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
Jill Wechsler is BioPharm International's Washington editor, 7715 Rocton Avenue, Chevy Chase, MD 20815, 301.656.4634, firstname.lastname@example.org