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The challenge will be to design a system that is flexible, yet appropriate, for the broad range of biological products and the varying quality control capabilities of different manufacturers.
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and filing supplements, moreover, apparently discourages manufacturers from upgrading equipment and modernizing outdated production systems.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).
That legislation divided manufacturing supplements into three categories: "major" changes require prior approval by FDA, while "minor" changes can be described in an annual report and need no supplemental filing. About two-thirds of supplements fall into the gray area of "moderate" changes, which require CBE and CBE-30 supplements. It took FDA years to issue new regulations implementing this policy, along with additional guidance describing 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. Unfortunately, manufacturers continue to have problems determining which changes require which kind of supplement. So FDA officials propose to start all over with new rules that better reflect current FDA risk-based regulatory approaches and scientific advances in manufacturing and quality control.
Some manufacturers propose eliminating CBE supplements altogether and providing needed information on moderate changes in annual reports. CBE supplements for packaging and testing site changes or for adopting equivalent or superior analytical methods appear unnecessary. At a minimum, FDA and industry see a need to redefine "major" and "moderate" changes and other commonly used terms. Phrases such as "moderate potential to adversely affect" a product are overly vague because almost any change has some potential to affect a product.
While broad reductions in CBE supplements may be appropriate for conventional drugs, such a general revision may not fit regulatory needs for biologics. CDER rejects only a handful of CBEs for drugs, but about 20% of postapproval changes for biologics raise questions and lead to requests for additional data. One idea for biologics is to use policies governing comparability protocols as a basis for managing postapproval changes. The challenge will be to design a flexible system, appropriate for the broad range of biological products and varying quality control capabilities of different manufacturers.
An important issue for manufacturers is for FDA to retain its current postapproval changes policy for legacy products that have extensive historical data on process parameters but little incentive to adopt QbD approaches. FDA acknowledges the need to continue aspects of the existing regulatory scheme to "accommodate those manufacturers who choose to continue operating within the current regulatory framework." But it will be a challenge for the agency to implement a modified approach for new products adopting QbD and design space approaches, while retaining current policies for older products with established manufacturing systems.
Policy revisions that rely more on annual reports to record postapproval-change information also point to the need to re-evaluate the format and content of these documents. Manufacturers also urge better integration of annual reports, filed with FDA, and annual product reviews, kept onsite for inspection. A reduction in prior approval and CBE supplements also shifts more responsibility to FDA's field force.
Jill Wechsler is BioPharm International's Washington editor, 301.656.4634, firstname.lastname@example.org