The US Food and Drug Administration requires manufacturers to report postapproval changes to process and product to ensure
drug quality throughout the product lifecycle. Current regulations for drugs and biologics set a fairly low threshold for
reporting, which encourages manufacturers to file supplements in raw materials, production process, equipment, or facilities
if there is any chance a change will affect product quality. Only a relatively short list of changes that have "minimal" potential
of harm can be submitted to the agency after-the-fact in an annual report.
FDA consequently is swamped with postmarketing submissions. Last year industry filed more than 2,600 supplements for new drugs
and biologics. About one-third require agency prior approval, and the rest are changes-being-effected (CBE) submissions which
manufacturers may implement pending FDA approval or after 30 days for a CBE-30 supplement. The Prescription Drug User Fee
Act (PDUFA) requires FDA to review 90% of prior approval supplements within four months and CBE supplements in six months.
The burdensome task of preparing and filing supplements, moreover, apparently discourages manufacturers from upgrading equipment
and modernizing outdated production systems. 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 quality
through the product lifecycle. FDA wants its rules to reward companies that adopt Quality by Design (QbD) approaches and risk
management models with reduced regulatory oversight in terms of modified manufacturing supplement filing requirements and
less frequent plant inspections.
The GMP modernization initiative thus provides a framework for reviewing manufacturing supplement filing requirements with
an eye to reducing the need to review low-risk manufacturing changes. FDA acknowledges that its current policy reflects a
desire for "extensive control over virtually every aspect of the manufacturing process," according to its announcement of
a February public meeting to discuss agency policy. The goal is to permit manufacturers with strong internal change control
systems to have more flexibility to make timely, low-risk improvements in processes without FDA approval. Such a risk-based
approach to post-marketing regulation also would permit agency staffers to focus oversight on those changes most likely to
have serious consequences for product safety and quality.
Helen Winkle, director of the Office of Pharmaceutical Science (OPS) in the Center for Drug Evaluation and Research (CDER),
acknowledged at the February meeting that FDA feels there is a "lack of flexibility" in current rules and wants to allow more
manufacturing changes to be made without coming to the agency. A first step is to revise current postapproval changes regulations
for drugs (section 314.70 of federal regulations), while also considering how to extend such a policy to biologics that are
governed by different regulations (section 601.12). The rules are very similar for both product categories, and CDER officials
would like a common approach for regulating well-characterized biotech therapies now under their purview. Although it may
be more difficult to reduce oversight of manufacturing changes for more complex biologics, officials in the Center for Biologics
Evaluation and Research (CBER) are examining ways to update postapproval reporting policies for vaccines, plasma derivatives,
and other biologics. CBER is revising its changes-to-be reported guidance for biological products to clarify opportunities
for reduced reporting of less risky changes, such as some modifications to water systems or adoption of new potency tests.
Meanwhile, CDER is reviewing comments from industry and other interested parties to the issues raised at the February public
meeting, as well as a subsequent workshop on FDA's Pharmaceutical Quality Initiative that was cosponsored by AAPS and ISPE.
And further discussion is scheduled for the May meeting of FDA's Pharmaceutical Sciences Advisory Committee.
Although there is broad agreement that the current supplement review system is outmoded and over-prescriptive, revising the
rules will not be that easy. Up until the 1990s, most postapproval manufacturing changes required FDA approval, particularly
those involving biologics. The agency launched initiatives in the mid-1990s to reduce reporting requirements for certain manufacturing
changes to drugs and certain well-characterized biotech products, efforts that were codified by the FDA Modernization Act
of 1997 (FDAMA).