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All therapeutics go through three phasese of clinical trial testing (phase 1, 2 and 3) before market authorization is possible and they are approved for use in patients. Because late stage clinical trials involve more subjects than early stage trials, larger scale production under “Good Manufacturing Production” must be in place – ideally to the scale and parameters required for final market authorization. In contrast, full Chemistry, Manufacturing and Controls information and testing (CMC as it is referred to in the industry) is not required for phase 1 trials. As trials progress to phase 2 and ultimately phase 3, formulation, analytical procedures, and manufacturing processes are refined and improved (see Figure). The extent of CMC, including pharmacological and toxicological studies, thus depends on phase of the IND, the duration of study, the dosage form, etc.
Indeed, it has been reported that roughly one-third of phase 2 candidates that do advance, do not have a scalable and commercially viable manufacturing process in place. This results at best in costly, game-changing delays or at worst in product discontinuation1.
Austrianova’s clinically tested Cell-in-a-Box cell encapsulation technology is the subject of a Drug Master File (DMF) that has been filed with FDA as well as included by PharmaCyte Biotech Inc., in their IND for a Phase 2B clinical trial for pancreatic cancer. Phase 2B studies are generally ‘mini-phase 3’ studies that provide data on efficacy as well as on safety.
The DMF filed with the US FDA by Austrianova contains proprietary, extensive CMC information, commensurate with a late stage clinical product. This information is a resource for ongoing Cell-in-a-Box products in development as well as for future products.
Austrianova also implements quality by design (QbD) in the manufacturing of its encapsulated cell therapies which are classified as advanced therapy medicinal products (ATMP). Both the US FDA and the European Medicines Agency (EMA) introduced QbD in international guidelines more than ten years ago. QbD is a science- and risk-based approach to drug development and manufacturing, and presents an opportunity to add value by building quality into the production process, thereby gaining a business advantage since iterations toward the target product profile are minimized, and the overall risk to the project is reduced. Importantly, for ATMPs such as encapsulated living cells, it is necessary to maintain sterility throughout the manufacturing process which makes the production process more complex when compared to most other products that can be terminally sterilized.
Interesting facts and figures
Some useful facts and figures have recently been reported. According to industry group PhRMA, it takes 10-15 years on average to develop one new medicine from initial discovery through regulatory approval. Tufts Center for the Study of Drug Development (CSDD) also recently reported that clinical research now takes longer than it used to. The costs of developing a new drug has been estimated2 as around $985 million according to a recent paper in JAMA, although this includes all costs from the beginning until getting a treatment on the market.
1. A. Kane, “Phase-Appropriate Formulation and Process Design,” Pharmaceutical Technology 40 (1) 2016. https://www.pharmtech.com/view/phase-appropriate-formulation-and-process-design
2. M. Derep “What’s the average time to bring a drug to market in 2022?” https://lifesciences.n-side.com/blog/what-is-the-average-time-to-bring-a-drug-to-market-in-2022