(543c) Coordinated API and Formulation Development Strategy Utilizing API Attribute Range Studies with Line of Sight to Commercial Process Nominations

To accelerate patient access to life-changing medication, the timelines for active pharmaceutical ingredient (API) process development, and the associated drug product formulation development, are often compressed. These accelerated timelines place drug substance and drug product teams in a position where critical decisions on formulation processes must be made before the commercial API route is finalized. Herein we present a coordinated development strategy that yielded a wide operating space for API process development while de-risking a dry granulation formulation process nomination. Early in development, a combined drug substance and drug product team generated API lots with a wide range of physical attributes and tested them in formulation development. A range of particle size distributions, morphologies, and aspect ratios were explored through recrystallizations, solvent system changes, and/or additional downstream processing. Across all API lots, formulation screening tests showed the strength development of neat API was acceptable with high tensile strengths at or above 2.0 MPa with less than 200 MPa compressive stress. Thus, the team de-risked the impact of API attributes on high drug load tablet formulations early in development. This enabled the drug product team to nominate a favorable dry granulation approach and provided the drug substance team with wide targets for their commercial process and API crystallization specifications.