(579a) Pharmaceutical Crystallization: A Manufacturing Process Perspective

Typically a number of critical quality attributes (CQAs) such as crystal structure and crystal component identification, purity, crystallinity, crystal size distribution (CSD), polymorphism and impurity, and stability are evaluated to assess the robustness, controllability, repeatability, and consistency of a pharmaceutical crystallization process. There are different ways to achieve in-depth process understanding and to realize rationale process control. This presentation provides several FDA research case studies to demonstrate the technical feasibility of real time process monitoring approaches for better understanding, design and control of pharmaceutical crystallization processes and product characterization. The case studies are:  1) Combined real-time PAT monitoring and process chemometrics for mapping the state of a pharmaceutical crystallization process; 2) Combined real-time PAT process monitoring and first-principle modeling for elucidating the nucleation mechanisms of a dynamic pharmaceutical crystallization process; 3) Combined real-time PAT process monitoring, Design of Experiments (DOE), and General Linear Modeling (GLM) to establish a hybrid approach for process characterization and process design space development; and 4) Integrated PAT approach for nucleation induction time measurement.  This presentation will briefly address some of the current opportunities in pharmaceutical crystallization, including switching from batch to continuous crystallization and several promising, novel technologies in the area of crystallinity monitoring, from a process engineering perspective.