To ensure drug quality throughout a product's life cycle, the US Food and Drug Administration requires manufacturers to report
changes in processes or products that could have even a moderate effect on product performance or safety. Current regulations
(21 CFR 314.70) set fairly strict guidelines for reporting postapproval changes. Companies file supplements even for routine revisions
in raw materials, production processes, equipment, and facilities if there is any chance a change will affect product quality.
Only a relatively short list of changes that have "minimal" potential for harm can be submitted to the agency after the fact
in an annual report.
FDA consequently is swamped with postmarketing submissions. Industry filed some 6000 supplements for new drugs, biologics,
and generics last year. About 2000 involve "major" changes that require FDA prior approval before a company can distribute
drugs produced by the altered system (see sidebar, "Sorting out supplements"). The supplement volume has grown steadily and
may accelerate more as industry mergers and reorganizations lead to plant closings and shifts to new manufacturing sites and
Risk and quality
The task of preparing and filing supplements is a huge burden for industry and FDA. Consequently, manufacturers think twice
about upgrading equipment or revising processes, even if it means forgoing opportunities to modernize outdated systems and
improve formulations. That reluctance runs counter to FDA's initiative to modernize current good manufacturing practices (CGMPs)
for the 21st century, which encourages manufacturers to adopt modern quality-control tools and systems able to ensure consistent
product quality, safety, and efficacy. FDA advocates a quality-by-design (QbD) approach for achieving the "desired state"
of quality drug manufacturing—one in which companies apply extensive knowledge about critical product and process parameters
and quality attributes to achieve continuous improvement throughout the product life cycle.
In Washington This Month
This CGMP-modernization initiative is five years old and provides a framework for taking a new look at manufacturing-supplement
filing requirements. FDA acknowledges that its current policy reflects a desire for "extensive control over virtually every
aspect of the manufacturing process," according to the announcement of a February public meeting to discuss agency proposals
for revising policies governing supplements and manufacturing changes. Companies adopting QbD approaches ideally would be
rewarded with reduced regulatory oversight in terms of modified manufacturing supplement filing requirements and less-frequent
FDA officials consequently are looking for ways to reduce the volume of supplements involving relatively low-risk changes
to process and product. That involves considering how a manufacturer's internal change-control system may allow more manufacturing
modifications to be made without FDA prior approval or oversight, explained Jon Clark, deputy director for policy at the Office
of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER).
Instead of a prescriptive and rules-based approach, FDA wants to leverage advances in manufacturing science to reduce the
need to review low-risk manufacturing changes. Manufacturers would gain more flexibility to make timely, low-risk improvements
in processes, and FDA would make more efficient use of its resources by not having to review many supplements. A risk-based
approach to postmarketing regulation also would permit agency staffers to focus oversight on those changes most likely to
have serious consequences for product safety and quality.