INTRODUCTION
FLEXIBILITY OF THE GMP
MANUAL CONTENTS
GMP APPLICATIONS AND EXEMPTIONS
Exemptions
Component Manufacturers
Remanufacturers
Custom Device Manufacturers
Contract Manufacturers
Contract Testing
Repackagers, Relabelers, and Specification
Developers
Initial Distributors of Imported
Devices
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.
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 failureto 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.
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, daytoday
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.
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. obtaining information on GMP requirements;
2. determining the appropriate quality system needed to control
the design, production and distribution of the proposed device;
3. designing products and processes;
4. training employees;
5. acquiring adequate facilities;
6. purchasing and installing processing equipment;
7. drafting the device master record;
8. noting how to change the device master records;
9. procuring components and materials;
10. producing devices;
11. labeling devices;
12. evaluating finished devices;
13. packaging devices;
14. distributing devices;
15. processing complaints and analyzing service and repair data;
16. servicing devices;
17. auditing and correcting deficiencies in the quality system; and,
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 xray
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 healthrelated 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
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:
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.
Accessory devices [807.20(a)(5)] such as hemodialysis tubing or
major diagnostic xray components, that are packaged, labeled,
and distributed separately to a hospital, physician, etc., for
healthrelated 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
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:
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 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.
Updated January 1, 1997
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