FDA Proposes New CMC "Regulatory Agreement"

Moheb Nasr, PhD, Director of the newly created Office of New Drug Quality Assessment at the US Food and Drug Administration, has proposed creating a “regulatory agreement” between FDA and sponsors to govern the chemistry, manufacturing, and controls (CMC) sections of new drug applications (NDAs).

Representatives of industry and FDA discussed the proposal at the Oct. 5-7 AAPS Workshop on Pharmaceutical Quality Assessment in North Bethesda, Maryland, as part of a broad examination of FDA’s planned overhaul of the way it reviews CMC submissions and regulates manufacturing quality.

The new agreement could provide a structure for the regulatory flexibility that FDA has said will be possible for manufacturers who demonstrate a thorough scientific understanding of their manufacturing processes. As proposed, the agreement would include binding CMC elements such as critical process parameters or critical quality attributes, and would define the boundaries of a design space within which manufacturers could implement changes with limited or no filing of manufacturing supplements.

During three breakout sessions held to discuss the proposal, workshop participants generally voiced support for a regulatory agreement because it could help all parties-industry sponsors, reviewers, and inspectors-focus on the most important aspects of a CMC application. “In the current system, the entire NDA functions like a regulatory agreement,” noted one industry participant. Participants raised concerns, however, about the legal implications of the term agreement and whether the agreement would end up being an additional requirement or burden on industry. Some also commented that for an agreement to be useful, it must be agency-wide; in other words, inspectors must have the same understanding as reviewers about the meaning and application of the agreement.

During the two-and-a-half-day workshop, attended by 600 people (about two-thirds of whom were from industry and the other third from FDA), participants met in a series of repeated breakout sessions to discuss key concepts underlying Nasr’s proposed “new paradigm” for CMC review. Key topics included the definition and use of design space, the use of pharmaceutical development information in CMC submissions, the handling of postmarketing changes, the use of a comprehensive quality overall summary (QOS) as part of CMC submissions, and whether the QOS could or should be a key tool for review of the submission, or simply an executive summary.

Yukio Hiyama, PhD, of Japan’s National Institute of Health Sciences, said Japan relies on a QOS as the primary review document. “We review the submission in half a day,” he said.

Throughout the meeting, the consensus was that implementing these concepts would be challenging and would require a critical transition period. Helen Winkle, director of the Office of Pharmaceutical Science, noted that in the transition, there would be early adopters, companies that would stay in the current paradigm, and those taking the middle ground, implementing moderate changes. “The middle group will be the hardest to manage,” she said. Winkle noted that the journey to change will require “moving into unfamiliar ground for everyone.”

–Laura Bush