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Why QbD is Critical for Breakthrough Therapeutics

The message at BioProcess International West conference last month could not have been clearer: if there is even the slightest possibility that your product will achieve breakthrough designation  from FDA, you should expect to do more process development and optimization early and incorporate Quality by Design (QbD) concepts as soon as possible in process development.

The growing importance of QbD was emphasized at every turn at the conference. BPTC Vice President Susan Dana Jones, Ph.D., spoke about the challenges associated with a singular focus on speed to IND if breakthrough therapy designation is obtained. The process knowledge and design information required to support a BLA filing may not be readily available when accelerated timelines from clone to clinic® are taken. Achieving the aggressive regulatory timelines made possible with breakthrough therapy designation may be impossible unless careful thought has gone into developing a supporting CMC strategy and providing all the necessary development history and process validation for the BLA.

When a coveted breakthrough therapy, fast track, priority review, and/or accelerated approval designation is awarded by FDA, things can get tough for a biotech company that hasn’t paid adequate attention to QbD early in development. Under one of these programs, a BLA filing based on Phase 2 data or just a single Phase 3 trial may be possible. However, this speed comes with a catch. Despite the shortened clinical development program, the company must still provide a full Chemistry, Manufacturing and Controls (CMC) package, including process development and validation, for Module 3 of the BLA. To match the shortened timeline made possible with breakthrough therapy designation, the CMC package may need to be ready at least three to five years earlier than usual.

PhRMA’s QbD working group has published a position paper that provides guidance for implementing QbD for biotechnology products and we addressed FDA’s current perspective on the application of QbD in an earlier blog. In addition, FDA has issued its own manual to guide CMC reviewers on how the ICH recommendations regarding QbD should be applied in regulatory submissions.

Fortunately, we also saw at BPI West that much progress has been made in designing the necessary equipment for QbD-based process development. Mario Becker and Kevin McHugh from Sartorius Stedim Biotech gave an insightful presentation on the state-of-the-art use of an integrated bioreactor, sensor and software platform to accelerate antibody development from bench scale to validated commercial-scale production, shaving critical time off the CMC development timeline while still providing the necessary data to support a BLA filing for a product with breakthrough therapy designation.

Now that companies are applying QbD in the development of protein therapeutics and recognizing the need for more CMC data earlier for products receiving one of FDA’s four designations for expedited review and approval, there is no excuse not to embrace the concepts of QbD early in development and make sure you have a good understanding of each manufacturing process step early on. Companies should also consider spending slightly more time and money to develop more complete process knowledge during initial process development rather than rushing to the IND. Unfortunately, today’s funding mechanisms reward speed to clinic and fail to reward a more judicious early development strategy that reduces process risk at later stages. And as always, companies must allocate their capital carefully.


Blog article by: Andreas Woppmann and Susan Dana Jones