Down with Supplements! - Pharmaceutical Technology

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Down with Supplements!
FDA is buried in postapproval manufacturing submissions and seeks to reduce the scope of changes that require agency scrutiny.

Pharmaceutical Technology

OPS director Helen Winkle acknowledged that FDA feels there is a "lack of flexibility" in the current rule and wants to allow more manufacturing changes to be made without notifying the agency. "We're inundated by supplements," she commented at the public meeting. FDA is reviewing and evaluating comments from industry and other interested parties. Following the February meeting, FDA sought industry input on these issues at a workshop on FDA's Pharmaceutical Quality Initiatives, which was cosponsored by the American Association of Pharmaceutical Scientists and the International Society of Pharmaceutical Engineers. Further discussion is scheduled for the May meeting of FDA's Pharmaceutical Sciences Advisory Committee. The agency plans to revise current regulations to permit a more flexible regulatory approach. New guidances would provide details for reporting different kinds of postapproval changes based on a company's quality-control capabilities.

Postapproval process

This latest effort to modify and clarify postapproval changes policy is not without precedent; FDA and industry have been collaborating since the early 1990s on ways to update the supplement process. FDA issued its first scale-up and postapproval changes guidance in 1995, which modified reporting requirements for changes in immediate-release solid oral dosage forms of new drugs and generics. Additional guidances reduced reporting requirements for low-risk changes in modified release, semisolid dosages and bulk active ingredients. FDA also issued new policies permitting reduced oversight of any minor changes in biotechnological manufacturing processes.

The FDA Modernization Act of 1997 codified agency authority to make such revisions in postapproval reporting requirements and sought rules to clarify a streamlined postapproval changes policy. After a long rule-writing and comment process, FDA published final rules in 2004 for reporting major, moderate, and minor changes to approved drugs, including generic products. Major changes require FDA prior approval, but minor changes can be described in an annual report and need no supplemental filing.

Sorting out supplements
Moderate changes tend to fall into a gray area. These have to be reported in a changes-being-effected (CBE) supplement that FDA reviews, but the changes can be implemented pending approval. Many moderate changes require a CBE-30 supplement, which establishes a 30-day waiting period during which FDA can review and block a change if warranted. FDA has issued additional guidance documents that describe whether a CBE-30, CBE, or prior-approval supplement should be filed for specific changes to drug components, manufacturing sites, production processes, product specifications, container closure systems, and labeling.

The new regulation and guidances, though, were out of date even before they were published. Not only do they ignore the relationship between company quality-control systems and postapproval regulations, but sponsors find it difficult to determine which changes require which kind of supplements, particularly when it comes to CBEs. So, FDA officials are going back to the drawing board to write new rules that better reflect current FDA risk-based regulatory approaches and scientific advances in manufacturing and quality control.

Meeting time frames

The current postapproval review system also imposes a heavy burden on FDA staff. The Prescription Drug User Fee Act sets specific performance goals for reviewing manufacturing supplements for new drugs and biologics. CDER and the Center for Biologics Evaluation and Research review prior-approval supplements within four months and CBE supplements in six months, but timely review is a continuing challenge.

CDER's Office of New Drug Quality Assessment reorganized last year to improve its ability to apply a pharmaceutical quality-assessment system to the application-review process. One important change was to establish a separate Division of Post-Marketing Evaluation (DPME) to review the 1800 supplements CDER receives each year for new drugs, about one third of which require prior approval. In the first year or two following market approval, manufacturers tend to submit two or three prior-approval supplements, primarily to implement important changes in manufacturing systems or facilities and in production-control systems.


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