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.
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
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
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.
Sorting out supplements
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.