GMP / QS regulation

Introduction
The current Good Manufacturing Practice (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,
manufacture, packaging, labeling, storage, installation, and servicing of finished 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 contained in Title 21 Part 820 of the Code of Federal Regulations. 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 Good Manufacturing Practice (GMP) / Quality System Regulation page has a link to the
Medical Device Quality Systems Manual: A Small Entity Compliance Guide, First Edition
which details the requirements of the new QS regulation and provides detailed guidance in the
following areas:
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.
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, 21
CFR 820.5 of the QS regulation. 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 21 CFR 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 the 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, 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.
Applicability of the GMP
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 21 CFR 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 21 CFR 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.
GMP 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 ( 21 CFR
820.198) or from general requirements concerning records 21 CFR 820.180. Sterile devices are
never exempted from GMP requirements. Medical devices manufactured under an
investigational device exemption (IDE) are not exempt from design control requirements under
21 CFR 820.30. 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 intraocular lens (IOL) under an IDE and meets the requirements of the
IDE regulation for IOL's (except for design controls 21 CFR 820.30); 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.
Types of Establishments Exempt from GMP
Component Manufacturers
A "component" is defined by 21 CFR 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 21 CFR 820.1 (a)(1). 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 as detailed under Manufacturers of Accessories .
Types of Establishments Subject to the GMP
Remanufacturers
Custom Device Manufacturers
Contract Manufacturers
Contract Testing Labs
Repackagers, Relabelers, and Specification Developers
Manufacturers of Accessories
Initial Distributors
Remanufacturers
A remanufacturer as defined in 21 CFR 820.3 (w) is any person who processes, conditions,
renovates, repackages, restores, or does any other act to a finished device that changes the
finished device's performance or safety specifications or intended use. 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 device master records, rebuilding
per the device 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 812.3 (b)) defines 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. 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
according to the manufacturer's specifications 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 purchasing assessment, the finished device
manufacturer is responsible for assuring that equipment and procedures used by a lab are
adequate and appropriate (21 CFR 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 820.3(o) and 21 CFR Part 807, Establishment Registration and Device
Listing for Manufacturers of Devices. Some definitions from 21 CFR 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.Distribution of domestic or 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 21 CFR 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
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 [21 CFR 820.30 (h)]. This activity, in turn,
requires an adequate device master record (21 CFR 820.181) and adequate document change
control [21 CFR 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.
Manufacturers of Accessories
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 are discussed in 21 CFR Part 807, Establishment Registration and Device
Listing for Manufacturers of Devices [21 CFR 807.20 (a)(5)]. These devices, 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.
Initial Distributors of Imported Devices
An initial importer (or initial distributor) takes first title to the devices imported into the U.S. and
further distributes the product. 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 Medical
Device Reporting, 21 CFR Part 804 or 803. 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 21 CFR 820.198, Complaint Files.