FDA Offers Practical Tips on How to Address CMC for BTD Products  

Manufacturers of breakthrough therapy (BTD) products often face challenges meeting all the CMC requirements for the NDA/BLA for their product. Similar issues are faced by those developing new products under the PRIME program in EU. This week the regulators published a detailed discussion using case studies on how manufacturers can satisfy regulatory requirements in the shortened time for such applications. FDA and EMA held a workshop last year in London to showcase various case studies where the regulators used risk-based approaches to lessen the CMC burden for BTD and PRIME products. This week the regulators jointly published the report of that workshop providing several examples of the how manufacturers met CMC requirements for their NDA/BLA/MAA applications using non-traditional scientific and regulatory approaches. The BTD/PRIME programs allow new products to be approved with reduced clinical and non-clinical data while expecting similar quality manufacturing standards as for other marketed drugs. The regulators are required to assure that the drugs and biologics they approve are manufactured under similar quality standards. Due to the shortened clinical data timelines, there is lesser time to complete all validation, compliance and control strategies for the application. However, the laws provide FDA and EMA to use risk-based approaches to relax the regulatory requirements for the CMC data in the NDA, reduce pre-approval data, and rely on post-market CMC data to meet the quality requirements. The kind of CMC relaxations allowed include allowing ongoing process verification to defer full process validation, concurrent validation, reduced process validation using alternate data, allowing use of alternative control strategies, risk-based relaxations for dealing it out of specification (OOS) events, relaxations in GMP requirements, allowing comparability data between clinical and commercial batches to address reduced number of commercial batches, using predictive models to extrapolate limited stability data, and using innovative regulatory tools to evaluate the quality of the to-be-marketed product. The detailed report of a workshop held last year, released this week, provides several case studies, presented jointly by the regulators and the involved manufacturers, highlighting specific issues, potential solutions, and final outcomes relevant to the CMC info for a new product. The report is an essential study for developers of BTD and PRIME products to understand the various pathways available to them for addressing CMC challenges. Although these case studies specifically address special products but in principle many of the concepts described can be used for non-BTD products as well.