Washington Report: Big Production

Manufacturing costs too much and is cumbersome to regulate. FDA's answer: Quality by design.
Dec 01, 2005


Jill Wechsler
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.

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.


CDER Reorganizes
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.

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.