Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

Abstract

Background: Pharmaceutical industry is witnessing increased pressure to introduce innovative and efficient processes for manufacturing Active Pharmaceutical Ingredients (APIs) in order to be competitive as well as to meet the stringent product quality requirements set by regulatory authorities. Crystallization with its ability to engineer the final product to the desired qualities such as purity, polymorphic form, particle size and shape is one of the most important steps involved in the manufacturing of APIs. Therefore, development of crystallization processes with better understanding of process parameters and their impact on quality of APIs and subsequently the drug products assume great significance for the pharmaceutical industry.

Methods: This review paper focuses on the application of PAT tools, an integral part of Quality by Design (QbD) approach, for better understanding, control, and design of crystallization processes in the manufacturing of APIs.

Results: Firstly, various steps involved in the drug development process are introduced briefly with emphasis on crystallization as one of the most important steps in manufacturing of drug products. Secondly, Critical Quality Attributes (CQAs) of drug products, their dependence on material attributes of APIs and role of crystallization in manipulating material attributes of APIs has been discussed. Finally, application of PAT tools such as advanced process analyzers for continuous monitoring, chemometric methods for multivariate data analysis, and control strategy for APIs crystallization processes has been reviewed along with some examples.

Conclusion: Application of PAT in crystallization of APIs facilitates development of robust processes that works within the design space to produce the drug products of consistent quality. Furthermore, it opens up the opportunities for continuous improvement of the process by generating knowledge base of existing processes.

Keywords: Active Pharmaceutical Ingredients (APIs); Quality by design; crystallization; pharmaceuticals; polymorphism; process analytical technology..