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.
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.
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.