May 1, 1996

5 Min Read
A BRIEF HISTORY OF FDA GOOD MANUFACTURING PRACTICES

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W. Fred Hooten, Regulatory and Compliance Consultant, Hogan & Hartson (Washington, DC)

Two years after the Medical Device Amendments of 1976 were enacted, FDA issued its final draft of the medical device good manufacturing practices (GMP) regulation, a series of requirements that prescribed the facilities, methods, and controls to be used in the manufacture, packaging, and storage of medical devices. Except for an update of organizational references and revisions to the critical device list included in the 1978 final draft's preamble, these regulations have remained virtually unchanged since they were published in the Federal Register on July 21, 1978. That does not mean, however, that their interpretation has not changed.

Several key events in the last 18 years have influenced the way FDA has interpreted and applied these regulations. The first occurred in 1987 with FDA's publication of the "Guideline on General Principles of Process Validation," which not only provided guidance but advised industry that device manufacturers must validate other processes when necessary to ensure that these processes would consistently produce acceptable results.

Two years later, in 1989, FDA published a notice of availability for design control recommendations titled "Preproduction Quality Assurance Planning: Recommendations for Medical Device Manufacturers." These recommendations fulfilled a promise made by the CDRH director to a congressional hearing committee to do something to prevent device failures that were occurring due to design defects, resulting in some injuries and deaths. It was also a warning to industry that FDA was moving to add design controls to the GMP regulation.

The next year, FDA moved closer to adding design controls, publishing the "Suggested Changes to the Medical Device Good Manufacturing Practices Regulation Information Document," which described the changes the agency was proposing to make to the GMP regulation. Comments asserted that FDA did not have the authority to add design controls to the GMPs, a point that became moot later that year when the Safe Medical Devices Act of 1990 (SMDA) became law. SMDA amended section 520(f) of the Federal Food, Drug, and Cosmetic Act to add "preproduction design validation" controls to the device GMP regulation.

SMDA also added to the FD&C Act a new section 803, which encouraged FDA to work with foreign countries toward mutual recognition agreements for the GMP and other regulations. Soon afterward, FDA began to actively pursue the harmonization of GMP requirements on a global basis.

Over the following two years, FDA took steps to ensure that manufacturers with device applications under review at the agency were also in compliance with GMPs. The first step was taken in 1991, when CDRH established its "reference list" program for manufacturers with pending premarket approval (PMA) applications, ensuring that no PMA would be approved while the device maker had significant GMP violations on record. In 1992 the program was extended to all 510(k)s. Under this umbrella program, 510(k)s would not be processed if there was evidence on hand that the site where the 510(k) device would be manufactured was not in compliance with GMPs.

On November 23, 1993, FDA acted on comments it had received three years earlier regarding its "Suggested Changes" document, publishing a proposed revision of the 1978 GMPs in the Federal Register. The proposal incorporated almost all of the 1987 version of ISO 9001, the quality systems standard compiled by the International Organization for Standardization. While supporting adoption of ISO 9001, most of the comments received from industry objected to the addition of proposals such as applying the GMP regulation to component manufacturers.

In July 1995 FDA published a working draft of the proposed final revised GMP regulation. As stated in that draft, the two reasons for the revision were to bring about the addition of design and servicing controls, and to ensure that the requirements were made compatible with those of ISO 9001 and EN 46001 (ISO 13485), the quality standard that manufacturers must meet if they select the European Union directives' total quality system approach to marketing.

Among the proposals in this version that drew the most fire from industry were the application of GMPs to component manufacturers and use of the term end of life, which was intended to differentiate between servicing and reconditioning. FDA agreed to delete most, but not all, of the objectionable requirements during an August 1995 FDA-industry meeting and the GMP Advisory Committee meeting in September 1995. The end-of-life concept was deleted from the GMPs but was retained in the medical device reporting regulation.

As the 1995 working draft now stands, it is very similar to the proposed ISO 13485 standard. To further harmonize the two documents, FDA's July 1995 working draft includes additions that incorporate the requirements of the 1994 revision of ISO 9001 that were not in the 1987 version.

FDA expects to publish a final GMP regulation in the Federal Register by the summer of 1996. Production requirements of the revised GMPs will probably be effective 60 to 90 days after publication of the final regulation, with the design and service requirements probably effective a year after publication.

Other changes are in the offing at FDA, some of which could help bridge the gap between the agency and industry. FDA has indicated that GMP inspections might be made by third parties. If that happens, these inspections would probably begin on a small scale with third parties doing follow-up to nonviolative inspections. But eventually third parties could play an important role in mitigating delays from FDA's reference list, which, while not now referred to by that name, is still in effect and not likely to be dropped by the agency. Although review of a 510(k) is not affected by the manufacturer being on the list, a 510(k) will not be approved until the manufacturing site is found to be in GMP compliance. The availability of third-party auditors to inspect those sites might speed the review process under those circumstances.

Also in the future is a training course for GMP specialists being prepared by the Association for the Advancement of Medical Instrumentation. If this course were incorporated into the FDA investigator certification training, it could help ensure that the GMP regulation is interpreted and applied uniformly by FDA, consultants, and the device industry.

W. Fred Hooten was formerly director of the Division of Enforcement III in the Office of Compliance at FDA's Center for Devices and Radiological Health (1992­1994).

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