Apply PAT to the Definition of Design Space to Enable the Control Strategy for Crystallization Processes

Process Analytical Technologies (PAT) have been widely used in the development and optimization of active pharmaceutical ingredient (API) processes, especially crystallization processes. In this talk, applications of a PAT-enabled crystallization platform to an API process will be described. Online IR has been applied to monitor the concentration and online FBRM to monitor the particle size distributions of APIs for the development and optimization of a crystallization process. As an important extension to QbD DOE work, to be able to dial in a reliable seeding point, a detailed solubility map of an API in a three-solvent system will also be illustrated. Furthermore, as a critical part of the QbD control strategy, an online NIR method has been established for controlling the composition of the process stream at the seeding point to ensure an efficient and robust crystallization process. The corresponding results of implementation at factory scale will also be highlighted. This approach has significantly enhanced our capability to explore the design space of crystallization processes and improved our ability to maintain the crystallization performance under unexpected disturbances and scale-up variations.