Enabling the Best Science for an API Commercial Route via Cross-functional Collaboration

The final chemical transformation and isolation in the synthesis of an Active Pharmaceutical Ingredient (API), referred to as the Pure Step, is often chemically simple but scientifically, operationally and strategically the most challenging. Pure step development is critical because it is used to determine and support the critical quality attributes (CQAs) for the API, which will have lasting impacts on the process. This presentation will detail specific challenges for an API that is isolated as a citrate salt, crystallized out of methanol and isopropanol. This citrate salt is then formulated via direct compression to make the deliverable for the patient. The salt crystallization is particularly challenging due to: (1) the propensity of the citrate salt crystal to form solvates, (2) the particle size control requirements, and (3) the variability in starting material purity. The team has had to execute targeted, rapid process development in order to support pilot plant API batches which will supply clinical trials, and simultaneously tech transfer the process to the manufacturing site overseas. This work has required not just the technical capabilities of the team, but has also required streamlined collaboration and flawless communication across both drug substance and drug product space. This presentation will detail the comprehensive and hefty process development work which was executed to support this pure step, focusing on the drug substance crystallization, and the impacts on the drug product space.