg stated that his firm had investigated this complaint and had determined
that the hospital did not normally use their filters, and that the nurse that had registered the complaint was
18 − 96
not familiar with its use. A company representative visited the hospital and talked with the nurse about
the application of the IV filter.
Mr. Fogg stated that the filter was designed for use at pressures under 600 mm of mercury, and that at
above 600 mm of mercury the filer would crack in such a way as to maintain the integrity of solutions on
the downstream side of the filter, and also prevent any air bubbles form getting into the system. M00210 is attached as Exhibit 23, pages 5-8. The labeling for the IV filter specifically states that the filter
is not to be used at above 600 mm pressure of mercury.
Review of the firm’s complaint file revealed 10 complaints registered since 12/78 (excluding the
above complaint), which the firm has assigned as number 91, 93, 94, 96, 97, 98, 100, 101, 102, and 103.
Three complaints concerned Minipor blood filters, four complaints concerned blood dialysis filters, and
three complaints concerned cardiovascular catheters concerning packaging defects, embedded particulate
matter, cracks and leaks.
Mr. Fogg stated that all complaints are evaluated and investigated. Mr. Thomas Romano stated he
evaluates all complaints to determine which department(s) should investigate the complaint. If available,
sample of the subject lot are re-tested to determine if the complaint can be duplicated. Complaints are
evaluated to determine if the complaint can be duplicated. Complaints are evaluated to determine if
changes in QC or production procedures are needed, and to see if there are any patterns. Dr. Turner
stated that during routine production, lots are subject to 100% checks and to a statistical check, in an
effort to prevent any defects from leaving the plant. Mr. Romano stated that copies of complaints and the
investigations are routinely routed to John Fogg, Dr. Paul Turner, and to William Pearl.
PROMOTION & DISTRIBUTION
Mr. Fogg stated that the firm distributes its filters nationwide, and overseas to Italy and Germany.
Filters are sold to distributors who, in turn, sell the filters to hospitals. The firm’s service representatives,
both here and abroad, give lectures on the applications and proper use of Cardio-Medical’s filters. Other
promotion is performed by salesmen who work for the distributors.
Mr. Fogg provided some recent shipments as follows:
of Cases of
Invoice And Date
Consignee
Number
Minipor IV Filters
(8 each)
B8925
3/14/84
Mt. Saint Holly Hospital
Canton, Ohio
20
B8845
3/2/84
Stainless Hospital
Toledo, Ohio
80
B9045
3/28/84
Major General Hospital
Boise, Idaho
60
B9051
3/29/84
VA Hospital
Cardiac, Oklahoma
30
B9054
3/30/84
B9055
2/29/84
General Hospital
Pleasure, Colorado
Molino Hospital
Molino, Italy
30
20
18 − 97
B9058
3/30/84
Hurt Hospital
Raine, North Dakota
30
B9069
4/2/84
Ritz Hospital
Frankforth, Germany
10
B9076
4/2/84
Cardio General Hospital
Vein, South Dakota
10
B9082
3/29/84
Heart and Lung Clinic
Dorothy, Kansas
20
W8474
3/16/84
Monitor Hospital
Laser, Pennsylvania
20
D21606
3/30/84
St. Alchemy Hospital
Cold, Vermont
15
The above invoices are attached as Ex. 25. The invoices are noted to reference the manufacturing
(sterilization date. This date is ink stamped on each carton (case). This coding and invoice system will
facilitate a recall, should one occur.
REFUSALS
There were no refusals during this inspection.
DISCUSSION WITH MANAGEMENT
At the close of the inspection, the FD 483, Inspection Observations, was presented to and discussed
with Mr. John (NMI) Fogg, President. Dr. Paul M. Turner, Quality Assurance Manager, was also present
during this discussion. Inspectional observations concerned five minor deficiencies in the device master
record. Mr. Fogg stated the point #1, acceptance criteria for components, had already been corrected and
gave me a copy of this document (see Ex. 8, Pg. 1). Mr. Fogg stated that the other deficiencies were
simply oversights and could easily be corrected. No additional suggestions were given. One comment
was made, which was that the firm discuss its proposed new EtO sterilization procedure with someone in
the Center for Devices and Radiological Health, as this proposed procedure does not appear to have been
commercially use. Mr. Fogg stated he believed a number of hospitals and small institutions were using
this new EtO sterilization procedure, but was not aware of any manufacturer using the procedure.
SAMPLES
There were no samples collected during this inspection.
EXHIBITS
8. QC Manual re: policy & organization
9. QA manager responsibilities
1. QC manager responsibilities
2. Metrology manual
3. Examples of calibration standards traceable to NBS
4. List of components used to manufacture filters
5. List of component suppliers
6. Component sampling and acceptance plan
7. Blood filter sampling & acceptance plan
8. Component supplier agreements
18 − 98
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Device master record operation sheets
Device master record
Sterility assurance procedures
LAL test procedures
Environmental air sampling procedures
USP/NF bubble point testing procedures
Device history record, blood filter, lot #00401, released
3/29/80
EtO residue study, 1976 & 1980
Safety/Toxicity study, 1976
EtO sterilization validation study, 1980
Letter, 2/1/84, from Acme Sterilizers
Shelf life study plan, 1976
Consumer complaints
Medical device complaint M-00210, dated 5/31/84
Invoices of 12 recent shipments
List of devices manufactured
Labeling for blood filters
ATTACHMENTS
1. CP 7378.830 Systems analysis report
2. CP 7378.830A Sterile device compliance program pages 2-10 &
15-18
Thomas E. Cardamone
Investigator 800
New York District
18 − 99
MODEL WARNING LETTER
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
RESPONSIBLE INDIVIDUAL, TITLE
FIRM NAME
FIRM’S COMPLETE ADDRESS
Dear
(Addressee)
,
During an inspection of your firm located in
(City, State) , on (dates) , our Investigator(s)
determined that your firm manufactures (type of device) . (Name of device) are devices as defined
by Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act).
The above-stated inspection revealed that these devices are adulterated within the meaning of Section
501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing,
packing, storage, or installation are not in conformance with the Good Manufacturing Practice (GMP) for
Medical Devices Regulation, as specified in Title 21, Code of Federal Regulations (CFR), Part 820, as
follows:
1. Failure to conduct planned and periodic audits of the quality assurance program in accordance with
written procedures. For example, no audits of the quality assurance program have been performed for at
least 3 years.
2. Failure to investigate the failure of a device to meet performance specifications after a device has
been released for distribution, and to make a written record of the investigation including conclusions and
,
follow-up. For example, there are no records of failure investigations for Model
S/N
, and Model
, S/N
, which were returned because they did not operate
properly.
3. Failure to maintain device history records for Model
manufactured in accordance with the device master record.
to demonstrate that the devices are
4. Failure to immediately review, evaluate and investigate any complaint pertaining to injury, death, or
any hazard to safety. For example, there is no record of the investigation of a report that a child’s death
at the Community Medical Ctr. on/or about Feb. 8, 1991.
associated with the use of Model
Additionally, the above stated inspection revealed that your devices are misbranded within the meaning
of Section 502(t)(2) of the Act, in that your firm failed to submit information to the Food and Drug
Administration as required by the Medical Device Reporting (MDR) Regulation, as specified in 21 CFR
Part 803. Specifically, you failed to submit an MDR report to FDA after receiving information which
reasonably suggested that one of your commercially distributed devices may have caused or contributed
to a death. The February 8, 1991, incident report from the Community Medical Center in which a child
standing in a crib fell over, caught his head in a “Y” formed by the crib rail and end post, and died,
should have been reported as a death.
This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your
responsibility to ensure adherence to each requirement of the Act and regulations. The specific violations
noted in this letter and in the FDA 483 issued at the closeout of the inspection may be symptomatic of
serious underlying problems in your firm’s manufacturing and quality assurance systems. You are
responsible for investigating and determining the causes of the violations identified by the FDA. If the
causes are determined to be systems problems, you shall promptly initiate permanent corrective actions.
18 − 100
Federal agencies are advised of the issuance of all Warning Letters about devices so that they may take
this information into account when considering the award of contracts. Additionally, no premarket
submissions for devices to which the GMP deficiencies are reasonably related will be cleared until the
violations have been corrected. Also, no requests for Certificates For Products For Export will be
approved until the violations related to the subject devices have been corrected.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations
may result in regulatory action being initiated by the Food and Drug Administration without further
notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties.
Please notify this office in writing within 15 working days of receipt of this letter, of the specific steps
you have taken to correct the noted violations, including an explanation of each step being taken to
identify and make corrections to any underlying systems problems necessary to assure that similar
violations will not recur. If corrective action cannot be completed within 15 working days, state the
reason for the delay and the time within which the corrections will be completed.
Your response should be sent to (Name) , Compliance Officer, Food and Drug Administration,
(City, State & Zip Code) .
Sincerely yours,
18 − 101
update: A. Lowery, 8-93
update: J. Puleo & A. Lowery, 5-9-96
edited: N. Freeman, 5/13/96
edited: J. Strojny, 5/15/96
edited: T. Cardamone, 6/21/96
revised: K.Trautman, 7/96
edited: J. Strojny, 8-13
Word Searches: chapter, U.S. Designated Agent, GMP, regulation, QS,
firm, guideline; K. Trautman comments included
edited: T. Cardamone, 8-15
edited: J. Strojny, 9-9 Quality System = QS after 1st reference
18 − 102
19 APPENDIXES
QUALITY SYSTEMS REGULATION ..................................................................xxappdx1.zip
APPLICATION OF THE MEDICAL DEVICE GMPS TO
COMPUTERIZED DEVICES AND MANUFACTURING PROCESSESxxappdx2.zip
In the electronic version - the above files are stored in zipped format to save disk space.
The above files are located on this disk and must be expanded using Pkware unzip or similiar file
expansion software.
19 − 103
<HEAD>
<TITLE>Text Version of the CGMP</TITLE>
</HEAD>
<BODY>
<center><IMG SRC = "newtst.gif"></center>
<center><H1>Text Version of the CURRENT GOOD MANUFACTURING PRACTICE (CGMP)
FINAL RULE</H1></center>
<P><P>
<center><h3><IMG SRC = "sb10.gif"></h3></center>
<P>
<HR>
<P>
<P>
<CENTER> <H2>WORKING DRAFT OF THE CURRENT GOOD MANUFACTURING
PRACTICE (CGMP) FINAL RULE</H2>
</CENTER>
<PRE>
July 1995
Office of Compliance
Center for Devices and Radiological Health
U.S. Food and Drug Administration
2098 Gaither Road
Rockville, MD 20850
20 − 1
Table of Contents
<A HREF="#1">NOTICE OF AVAILABILITY</A>. . . . . . . . . . . . . . . 1
<A HREF="#11">WORKING DRAFT OF THE CGMP FINAL RULE - PREAMBLE</A>. . . .
. . . . . . . . . . . . 11
<A HREF="#pSubpart A">General Provisions (Subpart A)</A>
<A HREF="#pSubpart B">Quality System Requirements (Subpart B)</A>
<A HREF="#pSubpart C">Design Controls (Subpart C)</A>
<A HREF="#pSubpart D">Document Controls (Subpart D)</A>
<A HREF="#pSubpart E">Purchasing Controls (Subpart E)</A>
<A HREF="#pSubpart F">Identification and Traceability (Subpart F)</A>
<A HREF="#pSubpart G">Production and Process Controls (Subpart G)</A>
<A HREF="#pSubpart H">Acceptance Activities (Subpart H)</A>
<A HREF="#pSubpart I">Nonconforming Product Subpart I)</A>
<A HREF="#pSubpart J">Corrective and Preventive Action (Subpart J)</A>
<A HREF="#pSubpart K">Handling, Storage, Distribution, and Installation (Subpart K)</A>
<A HREF="#pSubpart L">Packaging and Labeling Control (Subpart L)</A>
<A HREF="#pSubpart M">Records (Subpart M)</A>
<A HREF="#pSubpart N">Servicing (Subpart N)</A>
<A HREF="#pSubpart O">Statistical Techniques (Subpart O)</A>
<A HREF="#183">WORKING DRAFT OF THE CGMP FINAL RULE
REGULATION</A>. . . . . . . . . . . . . . . 183
<A HREF="#rSubpart A">General Provisions (Subpart A)</A>
<A HREF="#rSubpart B">Quality System Requirements (Subpart B)</A>
<A HREF="#rSubpart C">Design Controls (Subpart C)</A>
<A HREF="#rSubpart D">Document Controls (Subpart D)</A>
<A HREF="#rSubpart E">Purchasing Controls (Subpart E)</A>
<A HREF="#rSubpart F">Identification and Traceability (Subpart F)</A>
<A HREF="#rSubpart G">Production and Process Controls (Subpart G)</A>
<A HREF="#rSubpart H">Acceptance Activities (Subpart H)</A>
<A HREF="#rSubpart I">Nonconforming Product Subpart I)</A>
<A HREF="#rSubpart J">Corrective and Preventive Action (Subpart J)</A>
<A HREF="#rSubpart K">Handling, Storage, Distribution, and Installation (Subpart K)</A>
<A HREF="#rSubpart L">Packaging and Labeling Control (Subpart L)</A>
<A HREF="#rSubpart M">Records (Subpart M)</A>
<A HREF="#rSubpart N">Servicing (Subpart N)</A>
<A HREF="#rSubpart O">Statistical Techniques (Subpart O)</A>
20 − 2
<A NAME="1">NOTICE OF AVAILABILITY</A>
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 820
[Docket No. 90N-0172]
RIN No. 0905-AD59
Medical Devices; Working Draft of the Current Good Manufacturing Practice
(CGMP) Final Rule; Notice of Availability; Request for Comments; Public Meeting
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability and announcement of public meeting.
________________________________________________________________________
SUMMARY: The Food and Drug Administration (FDA) is announcing the availability of
a working draft of a final rule on the revision of the current good manufacturing practice
(CGMP) regulation for devices (quality system regulation). The quality system regulation
includes requirements related to the methods used in and the facilities and controls used
for: Designing, purchasing, manufacturing, packaging, labeling, storing, installing, and
servicing of medical devices intended for human use. The working draft contains a
number of changes made in response to the many comments received on the proposal to
amend the CGMP regulation, and it represents the agency's view of the necessary elements
of a CGMP regulation. In this document, FDA is also announcing a public meeting to be
held on the working draft. At a later time, FDA will announce a meeting of the Device
Good Manufacturing Practice Advisory Committee. The publication of this document is
intended to make the working draft of the quality system regulation available to the public
in order to give those who will attend the public meetings the opportunity to be informed
of the agency's current thinking on the final rule and to allow interested parties an
additional opportunity to comment before a final regulation is issued.
DATES: The public meeting will be held on Wednesday, August 23, 1995, from 9 a.m.
to 4:30 p.m. Should more time be needed, Thursday, August 24, 1995, has been set aside
for this purpose. Interested persons, whether or not they are able to attend, may submit
written comments on the issues described in this notice by (insert date 90 days after date
of publication in the Federal Register). Submit written notices of participation on or
before (insert date 15 days after date of publication in the Federal Register). Any final
regulation that may issue, after a thorough review of the comments received on this
working draft, will become effective 180 days following its publication in the Federal
Register. A transcript of the meeting will be available from the Dockets Management
Branch (address below).
ADDRESSES: The meeting will be held at the Parklawn Bldg, conference room D, 5600
Fishers Lane, Rockville, MD. There is no registration fee for this meeting. Submit
written requests to make a presentation at the meeting to the Dockets Management
Branch (HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr.,
Rockville, MD 20857. Submit written requests for single copies of the working draft of
the quality system regulation to the Division of Small Manufacturers Assistance (HFZ-220),
Food and Drug Administration, 1350 Piccard Dr., Rockville, MD 20850. Send two
self-addressed adhesive labels to assist the office in processing your request. Submit
written comments on the working draft to the Dockets Management Branch (HFA-305)
(address above). Requests and comments should be identified with the docket number
found in brackets in the heading of this document. A copy of the working draft and
received comments are available for public examination in the Dockets Management
Branch between 9 a.m. to 4 p.m., Monday through Friday. Copies of a facsimile of the
working draft, totaling approximately 230 pages (approximately 190 pages of draft
preamble and 40 pages of draft regulation), are available from CDRH Facts on Demand
(1-800-899-0281). Copies of the revision may also be obtained from the electronic docket
20 − 3
administered by the Division of Small Manufacturers Assistance and are available to
anyone with a video terminal or personal computer (1-800-252-1366).
FOR FURTHER INFORMATION CONTACT: Kimberly A. Trautman, Office of
Compliance, Center for Devices and Radiological Health (HFZ-341), Food and Drug
Administration, 2098 Gaither Rd., Rockville, MD 20850, 301-594-4648.
SUPPLEMENTARY INFORMATION:
I. Background
Manufacturers establish and follow quality systems to help ensure that their
products consistently meet applicable requirements and specifications. The quality
systems for FDA regulated products (food, drugs, biologics, and devices) are known as
CGMP's. CGMP requirements for devices (part 820 (21 CFR part 820)) were first
authorized by section 520(f) of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 360j(f)), which was among the authorities added to the act by the Medical Device
Amendments of 1976 (Pub. L. 94-295). The Safe Medical Devices Act (the SMDA) of
1990 (Pub. L. 101-629), enacted on November 28, 1990, amended section 520(f) of the
act, providing FDA with the explicit authority to add preproduction design validation
controls to the CGMP regulation. The SMDA also added a new section 803 to the act
(21 U.S.C. 383) which, among other things, encourages FDA to work with foreign
countries toward mutual recognition of CGMP requirements.
FDA undertook the revision of the CGMP regulation in part to add the design
controls authorized by the SMDA to the CGMP regulation, and in part because the
agency believes that it would be beneficial to the public, as well as the medical device
industry, for the CGMP regulation to be consistent, to the extent possible, with the
requirements for quality systems contained in applicable international standards, namely,
the International Organization for Standards (ISO) 9001:1994 "Quality Systems - Model
for Quality Assurance in Design, Development, Production, Installation, and Servicing"
(Ref. 1), and ISO working draft revision of ISO/DIS 13485 "Quality Systems - Medical
Devices - Supplementary Requirements to ISO 9001" (Ref. 2), among others. The
preamble to the November 23, 1993, proposal contains a detailed discussion of the history
of the device CGMP regulation, from the agency's initial issuance of the regulation
through FDA's decision to propose revising the regulation.
The agency's working draft embraces the same "umbrella" approach to CGMP
regulation that is the underpinning of the existing CGMP regulation. Thus, because this
regulation must apply to so many different types of devices, the regulation does not
prescribe in detail how a manufacturer must produce a specific device. Rather, the
regulation lays the framework that all manufacturers must follow, requiring that the
manufacturer develop and follow procedures, and fill in the details, that are appropriate to
a given device according to the current state-of-the-art manufacturing for that specific
device. FDA has made further changes to the proposed regulation, as the working draft
evidences, to provide manufacturers with even greater flexibility in achieving the quality
requirements.
II. Decision to Make a Working Draft Available for Comment
On November 23, 1993 (58 FR 61952), the agency issued the proposed revisions
to the CGMP regulation, entitled "Medical Devices; Current Good Manufacturing Practice
(CGMP) Regulations; Proposed Revisions; Request for Comments," and public comment
was solicited. After the proposal issued, FDA met with the Global Harmonization Task
Force (GHTF) Study Group in early March 1994, in Brussels, to compare the provisions
of the proposal with the provisions of ISO 9001:1994 and European Norm (EN) standard
EN 46001 "Quality Systems - Medical Devices - Particular Requirements for the
Application of EN 29001". The GHTF includes: Representatives of the Canadian
Ministry of Health and Welfare; the Japanese Ministry of Health and Welfare; FDA; and
industry members from the European Union, Australia, Canada, Japan, and the United
States. The participants at the GHTF meeting favorably regarded FDA's effort toward
harmonization with international standards. The GHTF submitted comments, however,
noting where FDA could more closely harmonize to achieve consistency with quality
system requirements worldwide. Since the proposal published, FDA has also attended
20 − 4
numerous industry and professional association seminars and workshops, including ISO
Technical Committee 210 "Quality Management and Corresponding General Aspects for
Medical Devices" meetings, where the proposed revisions were discussed.
The original period for comment on the proposal closed on February 22, 1994, and
was extended until April 4, 1994. Because of the heavy volume of comments and the
desire to increase public participation in the development of the quality system regulation,
FDA decided to publish this notice of availability in the Federal Register to allow
comment on the working draft, to be followed by two public meetings, as describe below,
before issuing a final regulation.
This working draft represents the agency's current views on how it would respond
to the many comments received, and on how the agency believes a final rule should be
framed. FDA solicits public comment on this working draft to determine if the agency has
adequately addressed the many comments received and whether the agency has framed a
final rule that achieves the public health goals to be gained from implementation of quality
systems in the most efficient manner.
III. Opportunity for Public Meeting
FDA intends to hold two public meetings on the revision of the quality system
regulation. One meeting, which will be held pursuant to 21 CFR part 10.65(b), is
scheduled for August 23, 1995. Interested persons who wish to participate in the public
meeting may, on or before (insert date 15 days after date of publication in the Federal
Register) submit a written notice of participation to the Dockets Management Branch
(address above). All notices submitted should be identified with the docket number found
in brackets in the heading of this document and should be clearly marked "Notice of
Participation". The notice should also contain the name, address, telephone number,
business affiliation of the person requesting to make a presentation, a brief summary of the
presentation, and the approximate time requested for the presentation.
Individuals or groups having similar interests are requested to consolidate their
comments and present them through a single representative. FDA may require joint
presentations by persons with common interests. FDA will allocate the time available for
the meeting among the persons who properly submit a written notice of participation. The
meeting is informal, and the rules of evidence do not apply.
Because of the complexity of the issues to be discussed at the public meeting, FDA
has concluded that it would not be beneficial to the meeting participants or the agency to
devote the entire meeting to public presentations. Therefore, after reviewing the notices
of participation and accompanying information, FDA will schedule each appearance and
notify each participant by mail or telephone of the time allotted to the person and the
approximate time the person's presentation is scheduled to begin. Each presentation will
be limited in time in order to provide sufficient time for prepared presentations by the
agency followed by a discussion period. The schedule of the public meeting will be
available at the meeting, and later it will be placed on file in the Dockets Management
Branch (address above).
Individuals and organizations that do not submit a notice of participation but
would like to testify will have the opportunity, if time permits. A transcript of the
proceedings of the public meeting, as well as all data and information submitted
voluntarily to FDA during the public meeting to discuss the working draft, will become
part of the administrative record and will be available to the public under 21 CFR 20.111
from the Dockets Management Branch (address above).
While oral presentations from specific individuals and organizations will be limited
during the public meeting, the written comments submitted as part of the administrative
record may contain a discussion of any issues of concern. All relevant data and
documentation should be submitted with the written comments.
There will also be a public meeting with the Device GMP Advisory Committee,
established under section 520(f)(1)(B) of the act, on the working draft. That meeting will
be governed by part 14 (21 CFR part 14) of FDA's administrative practices and
procedures regulations, which specifies the requirements for filing notices of appearance.
The tentative dates for the meeting are September 13 and 14, 1995. A notice of the exact
dates, time, and place for the meeting will appear in a future issue of the Federal
Register. After considering the written comments and the views expressed at the public
meeting and at the September advisory committee meeting, FDA will publish a final rule in
the Federal Register.
20 − 5
IV. References
The following information has been placed on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9 a.m. and 4 p.m.,
Monday through Friday:
(1) ISO 9001:1994 "Quality Systems - Model for Quality Assurance in Design,
Development, Production, Installation, and Servicing."
(2) ISO working draft revision of ISO/DIS 13485 "Quality Systems - Medical
Devices - Supplementary Requirements to ISO 9001."
V. Comments
Interested persons may, on or before (insert date 90 days after date of publication
in the Federal Register), submit to the Dockets Management Branch (address above),
written comments regarding this working draft. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to be identified
with the docket number found in brackets in the heading of this document. The working
draft and received comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday.
20 − 6
<A NAME="11">WORKING DRAFT OF THE CGMP FINAL RULE - PREAMBLE</A>
Approximately 280 separate individuals or groups commented on the proposal
published in the Federal Register on November 23, 1993. Of the comments received,
many were quite constructive and addressed numerous provisions of the proposal. Most
of the changes made from the proposal to the tentative final were made either in response
to specific comments or to better harmonize FDA requirements with international
standards, as many commentors generally requested. FDA's response to the comments
received on the proposal and explanations for the changes made from the proposal follow.
<A NAME="pSubpart A">A. General Provisions (Subpart A)</A>
i. Scope
1 The title of the regulation, as reflected in this subsection, has been changed from
the "Current Good Manufacturing Practices (CGMP)" regulation to the "Quality
System" regulation. This revision follows the suggestion underlying many
comments on specific provisions that FDA generally harmonize the CGMP
requirements and terminology to international standards. Both ISO 9001 and EN
46001 employ this terminology to describe the CGMP requirements. In addition,
this title accurately describes the sum of the requirements, which now include the
current good manufacturing practice requirements for design, purchasing, and
servicing controls. CGMP requirements now cover a full quality system.
FDA notes that the requirements embodied in this Quality System regulation have
been accepted worldwide as necessary to ensure that acceptable products are
produced. While the regulation has been harmonized with the medical device
requirements in the EU and the requirements proposed by Japan and Canada, it is
anticipated that other countries will adopt similar requirements in the near future.
2
Several comments expressed that section 820.1(a)(1) should not state that the
regulation establishes the "minimum" requirements because that implies that
compliance with the stated requirements may be insufficient. They suggested that
FDA delete the word "minimum," therefore, to avoid auditors searching for
additional requirements.
FDA does not believe that the provision would have required that manufacturers
meet additional requirements not mandated by the regulation, but has modified the
section to clarify its intent by stating that the regulation establishes the "basic"
requirements for manufacturing devices. The Quality System regulation provides a
framework of basic requirements for each manufacturer to use in establishing a
quality system appropriate to the devices manufactured and manufacturing
processes employed. Manufacturers must adopt current and effective methods and
procedures specific to each device they manufacture to comply with and implement
the basic requirements. The regulation provides the flexibility necessary to allow
manufacturers to adopt advances in technology, as well as new manufacturing and
quality system procedures as they become available.
During inspections, FDA will examine such procedures to assess whether a
manufacturer has established procedures and followed requirements that
are appropriate to a given device under the current state-of-the-art
manufacturing for that specific device. FDA investigators receive extensive
training to ensure uniform interpretation and application of the regulation
to the medical device industry. Thus, the agency does not believe that
FDA inspectors will cite deviations from requirements not contained in this
part. However, as noted above, FDA has altered the language of the scope
to make clear that additional, unstated requirements do not exist.
3
A few comments suggested eliminating the distinction between critical and
noncritical devices, thus eliminating the need for requirements distinct to critical
devices. Other comments disagreed, asserting that eliminating the distinction
would increase the cost of production without improving the safety and
20 − 7
effectiveness of low risk devices.
FDA agrees in part with the comments that suggest eliminating the distinction
between critical and noncritical devices and has eliminated the term "critical
device" from the scope, definitions, and regulation in sections 820.65, "Critical
devices, traceability" and 820.165, "Critical devices, labeling." However, FDA has
retained the concept of distinguishing between devices for the proposed
traceability requirements in section 820.65. As addressed in the discussion under
that section, FDA believes that it is imperative that manufacturers be able to trace,
by control number, any device where such requirements are necessary to assure the
protection of the public health.
The deletion of the terminology will bring the regulation in closer harmony with
International Organization for Standards (ISO) 9001:1994 "Quality Systems Model for Quality Assurance in Design, Development, Production, Installation,
and Servicing" and the quality systems standards or requirements of other
countries.
Finally, FDA notes that eliminating the term "critical device" and the list of critical
devices does not result in the imposition of many more requirements that are not
already being followed by a majority of the medical device industry.
4
Several comments recommended that the short list of Class I devices subject to
design control requirements be deleted from the regulation and be placed in the
preamble, to allow additions or deletions without requiring a change to the entire
regulation.
FDA disagrees that the list of devices subject to design control requirements
should be deleted from the regulation.
Placing the list in the regulation establishes the requirements related to those
devices, and is convenient for use by persons not familiar with, or who do not have
access to, the preamble. Further, FDA notes that individual sections of a
regulation may be revised independent of the remainder of the regulation. If the
list is revised, FDA will notify each known manufacturer by letter that FDA has
determined that the design control requirements apply, or no longer apply, to a
device.
5
Many comments stated that application of the regulation to component
manufacturers would increase product cost, with questionable value added to
device safety and effectiveness, and that many component suppliers would refuse
to supply components or services to the medical device industry. This would be
especially likely to occur, it was suggested, where medical device manufacturers
account for a small fraction of the supplier's sales.
FDA believes that because of the complexity of many components used in medical
devices, their adequacy cannot always be assured through inspection and test at the
finished device manufacturer. This is especially true of software and software
related components, such as microprocessors and microcircuits. Quality must be
designed and built into components through the application of proper quality
systems.
Further, FDA has encountered manufacturers who have conducted little or
no incoming tests or inspections on "critical" components and
subassemblies because they were produced at their "sister facility." These
manufacturers also attempted to preclude FDA from conducting CGMP
inspections, claiming that the subsidiaries were component manufacturers
and that FDA could only inspect the final assembly aspect.
However, FDA notes that the Quality System regulation now explicitly
requires that the finished device manufacturer assess the capability of
suppliers, contractors, and consultants to provide quality products pursuant
to section 820.50, "Purchasing controls." These requirements supplement
20 − 8
the acceptance requirements under section 820.80. Manufacturers must
comply with both sections for any incoming component or subassembly, or
service received, regardless of the finished device manufacturer's financial
or business affiliation with the person providing such products or services.
FDA believes that these purchasing controls will provide additional
assurance that suppliers, contractors, and consultants have adequate
controls to produce acceptable components.
Therefore, balancing the concerns of the medical device industry and the
agency's public health and safety concerns, FDA has decided to retain the
provision making the CGMP regulation applicable to those component
manufacturers who manufacture components specifically for use in a
medical device, but state its intention not to regularly inspect such
manufacturers. The agency will inspect component manufacturers only in
rare instances, where it determines that such inspection is necessary to
assure the safety and effectiveness of the device.
Instead, FDA will continue to focus its inspections on the finished device
manufacturer, and expects that such manufacturer will properly ensure that
the components it purchases are safe and effective. In this regard, the
agency emphasizes that test and inspect methods may not be sufficient to
assure acceptability for certain components, and the finished device
manufacturer may be required to ensure that its suppliers are in fact
complying with relevant CGMP provisions. FDA is also putting finished
device manufacturers on notice that the failure to comply with both
sections 820.50 and 820.80 will result in enforcement action.
6
One comment stated that the proposed section 820.1(a)(2) should be revised to
include the District of Columbia and the Commonwealth of Puerto Rico, as written
in the current regulation.
FDA agrees with the comment. These localities were inadvertently omitted and
have been added to the regulation.
7
Some comments on proposed section 820.1(c) recommended that the section be
deleted as it already appears in the act and does not allow for minor deviations
from the regulation. Others stated that the provision implies that FDA will subject
devices or persons to legal action, regardless of the level of noncompliance. Still
others suggested that only intentional violations of the regulation should give rise
to regulatory action.
FDA disagrees with all of these comments. The consequences of the failure to
comply, and the legal authority under which regulatory action may be taken,
should be written in any regulation so that the public may be fully apprised of the
possible results of noncompliance, and understand the importance of compliance.
FDA notes that the agency exercises discretion when deciding whether to pursue a
regulatory action and does not take enforcement action for every violation it
encounters. Further, FDA generally provides manufacturers with warning prior to
initiating regulatory action, and encourages voluntary compliance. The agency
also notes, however, that violations of this regulation need not be intentional to
place the public at serious risk, or for FDA to take regulatory action for such
violations.
In response to the concerns regarding the tone of the section, however, the title
has been renamed and the proposed section amended to explicitly state the legal
authority under which the regulation is promulgated, as well as the legal authority
related to noncompliances.
FDA has also deleted the specific provisions described in the section with which
the failure to comply would render the devices adulterated. The term "part"
includes all of the regulation's requirements.
20 − 9
8
A few comments on proposed section 820.1(c)(2) requested that the agency clarify
what FDA meant by requiring that foreign manufacturers "schedule" an inspection.
Others stated that the proposed language would prohibit global harmonization
because it would limit third party audits in place of FDA inspections.
FDA has moved the provision related to foreign manufacturers into a separate
section and has modified the language. The agency believes that it is imperative
that foreign facilities be inspected for compliance with this regulation and that they
be held to the same high standards to which U.S. manufacturers are held.
Otherwise, the U.S. public will not be sufficiently protected from potentially
dangerous devices and the U.S. medical device industry will be at competitive
disadvantage.
FDA intends to schedule inspections of foreign manufacturers in advance to ensure
availability due to varying holidays and shut down periods. However, the language
pertaining to the "scheduling" of such inspection is deleted to allow flexibility in
scheduling methods.
FDA disagrees that, as written, the language would prohibit inspections by third
parties. FDA may use third party inspections, as it uses other compliance
information, in setting its priorities and utilizing its resources related to foreign
inspections. In this regard, FDA looks forward to entering into agreements with
foreign countries related to CGMP inspections, where appropriate, that would
provide FDA with reliable inspectional information.
9
Two comments stated that the section on "Exemptions and variances," now
section 820.1(e), should require that FDA provide a decision on petitions within
sixty (60) days of receipt and state that the agency will take no enforcement action
with respect to the subject of the petition until a decision is rendered. The
comments said that the petition process is long and arduous, and not practical.
FDA disagrees with the comments. Currently, FDA is required by section
520(f)(2)(B) of the act (21 U.S.C. 360j(f)(2)(B)) to respond within 60 days of
receipt of the petition. When the 1978 CGMP regulation was published, there was
a prediction that FDA would be overwhelmed with petitions for exemption and
variance from the regulation. Over the past fifteen (15) years, since the CGMP
regulation first became effective, FDA has only received approximately 75
petitions. It is FDA's opinion that few petitions have been received because of the
flexible nature of the language of the CGMP regulation. FDA has attempted to
write the current regulation with at least the same degree of flexibility, if not more,
to allow manufacturers to design a quality system that is appropriate for their
device and operations that is not overly burdensome.
Guidelines for the submission of petitions for exemption or variance are available
from the Division of Small Manufacturers Assistance. The petition guidelines state
that FDA will not process a petition for exemption or variance while an FDA
inspection of a manufacturer is ongoing. Until FDA has approved a petition for an
exemption or variance, a manufacturer should not deviate from the requirements of
this regulation. FDA must first have the opportunity to ensure that the
manufacturer has established that an exemption or variance is warranted, to carry
out its obligation of ensuring that devices are safe and effective.
10 Several comments stated that the proposed requirements were not necessary for all
manufacturers, particularly small manufacturers with few employees and low risk
devices. Other comments stated that the documentation requirements were
excessive.
FDA generally disagrees with these comments. The provisions of the regulation
are considered to be the "basic" requirements for the design and manufacture of
medical devices. And, as noted in the previous response, the requirements are
written in general terms to allow manufacturers and designers to establish
procedures appropriate for their device and operations. Because the regulation
requirements are basic, they will apply in total to most manufacturers subject to the
20 − 10
regulation. However, the extent of the documentation necessary to meet the
regulation requirements may vary with the complexity of the design and
manufacturing operations, the size of the firm, the importance of a process, and the
risk associated with the failure of the device, among other factors. Small
manufacturers may design acceptable quality systems that require a minimum of
documentation and, where possible, automate documentation. In many situations,
documentation may be kept at a minimum by combining many of the
recordkeeping requirements of the regulation, for example, the production SOPs,
handling, and storage procedures.
When manufacturers or designers believe that the requirements are not
necessary for their operation, they may petition for an exemption or
variance from all or part of the regulation pursuant to section 520(f)(2) of
the act. In addition, FDA has added a similar variance provision in section
820.1(e)(2) which the agency can initiate where it determines that such
variance is in the best interest of the public health. Under this provision,
for instance, the agency may initiate and grant a variance to manufacturers
of devices during times of product shortages, where the devices are needed
by the public and may not otherwise be made available, where such
manufacturers can adequately assure that the manufacture of the devices is
likely to result in a safe and effective device.
The agency envisions this provision as a bridge, providing a manufacturer
the time necessary to allow it to fulfill the explicit requirements in the
regulation while providing an important and needed device to the public.
Thus, the variance would only be provided for a short period of time, and
then only when the device remained necessary and in short supply. Under
this provision, FDA will require a manufacturer to submit a plan detailing
the action it is taking to assure the safety and effectiveness of the devices it
manufactures and to meet the requirements of the regulation.
This agency initiated variance provision is in accordance with section
520(f) of the act (21 U.S.C. 360j(f)) which permits, but does not require,
FDA to promulgate regulations governing the good manufacturing
practices for devices and section 701(a) (21 U.S.C. 371(a)), which permits
FDA to promulgate regulations for the efficient enforcement of the act.
Because the statute does not mandate that the agency establish any
requirements for device GMP, the agency has the authority to determine
that the manufacturers of certain devices need not follow every
requirement of the regulation.
Further, the agency initiated variance provision is in keeping with the intent
of Congress that FDA prevent hazardous devices from reaching the
marketplace, H.R. Rep. No. 853, 94th Cong., 2d Sess. 25-26 (1976), and
the general intent of the act that the agency undertake to protect the public
health, in that the agency will only initiate such a variance where the
devices are needed and may not otherwise be made available and the
manufacturer can assure the agency that its procedures are likely to be
adequate and that it is actively pursuing full compliance, and the variance
will only be in effect for a limited time.
Proposed section 820.1(e) has been modified to include the above addition, to
reflect the title change of the regulation, and to provide the most current address
for the Division of Small Manufacturers Assistance.
ii. Definitions
1 Several comments were received regarding the definition of "complaint."
Commentors generally believed that the definition was unclear and could be
interpreted to include routine service requests, communications from customers
unrelated to the quality, safety, or effectiveness of the device, and internal
communications.
20 − 11
FDA agrees with the comments in part and has modified the definition to make
clear that communication from any of the sources mentioned in the comments
would be considered a "complaint," but only if the communication alleged some
deficiency related to the identity, quality, durability, reliability, safety,
effectiveness, or performance of the device. The definition is now very similar to
the definition used in the ISO working draft revision of ISO/DIS 13485 "Quality
Systems - Medical Devices - Supplementary Requirements to ISO 9001."
The regulation addresses service requests and in-house indications of
dissatisfaction under section 820.100, "Corrective and preventive action." This
section requires manufacturers to establish procedures to identify quality problems
and process the information received to detect and correct quality problems.
Information generated in-house relating to quality problems should be documented
and processed as part of this corrective and preventative action program as well.
With respect to service requests, section 820.200, "Servicing" states that
any service report relating to or concerning a death, injury, or hazard to
safety shall be considered a complaint and processed in accordance with
section 820.198, "Complaint files." All other service reports must be
analyzed for trends or systemic problems and when found, these trends or
systemic problems must be investigated according to the provisions of
section 820.100, "Corrective and preventive action."
2
One comment suggested that the agency delete the phrase, "used during device
manufacturing" in the definition of "component" because it was confusing and may
cause problems with certain aspects of distributor operations.
FDA agrees and has deleted the words "used during device manufacturing" from
the definition since it was not intended to differentiate between distributors and
manufacturers.
3
Several comments stated that the term "complete history" in the definition of
"control number" should be clarified or deleted in that it was unclear what a
complete production history was, and the term could be construed to require full
traceability for all component lots of any product containing a control number.
FDA disagrees. The control number is the means by which the history of the
device, from purchase of components and materials through distribution, may be
traced, where traceability is required. The definition does not require that a
manufacturer be able to trace the device whenever control numbers are used. In
fact, the definition itself does not establish any requirements. The agency notes,
however, that the manufacturer's traceability procedures should ensure that a
complete history of the device, including environmental conditions which could
cause the device to fail to conform to its specified requirements, can be traced and
should facilitate both investigation of quality problems and corrective action. FDA
also notes that the term "complete history" is contained in the current definition of
"control number," which has been part of the CGMP regulation for the past 15
years. The agency is not aware of any misinterpretation of the definition.
Therefore, FDA has retained the term "complete history" in the definition.
FDA has, however, amended the definition for added flexibility, to state that
symbols may be used, and has included the term "unit" for any device that is not
manufactured as a lot or batch.
4
The definition of "critical device" has been deleted for the reasons discussed above.
5
Several comments stated that the term "design history record" should be changed
because the acronym for the term was the same as that for device history record.
Other comments said the "design history record" should not need to contain
documentation of a "complete" design history. One comment stated that the
definition should allow reference to records containing the design history of the
device. A few comments stated that the term should be deleted altogether because
20 − 12
it was redundant with the definition of device master record (DMR).
FDA agrees in part with these comments and has changed the term "design history
record" to "design history file." In addition FDA has amended the provisions to
require that the file describe the complete design history, as it may not be
necessary to maintain a record of every step in the design phase, although the
whole history should be apparent from the document. In addition, sufficient
records must be maintained, or referenced in the file, to verify that the design was
developed in accordance with the design and development plan and other
applicable design requirements of the regulation.
FDA does not agree that the definition of the design history file and DMR are
redundant. The design history file should include, for example, the design and
development plan, design review results, and design validation and verification
results, as well as any other data necessary to establish compliance with the design
requirements. The DMR contains all of the procedures related to a specific device
established as required by this part and the most current manufacturing
specifications of the device, once the design specifications have been transferred
into production.
6
Two comments stated that the definition of "design output" should be revised
because it should not be necessary, and would be burdensome, to keep records of
and review the "results of a design effort at each design phase and at the end."
Other comments suggested that the design output definition should be restricted to
physical characteristics of the device.
FDA agrees in part, but has not deleted the phrase "results of a design effort at
each design phase and at the end" from the definition. The intent was not to
dictate when design phases would occur. Such phases will be defined in the design
and development plan. For example, a manufacturer may only have one design
phase for a new type of syringe. Thus, design output would constitute the results
of that one effort. The results of each design phase constitute the total design
output. The definition has been amended, however, to clarify that the final design
output becomes the basis for the device DMR and is not merely a duplication of
records.
FDA disagrees with the comments that suggest that the design output should be
restricted to physical characteristics of the device. Design output is more than just
the device specifications, but includes, among other things, the specifications for
the manufacturing process, the quality assurance testing, and the device packaging
and labeling. It is important to note that the design effort should not only control
the design aspects of the device itself, but everything about the device from the
initial determination to develop the design, through manufacturing and distribution,
until the end of life of the device.
7
A few comments received on the definition of "design review" stated that
proposing solutions to problems was not the role of the design review activity.
Two other comments expressed concern that the definition would require that each
design review be "comprehensive."
In response to the comments on the proper role of design review, FDA agrees that
the design review function is typically not responsible for establishing solutions,
although it may do so in many small operations. The definition has been amended
to make clear that the design review need not propose actual solutions, but should
propose that solutions to any problems discovered be developed.
Regarding the scope of each design review, each design review need not be
"comprehensive" for the entire design process but must be "comprehensive" for the
design phase being reviewed. However, at the end of the design process when the
design is transferred to production, all aspects of the design process should have
been reviewed.
20 − 13
A few other changes were made to harmonize with the definition in ISO
8402:1994 "Quality - Vocabulary."
8
Comments on the definition of "device master record" pointed out that the
definition is not consistent with the requirements of section 820.181, "Device
master record." Other comments stated that the definition should allow the
reference to records at some location.
FDA agrees with the comments that found the DMR definition and requirements
to be inconsistent and has amended the definition to be consistent with the
requirements set forth in section 820.181. FDA does not believe, however, that it
is necessary to modify the definition to include the referencing of records because
the DMR requirements in section 820.181 state that the DMR "shall include or
refer to the location of" the required information.
9
The definition for the term "end-of-life" was added because this term is used in the
definitions for "refurbisher" and "servicing" to help distinguish the activities of
refurbishing from those of servicing. FDA determined that such a distinction was
necessary, due to comments and ongoing confusion regarding the difference
between the two functions, and the different requirements applicable to the
functions.
FDA was unable to find an adequate definition of servicing and refurbishing
in any national or international standards documents that adequately
differentiated between the two. Therefore, in an effort to distinguish what
is considered to be repairable or serviceable, from what is considered to be
nonrepairable or requiring refurbishing, FDA has used the term "end-of-life," in both the
servicer and refurbisher definitions. Prior to the end-of-life, repair or maintenance is servicing. At
the end of life, the device is
rebuilt by a refurbisher. When a person refurbishes a device, he becomes
the "original device manufacturer" for the refurbished device.
10 The few comments received on the definition of "establish" indicated a concern
that the regulation would require too much documentation and be more onerous
than ISO 9001 requirements.
FDA disagrees. The term is only used where documentation is necessary. FDA
also notes that the quality system regulation is premised on the theory that
adequate written procedures, which are implemented appropriately, will likely
ensure the safety and effectiveness of the device. ISO 9001:1994 relies on the
same premise. The 1994 version of ISO 9001 broadly requires the manufacturer
to "establish, document, and maintain a quality system," which includes
documenting procedures for meeting the requirements.
The definition has been amended, however, in response to general comments
received, to clarify that a "document" may be written or electronic, allowing
flexibility for any type of recorded media.
11 FDA received comments questioning the addition of the wording that a "finished
device" includes a device that is intended to be sterile, but that is not yet sterile.
FDA disagrees with the comments, but has amended the definition to clarify its
position. Since the 1978 CGMP regulation was promulgated, FDA has been
questioned repeatedly regarding whether devices intended to be sold as sterile are
considered subject to the CGMP requirements, even though they have not yet been
sterilized. The agency had intended the new definition to make explicit the
application of the regulation to the manufacture of sterile devices that have yet to
be sterilized. Although FDA believes it should be obvious that such devices are
subject to CGMP requirements, some manufacturers have taken the position that
the regulation does not apply because the device is not "finished" or "suitable for
use" until it has been sterilized.
20 − 14
To better clarify its intent, FDA has amended to definition to add that all
devices that are capable of functioning, including those devices that could
be used even though they are not yet in their final form, are "finished
devices." Thus, devices that are intended to be sterilized, polished,
inspected and tested, or packaged or labeled by a purchaser/manufacturer,
among other activities, are finished devices prior to the completion of such
activity.
The distinction between "components" and "finished devices" was not
intended to permit manufacturers to manufacture devices without
complying with CGMP requirements by claiming that other functions, such
as sterilization, incoming inspection (where sold for subsequent minor
polishing, sterilization, or packaging), or insertion of software, will take
place. The public would not be adequately protected were this the case, as
any manufacturer could claim that a device was not a "finished" device
subject to the CGMP regulation because it was not in its "final" form.
This problem should be lessened with the application of the regulation to
components manufactured specifically for use as part of a medical device.
The term "for commercial distribution" was deleted from the definition of "finished
device" because it is not necessary for a device to be in commercial distribution to
be considered a finished device.
12 Two comments on the definition of "lot or batch" requested that the definition be
clarified: one to reflect that single units may be produced for distribution, the other
to indicate that what constitutes a lot or a batch may vary depending on the
context.
In response to the comments, FDA has modified the definition to make clear that a
lot or batch may, depending on circumstances, be comprised of one component or
finished device. Whether for inspection, or distribution, a lot or batch is
determined by the factors set forth in the definition; of course, a manufacturer may
determine the size of the lot or batch, as appropriate.
13 Several comments received on the definition of "executive management" objected
that the definition is inconsistent with ISO 9001. Others thought that FDA should
better define the level of management the term was intended to define.
FDA agrees with both concerns and has modified the definition by deleting the
second half, which appeared to bring executive authority and responsibility too far
down the organization chart. The term was intended to apply only to management
that has the authority to bring about change in the quality system and the
management of the quality system. Although such management would clearly have
authority over, for example, distribution, those who may have delegated
management authority over distribution would not necessarily have authority over
the quality system and quality policy. Accordingly, the definition has been
modified to include only those who have the authority and responsibility to
establish and make changes to the quality policy and quality system. It is the
responsibility of top management to establish and communicate the quality policy,
as defined in section 820.3(v), "quality policy," regardless of whether specific
functions are delegated. In addition, the term "executive management" has been
changed to "management with executive responsibility," to harmonize with ISO
9001:1994.
14 Several comments in response to the proposed definition of "manufacturer" stated
that refurbishers and servicers should be added to the definition of a
"manufacturer." Other comments requested deletion of contract sterilizers,
specification developers, repackagers, relabelers, and initial distributors from the
definition.
FDA agrees with the comments that refurbishers and servicers should be included
in the definition of a "manufacturer" to be consistent with the intent and
20 − 15
requirements of the Quality System regulation, since refurbishers and servicers may
have a significant impact on the safety and effectiveness of medical devices.
Further, such persons are in fact manufacturing and/or processing medical devices.
FDA's Compliance Policy Guide, CPG 7124.28, contains the agency's
current policy regarding the provisions of the act and regulations with
which persons who recondition or rebuild used devices are expected to
comply. This CPG is in the process of being revised in light of FDA's
current thinking. All persons who are refurbishers will now be expected to
comply with the applicable Quality System regulation requirements. A
definition of "refurbisher" has been added in section 820.3(y).
Servicers will be required to follow the requirements set forth in section
820.200 on "Servicing."
FDA disagrees with the comments that contract sterilizers, specification
developers, repackagers, relabelers, and initial distributors should be deleted from
the definition, primarily because all such persons may have a significant effect on
the safety and effectiveness of a device and on the public health. All of these
persons must be inspected to ensure that they are complying with the applicable
provisions. For example, initial distributors are required to maintain complaint
files under the Medical Device Reporting (MDR) regulation, and also may service,
or otherwise manufacture, devices they distribute. Similarly, a specification
developer initiates the design requirements for a device that is manufactured by a
second party for subsequent commercial distribution. Such developer is subject to
design controls.
15 One comment stated that the phrase "processes a finished device" should be
explained in the definition of manufacturer.
The phrase "processes a finished device" applies to a finished device after
distribution. Processing a device includes, among other things, repairing,
servicing, and reconditioning the device. Again, this phrase has been part of the
CGMP regulation definition for 15 years.
16 A number of comments on the definition of "manufacturing material," and on other
parts of the proposal containing requirements for "manufacturing material," stated
that while the control of manufacturing material is important, it need not be as
extensive as required throughout the regulation.
FDA agrees that, depending on the manufacturing material and the device, the
degree of control necessary will vary. FDA believes that manufacturing materials
must be assessed, found acceptable for use, and controlled. Therefore, the
regulation requires manufacturers to assess, assure acceptability of, and control
manufacturing materials to the degree necessary to meet the specified
requirements. The agency notes that international standards such as ISO
8402:1994 include manufacturing material in their definition of "product," to
which all requirements apply, and notes that FDA has added the same definition in
section 820.3(s) in its effort toward harmonization.
17 Other comments stated that the meaning of the phrase "or other byproducts of the
manufacturing process" is unclear, and should be deleted.
The term "or other byproducts of the manufacturing process" means those
materials or substances that naturally occur as a part of the manufacturing process
which are intended to be removed or reduced in the finished device. For example,
some components, such as natural rubber latex, contain allergenic proteins that
should be reduced or removed. The definition has been modified to include
"naturally occurring substances" to clarify the intent. Further, in a response to a
comment, "ethylene oxide" was removed as a specific example of "sterilant
residues," as it is unnecessary.
20 − 16
18 The comments received on the definition for "nonconforming" conveyed a general
sense that the definition was confusing, with various comments suggesting that
different parts of the definition be should deleted and one suggesting that the
definition be deleted altogether.
In response to these comments, the definition of "nonconforming" has been
deleted. However, the definition from ISO 8402:1994 for "nonconformity" was
added to ensure that the requirements in the regulation, especially those in sections
820.90, "Nonconforming product" and 820.100, "Corrective and preventive
action," are understood. FDA emphasizes that a "nonconformity" may not always
rise to the level of a product defect or failure, but a product defect or failure will
always constitute a nonconformity.
19 Several comments requested various revisions to the definition of "production" to
make it more clear and one thought that it was a common term and should be
deleted.
In response, FDA has deleted the definition for "production" because it should be
commonly understood.
As noted in response to comments on the definition of manufacturing material,
FDA has added a definition of "product," to conform to the definition in ISO
8402:1994 and to avoid the necessity of repeating the individual terms throughout
the regulation. Whenever a requirement is not applicable to any one type of
product, the regulation specifically states the product(s) to which the requirement
is applicable.
20 A few comments stated that the definition of "quality" should be changed to be
identical to ISO 8402. Others stated that the terminology adopted from ISO 8402,
"that bears on," is too broad and could cover every potential and imaginable factor.
Still others wanted to add the phrase, "as defined by the manufacturer" to the end
of the sentence.
FDA disagrees with the comments and believes that the definition is closely
harmonized to that in ISO 8402. FDA believes that the definition appropriately
defines quality in the context of a medical device, and does not believe that the
phrase from ISO 8402, "stated and implied needs," has a different meaning than
the phrase "fitness for use, including safety and performance" in the context of the
Quality System regulation. Further, "quality" is not just those aspects "defined by
the manufacturer," but is also those defined by customer need and expectation.
21 Many comments received on the "quality audit" definition suggested that the
definition should not state that it is an examination of the "entire" quality system
because that would require that every audit include the "entire" quality system.
FDA agrees that while the quality audit is an audit of the "entire" quality system,
audits may be conducted in phases, with some areas requiring more frequent audits
than other areas, and that each audit need not review the whole system. Internal
quality audits should be scheduled consistent with, among other things, the
importance of the activity, the difficulty of the activity to perform, and the
problems found. Audits must include a review and evaluation of all parts of a
quality system, including its procedures, records, and processes, among other
things. To avoid any misunderstanding, the word "entire" before quality system
has been deleted.
FDA emphasizes that if applied properly, internal quality audits can prevent
major problems from developing and provide a foundation for the
management review required by section 820.20(c), "Management review."
22 Other comments on "quality audit" stated that it is unclear what is meant by the
last sentence of the definition, namely, that "'[q]uality audit' is different
from...other quality system activities required by or under this part."
20 − 17
In response, FDA has deleted the last sentence. The purpose of the sentence was
to clarify that the internal audit requirement is different from, and in addition to,
the requirements for establishing quality assurance procedures and recording
results. On occasion, manufacturers have attempted to prevent FDA investigators
from reviewing such quality assurance procedures and results (for example, trend
analysis results) by stating that they are part of the internal quality audit report and
not subject to review during a GMP inspection. FDA disagrees with this position.
To clarify which records are exempt from routine FDA inspection, FDA has added
section 820.180(c).
23 One comment said that the word "executive" should be deleted from the definition
of "quality policy" because quality policy should be supported by all personnel, not
just those in executive management.
FDA agrees that all company personnel must follow the quality policy, however,
the definition is intended to make clear that the quality policy must be established
by top management and has therefore been retained. The term "executive
management" has been modified to "management with executive responsibility" to
be consistent with the revised ISO 9001:1994.
24 A few comments suggested using the definition of "quality systems" from ISO
8402 and 9001. Other comments on the definition of "quality system" said that the
term "quality management" should be defined.
FDA agrees in part with the comments. The term "specifications" has been deleted
to harmonize the definition with ISO 8402:1994. FDA does not agree that the
term "quality management" must be defined. A definition can be found in ISO
8402:1994 that is consistent with FDA's use of the term.
25 Several comments on the definition of "record" were received. Some thought the
term was too broad, giving FDA access to all documents and exceeding FDA's
inspection authority. Another comment requested clarification on what an
"automated document" was compared to an "electronic document."
FDA has modified the term "automated" in the definition in favor of the term
"electronic," to be consistent with the current terminology. FDA disagrees with
the other comments. The definition is intended to clarify that "records" may
include more than the traditional hardcopy procedures and SOPs, for example,
plans and notes. The definition is not intended to, and does not, subject a
manufacturer's records to FDA inspection where such records are unrelated to the
requirements of the regulation.
26 Several comments on the definition of "reprocessing" requested clarification
between that term and "refurbishing." Several other comments on the definition of
"reprocessing" stated that FDA should clarify that "reprocessing" was an activity
performed before a device is distributed.
In response, FDA has revised the definition of "reprocessing" to specify that
reprocessing is action taken before distribution. FDA has also added a definition
for "refurbisher." The definition proposed is similar to the definition from the
working draft revision of ISO/DIS 13485 "Quality Systems - Medical Devices Supplementary Requirements to ISO 9001." "Refurbishing" is action taken on a
device "which has been previously distributed and has reached its established end-of-life or
is considered to be nonrepairable," irrespective of whether the person
performing the activity takes ownership of the device or the device is resold.
Refurbishers are manufacturers.
27 A few comments stated that including the term "maintenance" in the definition of
"servicing" implies that preventative maintenance would be subject to the
regulation. Other comments said that it may not be desirable to return old devices
or devices that have received field modifications to the original specifications.
Therefore, the comments suggested deleting the last part of the definition that
20 − 18
states that "servicing" is returning a device to its specifications.
FDA meant for maintenance to be covered by the definition and has included the
term "maintenance" in the servicing definition to make that clear. "Maintenance" is
subject to the requirements in section 820.200, "Servicing." In response to the
comments regarding old or modified devices, FDA has modified the definition to
say that servicing is performed "after distribution for the purposes of returning it to
its safety and performance specifications so it will meet its original intended use,
prior to the device's established end-of-life." Servicing may take place on a
refurbished device as well.
28 Several comments were received on the definition of "special process," many
asking for clarification or adoption of the ISO definition, some stating that it is
impossible to 100 percent verify any process.
FDA has deleted the definition because the term "special process" is no longer
used in ISO 9001:1994, except in a note. FDA has, however, modified the
requirements of the regulation to reflect that, in many cases, testing and inspecting
alone may be insufficient to prove the adequacy of a process. One of the principles
on which the Quality Systems regulation is established is that all processes require
some degree of qualification, verification, or validation, and manufacturers should
not rely solely on inspection and testing to ensure processes are adequate for their
intended use.
29 Several comments on the definition of "specification" suggested that the term
should not apply to quality system requirements. One comment noted that the
definition in ISO 9001 pertains to requirements, not only documents.
In response, FDA has amended the definition to make clear that it applies to the
requirements for a product, process, service, or other activity. The reference to
the quality system has been deleted. FDA notes, however, that ISO 9001 does not
contain a definition for "specification," but uses the definition in ISO 8402.
30 Many comments were received on the definitions of "validation" and "verification."
Almost all stated that the two definitions overlapped and that there was a need to
rewrite the definitions to prevent confusion.
FDA agrees with the comments and has rewritten the two definitions to better
reflect the agency's intent. "Validation" is intended to be a process undertaken to
establish that the manufacturer's processes will consistently produce a desired
result or a product which meets its predetermined specification. The revised
definition follows from FDA's "Guideline on General Principles of Process
Validation" and is consistent with the definition contained in ISO 8402:1994. The
requirements for design validation are contained in section 820.30, "Design
controls."
The definition of "verification" now more closely parallels the definition in
ISO 8402:1994. "Verification" is not related to determining whether future
requirements will be met, but whether requirements for a particular device
or activity at hand have been met.
iii. Quality system
1 Several comments suggested that the requirement should be more general, in that
the more specific requirement that devices be safe and effective is covered
elsewhere in the regulation. The comments recommended that the quality system
requirements be harmonized with international standards and focus on requiring
that a system be established that is appropriate to the specific device and that
meets the requirements of the regulation.
FDA agrees in part with the comments and has modified the language as generally
suggested by several comments to require that the quality system be "appropriate
to the specific medical device manufactured and meet the requirements of this
20 − 19
part." This is the requirement of the current device CGMP regulation; however,
the Quality System regulation now includes requirements related to design,
purchasing, and servicing controls. As proposed, the provision was redundant
with section 820.1, which states that the intent of the Quality System regulation is
to ensure that finished devices will be safe and effective.
The specific requirements that effective quality system instructions and procedures
be established and effectively maintained are retained, however. As previously
noted, the quality system regulation is premised on the theory that the
development, implementation, and maintenance of procedures designed to carry
out the specific requirements will ensure the safety and effectiveness of devices.
Thus, the broad requirements in section 820.5 are in a sense the foundation on
which the specific requirements are built. Therefore, although several comments
suggested that the sections 820.5(a) and (b) should be deleted because other
sections of the regulation contain a specific requirement for procedures, FDA has
retained the requirements.
2
In addition, although comments stated that the terms "effective" and "effectively"
should be defined, FDA does not believe that the terms require a definition.
Instructions and procedures must be defined, documented, implemented, and
maintained in such a way that the requirements of this part are met. If they are,
they will be "effective."
<A NAME="pSubpart B">B. Quality System Requirements (Subpart B)</A>
i. Management responsibility
1 Several comments on section 820.20(a), "Quality policy," related to the use of the
term "executive management." A few comments stated that quality system
development and implementation is the responsibility of the chief executive officer,
but how he or she chooses to discharge the responsibility should be left to the
discretion of the manufacturer. Other comments stated that the requirement that
executive management ensure that the quality policy is understood is impossible
and should be deleted or rewritten.
FDA agrees in part with the comments. In response to the comments, FDA has
deleted the term "executive management" and replaced it with "management with
executive responsibility," which is consistent with ISO 9001:1994. Management
with executive responsibility is that level of management that has the authority to
establish and make changes to the company quality policy. The establishment of
quality objectives, the translation of such objectives into actual methods and
procedures, and the implementation of the quality system may be delegated. The
regulation does not prohibit the delegation. However, it is the responsibility of the
highest level of management to establish the quality policy and to ensure that it is
followed.
For this reason, FDA disagrees that the requirement that management ensure that
the quality policy is understood should be deleted. It is without question
management's responsibility to undertake appropriate actions to ensure that
employees understand management's policies and objectives. Understanding is a
learning process achieved through training and reinforcement. Management
reinforces understanding of policies and objectives by demonstrating a
commitment to the quality system, visibly and actively on a continuous basis. Such
commitment can be demonstrated by providing adequate resources and training to
support quality system development and implementation. In the interest of
harmonization, the regulation has been amended to be very similar to ISO
9001:1994.
2
Two comments stated that the words "adequate" and "sufficient" should be deleted
from section 820.20(b), "Organization," as they are subjective and too difficult to
define. One comment thought that the general requirements in the subsections are
addressed by section 820.25, "Personnel."
FDA agrees that the requirement for "sufficient personnel" is covered in sections
20 − 20
820.20(b)(2), "Resources" and 820.25, "Personnel," both of which require each
manufacturer to employ sufficient personnel with the training and experience
necessary to carry out their assigned activities properly. The phrase is therefore
deleted. However, FDA has retained the requirement for establishing an "adequate
organizational structure" to ensure compliance with the regulation because such an
organizational structure is fundamental to a manufacturer's ability to produce safe
and effective devices. Further, the agency does not believe that the term is
ambiguous. The organizational structure established will be determined in part by
the type of device produced, the manufacturer's organizational goals, and the
expectations and needs of customers. What may be an "adequate" organizational
structure for manufacturing a relatively simple device, may not be "adequate" for
the production of defibrillators.
3
A number of comments on section 820.20(b)(1), "Responsibility and authority,"
subsections (i) through (v), objected to the section, stating that it was too detailed
and confusing, and that the wording was redundant with other sections of the
proposal.
FDA agrees generally with the comments in that the subsections merely set forth
examples of situations in which independence and authority are important, but the
broad requirement is for the necessary independence and authority to be provided
as appropriate to every function affecting quality. Therefore, the examples
provided in (i) through (v) are deleted. FDA emphasizes that it is crucial to the
success of the quality system for the manufacturer to ensure that responsibility,
authority, and organizational freedom (or independence) is provided to those who
initiate action to prevent nonconformities, identify and document quality problems,
initiate, recommend, provide, and verify solutions to quality problems, and direct
or control further processing, delivery, or installation of nonconforming product.
4
Several comments on section 820.20(b)(2), "Verification resources and personnel"
stated that requiring "adequately" trained personnel was subjective and interpretive
and that the section was not consistent with ISO 9001.
FDA agrees that the section is not consistent with ISO 9001, and has adopted the
language used in ISO 9001:1994, section 4.1.2.2, "Resources." The provision is
now more appropriately a broad requirement that the manufacturer provide
adequate resources for the quality system, and is not restricted to the verification
function. FDA acknowledges that section 820.25(a), "Personnel" requires that
sufficiently trained personnel be employed. However, this section on "Resources"
emphasizes that all resource needs must be provided for, including monetary as
well as personnel resources. In contrast, section 820.25(a) addresses specific
education, background, training, and experience requirements for such personnel.
5
Comments on section 820.20(b)(3), "Management representative" stated that the
management representative should not be limited to "executive" management. A
few comments stated that the appointment should be documented.
The agency agrees that the responsibility need not be assigned to "executive"
management and has modified the requirement to allow management with
executive responsibility to appoint a member of management. When a member of
management is appointed to this function, potential conflicts of interest should be
examined to ensure that the effectiveness of the quality system is not
compromised. In addition, in response to many comments, the requirement was
amended to make clear that the appointment of this person must be documented,
moving the requirement up from subsection (ii). The amended language is
consistent with ISO 9001:1994.
6
A few comments stated that the improvement of the quality system is not a specific
requirement under the Food, Drug, and Cosmetic Act and the reference to such
improvement in subsection 820.20(b)(3)(ii) should, therefore, be deleted.
FDA agrees in part with the comments and has deleted the requirement that the
20 − 21
person appointed under this section provide information for improving the quality
system. The provision implied that the manufacturer must go beyond the
requirements of the regulation. FDA notes, however, that information collected in
complying with this section and section 820.100, "Corrective and preventive
action" should be used not only for detecting deficiencies and for subsequent
correction of the deficiencies, but to continuously improve the device and quality
system.
Further, FDA has amended this section to change "executive management" to
"management with executive responsibility" for consistency with the definition.
7
Many comments stated that the report required by section 820.20(c),
"Management review" should not be subject to FDA review, due to the same
liability and self-incrimination concerns related to the internal audit.
FDA agrees in part with the comments. The proposed regulation did not state
FDA's intentions with respect to inspectional review of the results of the required
management review. After careful consideration of the comments, FDA agrees
that it will not request to inspect and copy the reports required by the section when
conducting routine inspections to determine compliance with this part. FDA
believes that refraining from routinely reviewing these records may help ensure
that the audits are complete and candid, and of maximum use to the manufacturer.
FDA may require that management with executive responsibility certify in writing
that the manufacturer has complied with the requirements of section 820.20(c),
however. FDA will review the written procedures required by section 820.20(c),
as well as all other records required under section 820.20.
8
A few comments stated that the management review should not be dictated by
established review procedures because management level employees should be
fully capable of reviewing documents without a written procedure.
As noted above, FDA has retained the requirement for establishing procedures to
conduct the required quality system review in section 820.20(c). FDA believes
that a manufacturer can establish procedures flexible enough for management to
vary the way in which a review is conducted, as appropriate. Procedures should
require that the review be conducted at appropriate intervals and should be
designed to ensure that all parts of the quality system are adequately reviewed. A
manufacturer may, of course, develop procedures that permit review of different
areas at different times, so long as such review is sufficient to carry out the
objectives of this section. If there are known problems, for example, a "sufficient
frequency" may be fairly frequent. Further, since FDA will not be reviewing the
results of such reviews, FDA must be assured that this function will occur in a
consistent manner.
9
A few comments stated that section 820.20(c) should be deleted because it
duplicates the quality audit required by section 820.22.
FDA disagrees that section 820.20(c) duplicates the requirements in section
820.22. The purpose of the management reviews required by section 820.20(c) is
to determine if the manufacturer's quality policy and quality objectives are being
met, and to ensure the continued suitability and effectiveness of the quality system.
An evaluation of the findings of internal and supplier audits should be included in
the section 820.20(c) evaluation. The management review may include a review of
the following: the organizational structure, including the adequacy of staffing and
resources; the achieved quality of the finished device in relation to the quality
objectives; combined information based on purchaser feedback, internal feedback
(such as results of internal audits), process performance, product (including
servicing) performance, among other things; and internal audit results and
corrective and preventive actions taken. Management should also review
periodically the appropriateness of the review frequency, based on the findings of
previous reviews. The quality system review process in section 820.20(c), and the
20 − 22
reasons for the review, should be understood by the organization.
The requirements under section 820.22, "Quality audit" are for an internal audit
and review of the quality system to verify compliance with the Quality System
regulation. The review and evaluations under section 820.22 are very specific.
During the internal quality audit, the manufacturer should review all procedures to
ensure adequacy and compliance with the regulation, and determine whether the
procedures are being effectively implemented at all times. In contrast, as noted
above, the management review under section 820.20(c) is a broader review of the
organization as a whole to ensure that the quality policy is implemented and the
quality objectives are met.
ii. Quality Audit
1 A few comments suggested that FDA delete the requirement that persons
conducting the audit be "appropriately trained" from the second sentence of
820.22(a) because it is subjective and not consistent with ISO 9001.
FDA has deleted the requirement from this section because section 820.25,
"Personnel" requires that such individuals be appropriately trained. Further, FDA
has attempted to better harmonize with ISO 9001, which does not explicitly state
personnel qualifications in each provision. Similarly, in response to general
comments suggesting better harmonization, FDA has added the requirement that
the audit "determine the effectiveness of the quality system," as required by ISO
9001:1994. This requirement underscores that the quality audit must not only
determine whether the manufacturer's requirements are being carried out, but
whether the requirements themselves are adequate.
2
Some comments stated that requiring "individuals who do not have direct
responsibility for the matters being audited" to conduct the audits is impractical
and burdensome, particularly for small manufacturers.
FDA disagrees. Both small and large manufacturers have been subject to the
identical requirement since 1978 and FDA knows of no hardship, on small or large
manufacturers, as a result. A small manufacturer who believes that it can ensure
that the audit will be appropriately conducted without independence may apply for
a variance or an exemption, pursuant to section 820.1(e). However, small
manufacturers must generally establish independence, even if it means hiring
outside auditors, because the failure to have an independent auditor could result in
ineffective audit.
Manufacturers must realize that conducting effective quality audits is
crucial. Without the feedback provided by the quality audit and other
information sources, such as complaints and service records, manufacturers
operate in an open loop system with no assurance that the process used to
design and produce devices is operating in a state of control. ISO
9001:1994 has the same requirement for independence from the activity
being audited.
3
Several comments claimed that the last sentence in section 820.22(a), requiring
that follow-up corrective action be documented in the audit report, made no sense.
The comments said that corrective action would be the subject of a follow-up
report.
It was the agency's intent that the provision require that where corrective action
was necessary, it would be taken and documented in a reaudit report. The
provision has been rewritten to make that clear. The new section should also
clarify that a reaudit is not always required, but where it is indicated, it must be
conducted. The report should verify that such corrective action was implemented
and effective. Because FDA does not review these reports, the date on which the
audit and reaudit was performed must be documented, and will be subject to FDA
review. The revised reaudit provision is consistent with ISO 9001:1994.
20 − 23
4
Many comments were received on section 820.22(b) regarding the reports exempt
from FDA review. Most of the comments objected to FDA reviewing evaluations
of suppliers. FDA has decided not to review such evaluations at this time and will
revisit this decision after the agency gains sufficient experience with the new
requirement to determine its effectiveness. A thorough response to the comments
is found with the agency's response to other comments received on section 820.50,
"Purchasing controls." FDA has moved the section regarding which reports the
agency will refrain from reviewing from section 820.22(b) to new section
820.180(c), "Exemptions," under the related records requirements. FDA believes
this organization is easier to follow.
iii. Personnel
1 A few comments stated that the requirement in section 820.25, "Personnel" for the
manufacturer to employ "sufficient" personnel should be deleted because whether
there are "sufficient" personnel is a subjective determination, and it is unnecessary
to require it since the manufacturer will know how best to staff the organization.
A few other comments stated that the provision should not base the personnel
requirements on ensuring that the requirements of the regulation are "correctly"
performed because no manufacturer can ensure that all activities are performed
correctly.
FDA disagrees with the suggestions that these terms be deleted. Whether
"sufficient" personnel are employed will be determined by the requirements of the
quality system, which must be designed to ensure that the requirements of the
regulation are properly implemented. In making staffing decisions, a manufacturer
must ensure that persons assigned to particular functions are properly equipped,
and possess the necessary education, background, training, and experience to
perform their function correctly. That mistakes may occur is beside the point.
Further, FDA agrees that the manufacturer must determine for itself what
constitutes "sufficient" personnel with proper training, among other things, in the
first instance. However, if the manufacturer does not employ sufficient personnel,
or personnel with the necessary qualifications to carry out their functions, the
manufacturer will be in violation of the regulation. FDA has often found that the
failure to comply with this requirement leads to other significant regulatory
violations.
2
In section 820.25(b), "Training," FDA deleted the requirement that employees be
trained "by qualified individuals" because section 820.25(a) requires this. FDA
retained the rest of section 820.25(b), although several comments suggested
deleting the specific requirements in the last two sentences in favor of a broad,
general requirement that personnel be trained. FDA believes that it is imperative
that training cover the consequences of improper performance so that personnel
will be apprised of defects that they should look for, as well as be aware of the
effect their actions can have on the safety and effectiveness of the device. In
addition, FDA also disagrees with comments that suggested that only "personnel
affecting quality" should be required to be adequately trained. In order for the full
quality system to function as intended, all personnel should be properly trained.
Each function in the manufacture of a medical device must be viewed as integral to
all other functions.
3
Many comments objected to the proposed requirements of 820.25(c),
"Consultants," stating that requiring a manufacturer to chose consultants that have
sufficient qualifications, and to keep records subject to FDA review of all
consultants used, along with a copy of their curriculum vitae and list of previous
jobs, would unreasonably interfere with the manufacturer's business activities and
restrict the right of a manufacturer to hire consultants on any basis it chooses.
Other comments said that a manufacturer's employment of a consultant has the
same potential impact on the safety and effectiveness of medical devices as
employment of any other contractor for services, and that consultants should,
therefore, be covered by section 820.50, "Purchasing controls."
20 − 24
FDA agrees in part with these comments. Although employing a consultant is a
business decision, where a manufacturer hires consultants that do not have
appropriate credentials, and manufacturing decisions are made based on erroneous
or ill conceived advice, the public suffers. Of course, the manufacturer is still
ultimately responsible for following the CGMP requirements, and will bear the
consequences of a failure to comply. And, FDA notes that the use of unqualified
consultants has led to regulatory action for the failure to comply with the CGMP
regulation. But this is little consolation to those who may be harmed by the
devices. Thus, because of the significant impact a consultant can have on the
safety and effectiveness of a device, FDA believes that some degree of control is
required in the regulation.
The requirements are revised somewhat in response to comments,
however, to reflect that it is not FDA's goal to dictate whom a
manufacturer may use as a consultant, but to require that a manufacturer
determine what it needs to adequately carry out the requirements of the
regulation and to assess whether the consultant can adequately meet those
needs. The requirements related to consultants have been added in section
820.50, "Purchasing controls" because a consultant is a supplier of a
service.
<A NAME="pSubpart C">C. Design Controls (Subpart C)</A>
1 Many comments were submitted in response to the addition of design control
requirements in general, many questioning how this new requirement would be
implemented and enforced. For instance, several comments stated that the design
control requirements do not reflect how medical devices are actually developed,
because the concept of a design rarely originates with the manufacturer, who may
not become involved until relatively late in the design evolution. Others expressed
concern that FDA investigators will second-guess design issues in which they are
not educated or trained, and the opinion that the investigator should not debate
whether a medical device design is "safe and effective."
FDA disagrees. The design control requirements are not intended to apply to the
development of concepts and feasibility studies. However, once it is decided that a
design will be developed, a plan must be developed for establishing the adequacy
of the design requirements and ensuring that the design that will eventually be
released to production meets the approved requirements.
Those who design medical devices must be aware of the design control
requirements in the regulation and comply with the applicable requirements of the
regulation. Unsafe and ineffective devices are often the result of informal
development that does not ensure the proper establishment of design requirements
and does not provide for proper assessment of the device requirements, which are
necessary to develop a medical device with the proper level of safety and
effectiveness for the intended use of the device and needs of the user.
FDA investigators will not inspect a device under the design control requirements
to determine whether the design was appropriate, or "safe and effective," but will
evaluate the process, the methods, and the procedures that a manufacturer has
established to implement the requirements for design controls. If the investigator
finds during an inspection that distributed devices are unsafe or ineffective, the
investigator has an obligation to report the observations to the Center for Devices
and Radiological Health (CDRH).
2
Several comments expressed concern that the application of design controls would
severely restrict the creativity and innovation of the design process and suggested
that FDA should not begin application of the regulation too early in the design
development process.
FDA disagrees with the comments. It is not the intent of FDA to interfere with
creativity and innovation, and it is not the intent of FDA to apply the design
control requirements to the research phase. Instead, the regulation establishes
requirements for the establishment of procedures to ensure that whatever design is
ultimately transferred to production is in fact a design that will translate into a
20 − 25
device that properly performs according to its intended use and meets the user's
needs.
To assist FDA in applying the regulation, manufacturers should document the flow
of the design process so that it is clear to the FDA investigator where research
ends and development of the design begins.
3
A few comments stated that design controls should not be retroactive and that
ongoing design development should be exempted.
FDA agrees in part. FDA did not intend the design requirements to be retroactive,
and section 820.30, "Design controls" will not require the manufacturer to apply
such requirements to already distributed devices. When the regulation becomes
effective, it will apply to designs that are within the design and development phase,
and manufacturers will be expected to have the design and development plan
established. The manufacturer should identify at what stage that design is in for
such devices, and will be expected to comply with the established design and
development plan and the applicable parts of section 820.30 from that point
forward to completion. It will not be mandatory for designs to be recycled
through previous phases, however, that have been completed.
However, when changes are made to new or existing designs, the design
controls of section 820.30 must be followed to ensure that the changes are
appropriate, and that the device will continue to perform as intended. FDA
notes that the current device CGMP regulation contains requirements for
specification controls and controls for specification or design changes
under section 820.100(a).
4
One comment asked how the proposed design controls would apply to
Investigational Device Exemption (IDE) devices, since devices under an approved
IDE are now exempt from the CGMP regulation.
Devices being evaluated under an IDE were exempted from the current device
CGMP regulation because it was believed that it was not reasonable to expect
manufacturers to set up full scale manufacturing facilities and procedures to
manufacture devices that may never be approved for commercial development and
distribution. However, manufacturers conducting IDE studies were required to
manufacture the devices used in the studies under a state of control.
With respect to the new regulation, FDA believes that it is reasonable to
expect manufacturers who design medical devices to develop the designs
complying with design control requirements and that imposing such
requirements is necessary to adequately protect the public from potentially
dangerous devices. The design control requirements are basic controls
needed to ensure that the device being investigated will be the same or
similar to the device later produced for commercial distribution. FDA
intends to amend the IDE regulation to clearly state that IDE devices are
not exempt from section 820.30, "Design controls" in the Quality System
regulation.
5
One comment recommended that because design controls are a major addition to
the regulation, the effectiveness date for design controls should be delayed to 18
months after publication of the final regulation.
FDA has stated its intentions to add design controls to the CGMP requirements for
over six years. In 1989, CDRH published recommendations for preproduction
quality assurance entitled "Preproduction Quality Assurance Planning:
Recommendations for Medical Device Manufacturers." In November of 1990,
FDA published suggested design control requirements in the document "Suggested
Changes to the Medical Device Good Manufacturing Practices Regulation
Information Document." Hence, the agency believes that the device industry has
had ample notice and time to prepare and implement design controls.
20 − 26
6
A few comments objected to FDA requiring design controls for any Class I
devices.
FDA believes that, for the Class I devices listed, design controls are
necessary and has retained the requirements. Those relatively few devices,
while Class I, require close control of the design process to ensure that the
devices perform as intended, given the serious consequences that could
occur if their design was flawed and the devices were to fail to meet their
intended use. In fact, some of the devices included on the list have
experienced failures due to design related problems that have resulted in
health hazards, injuries, or death. Further, verification, or even validation,
cannot provide the assurance of proper design for some devices, such as
those containing software. FDA notes that design controls for computer
software is believed to be necessary for many industries, even those not
concerned with safety. Thus, all automated devices must be developed
under the design control requirements.
7
A couple of comments suggested that FDA lacked the authority to establish the
design control requirements.
FDA disagrees. The plain language of the statute and the legislative history make
clear that FDA has the authority to impose those controls necessary to ensure
proper device design. SMDA gave FDA explicit authority to include design
validation controls, to "include" a process to assess the performance of the device.
Section 520(f)(1)(A) of the act (21 U.S.C. 360j(f)(1)(A)). This language thus
makes clear that FDA is not limited to one process control related to design.
Further, in adding the CGMP design provision, Congress noted that while it was
aware that FDA contended that it had the authority to require design validation
without explicit language to that effect, there was some question whether the
authority would permit the agency to promulgate a "comprehensive device design
validation regulation." H.R. Rep. No. 808, 101st Cong., 2d Sess. 23 (emphasis
added). Congress stated that the amendment to the statute was necessary because
almost half of all device recalls over a five year period were "related to a problem
with product design." Id.
In addition, the purpose of the CGMP requirements is to "assure that [a]
device will be safe and effective and otherwise in compliance with [the]
Act)." Section 520(f)(1)(A) of the act (21 U.S.C. 360j(f)(1)(A)). Thus,
to carry out the objectives of the act, FDA believes that the design controls
required by the regulation are those which are necessary to ensure a
properly designed device, capable of performing as intended by the
manufacturer and as needed by the user. There is a thorough discussion on
the evolution of and need for the design controls in the preamble to the
November 23, 1993, proposal (58 FR 61592).
8
Several comments stated that FDA has underestimated the complexity of a design
project in requiring that the plans identify "persons responsible for each activity" in
section 820.30(b).
FDA agrees with the comments and has revised section 820.30(b) to require the
plan to describe or reference design activities and define responsibility for
implementing the activities, rather than requiring that the plan identify each person
responsible for carrying out each activity. In making this change, FDA notes that
section 820.20(b)(1) requires manufacturers to establish the appropriate
responsibility for activities affecting quality, and emphasizes that the assignment of
specific responsibility is important to the success of the design control program
and to achieve compliance with the regulation. The requirements under section
820.30(b) are very similar to the requirements in ISO 9001:1994, section 4.4.2 and
4.4.3.
9
A few comments stated that the requirement for the design and development plan
to describe "any interaction between or among different organizational and
20 − 27
technical groups" should be deleted because it is overly broad, unnecessary, and
burdensome. One comment said that the communication expected between these
groups should be clarified.
In response, FDA has amended the requirement to provide that interfaces with
different groups or activities shall be included in the plan. Many organization
functions, both inside and outside the design organization, may contribute to the
design process. For example, interfaces with marketing, purchasing, regulatory
affairs, manufacturing, service groups, and information systems, among other
groups, may be necessary during the design development phase. To function
effectively, the design plan must establish the roles of these groups in the design
process and describe the information that should be received and transmitted.
10 One comment stated that the requirement that manufacturers establish a design
plan completely ignores the creative and dynamic process of designing by requiring
a plan to have complete design and testing criteria established, with specifications,
before the design process is started.
FDA disagrees with the comment. Section 820.30(b) does not require
manufacturers to complete design and testing criteria before the design process
begins. This section has been revised to state that "plans shall be reviewed,
updated, and approved as design and development evolves," indicating that
changes to the design plan are expected. A design plan typically includes at least
proposed quality practices, assessment methodology, record-keeping and
documentation requirements, and resources, as well as a sequence of events
relative to a particular design or design category. These may be modified and
refined as the design evolves. However, the design process can become a lengthy
and costly process if the design activity is not properly defined and planned. The
more specifically the activities are defined up front, the less need there will be for
changes as the design evolves.
11 Several comments stated that the requirement of ISO 9001 that "incomplete,
ambiguous or conflicting requirements shall be resolved with those responsible for
imposing these requirements" should be added to section 820.30(c), "Design
input," because it is important that the regulations identify the method of resolving
conflicting information.
FDA agrees in part with the comments, in that it is important that incomplete,
ambiguous, or conflicting requirements be resolved with those responsible for
imposing these requirements. However, FDA notes that this must be done to
"ensure that the design requirements are appropriate and address the intended use
of the device," as required under section 820.30(c). Therefore, this requirement is
inherent in the requirements of section 820.30(c) and need not be added to the
language of the regulation.
12 One comment stated that the language contained in section 820.30(c) should more
closely match that of ISO 9001. Many other comments stated that the provision
should not require the input requirements to "completely" address the intended use
of the device because inputs could never "completely" address the intended use.
FDA agrees with the harmonization comment and has revised the language to
incorporate the requirement of clause 4.4.4, "Design input" of ISO 9001:1994.
FDA does not believe that it is necessary to have identical language to harmonize
quality system requirements. ISO 9001:1994, section 4.4.1, "General" requires
that the manufacturer "establish and maintain documented procedures to control
and verify the design of the product in order to ensure that the specified
requirements are met." FDA's regulation, under section 820.30(a), imposes the
same requirements.
Regarding the comments on the requirement that input requirements completely
address the intended use of the device, FDA recognizes that the provision could be
interpreted to impose a burden that may not always be possible to meet and has
20 − 28
deleted the word "completely." FDA did not intend the provision to suggest that a
manufacturer must foresee events that are impossible to have imagined.
FDA emphasizes, however, that the section requires the manufacturer to
ensure that the design input requirements are appropriate to ensure that the
device will perform to meet its intended use and the needs of the user. In
doing this, the manufacturer must assess and set the proper level of safety
and effectiveness that is commensurate with the intended use of the device.
This process involves defining the performance characteristics, safety and
reliability requirements, environmental requirements and limitations,
physical characteristics, applicable standards and regulatory requirements,
and packaging, and labeling requirements, among other things, and refining
the design requirements as verification results are established. For
example, when establishing the physical characteristics of a device, the
manufacturer should conduct appropriate human factors studies, analyses,
and tests from the early stages until the point of interface with the user and
patient is fixed. The procedures used (for instance, task/function analyses,
mockup reviews, user tests, among others) should ensure that the
characteristics of the user population and operating environment are
considered throughout the process.
13 A few comments stated that the requirement under section 820.30(c) that "design
input shall be reviewed and approved by a designated qualified individual" should
be deleted as it implies that one person must be designated to review and approve
a design, and that there may not be one person that is qualified to assess all of the
design input requirements. Addressing the same point, several comments
suggested that the provision be revised to allow for more than one person to
review and approve the design. One comment said that the FDA requirement
appears to be at odds with the team approach.
FDA agrees with the concern expressed by the comments and has modified the
requirement to allow more than one individual to review and approve the design
input. FDA endorses the team approach and believes that designs should be
reviewed and evaluated by all disciplines necessary to ensure the design input
requirements are appropriate.
14 Two comments stated that section 820.30(c) should be reworded to focus on
systems for assuring adequate design input, not on the input itself.
FDA agrees that procedures for ensuring appropriate design controls are of the
utmost importance and has modified the section to clarify that the manufacturer
must establish and maintain procedures to ensure that the design requirements are
properly addressed. FDA made this change to the other subsections as well, but
notes that section (a), "General" requires the manufacturer to establish and
maintain procedures to verify the design of the device in order to ensure that
specified design requirements are met. The sections that follow set forth some of
the specific requirements for which procedures must be established. It should be
emphasized that the input itself must also be appropriate; the requirement is for the
procedures to be defined, documented, and implemented. Thus, if the input
requirements related to a device fail to address the intended use of the device, for
example, the manufacturer has failed to comply with the provision.
One additional comment on this section said that the design input requirements
should include not only the device's intended use and needs of the user, but the
environmental limits of where it will be used.
FDA agrees with the comment, but believes that identifying and establishing the
environmental limits for safe and effective device operation is inherent in the
requirements for ensuring that a device is appropriate for its intended use. A
device cannot meet its intended use requirements if it is adversely affected by the
environment. Some factors that must be considered when establishing inputs
include, as applicable, a determination of energy (for example, electrical, heat, and
20 − 29
electromagnetic fields), biological affects (for example, toxicity and
bioincompatibility) and environmental affects (for example, electromagnetic
interference and electrostatic discharge).
15 Several comments stated that section 820.30(f), "Design output," should be
rewritten or deleted because many of the requirements were already stated in
sections 820.30(d), "Design verification" and (e), "Design review" and, if retained,
should be reordered similar to ISO 9001.
FDA agrees in part with the comments and has rewritten the requirements of
design output to be consistent with ISO 9001:1994 section 4.4.5, "Design output"
and reordered the sections to be consistent with ISO 9001:1994 ordering. FDA
retained the provision, however, because it does not agree that the section is
redundant with the sections on design verification and validation and review.
Design output are the design specifications which should meet design input
requirements, as confirmed during design verification and validation and ensured
during design review. The output includes the device, its packaging and labeling,
associated specifications and drawings, and production and quality assurance
specifications and procedures. These sections are not redundant, but dependent on
each other.
16 One small manufacturer commented that the problems that section 820.30(e),
"Design review" requirements are meant to reveal involve coordination,
cooperation, or communication difficulties among the members of an organization
and that these difficulties do not exist in a small company. Therefore, the comment
stated that the design review requirements should not apply to small
manufacturers.
The purpose of conducting design reviews during the design phase is to ensure that
the design satisfies the design input requirements for the intended use of the device
and the needs of the user. Design review includes the review of design verification
activities to determine whether the design outputs meet functional and operational
requirements, the design is compatible with components and other accessories, the
safety requirements are achieved, the reliability and maintenance requirements are
met, the labeling and other regulatory requirements are met, and the
manufacturing, installation, and servicing requirements are met, among other
things. Design reviews should be conducted at major decision points during the
design phase.
For a large manufacturer, design review provides an opportunity for all
those who may have an impact on the quality of the device to provide
input, including, manufacturing, quality assurance, purchasing, sales, and
servicing divisions. While small manufacturers may not have the broad
range of disciplines that may be found in a large company, and the need to
coordinate and control technical interfaces may be lessened, the principles
of design review still apply. The requirements under section 820.30(e) will
allow small manufacturers to tailor a design review that is appropriate to
their individual needs.
17 Several comments stated that to demand that every design review be conducted by
individuals who do not have direct responsibility for design development is
impractical, especially for small companies.
FDA never intended to mandate that an individual without design responsibility
conduct the design reviews and, to clarify its position, has rewritten the
requirements. The requirement now states that an individual not directly
responsible for design development shall be assigned to participate in the design
reviews. This requirement will provide an "objective view" from someone not
working so closely on the design project, to ensure that the requirements are met.
In making this change, FDA also notes that it was not FDA's intention to prohibit
those directly responsible for the design from participating in the design review.
20 − 30
18 One comment stated that as part of the systematic design review of the adequacy
of the device requirements, and to identify problems with the design, it is
occasionally necessary to produce a prototype device and have it evaluated by a
physician who is an expert in the area of the device's intended use. Thus, the
commentor believed that the regulation should be revised to allow a means for a
manufacturer to ship a prototype device to a physician for evaluation.
FDA disagrees with the comment. The regulation does not prohibit the shipment
of prototypes for clinical or other studies. Prototypes used in clinical studies
involving humans may be shipped in accordance with the IDE provisions in part
812.
19 One comment stated that the wording of section 820.30(e) implies that only one
design review is expected, and that design review should be conducted at several
stages of product development.
FDA agrees with the comment and has rewritten the requirement to make clear
that design reviews must be conducted at appropriate stages of design
development, which must be defined in the established design and development
plan. This may be one, or more than one, design review, depending on the plan
and the complexity of the device.
20 A few comments stated that section 820.30(d), "Design verification," should be
rewritten and reordered similar to ISO 9001.
FDA agrees with the comments and has rewritten and reordered this section to be
consistent with ISO 9001:1994. The language in revised section 820.30(f)
incorporates the requirement of ISO 9001:1994, sections 4.4.7, "Design
verification" and 4.4.8, "Design validation."
Under the revised provision, the design must be verified and validated. It is
important to note that design validation follows successful design
verification, and that design verification is not a substitute for design
validation. Design validation should be performed under defined operating
conditions and on the initial production units, lots, or batches to ensure
proper overall design control and proper design transfer. Design validation
may also be necessary in earlier stages, prior to product completion and
multiple validations may need to be performed if there are different
intended uses.
Proper design validation cannot occur without following all the
requirements set forth in the design control section of the regulation.
21 Several comments stated that adequate controls for verification of design output
are contained in proposed section 820.30(d), "Design verification," and repeated in
proposed section 820.30(f), "Design output." One comment stated that this
section will place undue burden on designers and require additional documentation
which will add little value to a device's safety and effectiveness.
FDA disagrees with the comments. Revised section 820.30(f), "Design
verification and validation" requires verification and validation of the design
output. Section 820.30(d), "Design output" requires that the output be
documented in a fashion that will allow for verification and validation. These
sections thus contain different requirements that are basic to establishing that the
design output meets the approved design requirements or inputs, and the user
needs and intended uses. Both requirements are essential to assuring the safety
and effectiveness of devices. FDA does not foresee these requirements placing
undue burden on designers nor requiring additional documentation with no value
added. These requirements are considered to be basic requirements to assure the
proper performance, and, therefore, the production of safe and effective devices,
and are acknowledged and accepted as such throughout the world.
20 − 31
22 Several comments stated that the term "hazard analysis" should be defined in
reference to design verification.
FDA has deleted the term "hazard analysis" and replaced it with the definition of
"risk analysis." FDA's involvement with the ISO Technical Committee (TC) 210
made it clear that "risk analysis" was the comprehensive and appropriate term, not
"hazard analysis." When conducting a risk analysis, manufacturers are expected to
identify possible hazards associated with the design in both normal and fault
conditions. The risks associated with the hazards should then be calculated in both
normal and fault conditions. If any risk is judged unacceptable, it should be
reduced to acceptable levels by the appropriate means, for example, by redesign or
warnings, among others. An important part of risk analysis is ensuring that
changes made to eliminate or minimize hazards do not introduce new hazards.
Tools for conducting such analysis include Failure Mode Effect Analysis (FMEA)
and Fault Tree Analysis (FTA), among others. The definition rather than the
actual term "risk analysis" is used in the regulation because there are several
activities and bills currently pending in Congress related to "risk analysis" or "risk
assessment" and FDA did not want to confuse its intentions with efforts ongoing in
Congress.
23 One comment stated that FDA should provide additional guidance regarding
software validation and hazard analysis and what investigators will expect to see.
FDA believes that sufficient domestic and international guidelines are available to
provide assistance to manufacturers for the validation of software and risk analysis.
For example, "Review Guidance for Computer Controlled Medical Devices
Undergoing 510(k) Review," August 1991; "A Technical Report, Software
Development Activities," July 1987; and ISO-9000-3 contain computer validation
guidance.
24 One comment stated that for some design elements it may be more appropriate to
reference data from another prior experimentation rather than conduct new testing,
and that the requirement to list verification methods should be modified.
FDA agrees in part with the comment. The revised language of section 820.30(f)
will permit the use of data from prior experimentation, when applicable. When
using data from previous experimentation, manufacturers must ensure that it is
adequate for the current application.
25 A couple comments stated that the requirement for design verification to include
software validation and hazard analysis, where applicable, was ambiguous, and
may lead an FDA investigator to require software validation and hazard analysis
for devices in cases where it is not needed.
FDA disagrees with the comments because software must be validated or verified,
and a risk analysis must be conducted, for all devices subject to design controls.
FDA believes that such controls are always needed, given the unique nature of
software, and that these controls are the minimum necessary to assure that
software will perform as intended. FDA has removed the phrase "where
applicable."
26 One comment stated that by explicitly mentioning only software validation and
hazard analysis as requirements of design verification, FDA was missing the
opportunity to introduce manufacturers to some powerful and beneficial tools for
better device designs and problem avoidance.
FDA disagrees, because the manufacturer must apply current methods and
procedures, appropriate for the device, to verify and validate the device design
under the regulation. FDA need not, therefore, list all known methods for meeting
the requirements. A tool that may be required to adequately verify and validate
one design may be unnecessary (although useful) to verify and validate another
20 − 32
design.
27 One comment questioned whether design verification can be conducted using
prototypes or machine shop models.
FDA understands that it is not always practical to conduct clinical studies on
finished production units and, therefore, the use of prototypes in clinical studies is
acceptable. When prototype designs are used on humans they must be verified as
safe to the maximum extent feasible. Full verification of the design, however,
cannot be determined by testing prototypes because the actual devices produced
and distributed are seldom the same as the prototype. The final verification,
therefore, must include the testing of actual production devices under actual or
simulated use conditions.
28 Section 820.30(g), "Design transfer" has been revised in response to the many
comments objecting to the requirements in this section. Specifically, the proposed
requirement for testing production units under actual or simulated use conditions
was rewritten and moved to current section 820.30(f), "Design verification and
validation."
FDA believes that testing actual production units under actual or simulated use
prior to distribution is crucial for ensuring that only safe and effective devices are
distributed and has therefore retained the requirement. ISO 9001:1994 discusses
this concept in notes 12 and 13. As noted in the immediately proceeding
comment, it is not always possible to determine the adequacy of the design by
successfully building and testing prototypes or models produced in a laboratory
setting. Prototypes may differ from the finished production devices. When
moving from laboratory to full-scale production, standards, methods, and
procedures may not be properly transferred and manufacturing processes may be
added. Often, changes not reflected in the prototype may be made in the product
to facilitate the manufacturing process. Proper testing of devices that are
produced using the same methods and procedures as those to be used in routine
production will prevent the distribution of many unacceptable medical devices.
Typically, the confirmation of the device specifications, production methods, and
procedures is obtained through process validation and product verification; process
validation includes the testing of finished devices under actual or simulated use
conditions.
The requirement for testing from the first three production lots or batches has been
deleted, however. While FDA believes that three production runs during process
validation is the accepted standard, all processes may not be defined in terms of
lots or batches. The number three is currently considered to be the acceptable
standard because it is said "once is luck, two is a fluke, and three is a trend."
Therefore, although the specific number requirement is deleted, FDA expects
validation to be carried out properly in accordance with accepted standards, and
will inspect for compliance accordingly.
Revised section 820.30(g) now contains a general requirement for the
establishment of procedures to ensure that the design basis for the device is
correctly translated into production methods and procedures. This is the same
requirement that is contained in section 820.100(a) of the current device CGMP
regulation.
29 Several comments stated that proposed section 820.30(h), "Design release," was a
duplication of requirements in other sections of 820.30 and should be deleted.
FDA agrees in part with the comments and has moved the requirement for design
output to be reviewed and approved to the current section 820.30(d), "Design
output." The remainder of the requirements have been deleted.
30 A few comments stated that the requirements of section 820.30(h) would prohibit
the release of components, partial designs, and production methods before the
20 − 33
design was final because the requirement mandates a review of all drawings,
analysis, and production methods before allowing the product to go into
production.
FDA did not intend the requirements of section 820.30(h) to prohibit
manufacturers from beginning the production process until all design activities
were completed. The intent of the requirement was to ensure that all design
specifications released to production have been approved and verified or validated
before they are implemented as part of the production process. That requirement
is now explicitly contained in section 820.30(d).
31 Several comments on section 820.30(i), "Design changes" stated that it is
unnecessary to control all design changes and to do so would inhibit change and
innovation.
FDA disagrees with the comments. It is not the intent of the regulation to mandate
that all design changes be documented and evaluated to the same extent, although
they must all be documented and evaluated. The documentation and evaluation
should be in direct proportion to the significance of the change. Procedures must
ensure that after the design requirements are established and approved, changes to
the design are also reviewed, validated (or verified where appropriate), and
approved. Otherwise, a device may be rendered unable to properly perform, and
unsafe and ineffective. ISO 9001:1994, section 4.4.9, similarly provides that "all
design changes and modifications shall be identified, documented, reviewed, and
approved by authorized personnel before their implementation."
32 One comment on section 820.30(i) stated that validation of design changes is not
always necessary and the regulation should provide for other methods to be used.
FDA agrees with the comments and has amended the requirement to permit
verification where appropriate. For example, a change in the sterilization process
of a catheter will require validation of the new process, but the addition of
chromium to a stainless steel surgical instrument may only require verification
through chemical analysis. Where a design change cannot be verified by
subsequent inspection and test, it must be validated. The designation for this
section is now 820.30(h), since the section on "Design release" has been deleted.
33 Many comments noted that the acronym for design history record (DHR) was the
same as that of "device history record" (DHR), and suggested that the name of the
"design history record" be changed.
FDA agrees and has changed the name to "design history file" (DHF). The section
is now designated as 820.30(i), "Design history file," since the section on "Design
release" has been deleted.
34 Several comments stated that the requirements of the "design history record"
should be deleted because they were redundant with the requirements of the
"device master record" (DMR).
FDA disagrees with the comments. The DMR contains the documentation
necessary to produce a device. The final design output from the design phase,
which are maintained or referenced in the DHF, will form the basis or starting
point for the DMR. Thus, those outputs must be referred to or placed in the
DMR. The final design output includes the final device and process specifications
and drawings, as well as all instructions, and procedures that are used for
purchasing production, installation, maintenance, and servicing. The design history
file, in contrast, contains or references all the records necessary to establish
compliance with the design plan and the regulation, including the design control
procedures. It illustrates the history of the design.
35 A few comments stated that the requirements of the design history record should
allow a single design history record for each device family or group having
20 − 34
common design characteristics.
FDA disagrees with the comments and again notes that the intent of the design
history file is to document, or reference the documentation of, the actual activities
carried out to meet the design plan and requirements of section 820.30. A design
history file is, therefore, necessary for each specific design developed. The design
history file must provide specific documentation showing the actions taken with
regard to each device design, not generically link similar devices together and give
an overview of how the output was reached.
36 One comment stated that the requirement that the DHF contain "all" records
necessary to demonstrate that the requirements are met should be deleted because
not "all" efforts need documentation.
FDA received similar comments on almost every section of the regulation that had
the word "all." The requirement does not state that all records must be contained
in the DHF, but that all records necessary to demonstrate that the requirements
were met must be contained in the file. Such records are necessary to ensure that
the final design conforms to the design specifications. Depending on the design,
that may be relatively few records. FDA cautions manufacturers who do not
document all their efforts that if something is not documented, the information and
experience of that effort may be lost, thereby possibly requiring activities to be
duplicated or repeated.
<A NAME="pSubpart D">D. Document Controls (Subpart D)</A>
1 One comment stated that Subpart D should be titled "Document controls" instead
of "Document and Record Controls" because the "record" requirements are
addressed in Subpart M.
FDA agrees and has substituted "controls" for "record."
2
One comment stated that document retrieval of obsolete or unneeded documents
should be performed to maintain integrity of the product configuration and the
quality system. The commentor suggested adding a requirement for a verification
step for document distribution and retrieval to ensure this important element of a
quality system is performed correctly.
FDA agrees in part with the comment. The verification of document distribution
and retrieval is a very important and can directly affect the quality of a product.
The general requirement of section 820.40, which requires that the manufacturer
establish and maintain procedures to control all documents, including those that
are obsolete and/or to be removed, in conjunction with section 820.40(b), would
require that such retrieval (or prevention of use) of obsolete documents be verified.
3
A few comments stated that section 820.40, "Document controls" should be
rewritten to be similar to ISO 9001 and to delete the requirement that documents
be "accurate," given that commentors feared that violations could be established
for typographical errors.
FDA agrees in part with the comments and has rewritten the section, following
ISO 9001, to be a general requirement for procedures to control documents that
are required under the regulation. The procedures established must ensure control
of the accuracy and usage of current versions of the documents and the removal or
prevention from use of obsolete documents, among other things, as well as ensure
that the documentation developed was adequate to fulfill its intended purpose or
requirement. FDA retained the requirement that the procedures ensure that
documents are accurate and meet the requirements of the regulation because that is
the purpose of controlling the documents. FDA notes that a typographical error
can change the intended meaning of a document and have disastrous
consequences.
20 − 35
4
Several comments on section 820.40(a), "Document approval and issue," as well
as other sections throughout the regulation, suggested that the term "signature" be
replaced by the term "identification." Such a change would allow for electronic or
computerized identification in lieu of formal written signatures.
FDA is aware that many documentation systems are now maintained electronically,
and is in the process of developing an agency-wide policy that will be implemented
through rulemaking on the use of electronic signatures. The agency identified
several important issues related to the use of such signatures, including how to
ensure that the identification is in fact the user's "signature." These issues are
discussed in FDA's advance notice of proposed rulemaking on the use of electronic
signatures, published in the Federal Register on July 21, 1992 (57 FR 32185) and
proposed regulation, published in the Federal Register on August 31, 1994, (59
FR 45160). Therefore, FDA has not revised the regulation to permit
"identification," but notes that the Quality System regulation's use of the term
"signature" will permit the use of whatever electronic means the agency determines
is the equivalent of a handwritten signature when a regulation is finalized.
FDA has, however, revised the requirement in section 820.40(a) to make
clear that the documents that must be reviewed and approved are those
established to meet the requirements of this part.
5
Several comments stated that section 820.40(b), "Document distribution" should
be rewritten to be consistent with ISO 9001.
In response, FDA has deleted the section. The requirements for making
documents available at all appropriate locations (ISO 9001:1994 section 4.5.2(a))
and the requirements for promptly removing obsolete documents (ISO 9001:1994
section 4.5.2(b)) have been moved, in revised form, to section 820.40(a). In
response to comments, FDA has added that obsolete documents, in lieu of being
promptly removed from points of use, may be "otherwise prevented from
unintended use."
6
Several comments suggested major changes to section 820.40(c), "Documentation
changes." Some stated that the requirements should be revised to be consistent
with ISO 9001. Others stated that the requirements related to validation should be
rewritten and moved to another section under this part, because this section should
only address document changes, not device changes. Several comments stated that
the reference to determining whether a 510(k) or PMA is required after making
changes to a device should be deleted because it is covered under different parts of
the act and regulations.
FDA agrees with many of the comments and has substantially rewritten this
section, now designated as section 820.40(b), to relate specifically to changes to a
document. The requirements are now very similar to the ISO 9001:1994
requirements in section 4.5.3. FDA has retained the requirement that the approved
changes must be communicated in a timely manner to appropriate personnel. FDA
has had many experiences where manufacturers made corrections to documents,
but the changes were not communicated "in a timely manner" to the personnel
utilizing the documents. The result of these untimely communications was the
production of defective devices.
In addition, FDA moved the requirement for validating changes to specifications,
methods, or procedures to section 820.70(b), "Production and process changes,"
where it more appropriately belongs.
7
One comment stated that the requirement in section 820.40(c) for changes to be
"approved by individuals in the same functions/organizations that performed the
original review and approval, unless specifically designated otherwise" is
unrealistic and does not reflect the way things are done in real life.
FDA disagrees that the requirement should be deleted and notes that this is a
20 − 36
requirement of ISO 9001:1994 as well. The intent of the requirement is to ensure
that those who originally approved the document have an opportunity to review
any changes since these individuals typically have the best insight on the impact of
the change. The requirement is flexible, however, because it permits the
manufacturer to specifically designate individuals who did not perform the original
review and approval to review and approve the changes. To designate such
individuals, the manufacturer will need to determine who would be best suited to
perform the function, thus ensuring adequate control over the changes. In this
way, review and approval will not be haphazard.
8
One comment on section 820.40(d), "Documentation change record," stated that
this section should be deleted because the other sections adequately covered the
proposed requirements. Two comments suggested replacing the section with the
requirements of section 4.5.2 of ISO 9001.
FDA has deleted this section and placed the revised requirements in sections (a)
and (b). The general requirement of section 820.40 now requires the manufacturer
to establish adequate procedures to control all documents required to be
established, maintained, and removed. The procedures must cover the specific
requirements in sections (a) and (b). Thus, the manufacturer must establish a
procedure for ensuring that only the current and approved version of a document
is used, achieving the objective of the "list, index, or equivalent document control
procedure."
The other requirement in section 820.40(d), "Document change record" was to
maintain a record of changes, to include a description of the changes, among other
things. FDA has retained this requirement and has moved it into section
820.40(b), "Document changes" because the agency believes this information to be
important and useful when investigating and performing corrective or preventative
actions.
FDA believes the sections on "Document Controls" now adequately harmonize
with ISO 9001:1994 sections 4.5.1, 4.5.2, and 4.5.3.
<A NAME="pSubpart E">E. Purchasing Controls</A>
1 One comment stated that the proposed CGMP regulation omits any discussion of
contract reviews, such as that contained in ISO 9001 section 4.3. Rather than
leaving these procedures to the interpretations of individual manufacturers and
inspectors, the commentor believed that FDA should explicitly state its general
policy regarding contract reviews in the regulation.
FDA does not disagree with the contract review requirements of ISO 9001:1994,
but believes these provisions are already reflected in requirements within the
proposed regulation, such as section 820.50, "Purchasing controls." Therefore,
the agency has not added the requirement.
2
One comment stated that the requirements in section 820.50 amount to
overregulation. The commentor stated that components are purchased by
providing a specification sheet. They are then inspected upon receipt, and
defective components are returned. Under section 820.50, the manufacturer
would be required to spend more time on paperwork, and product would still have
to be inspected upon receipt. Another comment stated that the cost of the quality
assurance documentation program is going to be significantly higher for a company
who runs a Just In Time (JIT) program than what FDA estimated.
FDA disagrees with the comments. The regulation has been written to allow more
flexibility in the way manufacturers may ensure the acceptability of products and
services. Under the requirements, each manufacturer must clearly define in the
procedures the type and extent of control they intend to apply to products and
services. Thus, a finished device manufacturer may choose to provide greater in- ........
house controls to ensure that products and services meet requirements, or to
20 − 37
ensure that the supplier adopts measures necessary to ensure acceptability, as
appropriate. FDA believes that, generally, an appropriate mix of supplier and
manufacturer quality controls are necessary. However, finished device
manufacturers who conduct product quality control solely in-house must also
assess the capability of suppliers to provide acceptable product. Where audits are
not practical, this may be done through, among other means, historical data,
monitoring and trending, and inspection and test data.
FDA notes that the degree of supplier assurance necessary to establish
compliance may vary with the type and significance of the product or
service purchased and the impact of that product or service quality on the
quality of the finished device. If a device manufacturer has established
confidence in the supplier's ability to provide acceptable products or
services, certification with test data may be acceptable.
Thus, FDA believes that the flexibility of the regulation will allow
manufacturers to implement JIT procedures without additional cost. In
fact, the new regulation is more conducive to JIT practices by requiring the
assessment or evaluation of product or services up front, thereby lessening
the degree of in-house control that may be necessary, as compared to
emphasizing incoming test and inspection under the current CGMP
requirements.
3
One comment stated that "manufacturing materials" should be deleted from the
first sentence of this section as the assessment of the manufacturers of
manufacturing materials would be a monumental task.
FDA disagrees with the comment. The first sentence of section 820.50 is rewritten
to be a general requirement that each manufacturer must establish procedures to
ensure that received product and services (purchased or otherwise) conform to
specified requirements. All manufacturers are expected to apply controls to
manufacturing materials appropriate to the manufacturing material, the intended
use, and the effect of the manufacturing materials on safety and effectiveness.
For example, the procedures necessary to ensure that a mold release agent
conforms to specified requirements may be less involved than the procedures for
controlling latex proteins. The provision allows the manufacturer the flexibility of
establishing the procedures to meet its needs and to ensure that the product
conforms to specified requirements.
4
Several comments said that it was unclear what FDA meant by the phrase "or held
by other persons under contract conform to specifications" and that this phrase
should be deleted.
FDA agrees with the comments and has deleted the phrase. The phrase was
intended to mean devices and components which were purchased or processed in
some manner by other organizations. Section 820.50 now applies to "purchased
or otherwise received product" to convey this meaning. FDA emphasizes that the
requirements apply to all product received from outside of the finished device
manufacturer, whether payment occurs or not. Thus, a manufacturer must comply
with these provisions when it receives product or services from its "sister facility"
or some other corporate or financial affiliate.
5
One comment said that FDA should delete the last sentence of general section
820.50 because it is unnecessary for manufacturers to develop specifications for
services that are unrelated to product or process quality, and because the terms
"service" and "other persons" lack definition.
FDA disagrees. First, as used in the regulation, "service" means parts of the
manufacturing or quality system that are contracted to others, for example, plating
of metals, testing, and sterilizing, among others. Second, FDA believes that all
suppliers of such a service must be assessed and evaluated, just like a supplier of a
good or product. As always, the degree of control necessary is related to the
20 − 38
product or service purchased. FDA has, however, deleted the term "provided by
other persons" because it was unnecessary.
6
One comment stated that many suppliers of components to the medical device
industry have their quality systems certified to an ISO 9000 standard by an
independent third party auditor, and that such registration of component
manufacturers should be considered in vendor assessment plans.
FDA agrees in part with the comment in that certification may play a role in
evaluating suppliers, but cautions manufacturers against relying solely on
certification by third parties as evidence that suppliers have the capability to
provide quality products or services. FDA has found during inspections that some
manufacturers who have been certified to the ISO standards have not had
acceptable problem identification and corrective action programs. Therefore, the
initial assessment or evaluation, depending on the type and potential effect on
device quality of the product or service, should be a combination of assessment
methods, to possibly include third party or product certification. However, such
assessment or evaluation may not be relied on exclusively.
7
FDA added consultants to section 820.50(a) in response to the comments from
section 820.25(c).
8
One comment on section 820.50(a) stated that listing all suppliers and maintaining
documented supplier assessment criteria is an excessive requirement for certain
low risk components and manufacturing materials. The commentor stated that it is
appropriate for the manufacturer to establish a documented, justified supplier
quality program based on risk. Another comment stated that the requirement
would require manufacturers to assess all potential suppliers which would place
many small and medium size firms under extreme duress. Another comment stated
that section 820.50(a) is open to interpretation that all suppliers and contractors
must undergo either on-site or "paper" assessment of their quality system and that
some suppliers may not be willing to undergo an assessment, even though they
supply a material critical to the performance of a device.
After evaluation of all of the comments on section 820.50, FDA has decided to
change the wording of section 820.50(a) and adopt the wording of ISO 9001 to
make clear that manufacturers have flexibility in determining the degree of
assessment and evaluation necessary for suppliers, contractors, and consultants. In
addition, the requirement for manufacturers to establish assessment criteria has
been modified. Each manufacturer must now define the type and extent of control
it will exercise over suppliers, contractors, and consultants. This is consistent with
the 1994 version of ISO 9001.
The type and extent of the controls that would be required may vary with the
difficulty of the service, the importance of the product or service, and the impact
the product or service may have on the safety and performance of the device. For
example, the extent of control that must be exercised over products and contract
services that are significant to the proper functioning and safety of the device
would be greater than that which may need to be exercised over less significant
product or services. The controls applied should include on-site auditing, where
feasible and appropriate. However, other means such as receiving inspection and
test, evaluation of past history, or monitoring of incoming quality, depending on
product and service, may be acceptable. Typically an appropriate mixture of
assessment and incoming inspection and test is necessary for proper control.
9
One comment said that requiring evaluation of potential suppliers, contractors, and
consultants "on the basis of their ability to meet requirements" is vague and should
be clearly defined.
FDA disagrees that the phrase is vague. Suppliers, contractors, and consultants
selected by manufacturers of medical devices should have a demonstrated
capability of providing products and services that meet the requirements
20 − 39
established by the finished device manufacturer. The capability of the products or
services should be reviewed at intervals consistent with the significance of the
product or service provided and should demonstrate that they conform to specified
requirements.
10 One comment questioned the usefulness of section 820.50, given that the
requirements under section 820.80, "Receiving, in-process, and finished device
acceptance" require manufacturers to establish and maintain procedures for
acceptance of incoming components.
The intent of section 820.50 is to ensure that device manufacturers select only
those suppliers, contractors, and consultants who have the capability to provide
quality product and services. As with finished devices, quality cannot be inspected
or tested into products or services. Rather, the inherent quality of a product or
service is established during the design of that product or service, and achieved
through proper control of the manufacture of that product or the performance of
that service. Section 820.50 thus mandates that products be manufactured and
services be conducted under appropriate quality assurance procedures. Finished
device manufacturers are required under section 820.50 to establish the
requirements for, and capability of, suppliers, contractors, and consultants to
provide quality products and services.
Section 820.80 is specific to a device manufacturer's incoming inspection and test
(or "acceptance") program. While finished device manufacturers are required to
assess the capability of suppliers, contractors, and consultants to provide quality
products and services, inspections and tests, and other verification tools, are also
an important part of ensuring that the finished device conforms to approved
specifications. The extent of incoming acceptance activities can be based in part
on the degree the supplier has demonstrated a capability to provide quality
products or services. An appropriate product and services quality assurance
program includes a combination of assessment techniques. Inspection and test is
just one method which can be utilized to the extent appropriate for the significance
of the device and the impact the product or service has on the safety and
performance of the finished device.
11 One comment stated that it was not clear how a manufacturer could evaluate an
off-the-shelf component that is purchased from a distributor rather than directly
from its manufacturer, and stated that it would not be helpful to audit the
distributor.
FDA agrees that auditing a distributor would not meet the intent of section 820.50.
Manufacturers should remember that the purpose of assessing the capability of
suppliers is to provide quality products and to provide a greater degree of
assurance, beyond that provided by receiving inspection and test, that the products
received meet the finished device manufacturer's requirements. The agency
recognizes that finished device manufacturers may not always be able to audit the
original manufacturer. In such cases, the manufacturer must apply other effective
means to assure that products are acceptable for use.
12 Many comments from both domestic and foreign firms in response to proposed
section 820.22(b) said that making supplier audit reports subject to FDA review
will have a major adverse impact on the relationships between the finished device
manufacturers and their suppliers and service providers. Some stated that the
requirement will cause suppliers to refuse to sell components to medical device
manufacturers, especially suppliers who provide only a small part of their
production to device manufacturers. Others said that this policy is not consistent
with FDA's policy for internal audits.
FDA recognizes that quality audits of suppliers have a significant and
demonstrated value as a management tool for corrective action, quality
improvement, and overall assurance of component and service quality, and does
not seek to undermine their value. Therefore, based on the concerns raised by the
20 − 40
comments, FDA will not at this time review supplier audit reports during a routine
FDA inspection for compliance with this part, as noted in section 820.180(c),
"Exceptions." As noted in response to earlier comments, FDA intends to revisit
this decision in the future. The audit procedures and assessment criteria, the
evaluation procedures, and other documents that demonstrate conformance with
section 820.50 will be subject to review by an FDA inspector.
13 One comment stated that it was unclear what is meant by the requirement to
specify "quality requirements" that must be met for suppliers, contractors, and
consultants, as stated in section 820.50(a).
The term "quality requirements" means the quality control and quality assurance
procedures, standards, and other requirements necessary to assure that the product
or service is adequate for its intended use. FDA does not believe the term is
unclear.
14 Several comments on section 820.50(b), "Purchasing forms" suggested that the
term "forms" be replaced by "data." Other comments stated that use of the term
would not allow electronic data exchange. One comment stated that the use of an
exclusive form for purchasing is unnecessary and redundant, and that it is unduly
burdensome to require detailed documentation on those commonly available items
such as fasteners. The comment stated that it is common practice to use prints or
drawings to fulfill the purpose of the form.
FDA agrees in part with the comments, but does not believe that section 820.50(b)
prohibits the use of drawings or prints, assuming that the documents contain data
clearly describing the product or service ordered, and that the specified
requirements are met. However, section 820.50(b) has been rewritten and now
requires manufacturers to establish purchasing "data." This provides each
manufacturer with the flexibility to use both written and electronic means to
establish purchasing information.
15 One comment stated that the inclusion of an additional provision mandating that
suppliers notify manufacturers of any change in their product or service places an
undue burden on suppliers and inhibits their ability to make minor adjustments
within the parameters of agreed upon specifications and quality requirements.
Many other comments stated that the requirement of section 820.50(b) is feasible
only for components that are custom made for the manufacturer, and is
meaningless for off-the-shelf components purchased from distributors. Other
comments state that the requirement is part of the current CGMP regulation and
experience has shown that suppliers are not willing to supply device manufacturers
with such information.
FDA agrees in part with the comments and has amended the requirement to state
that such agreement must be obtained "where possible." FDA still believes that
this change information is very important to the manufacturer, and that the
manufacturer should obtain information on changes to the product or process.
Where a supplier refuses to agree to provide such notification, depending on the
product or service being purchased, it may render him an unacceptable supplier.
However, where the product is in short supply and must be purchased, the
manufacturer will need to heighten control in other ways.
16 One comment stated that section 820.50(b) should incorporate a provision that the
manufacturer may cite published standards in purchasing forms as one suitable
method for specifying purchased item quality requirements.
That addition is unnecessary, in FDA's estimation, because the regulation permits
manufacturers to clearly describe or reference requirements. A reference could be
to a standard.
17 One comment stated that it is unclear whether the requirement for a signature to
approve purchasing documents pertains to approval of the form used for
20 − 41
purchasing or approval of the individual purchasing transaction. The comment
also stated that a signature approval by transaction is not practical for firms using
electronic document transmittals.
FDA has rewritten the requirement to be more clear. The requirement is for
approval of purchasing data or information used to purchase a product or service.
Thus, each manufacturer must review and approve the purchasing data before
release of the data. FDA addressed the use of electronic signatures in response to
another comment, and notes briefly that FDA is in the process of developing an
agency-wide policy on the use of electronic signatures.
18 One comment stated that purchasing is carried out verbally in many small firms,
without the use of component-specific purchasing forms, and that the regulation
should be revised to allow such verbal purchasing to continue.
FDA disagrees with the comment. About 15 percent of the recalls each year are
due to unacceptable purchased products. Many of these products are unacceptable
because the finished device manufacturer did not properly describe the product.
The requirements for purchased products and services must be documented to
ensure that the supplier, contractor, and consultant provide a product or service
which conforms to specified requirements. This requirement, and the goal it seeks
to achieve, are applicable to both small and large companies.
19 One comment stated that the requirement that purchasing forms spell out the
specifications for manufacturing materials in all cases is excessive, and that the
need for specifications should be based on the criticality of and risk associated with
the use of the specific manufacturing material.
FDA agrees that the specifications for many manufacturing materials may be so
well established that the trade name of the product may be sufficient to describe
the material needed. For other materials, specific written specifications may be
necessary to ensure that the materials desired are received. The extent of the
specification detail necessary to ensure that the product or service purchased meets
requirements will be related to the nature of the product or service purchased,
taking into account the effect the product or service may have on the safety or
effectiveness of the finished product, among other factors. The term
"specification" has been replaced with the term "specified requirements" to better
reflect the intent of the requirement.
<A NAME="pSubpart F">F. Identification and Traceability (Subpart F)</a>
i. Identification
1 A few comments on sections 820.60, "Identification and traceability" and 820.65,
"Critical device, traceability" stated that the two sections should be rewritten to
delete the distinction between critical and noncritical devices. Some stated it
should be consistent with ISO.
FDA agrees in part with the comments and has rewritten section 820.60 to be
consistent with ISO 9001:1994. The term "critical device" is also deleted, and
traceability, where necessary to assure the protection of the public health, is
addressed solely in section 820.65.
2
One comment stated that manufacturing materials should be deleted from section
820.60, as the requirements are excessive and not cost justifiable with regard to
such materials.
FDA disagrees with the comment. The purpose of section 820.60 is to ensure that
all products, including manufacturing materials used in the manufacture of a
finished device, are properly identified as to their current status, for example,
whether they are accepted, rejected, or reworked. This requirement is intended to
help prevent inadvertent use or release of unacceptable product into
manufacturing. It is as important that the proper manufacturing materials be used
20 − 42
as it is that the proper component be used.
ii. Traceability
1 A few comments state that section 820.65, "Critical devices, traceability" implies
that traceability requirements exist for all devices.
As noted above, FDA has deleted the critical device terminology and distinction in
response to comments requesting such deletion, and section 820.65 is now entitled
"Traceability." The revised section tracks the language of the act, and requires
that a manufacturer be able to trace, by control number, any device where
necessary to assure the protection of the public health. See Section 520(j) of the
act (21 U.S.C. 360j(j)). Such products would include those whose failure could
result in serious injury or harm to the user. At a minimum, traceability would be
required for the critical devices as defined and listed in the Federal Register
Notice of March 17, 1988, and for in vitro diagnostic products (21 CFR
809.10(a)(9)), due to the specific nature and individuality of the reagents used.
This change is also consistent with the overall changes to the CGMP regulation
that were proposed on November 23, 1993. The new CGMP regulation would not
distinguish between devices, but makes many of the requirements previously
applicable only to critical devices applicable to all devices, but provide the
manufacturer the ability to tailor its procedures to the specific device being
manufactured. FDA will notify a manufacturer directly, by letter, when it
determines that a device of that manufacturer is subject to the traceability
requirement. Manufacturers may find it advantageous, however, to provide lot,
unit, or batch traceability for devices for which traceability is not a requirement to
facilitate control and limit the number of devices that may need to be recalled due
to defects or violations of the act.
2
Another comment on section 820.65 stated that critical device component
traceability could be interpreted to be required for almost all electronic
components and other components in a critical device. The commentor stated that
the extent of component traceability should be left to the manufacturer's discretion,
since it is an economic risk decision.
FDA disagrees that the traceability determination should be based solely on
economic risk. As noted in the preamble to the November 23, 1993, proposal (58
FR 61964), where traceability is important to prevent the distribution of devices
that could seriously injure the user, traceability of components must be maintained
so that potential and actual problem components can be traced back to the
supplier.
The revised requirement mandates traceability of components where
necessary to assure the protection of the public health. The critical
component definition in the current CGMP regulation may be used as
guidance. However, to carry out the requirement of the revised provision,
the manufacturer should perform risk analysis first on the finished device,
and subsequently on the components of such device, to determine the need
for traceability. Both FDA and the authors of ISO/DIS 13485 believe that
the extent of traceability for implantable devices should include all
components and materials used when such products could the medical
device not to satisfy its specified requirements.
<A NAME="pSubpart G">G. Production and Process Controls (Subpart G)</A>
i. Production and process controls
1 A few comments stated that the requirements in section 820.70(a), "Production
and process control" are similar to those in ISO 9001, but that ISO 9001 makes
clear that the requirements apply only "where applicable" and where deviations
from device specifications would "directly affect quality." The comments suggest
that FDA similarly employ such language to avoid being too restrictive and overly
burdensome.
The requirements in section 820.70(a) are intended to ensure that each
20 − 43
manufacturer produces devices that conform to their specifications. Thus, where
any deviations from specification could occur during manufacturing, the process
control procedures must describe those controls necessary to ensure conformance.
Those controls listed may not always be relevant; similarly others may be
necessary. For example, where deviations from device specifications could occur
as a result of the absence of written production methods, procedures, and
workmanship criteria, such production controls are required. Thus, FDA has
retained the provision, but revised it slightly to conform to current section
820.100(b)(1).
As noted, the process controls requirement applies when any deviation from
specifications could occur. FDA believes that such deviations must be controlled,
and that linking the requirement to deviations that directly affect quality is
inappropriate and subjective, and that it could lead to the manufacture of
potentially dangerous devices through the lack of control of processes known to
directly affect a device's specifications. Therefore, the provision has not been
restricted in this manner.
2
One comment stated that the second sentence of proposed section 820.70(a) was
too restrictive, in that some processes can be accomplished by adequately trained
personnel without the use of procedures.
FDA disagrees with the comment because the establishment of procedures is
intended to ensure consistency in manufacture. The procedures may be tailored
under the requirement, as written, to cover only those controls necessary. The
procedures must describe whatever process controls are necessary to ensure that a
device meets its specifications. FDA notes that the deletion of the word "all" does
not alter the requirements; all processes must be controlled wherever any
deviations could occur.
In addition to these changes, FDA has added the requirement that production
processes be "monitored" because a manufacturer must continually monitor a
controlled process to ensure that the process remains in control.
3
FDA deleted the requirement for process controls related to "installation and
servicing" from section 820.70(a)(1) and (2) in response to comments. Such
control is adequately assured by the requirements in sections 820.126,
"Installation" and 820.200, "Servicing."
4
One comment noted that there is no longer a requirement that process changes be
validated.
Revised section 820.70(b), "Production and process changes," addresses the
requirement for production and process changes to be validated, except where the
change is fully verified. This requirement for validation was moved from section
820.40(c), in revised form, to this section. Verification of changes was added to
give the manufacturer the flexibility to verify changes that can be tested and
inspected because FDA believes that validation is not always necessary. FDA has
provided guidance on when changes are expected to be validated in its "Guideline
on General Principles of Process Validation." The agency notes that wherever
variables may influence a process, the process must be validated. A few examples
of processes that must be validated include sterilization, molding, and welding.
5
The EU Commission stated that environmental conditions only affect the quality of
certain devices and that the requirements should, therefore, be restricted in their
application. Other comments stated that the requirements in section 820.70(b),
"Environmental control" were not consistent with the requirements in current
CGMP section 820.46.
FDA agrees that environmental controls must be established where necessary to
control adverse effects and believes that the regulation was restrictive in its
application by requiring that a control system be established that would "prevent
20 − 44
contamination or other adverse effects." However, FDA has revised the provision,
to clarify it and to better harmonize with the working draft of ISO/DIS 13485.
In harmonizing, FDA has added the requirement in newly designated
section 820.70(c), "Environmental controls," for the manufacturer to
establish and maintain requirements for the environment to which product
is exposed. FDA believes such a requirement is a necessary precursor to
the requirement for controlling the environmental conditions that could
have an adverse effect on the device.
The requirements for procedures to ensure control of conditions, periodic
inspection of control systems, and documentation and review of results are similar
to the existing CGMP requirements. However, the specific list of conditions to be
considered for control, which were carried over from the CGMP regulation to the
proposal, were deleted in response to a comment from the Global Harmonization
Task Force that the list would be better suited for a guidance document. FDA
agrees that it is not necessary to give examples of conditions that may need
controlling in a regulation, and notes that lighting, ventilation, space, temperature,
humidity, air pressure, filtration, airborne contamination, and static electricity are
among many conditions that should be considered for control.
6
One comment stated that the last sentence of section 820.70(b) should be deleted
because it is redundant with the audits required in section 820.22(a). Another
comment said that environmental conditions are currently reviewed via internal
audit, which an FDA inspector cannot review.
FDA disagrees with the comments. The inspection and review of environmental
control systems are routine quality assurance functions that are part of the
production quality assurance program. The audits required by section 820.22(a)
are audits of the quality system, conducted to ensure the adequacy of and
conformance with the quality system requirements. The requirement to conduct a
quality audit is in addition to other provisions in the regulation which require that a
manufacturer review its specific controls, among other things, to ensure the
requirements are met. FDA may review and copy the inspection results of
environmental control systems.
7
The Global Harmonization Task Force commented that the requirements of section
820.70(c), "Cleaning and sanitation" should be placed in guidance.
After careful consideration, FDA agrees that a separate section on cleaning and
sanitation is unnecessary. The objective of section 820.70(c) is adequately met
through the requirement of section 820.70(e), "Contamination control," and
820.70(a), the general process control procedure requirement. Contamination
control must include establishing and maintaining adequate cleaning procedures
and schedules, if such control is necessary to meet manufacturing process
specifications. In addition, section 820.25, "Personnel" requires that employees
have a thorough understanding of their job functions, which would include a
requirement that the appropriate employees comprehend the cleanliness and
sanitation procedures.
8
The Global Harmonization Task Force and others commented that the specific
requirements of proposed subsections 820.70(d)(1) through (3) should be deleted
and placed in guidance because they are redundant with the first sentence in
section 820.70(d), "Personnel health and cleanliness."
FDA agrees with the comments and has deleted the subsections. FDA has also
rewritten the section now entitled "Personnel" to require procedures to achieve the
desired result, rather than dictate the means to achieve the result. The section as
rewritten thus provides the manufacturer more flexibility and is consistent with the
working draft of ISO/DIS 13485. Under this section, a manufacturer's
requirements must not permit unclean or inappropriately clothed employees, or
employees with medical conditions, to work with devices where such conditions
20 − 45
could adversely effect the quality of the product. The requirements must also
establish acceptable clothing, hygiene, and personal practices, as applicable to the
device being manufactured.
FDA also added the requirement, from ISO/DIS 13485, that personnel who are
working temporarily (such as maintenance and cleaning personnel) under special
environmental conditions (such as a clean room) be appropriately trained or
supervised by someone trained to work in such an environment.
9
One comment stated that the requirements of section 820.70(e), "Contamination
control" should be deleted and placed in guidance.
FDA has rewritten the section to delete the specific references to contaminants that
probably gave rise to the suggestion that the section would be more appropriate as
guidance. The section now contains a broad requirement for the establishment of
procedures to prevent contamination of equipment or product by any substance
(whether hazardous, contaminants generated by the manufacturing process, or
otherwise) that could adversely affect the device. Again, this revision adds
flexibility.
10 One comment on section 820.70(e), "Contamination control" stated that the
reference to manufacturing materials should be deleted because it is redundant with
section 820.70(g), "Equipment."
FDA disagrees with the comment because section 820.70(e) requires procedures
to ensure that manufacturing materials do not become contaminated. The section
still contains the requirement for manufacturing materials contamination control
through use of the new term "product," which includes manufacturing material.
Section 820.70(g), in contrast, establishes requirements related solely to the
equipment used in the manufacturing process. And section 820.70(h),
"Manufacturing material," addresses requirements for the removal or limitation of
manufacturing materials which could adversely affect the device. Thus, these
sections are distinct and are intended to achieve different objectives.
11 One comment on proposed section 820.70(b), "Environmental controls" requested
that FDA delete reference to "facilities" inspection and limit the requirement to
review of the control system, as currently contained in the CGMP regulation.
In response, FDA reworded the requirement for the inspection to be related to the
control systems required by revised section 820.70(c), "Environmental Control."
This requirement mandates that the control system at the facility actually be
inspected. FDA has, however, added a new section 820.70(f), "Buildings," that
requires that buildings be of suitable design and contain sufficient space to allow
for the proper manufacture of devices. The section is worded similarly to the
existing CGMP regulation section 820.40, and is intended to achieve the same
objectives as that section.
12 The only two comments received on proposed section 820.70(f), "Sewage and
refuse disposal," recommended that the section be deleted because it was
unnecessary and/or covered by other federal regulations.
The section has been deleted because the requirements are adequately covered in
the current requirements under sections 820.70(e), "Contamination control" and
820.70(c), "Environmental control." Pursuant to these sections, sewage, trash,
byproducts, chemical effluvium, and other refuse that could affect a device's safety,
effectiveness, or fitness for use must be adequately controlled and disposed of.
13 Two comments stated that the requirement related to equipment in section
820.70(g) should ensure that equipment meets "specified requirements" not be
"adequate for its intended use" because intended use is determined during the
design phase, and because it is easier to assess whether equipment meets specified
requirements.
20 − 46
From these comments, FDA can see that the requirement should be revised
because it may have been misinterpreted. The requirement is reworded as
suggested. Under the requirement, the equipment must be appropriately designed
to facilitate maintenance, adjustment, cleaning, and use. It must also meet the
requirements that are necessary to ensure its proper functioning for the
manufacture of the device. Hence, it must be "adequate for its intended use."
14 A few comments stated that not all equipment requires maintenance, and the
requirement for a maintenance schedule in section 820.70(g)(1) should be revised
to make that clear.
FDA agrees that not all equipment may require maintenance and notes that the
general requirement of section 820.70(a) requires process control procedures that
describe those controls which are necessary. Therefore, FDA did not revise the
requirement.
15 The Global Harmonization Task Force recommended that the second sentence of
section 820.70(g)(1), which requires that the maintenance schedule be posted or
readily available, be deleted and placed in guidance.
After consideration of the application of the requirement, FDA has deleted the
requirement. The requirement under general section 820.70(g), for a manufacturer
to ensure that equipment meets specified requirements, would require that the
manufacturer ensure that maintenance is carried out on schedule to comply with
the requirement. FDA expects that the schedule, to satisfactorily meet this
requirement, would be posted on or near the equipment to be maintained, or
otherwise made readily available to appropriate personnel. Deletion of the
requirement, however, permits the manufacturer added flexibility in ensuring that
the requirement is met.
16 One comment stated that companies are moving to computerized systems to
schedule and document preventative maintenance and that the requirement for a
"written record" in the third sentence of section 820.70(g)(1) should, therefore, be
revised.
FDA agrees and has amended the requirement to require "[r]ecords," permitting
the use of written or electronic recording, pursuant to section 820.3(x).
17 Several comments stated that sections 820.70(g)(2), "Inspection," and
820.70(g)(3), "Adjustment," should be deleted and placed in guidance because the
requirements are adequately covered under the requirements in section
820.70(g)(1).
FDA believes that to adequately ensure that equipment continues to meet its
specifications, and to ensure that inherent limitations and allowable tolerances are
known, these specific requirements are imperative. Both of these sections are
requirements in the CGMP regulation currently and the agency has found them to
be both useful and necessary.
18 One comment stated that requiring the removal of manufacturing material to be
documented in proposed section 820.70(g)(4), "Manufacturing material" will result
in impossible requirements, such as the requirement to document how much
cutting oil is lost during a metal removing operation, such as drilling.
FDA disagrees because the section (now section 820.70(h)) merely requires that
the fact that manufacturing material was removed be documented, not how much
was removed or how much was lost due to processing. This requirement is
carried over from the current device CGMP regulation, section 820.60(d).
19 One comment on section 820.70(h), "Automated processes," (now section
820.70(i)) stated that the section should be revised to reflect that software used in
20 − 47
such systems must be validated for "its intended use," not simply validated.
Another comment stated that most companies buy software currently available on
the market and do not make changes to the software. It was recommended that
this section allow for use of outside personnel for validation runs and not
necessarily require the development of a software validation procedure. Related to
commercially available software, one comment suggested that the section should
allow verification rather than validation.
FDA has modified the requirement to mandate validation for the intended use of
the software. In addition, the requirement that the software be validated by
individuals designated by the manufacturer has also been deleted to make clear that
validation may be performed by those other than the manufacturer. However,
whether the manufacturer designates its own personnel or relies on outside
assistance to validate software, there must be an established procedure to ensure
validation is carried out properly.
FDA has maintained the requirement for validation, however, because the
agency believes that it is necessary that software be validated to the extent
possible to adequately ensure performance. Where source code and design
specifications cannot be obtained, "black box testing" must be performed to
confirm that the software meets the user's needs and its intended uses.
FDA emphasizes that manufacturers are responsible for the adequacy of the
software used in their devices, and activities used to produce devices. When
manufacturers purchase "off-the-shelf" software, they must ensure that it will
perform as intended in its chosen application.
20 Several comments on "automated processes" stated that the term "data processing
systems" was unclear and its inclusion rendered the requirement too broad.
FDA disagrees. The phrase "automated data processing" is contained in the
current device CGMP regulation under section 820.195, "Critical devices,
automated data processing" and has not been misunderstood or considered to be
unclear. Software used in data processing systems, whether it be in the designing,
manufacturing, distributing, tracking, or quality system areas, must be validated.
ii. Process validation
1 A few comments on proposed section 820.75, "Special processes" stated that the
meaning of the term "special processes" was unclear. Other comments stated that
FDA should provide examples of processes that would be considered "special
processes."
In response to the comments, the term "special processes" has been dropped from
the regulation. The section now requires that all processes which cannot be fully
verified by an inspection and test method be validated. Examples of such
processes include sterilization, aseptic processing, injection molding, and welding,
among others. As the explanation for section 820.70(b), "Production and process
changes" noted, whenever variables exist in a process, the process must be
validated. The validation process used under this requirement must ensure that
predetermined specifications are consistently met. The new section, entitled
"process validation" is consistent with ISO 9001:1994.
2
Several comments were received on parts (1) through (4) of section 820.75 that
stated that the requirements were redundant to other parts of the regulation and
should be modified or deleted.
FDA disagrees with the comments and believes that, due to the importance of
process validation and correct performance of the process validated, the
requirements are necessary. The requirements have been rearranged in the revised
section.
3
Comments on the first sentence of section 820.75(b) stated that the intent was
20 − 48
unclear and unrealistic.
Given that it was believed by commentors to be unclear, FDA has revised the
requirements. The section's requirements (as proposed and as revised) apply to the
performance of a process after the process has been validated. In contrast, section
820.75(a) relates to the actual validation of the process. The revised section,
which is now section 820.75(d), requires that the dates on which the process was
performed, the person performing it, and the major equipment used, where
appropriate, be documented. In addition, section 820.75(d) requires that
monitoring and control methods and data be recorded. FDA believes that the new
arrangement of section 820.75 should clear up any confusion.
FDA notes that it is always "appropriate" to document the equipment used
in the process where the manufacturer uses different equipment on different
manufacturing lines. To investigate a problem with the device, the
manufacturer will need to know which tester was used, since the problem
could be with the equipment itself, rather than the device.
<A NAME="pSubpart H">H. Acceptance Activities (Subpart H)</A>
i. Receiving, in-process, and finished device acceptance
1 One comment stated that the emphasis on testing and inspection in section 820.80
completely ignores the quality goals, the benefit of requiring purchasing controls,
and statements made in the preamble of the proposal reflecting FDA's negative
opinion about manufacturers relying solely on testing and inspection.
FDA agrees with the comment and has replaced the term "inspection and test" with
"acceptance activities" in section 820.80. Further, FDA defines "acceptance
activities" to include inspections, test, and other verification activities, such as an
appropriate mix of supplier audits and inspection and test. In addition, with a
documented history of acceptable received product or services from a supplier, the
degree of inspection and test necessary may change.
2
One comment stated that recordkeeping is a significant cost factor in the operation
of a total quality system, and that the revised CGMP regulation should not add
cost through duplication of documentation. The comment said that the
requirement to record all quantitative data seems inappropriate and of little value.
FDA agrees that one goal of a quality systems regulation should be to avoid
unnecessary duplication of documentation. FDA believes that the proposed quality
system regulation requires the minimum documentation necessary to ensure that
safe and effective devices are designed and produced. FDA similarly believes that
maintaining records of results of acceptance activities is imperative to ensuring that
nonconforming product is not used or distributed. FDA has, however, deleted the
requirement for recording the results of inspections and testing from section
820.80(a) because section 820.80(e) requires that the results of all acceptance
activities be recorded. The requirement in subsection (a) was therefore
unnecessary.
3
Several comments stated that proposed section 820.80(b), "Receiving inspection
and testing," did not allow for urgent use of incoming items. The comments said
that urgent use should be permitted if forward traceability is maintained so that
recall and replacement is possible if the material is subsequently found to be
nonconforming.
FDA agrees in part with the comments because FDA has permitted manufacturers
to use incoming items that had not yet been proven acceptable for use, provided
that the manufacturer maintained control of the unapproved items and could
retrieve the product that contained the unapproved items before distribution.
Therefore, the requirement that product "shall not be used or processed until ...
verified" is deleted from section 820.80(b), now entitled "Receiving acceptance
activities." However, FDA emphasizes that while the product can be used in
production prior to verification, it cannot be distributed prior to verification. FDA
20 − 49
will not permit the distribution of unapproved product through an urgent use
provision.
4
One comment stated that the requirements in section 820.80(b) were too specific
and did not allow flexibility.
In addition to the changes noted above, FDA has deleted the requirement that
"individual(s) designated by the manufacturer shall accept or reject incoming"
product. FDA does not believe this requirement is necessary in section 820.80(b)
because section 820.80(e) requires that the identification of the individual(s)
conducting the acceptance activities be recorded.
5
Several comments stated that an absolute requirement under proposed section
820.80(c), "In-process inspection and testing," for in-process testing is inconsistent
with the preamble, which states that an appropriate mix of controls should be
established. Other comments stated that in-process inspection and testing is
unnecessary if the process is validated and the devices are subject to final
inspection.
FDA agrees with the comments in part, but believes that the section as now
written does not mandate in-process inspection and testing. The requirement
states that in-process product must be held until the required inspection and test,
or other verification activities, have been performed. FDA acknowledges that in- ........
process acceptance activities may not be necessary for every device, for example,
medical socks.
6
FDA received a similar comment on proposed section 820.80(d), "Final inspection
and test," which said that the provision requires finished device inspection for all
devices, without defining what inspection is expected. It was alleged that the
section would be interpreted as requiring actual product inspection, which has
been shown to be ineffective as a means of controlling product quality.
FDA has rewritten section 820.80(d) to require that manufacturers establish and
maintain procedures for finished device acceptance to ensure that each production
run, lot, or batch of finished devices meet specified requirements. Manufacturers
have the flexibility to choose a combination of methods, including finished device
inspection and test, provided such methods will accomplish the required result.
7
One comment stated that signatures should not be the only approved method for
identification of the individual(s) responsible for release. The commentor stated
that use of inspection stamps and individual's initials should be allowed.
FDA believes that it is important for the person responsible for release to have
personally documented and dated that release. This cannot be determined through
use of an inspection stamp. FDA has retained the requirement for a signature.
8
Several comments on proposed section 820.80(e), "Inspection and test records"
stated that manufacturers should not be required to record the use of general
equipment in inspection and test records, because this requirement would be
burdensome to large manufacturers who use many common pieces of equipment.
FDA agrees that it may not be necessary to document every piece of equipment
used in acceptance activities. The requirement now provides that equipment used
shall be documented "where appropriate." For some critical operations and
testing, identification of the equipment used will be imperative for proper
investigations into nonconforming product.
9
One comment stated that the record requirements under section 820.80(e) are
overly prescriptive and go well beyond ISO 9001's comparable requirements. The
commentor stated that recordkeeping should be specified by the manufacturer in
the spirit of ISO 9001, and should include only the minimum records necessary to
show that finished device inspections are performed in accordance with established
20 − 50
procedures.
The requirements, as revised, are similar to those required under ISO 9001:1994.
Certain information must be captured on acceptance records for the records to be
useful in evaluating nonconformance. Through many years of experience, FDA
has determined what information it believes to be a minimum requirement for these
records. Section 820.80(e) reflects that determination.
ii. Inspection, measuring, and test equipment
1 One comment stated that it is unclear what is meant by the requirement in section
820.84, "Inspection, measuring, and test equipment" that equipment be capable of
producing "valid results." The comment stated that such equipment may be
"suitable for its intended purpose" and still not always "produce valid results."
FDA believes that the term is commonly understood and notes that it has been in
the CGMP regulation under section 820.61 for 15 years. The requirement is for
the equipment to work properly, thereby providing "valid results."
FDA revised the requirement to make clear that the procedures must also ensure
that the equipment is maintained.
2
A few comments stated that the last sentence in section 820.84(a), "Calibration" is
unnecessary because the requirement for trained personnel is redundant with
section 820.25(a), "Personnel."
FDA agrees and has deleted this sentence.
3
Several comments stated that section 820.84(b), "Calibration standards" should
allow for the use of international standards.
FDA agrees and has rewritten the section to allow for the use of international
standards. The standards used must be generally accepted by qualified experts as
the prevailing standards.
4
FDA has deleted the requirement in section 820.84(c) for calibration records to be
"maintained by individuals designated by the manufacturer" because, on further
reflection, the agency believes such a requirement is unnecessary. As long as the
required records are maintained and displayed or readily available as required, the
objective of the section, ensuring that calibration is performed and acceptable, will
be met.
5
Two comments suggested deleting section 820.84(d) because they believed it was
unnecessary to establish procedures to maintain equipment, since most
manufacturers simply store equipment in protective covers.
As already noted, FDA has moved the requirement for establishing maintenance
procedures into the general requirement in section 820.84. FDA has retained the
specific requirements for the maintenance procedures, however, because some
equipment requires special handling, preservation, and storage. For example, the
temperature and humidity of a room may affect the equipment and procedures
would need to be established taking those factors into account.
FDA has added the requirement for the maintenance of test software in section
820.84(d) to be consistent with ISO 9001:1994, section 4.11.1.
6
Several comments stated that proposed section 820.84(e), "Facilities" should be
deleted because it is redundant with the requirements under section 820.70(g) and
the general requirements of section 820.84.
FDA agrees that general section 820.84 would require procedures to ensure that
equipment is protected from adjustments that could invalidate the calibration, in
that the section requires procedures to ensure that equipment is properly
20 − 51
maintained. This maintenance must ensure that equipment is not inadvertently
adjusted. The additional procedures that require equipment to be routinely
calibrated, inspected, and checked, will also ensure that improperly calibrated
equipment is not used. Therefore, FDA has deleted section 820.84(e). FDA notes
that the failure to ensure against such event would be a violation of section 820.84,
as well as section 820.70(g).
iii. Inspection and test status
1 Several comments on section 820.86, "Inspection and test status" stated that the
requirements of the section were not flexible enough to allow identification of the
inspection and test status of product by various means, given that the requirement
is for the status to be "visible."
FDA agrees that the inspection and test status may be identified by any method
that will achieve the result, which might include acceptable computerized
identification. The section has been rewritten to reflect this intent, and is now
consistent with ISO 9001:1994.
2
FDA has deleted section 820.86(b) which required that records identify those
responsible for release of the product, because the agency believes that the records
required by section 820.80(e) will necessarily identify those responsible for release
of product.
<A NAME="pSubpart I">I. Nonconforming Product (Subpart I)</A>
1 FDA has rewritten section 820.90, "Nonconforming product" to utilize the term
"product" throughout, as defined in section 820.3(s), for both shorthand purposes
and consistency with ISO 9001:1994.
2
One comment suggested deleting the term "inadvertently" and adding the word
"distributed" before "installed" in section 820.90(a).
FDA has deleted th