These notes are based in part on the Medical Device Quality Systems Manual: A Small Entity Compliance Guide, 1st edition by Andrew Lowery, Judy Strojny, and Joseph Puleo of the FDA's Division of Small Manufacturers Assistance, Office of Health and Industry Programs (HSS Publication FDA 97-4179, December 1996). This manual is an update of Medical Device Good Manufacturing Practices Manual, 5th Edition (HHS publication FDA 91-4179) and incorporates changes required by the Safe Medical Devices Act of 1990 and the Medical Device Amendments of 1992.
The regulation described here is 21 CFR Parts 808, 812, and 820 (Medical Devices; Current Good Manufacturing Practice (CGMP) Final Rule; Quality System Regulation) published in the Federal Register, Vol. 61, No. 195 on October 7, 1996. The current GMP requirements was harmonized with the previous (1994) version of the ISO 9000 series quality standards. The FDA GMP requirements are slightly more extensive than ISO 9000 series standards because they include extensive coverage of labeling, and complaint handling. The current GMP regulation was promulgated under section 520 of the Food, Drug and Cosmetic (FD&C) Act.
The Quality System (QS) regulation and the basic Good Manufacturing Practices (GMP) requirements apply to all manufacturers and distributors of 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 Medical Device Quality Systems Manual: A Small Entity Compliance Guide, 1st edition to assist manufacturers in complying with the requirements. 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). 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 "component" is defined by 820.3(c) as "any raw material, substance, piece, part, software, firmware, labeling, or assembly that 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.
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. The QS regulation applies to their manufacture.
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)]. While custom devices are not exempt from the GMP requirements, current FDA policy is to not inspect manufacturers of custom devices. Manufacturers of custom devices should comply with the GMP considering the benefits it provides and flexibility it allows. This exemption was recently abused by some medical laser manufactures. The FDA has since been quite aggressive regarding what constitutes a custom device.
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 also responsible for maintaining a complaint file and processing complaints.
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 |
The Quality System regulation indicates the required end results rather than specifically prescribing how manufacturers are to comply with the regulation. It is the responsibility of the manufacturers to use good judgment when developing quality systems that appropriately applies the QS regulation to their specific products and operations.
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 must ensure that the quality policy is understood, implemented, and maintained at all levels of the organization. This means each manufacturer must establish the appropriate responsibility, authority, and interrelation of all personnel who manage, perform, and assess work effecting quality, and provide the independence and authority necessary to perform these tasks.
The quality system must 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.
Design Controls -- The QS requires documentation and management of the interfaces among groups, personnel training, design planning, development of specifications (design input), design review, design output, design verification (confirmation that the design output meets the design input requirements) and validation (confirmation by examination and provision of objective evidence that the particular requirements for the intended use can be consistently fulfilled).
Process Validation -- The QSR requires establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.
Personnel -- The QSR requires personnel involved in design, manufacturing, quality assurance, auditing, complaint processing, servicing, etc. be properly trained, both by education and experience.
Buildings and Environment -- The QSR requires the buildings and environment in which components, devices and records are received, processed, built or stored be controlled so that finished devices will consistently meet the specifications established by the manufacturer.
Equipment and Calibration -- The QSR requires each manufacturer develop, conduct, control and monitor production processes to ensure that devices conform to their specifications. All equipment used to manufacture a device must be appropriately designed, constructed, placed and installed to facilitate maintenance, adjustment, cleaning and use.
Device Master Record (DMR) -- The QSR requires all of the routine documentation required to manufacture devices that will consistently meet company requirements be kept in the DMR. The DMR is a compilation of records containing the procedures and specifications for a finished device. The design output forms the basis of the DMR. 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 users of the documents.
Document and Change Control -- The QSR requires formal procedures be established for changes to documents that make up the DMR. These change control 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, 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.
Purchasing and Acceptance Activities -- The QSR requires the ability of component suppliers, consultants and contractors to meet specified requirements be documented. Possible appropriate methods of accomplishing this goal include audits, checking with other clients, and previous performance data. If prior assessment is not possible, the manufacturer should assess the service as it is being performed. Assessments must be documented. Procedures for accepting incoming product must also be established and maintained. Various acceptance activities may include inspections, tests, and other forms of verification.
Labeling -- The QSR requires devices be properly labeled. Proper labeling includes adequate directions for use (except for prescription devices), sterility information . Labeling also must not be false or misleading in any particular. The wording and integrity of labels also must be appropriate for the intended use of the device. Labels also must be controlled to assure that they are correct, current and are applied to the correct devices. All written, printed or graphic matter on the device or any of its containers or wrappers, or accompanying the device is considered to be labeling.
Product Evaluation -- The QSR requires documented evidence showing 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.
Packaging -- The QSR requires medical device packaging that protects devices during handling and shipping, and from the environment and microorganisms until the packaging is opened. This includes allowing for any necessary sterilization. Packaging may 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.
Storage, Distribution and Installation -- The QSR requires controls be in place to assure that only correctly labeled, packaged and approved finished devices are distributed and, where appropriate, installed. Manufacturers should use a first-in, first-out (FIFO) distribution system when fitness for use of a device deteriorates over time. When a controlled environment is necessary to prevent abnormal deterioration of a product, the environment should be specified, controlled, and monitored according to specifications in the device master record. Installation requires verification that the device meets acceptance criteria.
Complaints -- The QSR requires manufacturers to review, evaluate and, when appropriate, investigate complaints. Manufactures must establish and maintain written procedures describing the process used to perform these activities and designate a responsible individual or entity to perform these tasks. A complaint is defined 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" in Section 820.3(b) of the regulation.
Servicing -- The QSR requires service be conducted by appropriately trained and experienced service personnel and verification that the serviced device meets acceptance criteria. 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.
Quality Systems Audits -- The QSR requires that a documented independent inspection and review of a quality system be 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.
Factory Inspections -- Section 704(a) of the Food, Drug, and Cosmetic (FD&C) Act gives FDA the authority to conduct GMP inspections of medical device manufacturers. An FDA investigator examines facilities, manufacturing processes, records and corrective action programs during these inspections. The results provide information necessary to evaluate a manufacturer's compliance with the device QS regulation (21 CFR 820).