Attribute Ranging as a Coordinated Strategy between Drug Substance and Drug Product to Accelerate Commercial Process Nomination.

Abstract

To make investigational drug candidates available to patients sooner, timelines for drug development are becoming shorter. Synthesis route scouting for active pharmaceutical ingredients (API) and drug product development often must occur simultaneously, requiring formulators to make decisions regarding drug product process selection before commercial API route finalization. Alternatively, the formulation strategy may be locked, thereby constraining drug substance processes with strict API attribute requirements. Critical quality attributes of the drug product can depend heavily on the API, yet final physical attributes may not be known early on in development. Furthermore, the desire to reduce pill burden means higher drug loading in formulations, leaving little room for excipients to compensate for suboptimal API performance. The opposing challenges of API synthetic route and drug product formulation development typically lead to elongated development timelines requiring an iterative approach. In this work, a coordinated strategy was designed and implemented to deliberately range API attributes via crystallization and milling techniques to enable robust assessment of downstream manufacturing and significantly reduce the time for final process selection. The study presented was conducted on a protease inhibitor targeted for treatment of Covid-19. Given the emergent need for treatment options, this dramatically accelerated approach was crucial for potential emergency use authorization (EUA).