Medical Device Link.

Originally Published PMPN April 2003

REGULATORY FOCUS

FDA focuses efforts on draft guidances for 21 CFR Part 11 and comparability protocols.

Erik Swain

As part of its efforts to revise the Current Good Manufacturing Practices (CGMP) program, FDA has undertaken several initiatives. Among them are revamping guidances on electronic records and signatures and offering guidance on comparability protocols for postapproval changes.

A summary progress report, which was issued by the agency in February 2003, can be viewed at http://www.fda.gov/cder/gmp/21stcenturysummary.htm. It states that, among other things, the agency has accomplished the following:

• The issuance of a draft guidance clarifying the scope and application of 21 CFR Part 11, which covers electronic records and signatures. For more on this guidance, see the news article in this issue.
• The issuance of a draft guidance showing manufacturers when and how to submit comparability protocols for postapproval changes, and what should be in them. The guidance can be viewed at http://www.fda.gov/cder/gmp/5427dft.PDF.

A comparability protocol is a well-defined written plan for assessing the effect of specific postapproval changes on the identity, strength, quality, purity, and potency of a drug. It specifies the tests that will be performed, the analytical procedures that will be used, and the acceptance criteria that will be defined for any manufacturing or packaging changes. Its inclusion may allow for a reduced reporting category. It may also make FDA less likely to request additional information to support proposed changes, possibly allowing for faster implementation.

The new guidance outlines when a comparability protocol might be useful and when it is inappropriate. It also covers how it should be submitted, what to do if acceptance criteria are not met, how to ensure it does not become obsolete, how to revise it, and what information to include.

• A change in policy on warning letters. Beginning March 1, 2003, all drug CGMP warning letters will be reviewed by the relevant center before being sent. Any inconsistencies in the enforcement from field office to field office or inspector to inspector may be resolved before a warning letter is issued.
• The possible creation of dispute resolution procedures pertaining to CGMPs. A working group has proposed an informal dispute resolution process that would occur prior to the formal issuance of a Form-483 observation. Firms would be encouraged to discuss with an investigator any observation that investigator noted that the firm believes is not justified from a scientific standpoint. The investigator would then consult with the relevant district or center if needed. If the dispute is not resolved at that stage, the firm would then be allowed to request formal dispute resolution with the district office. If the district agreed with the firm, the firm would be notified and the process would be resolved. If it disagrees with the firm, the district would forward the issue to the relevant program center, which would render a final decision. If a firm disagrees with that decision, it would be able to appeal to a proposed FDA dispute resolution panel.
• The clarification of the purpose of Form 483. Issuances will now be accompanied by a notice that states the observations are "inspectional observations, and do not represent a final agency determination regarding your compliance." An agency phone number will be provided in case of objections.
• The reorganization of the Office of Compliance. The new organization chart can be found at http://www.fda.gov/cder/Offices/Compliance/OffofComplianceorgchart.htm.
• The formal introduction of product specialists to inspection teams. A working group found that a pilot program, because of the extra scientific input, added value to the regulatory process, and a formalized program would ensure a consistent risk-based approach for all drug centers. It recommends defining the areas where specialists are needed and outlining how they should be used.
• The likely implementation of a "Pharmaceutical Inspectorate," a group of highly trained experts that would perform quality inspections of high-risk firms.

Comments on the summary progress report or on the activities of the initiative should be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number 03N-0059.

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