FDA to Review Manufacturing Change Regulations

The Food and Drug Administration (Rockville, MD, www.fda.org) has announced a public meeting on February 7, 2007, to solicit comments that FDA should consider when developing revisions to its regulations regarding chemistry, manufacturing, and controls (CMC) supplements, and other changes to approved marketing applications for human drugs. The meeting is part of the agency’s effort to make it easier for companies to improve their manufacturing operations postapproval while still ensuring product quality.

The rules governing changes to manufacturing processes for approved products appear in 21 CFR 314.70. Section 314.70, as amended in April 2004, requires manufacturers to assess the effects of manufacturing changes on the identity, strength, quality, purity, and potency of a drug as those factors relate to the safety or effectiveness of the product, and categorizes all changes beyond the established variations into one of three groups-major, moderate, or minor.

Major changes require an applicant to submit and receive FDA approval of a supplement before distribution of the product with the manufacturing change. Moderate changes require submitting a supplement at least 30 days before distribution of the product or, in some cases, submitting a supplement at the time of distribution. Minor changes require notifying FDA of the changes only in an annual report.

FDA is now evaluating how it could revise section 314.70 to allow for more manufacturing changes to be made without prior FDA approval, using a firm’s internal change control system. It also is evaluating how it could revise the section to allow for consideration of risk-based approaches, based on manufacturing process understanding, including prior knowledge of similar products, and overall quality systems to provide an enhanced risk-based approach to the CMC regulatory process.

As FDA notes in the meeting announcement, the agency traditionally has exercised extensive control over every aspect of the manufacturing process, and that approach has contributed to pharmaceutical companies’ reluctance to change their manufacturing processes and equipment-even to improve them. Since the launch of the “Pharmaceutical cGMPs for the 21st Century” initiative in 2002, which included a guidance on how to apply process analytical technology, the agency has been trying to encourage companies to apply modern tools to help detect and correct manufacturing deficiencies, as well as risk management approaches to apply resources to the areas that pose the greatest potential risk to drug quality.

At the public meeting, FDA will solicit comments on issues that should be considered if FDA decides to proceed with revisions to section 314.70. Some of the discussions at the public meeting will focus on the feasibility of the agency to move toward a more risk-based oriented strategy for regulating postapproval CMC changes outside of the formal application review process and the inspectional approaches the agency might consider to evaluate manufacturing changes while ensuring public safety.

A three-day meeting on FDA’s new risk-based approach will be held in Bethesda, MD, February 28–March 2, 2007. That session is cosponsored by the American Association of Pharmaceutical Scientists and the International Society for Pharmaceutical Engineering.