An Integrated Process Analytical Technology (PAT) Approach for Pharmaceutical Crystallization Process Understanding to Ensure Product Quality and Safety: FDA Scientist’s Perspective

In this review, a brief overview of the current regulatory science framework pertinent to pharmaceutical crystallization and process characterization is made first. The FDA’s scientific research on pharmaceutical crystallization process understanding and product characterization is then illustrated via several aspects: (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. Finally, some of the current challenges and future outlook on pharmaceutical crystallization process and product characterization across the pipeline, from drug substance to drug product development, manufacturing, and process scale-up to ensure product quality and safety, and ultimately to protect and promote public health is discussed from both a regulatory science and process engineering point of view.