Washington Report: Big Production

Traditionally A Low-profile, unglamorous operation at pharmaceutical companies, drug manufacturing has emerged as a critical issue in improving product safety and market success. In the wake of last year's flu vaccine shortage, a recent spate of product recalls, and the supply problems that are currently overwhelming makers of pandemic therapies and treatments, it has become increasingly obvious that today's costly and wasteful production systems need to be replaced. FDA is looking specifically at the quality-by-design approach (QbD), which shifts the emphasis from testing the final product to building quality into the manufacturing process from the beginning.

Jill Wechsler

Drug manufacturing now accounts for 25 percent of industry expenses—as much as R&D—and it takes years to bring up a new production site, explained FDA deputy commissioner Janet Woodcock at an October workshop sponsored by FDA and the American Association of Pharmaceutical Scientists (AAPS). The results: drug shortages, slowed development, delayed access to new products, and intensive regulatory oversight. The agency reviews many more post-approval supplemental applications than should be necessary, and reviewers make inconsistent decisions and fail to adjust oversight to product risk.

Woodcock and colleagues agree that in view of FDA's limited resources and growing workload, the agency can no longer afford to spend months assessing applications, or weeks inspecting manufacturing facilities. While FDA may be receiving fewer new drug applications (NDAs) for truly innovative therapies, it has been overwhelmed this past year with some 800 abbreviated NDAs (ANDAs) for generic drugs and thousands of supplements. And many of these applications involve complex products that require high-level expertise to evaluate.

FDA's initiative to modernize good manufacturing practices (GMPs) has built a foundation for the QbD approach. The three-year GMP exercise concluded its first phase last fall when the agency issued several documents describing how industry should assess product risk, establish systems to correct problems, engineer manufacturing changes, and create internal quality units to manage these activities. Now FDA's Center for Drug Evaluation and Research (CDER) is implementing these concepts by reorganizing agency review activities (see "CEDR Reorganizes"). The aim is to reward manufacturers that develop modern control and test methods based on a scientific understanding of critical product attributes. Such strategies will permit continuous improvement in process and product, with less regulatory oversight.

CDER Reorganizes

This quality approach also applies to generic drugs and biotech therapies, and may be the key to establishing a pathway for approving generic versions of biologics. At the annual meeting of the Generic Pharmaceutical Association (GPhA) in October, Helen Winkle, director of CDER's Office of Pharmaceutical Science (OPS), linked efforts to apply QbD principles to generic drugs with establishing a scientific rationale for follow-on proteins. OPS aims to develop a "common scientific decision framework for addressing uncertainty" in new drugs, generics, and biotechnology products, Winkle said.

Cold Feet

To implement its new approach, FDA has to persuade pharma companies to share information on QbD activities with the Agency. Many manufacturers already are using innovative methods to design formulations and to adjust process parameters. But they are reluctant to tell FDA about the fits and starts of product development for fear that information about formulation failures and rejected test methods will only raise new questions from agency reviewers and inspectors.

To overcome these concerns, CDER has launched an NDA pilot program that offers "early adopters" extra hand-holding and speedier review of applications that contain QbD information. Several manufacturers have signed up, and CDER would like to have 12 applications on deck by next March.

FDA officials also are floating the idea of negotiating "regulatory agreements" with manufacturers for newly approved drugs. Woodcock suggested at the AAPS workshop that a sponsor and FDA could agree on critical product attributes at time of approval and reduce oversight later for post-market changes that occur within those established parameters.

Team Approach

To deal with more science-based applications, OPS is overhauling its review process to provide more consistent and more timely approval decisions. This will be the case particularly for applications filed electronically and based on the Common Technical Document (CTD), a uniform market application for drugs and biologics that is being adopted by regulatory authorities around the world. The CTD summary provides a format that gives FDA most of the data needed for review, with links to supporting documentation, such as batch records and stability data. The summary includes a pharmaceutical development report in which an applicant can describe how it arrived at its final formulation, specifications, and manufacturing approaches, including failures and false starts.

To assess electronic CTDs efficiently, OPS is making changes in how it reviews chemistry and manufacturing information in applications. Instead of leaving the job to one chemist, NDAs will be handled by teams that can draw on specialists when appropriate. In addition, a separate review office will process manufacturing supplements under a new system that will cull out low-risk submissions that may not require agency evaluation. This effort to reduce the number of manufacturing supplements requiring prior approval will increase reliance on company annual reports to monitor and report quality-related events, such as batch failures and out-of-specification results.

Asking Questions

ANDAs have been experiencing exponential growth at a time when FDA resources have remained static. As a result, there has been talk about instituting user fees for generics makers, according to CDER director Steven Galson. While that debate moves forward, OPS' Office of Generic Drugs (OGD) is proposing a new review system to streamline the review of ANDAs while encouraging manufacturers to implement quality-by-design systems. Part of the plan is a question-based review (QbR) system that will guide reviewers in assessing applications. The questions will also alert manufacturers to issues that OGD considers most critical in documenting drug quality, and provide a format for manufacturers to explain critical process parameters and how drug substance and formulation variables affect product performance.

Although OGD is not requiring companies to use the new system, staffers say that applications based on the old format or submitted on paper will be more difficult to review. Conversely, generic drug makers filing e-applications with complete development reports may move through the process faster. And manufacturers that include QbD information in their applications may receive a lower "risk score" for new products—which means more latitude in making post-market manufacturing changes without prior approval.

Despite promises of regulatory relief, manufacturers have not been jumping on the quality assessment bandwagon. Pharma companies are only beginning to use the CTD, and electronic CTDs are rare. In the end, each manufacturer has to decide whether possible reductions in regulatory burden justify the upfront costs of implementing QbD systems. Such decisions may differ for legacy products compared with new development programs. Worldwide acceptance of quality-based manufacturing systems by regulators may make new quality approaches more attractive, as would evidence that QbD approaches can yield safer and more reliable medicines for everyone.

Jill Wechsler is PharmExec's Washington correspondent. She can be reached at jwechsler@advanstar.com