Department of Chemical Engineering, Biotechnology, and Environmental Technology, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark.
Curr Pharm Des. 2018;24(21):2456-2472. doi: 10.2174/1381612824666180629111632.
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.
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.
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.
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.
制药行业面临着越来越大的压力，需要引入创新和高效的工艺来生产原料药 (API)，以保持竞争力并满足监管机构设定的严格产品质量要求。结晶技术具有将最终产品工程化为所需质量（如纯度、多晶型形式、粒径和形状）的能力，是 API 制造中最重要的步骤之一。因此，更好地了解工艺参数及其对 API 质量的影响，并将其应用于结晶工艺的开发，对于制药行业具有重要意义。
本文综述重点介绍了 PAT 工具的应用，这是质量源于设计 (QbD) 方法的一个组成部分，用于更好地理解、控制和设计 API 制造中的结晶工艺。
首先，简要介绍了药物开发过程中的各个步骤，重点介绍了结晶技术作为药物产品制造中最重要的步骤之一。其次，讨论了药物产品的关键质量属性 (CQA)、它们对 API 材料属性的依赖性，以及结晶在操纵 API 材料属性方面的作用。最后，综述了 PAT 工具的应用，如先进的过程分析仪用于连续监测、多元数据分析的化学计量学方法，以及 API 结晶工艺的控制策略，并结合一些实例进行了讨论。
PAT 在 API 结晶中的应用有助于开发稳健的工艺，使工艺在设计空间内运行，以生产具有一致质量的药物产品。此外，它通过生成现有工艺的知识库，为工艺的持续改进提供了机会。
