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

Abstract

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.

Tuning the Crystal Habits of Organic Explosives by Antisolvent Crystallization: The Case Study of 2,6-dimaino-3,5-dinitropyrazine-1-oxid (LLM-105)

“…Crystallization is a widely used technology in the petrochemical, chemical, food, pharmaceutical, and explosive industries [1,2]. Over the past several decades, the development of crystallization methods has been accelerated due to the increasing number of requests for crystals with specific properties [3].…”

Process Design for Antisolvent Crystallization of Erythromycin Ethylsuccinate in Oiling-out System

“…Process analytical technology (PAT) is defined as a system for design, analysis, and control of manufacturing processes through timely measurement of critical quality and performance attributes 37,38 . Problems including time delay for analysis and the solution change caused by sampling process can be avoided with real-time monitoring.…”

Improved Understanding of Cefixime Trihydrate Reactive Crystallization and Process Scale-up with the Aid of PAT

“…Online imaging has proved to be a useful tool for monitoring crystallization processes. [16][17][18][25][26][27][28] Although accurate identification of the polymorphic form of crystals should be based on XRD, if the shape of two different polymorphs is very different, on-line imaging can also be used for polymorph identification. 27 In this work, the 2D Vision Probe provided by Pharma Vision (Qingdao) Intelligent…”

“…PAT instrument studied for crystallization includes ATR-FTIR, online imaging, ultrasound, and Raman; and the work has been reviewed in some review and research articles. [16][17][18][19][20][21][22][23] In this work, on-line imaging and ATR-FTIR were used to find and define the operational envelopes leading to desired CSDs. The PAT instrument was applied during experiments to qualitatively and quantitatively characterize the crystal growth of azithromycin and polymorph transition and study the effects of several variables including the addition of water as an anti-solvent, temperature, and stirrer speed.…”