Genentech has 2 QbD proposals to CDER as EMEA seeks ways to ease difficulties for biotech drugs.(Quality by Design)

ATLANTA -- FDA has accepted two proposals from Genentech for a Center for Drugs pilot to make it easier for biotech products to use Quality by Design for review, and the agency, along with its European counterparts, is trying to ease the path.

In June 2008, CDER's Office of Biotechnology Products announced a pilot program to resolve these challenges, with the participation of manufacturers like Genentech. The announcement stated: "Under quality by design, manufacturing will depend on a risk-based approach linking attributes and processes to product performance, safety, and efficacy." The FDA wants to set parameters for a new quality-by-design approach that "will focus on critical quality attributes related to chemistry, formulation, and process design."

Genentech has had two proposals accepted and "will endeavor to define critical quality attributes and critical process parameters and will seek to define the design space we'd like the agency to approve," advised Lynne Krummen, Genentech's Senior Director, Regulatory Affairs, at a session on QbD at the annual BIO convention here May 19.

Once this is done, she expects that movement within the design space should be allowed. She also said: "I expect we will have expanded comparability protocols, but will also be exploring whether we could look at expanded comparability protocols that would allow us to shift licensed products among our licensed facility network." Discussing challenges Genentech has experienced with the pilot, Krummen said: "Post-approval changes outside the design space still represent challenges to market-wide implementations."

Krummen also acknowledged "the unprecedented openness of the FDA and EMEA to discuss concepts and implementation options." She noted that FDA has completed a QbD pilot program for NDAs and has just opened a similar pilot for large molecules. Krummen also informed the audience that "EMEA is revising the Variations Guidance to include concept of Design Space and has adopted a new Monoclonal Antibody guidance that allows the use of platform knowledge to support license claims."

When asked what regulatory relief Genentech can expect from the FDA for their filings, Krummen responded: "I think that the degree of regulatory relief results from the degree of process understanding that's demonstrated. A comprehensive analysis of the risk of your process done by a method that can be repeated and controlled in your quality system ... sets you up well to have some ability to manage changes that are relatively low risk, either with minimal preapproval time or in a CBE30 type of mode. What we're looking for is to ... have the agency look at that methodology and agree it's a sound methodology to go for."

Amit Banerjee, PhD, Research Fellow for Pfizer Global Research and Development, said QbD has great value--the reduction of post-approval regulatory submission, recalls, cost, regulatory burdens, meaningless regulations or compliance exercises, and BLA documentation.

However, Banerjee said QbD implementation in biotech products has been difficult to establish because "the link between a product attribute and clinical performance is not often well understood." He went on to say that improvements are needed in "regulatory flexibility, process understanding, application of technology, quality, regulatory review criteria, transparency of risk assessments, and global harmonization."

Discussing Pfizer's QbD approach, called Right First Time (RFT), Banerjee said it addresses process design and scale up/scale down strategy. Pfizer also develops a Process Understanding Plan (PUP), which it derives from process development experience, pilot/GMP scale experience, prevalidation runs, and process characterization studies--LPQ (small-scale experiments).

According to Banerjee, the company is dedicating resources to "examine how to link process parameters to quality attributes," although he admitted, "It's difficult to identify quality attributes truly critical to safety and efficacy, and their acceptable boundaries."

Closing out the discussion by commenting on QbD challenges internationally, Krummen said: "On the positive side I think there's been quite a lot of openness of health authorities throughout ICH regions to the concept of QbD and particularly the concept of design space ... In the FDA's pilot program we can have access to discuss assumptions prior to filing. The method for having that same kind of access in Europe, etc., is not that clear. And then there's the level of detail that'll be expected in filings to support our conclusions and that's something we need to work more on."

By Tara Y. Coyt

Atlanta Correspondent

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