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By Bhavishya Mittal

Bhavi MittalOver the past 10-15 years, a tremendous amount of effort has been placed in developing high potency, oncology-based drug products in numerous pharmaceutical companies. In the meanwhile, FDA has introduced the Breakthrough Therapy Designation (BTD) with the intention to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for BTD require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. BTD includes all of the fast track program features, as well as more intensive FDA guidance on an efficient drug development program.

The AAPS Manufacturing Science and Engineering (MSE) section successfully organized and moderated the open forum “Streamlining Manufacturing and Scale-up to Support ‘Breakthrough Therapy’ Designation for Solid Oral Dosage Forms” at the 2014 AAPS Annual Meeting and Exposition. Held on November 4, the event was attended by nearly 40 people. Speakers included Raymond Skwierczynski, Ph.D. (Senior Director, Takeda), Dan Blackwood (Associate Research Fellow, Pfizer), Gregory Connelly, Ph.D. (Senior Scientist, Vertex), and Sarah Pope‐Miksinski, Ph.D. (Acting Director-ONDQA, FDA). They provided their perspectives on various aspects of chemistry, manufacturing, and control (CMC) considerations for BTD development programs. The programming of the open forum was designed to strike an appropriate balance between technical knowledge, strategic decision-making, and regulatory insight.

Skwierczynski presented a brief history of early-access and expedited-approval programs, and discussed the evolution of BTD. He elaborated on the inherit complexities of oncology CMC development, strategies to overcome these complexities, and approaches that can be taken to meet FDA’s expectations for manufacturing and product quality. His signature tagline was “All of the answers will be found in the pre-formulation report”. Very well said, indeed!

Blackwood elaborated on the upcoming concept of increasing speed to market through a portable, continuous, miniature, and modular (PCM&M) approach to drug product manufacturing. He presented the current state of batch processes and its application to BTD products. In his vision for the future, PCM&M is a rational approach that incorporates experiments, engineering models, process analytical technology (PAT), and advanced process controls to allow for rapid development and sustained manufacturing for BTD drugs.

Connelly further discussed the state of the manufacturing technology by showcasing Vertex’s “fearless” approach towards continuous manufacturing and the layout of its facility dedicated to this new field. He also discussed the drivers for PAT in continuous manufacturing and how it can help in maintaining quality assurance and knowledge management. From his presentation, it was clear that continuous manufacturing and PAT can enable efficient CMC development of BTD drugs.

Pope-Miksinski provided the FDA’s perspective on BTD. She clarified that the review process for BTD drugs will involve senior managers and experienced review staff (as appropriate) to facilitate a collaborative and cross-disciplinary review. She acknowledged that accelerated manufacturing development programs are likely to have less information than typically available, which poses a challenge for both applicant and regulatory bodies. But in her view, active communication between FDA and the pharmaceutical industry can help in developing innovative risk-mitigation strategies that ensure product safety and reduce quality-related product risk to an acceptable level.

It was clear from these presentations that there are new scientific, technological, and strategic developments that address the CMC concerns of BTD drugs. The FDA is encouraging the industry to jointly participate in the exploration and adoption of novel strategies to assess the quality of the BTD therapies.

The future looks bright for BTD drugs!

Bhavishya Mittal is a senior scientist at Takeda Pharmaceuticals (Cambridge, MA). His research interests include formulation design, process engineering, scale-up, and computational modeling of unit operations for solid oral dosages.