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By Stephanie Krogmeier and Antoinette Paone

StephanieKrogmeierAntoinettePaone2Last year, Commissioner of the Food and Drug Administration (FDA) Margaret Hamburg, M.D., said, “No matter how good your (clinical) data and how important the unmet need, approval also hinges on whether you have a manufacturing facility ready to go and a plan in place for scaling up production so you can manufacture your new drug… .”

This quote is especially relevant when considering the new breakthrough designation for expedited programs from FDA. A breakthrough therapy designation is granted for “a drug that is intended to treat a serious condition … and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies(FDA Guidance for Industry [Draft June 2103]: Expedited Programs for Serious Conditions – Drugs and Biologics). This designation allows for expedited development through intensive guidance on efficient drug development and organizational commitment involving senior managers from FDA. In other words, the breakthrough therapy designation is “intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of serous or life-threating conditions” (FDA Guidance for Industry [Draft June 2103]: Expedited Programs for Serious Conditions – Drugs and Biologics).

However, expedited development under a breakthrough designation can lead to challenges on the manufacturing side. The chemistry, manufacturing, and controls (CMC) challenges for expedited development include addressing scale-up issues early in development and preparing a stability program and validation plan that will keep CMC off the critical path. For example, pivotal clinical trial material is typically manufactured at pilot scale or less (≤ 1/10th commercial scale), and the process and formulation design may not be directly scalable. In addition, traditional process validation requires three batches at commercial scale to be completed prior to launch and typically 12 months of drug product stability data in commercial packaging is required prior to submission of the new drug application.

The most effective way to address these issues is through innovation. Innovation comes in many forms and includes quality by design, continuous manufacturing, and real time release. These types of innovation are endorsed by FDA, as stated in the 2004 FDA Guidance for Industry: PAT— A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance: “Gains in quality are likely to come from reduced cycle times, real time release, and facilitating continuous processing to improve efficiency and manage variability.”

In conclusion, industry and regulators need to work together to embrace innovation to advance CMC capabilities and facilitate accelerated development of breakthrough products.

Stephanie Krogmeier, Ph.D., is a director of Global CMC Regulatory Affairs Strategy at Vertex Pharmaceuticals. She received her degree in pharmaceutical chemistry from the University of Kansas in 2005. Antoinette Paone, M.S., M.B.A., is a vice president of Global Regulatory Affairs Strategy at Vertex Pharmaceuticals. She received her degree in chemistry from Yale University and her M.B.A. from Bentley University.