After three years of talking about modernizing how industry develops and produces new pharmaceuticals, Food and Drug Administration
(FDA) officials are taking action to encourage the implementation of new quality-based manufacturing approaches. Last year's
flu vaccine shortage, recent product recalls, and supply problems that overwhelm makers of pandemic treatments highlight the
importance of replacing costly and wasteful production systems with innovative quality-by-design (QbD) approaches that regulators
can evaluate more efficiently.
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
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.