Regulatory Beat: New Policies Seek to Spur Biopharmaceutical Development

Published on: 
BioPharm International, BioPharm International-06-01-2005, Volume 18, Issue 6

Last year's catastrophic flu vaccine shortage and escalating Congressional debate over drug safety continue to shine the spotlight on biotech product manufacturing. FDA officials are under pressure to address concerns about access to quality biotech products, while also encouraging the development of new treatments to meet patient needs.

Last year's catastrophic flu vaccine shortage and escalating Congressional debate over drug safety continue to shine the spotlight on biotech product manufacturing. FDA officials are under pressure to address concerns about access to quality biotech products, while also encouraging the development of new treatments to meet patient needs. Meanwhile, Congress is weighing incentives for developing new counter-bioterrorism treatments (see sidebar).

Jill Wechsler

While the design of clinical and pre-clinical studies absorbs considerable attention in the biomedical research world, manufacturing science has emerged as a critical element in moving products from clinical testing to commercial scale-up. Ensuring access to consistently high-quality biotech therapies, vaccines, and blood products is the focus of efforts by the Center for Biological Evaluation and Research (CBER) to spur new product development. This topic was explored at a CBER workshop last October (2004) on opportunities for collaboration with industry and other stakeholders under FDA's "Critical Path" initiative.


To ensure that early studies will lead to quality products, CBER officials are emphasizing the value of discussing critical manufacturing issues with sponsors early in the clinical development process. CBER's Office of Compliance and Biologics Quality (OCBQ), now headed by Mary Anne Malarkey, is encouraging this approach, especially for companies considering novel methods for scale-up, product sampling, manufacturing process control, or compliance with good manufacturing practices (GMPs). Meetings to address topics such as appropriate containers and shipping is particularly critical for cellular and gene therapies. Despite ever-tightening resources, OCBQ is offering decision-making assistance on raw material selection, sampling techniques, product shipping, technology transfer, manufacturing scale-up and automation, and other key activities.



Increased interaction with manufacturers not only will help industry achieve high quality manufacturing on a consistent basis, but also may assist CBER in evaluating its regulatory process and identifying opportunities for collaborative science to promote innovation. In recent years, CBER research programs have supported the development of new methods for conjugate vaccine synthesis, prion inactivation and testing, and standards for influenza seed strains.

Incentives for Countermeasures

At the Food and Drug Law Institute (FDLI) annual meeting in April, CBER director Jesse Goodman described continuing efforts to gain manufacturer input in setting priorities for cross-cutting collaborative research that could develop:

  • well-characterized cell banks and new safety assays for vaccine and biologics production

  • characterization of cell therapies to provide links to standardized clinical and laboratory outcomes

  • methods to validate pathogen inactivation for blood, plasma, tissues, and other products

  • multipathogen rapid detection methodologies

  • improvements to the longevity and storage of blood and tissues

  • new flu vaccine assays, standards, and reagents.


Efforts to ensure the quality of biotech products also derive from FDA's GMP modernization campaign. While biotech manufacturers have incorporated many elements of a more risk-based oversight system into operations, the search continues for new ways to ensure product quality.

One current initiative seeks to help manufacturers adapt marketed products to meet changing needs and technological advances by setting more appropriate product specifications and limits. The current system has been criticized for relying on end-product testing to ensure that production batches are similar to batches tested in the clinic. This approach, though, fails to explain the relationship between specifications and desired clinical outcomes. Product specifications often are too wide, too tight, overly rigid, or irrelevant to clinical performance and thus frequently lead to excessive out-of-specification results that can be very costly.

The need to develop a more rational approach for establishing and using specifications through the biotech product life cycle was examined last October (2004) at a workshop sponsored by FDA, industry, and the American Association of Pharmaceutical Sciences (AAPS). Some 200 attendees explored the role of specifications and limits in ensuring that biological products are made with the appropriate identity, strength, quality, purity, and potency to ensure a predictable clinical effect and provide a standard for monitoring consistency in a manufacturing process.

The discussion clarified that "specifications" are important parameters that a product must meet, while "limits" apply to less critical measures that a product should meet. Participants acknowledged that specifications may not be needed for certain product attributes that demonstrate little batch-to-batch variation or sensitivity to manufacturing change, explained Keith Webber, director of the Office of Biotechnology Products in FDA's Center for Drug Evaluation and Research (CDER). The challenge is to identify which quality attributes should be specified and which are less critical for ensuring product quality, a topic discussed at a March (2005) workshop on setting specifications for drugs, co-sponsored by FDA and the Pharmaceutical Quality Research Institute.


FDA officials and industry leaders advocate a more proactive approach to measuring product quality and performance. This involves gaining a thorough understanding of the properties of drug substances and how product formulation and process factors impact product performance and design. It also may involve revising the Q6 guidelines developed by the International Conference on Harmonization (ICH). These standards define basic approaches for setting acceptance criteria for drugs (Q6A) and biologics (Q6B), including the collection of relevant data from production batches used in clinical studies to establish a reasonable range of expected analytical and manufacturing variability.

The Q6 guidelines now appear outdated in light of regulatory support for more sophisticated manufacturing assessment approaches. ICH representatives are considering options for adapting Q6 definitions and concepts to process analytical technology guidelines and risk-based regulatory approaches.

As a first step, ICH wants manufacturers to explain drug development and production processes more fully in applications that utilize the Common Technical Document (CTD). The ICH Q8 draft guideline outlines proposed contents for the pharmaceutical development section of CTD regulatory submissions. It discusses approaches for understanding product formulation and manufacturing methods through "quality by design," a process for assessing product and process characteristics during clinical development and using this information to construct models for desired attributes. The ICH Q8 proposal is slated for further discussion and adoption at the next ICH meeting in November (2005), with a final adoption goal of November 2006.

Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634,