Regulatory Beat: FDA Seeks to Ensure Product Quality and Streamline Regulation

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BioPharm International, BioPharm International-12-01-2005, Volume 18, Issue 12

This quality approach to biotech manufacturing may also establish a pathway for approving generic versions of biotech therapies.

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.

Jill Wechsler

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.



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.

On the policy side, this quality approach to biotech manufacturing may also establish a pathway for approving generic versions of biotech therapies. At the annual meeting of the Generic Pharmaceutical Association (GPhA) in October, OPS director Winkle linked efforts to apply QbD principles for generic drugs to 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. All products, she noted, should apply QbD principles so that drug design is based on prior knowledge and a sound understanding of critical parameters. FDA still has to address legal and scientific issues related to follow-on proteins, Winkle said, but QbD approaches may support such efforts.


The difficulty of effectively assessing more science-based chemistry manufacturing data in applications is prompting changes in OPS' review structure for drugs. Instead of assigning one chemist to oversee a product, applications are now being assigned to review teams that can draw on engineers, microbiologists, and other specialists when appropriate. This may involve consultation with OBP if additional biological characterization expertise is needed.

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 supplements requiring prior approval will increase reliance on company annual reports to monitor and report quality-related events for marketed drugs, such as batch failures and out-of-specification results.

FDA is also encouraging manufacturers to file applications electronically 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's Quality Overall Summary (QOS) provides an upfront overview indicating the complexity of a product and what kind of review team is needed to assess it. The summary links to parts of the CTD and to supporting documentation. The summary includes a pharmaceutical development report where an applicant can describe how it arrived at its final formulation, specifications and manufacturing approaches, including failures and false starts.


To implement this approach, FDA has to convince pharma companies to share information on QbD activities with the agency. Many manufacturers are already using innovative methods to design formulations and adjust process parameters. However, 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 raise new questions from agency reviewers and inspectors. And few manufacturers are using the CTD exclusively. Electronic CTDs are even more rare.

OBP emphasizes that its researchers/reviewers already have considerable expertise in biological characterization of protein products and in fermentation and purification processes, equipping them to appropriately evaluate innovative processing methods. FDA is providing further training of OBP reviewers to enhance their understanding of PAT, QbD, and new analytical techniques to assure the industry that reviewers will comprehend innovative approaches to quality testing and control.

To address concerns about benefits that may result from changes in current systems, FDA officials also are proposing the idea of negotiating "regulatory agreements" with manufacturers for newly approved products. Woodcock suggested at the AAPS workshop that a sponsor and FDA could agree on product attributes at time of approval and reduce oversight later for changes that occur within established parameters.

In the end, manufacturers will have to make decisions in regards to whether possible reductions in regulatory burden justify upfront costs of implementing QbD systems. World-wide 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 BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634,