Drug manufacturing now accounts for 25 percent of industry expenses — as much as R&D — and it takes years to bring up new production site to full capacity, explained FDA deputy commissioner Janet Woodcock at an October workshop sponsored by FDA and the American Association of Pharmaceutical Scientists (AAPS). The current process, she added, results in product shortages, slowed drug development, delayed access to new therapies and intensive regulatory oversight marred by inconsistent decisions and a failure to adjust oversight to product risk.
Moreover, FDA faces ever tighter resources, making it impossible to spend months assessing poorly organized applications or weeks inspecting manufacturing facilities, observed Helen Winkle, director of the Office of Pharmaceutical Science (OPS) in FDA's Center for Drug Evaluation and Research (CDER), at the October Regulatory Affairs Professional Society (RAPS) annual meeting in Baltimore. While FDA may be receiving fewer applications for truly innovative therapies, many of the applications filed involve more complex products that require high-level expertise for appropriate evaluation. Manufacturers also are submitting hundreds of investigational new drug applications (INDs) and thousands of manufacturing supplements, adding to the agency's mushrooming workload.The remedy lies in establishing a system that rewards manufacturers for adopting modern processing and testing approaches and for submitting information to FDA that documents such efforts. The agency's initiative to modernize good manufacturing practices (GMPs) has built a foundation for the QbD approach. This three-year exercise concluded its first phase last fall by issuing documents describing how manufacturers of drugs and biologics should assess product risk, establish systems to correct problems, engineer manufacturing changes, and create internal quality units to manage these activities. FDA is implementing these concepts by encouraging manufacturers to develop a scientific understanding of critical product attributes that will permit continuous improvement in process and product with less regulation.
CRITICAL FOR COMPLEX PRODUCTS
QbD is particularly important for highly variable, complex biotech products that are difficult to fully characterize and sensitive to small changes in manufacturing and impurity profiles. The current practice for ensuring quality is to test and reject production lots that fail to meet stated standards, explained Barry Cherney of OPS' Office of Biotechnology Products (OBP) at the October meeting of FDA's Advisory Committee for Pharmaceutical Science. Instead, QbD means fully understanding how the process affects critical quality attributes such as potency, bioavailability, biodistribution, and immunogenicity. The goal is to reduce immunogenicity problems and establish specifications that relate product quality to safety and efficacy.
Such knowledge presently is very limited for many biotech products, Cherney pointed out. OBP encourages manufacturers to use protein engineering as a model to better understand the relationship between structure and product functions. Improved analytical techniques can even requalify cell banks, Cherney noted. Manufacturers will be able to identify and control critical sources of product variation, such as raw materials and operations, possibly through in-process testing methods that involve process analytical technology (PAT). By identifying the intended functions of an operating unit and the critical product attributes they may affect, a manufacturer can establish desired limits of the attribute as well as critical variables for the process step, efforts that can help establish a product's "design space."
In return for demonstrating enhanced process understanding, FDA may offer regulatory relief. Manufacturers able to demonstrate that a validated process is capable of removing impurities to appropriate levels may not have to routinely measure impurities when operating under a validated state, Cherney suggested.