Patel Darshan C, Lyu Yaqi Fara, Gandarilla Jorge, Doherty Steve
Process Research and Development, AbbVie Inc., North Chicago, IL 60064, United States; Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX 76019, United States.
Process Research and Development, AbbVie Inc., North Chicago, IL 60064, United States.
Anal Chim Acta. 2018 Apr 3;1004:32-39. doi: 10.1016/j.aca.2017.11.070. Epub 2017 Dec 12.
In-process sampling and analysis is an important aspect of monitoring kinetic profiles and impurity formation or rejection, both in development and during commercial manufacturing. In pharmaceutical process development, the technology of choice for a substantial portion of this analysis is high-performance liquid chromatography (HPLC). Traditionally, the sample extraction and preparation for reaction characterization have been performed manually. This can be time consuming, laborious, and impractical for long processes. Depending on the complexity of the sample preparation, there can be variability introduced by different analysts, and in some cases, the integrity of the sample can be compromised during handling. While there are commercial instruments available for on-line monitoring with HPLC, they lack capabilities in many key areas. Some do not provide integration of the sampling and analysis, while others afford limited flexibility in sample preparation. The current offerings provide a limited number of unit operations available for sample processing and no option for workflow customizability. This work describes development of a microfluidic automated program (MAP) which fully automates the sample extraction, manipulation, and on-line LC analysis. The flexible system is controlled using an intuitive Microsoft Excel based user interface. The autonomous system is capable of unattended reaction monitoring that allows flexible unit operations and workflow customization to enable complex operations and on-line sample preparation. The automated system is shown to offer advantages over manual approaches in key areas while providing consistent and reproducible in-process data.
在研发和商业化生产过程中，过程取样和分析是监测动力学曲线以及杂质生成或排除情况的一个重要方面。在药物工艺研发中，大部分此类分析所选用的技术是高效液相色谱法（HPLC）。传统上，用于反应表征的样品提取和制备都是手动进行的。这可能很耗时、费力，对于较长的工艺过程而言并不实际。根据样品制备的复杂程度，不同分析人员可能会引入变异性，而且在某些情况下，样品在处理过程中的完整性可能会受到影响。虽然有用于HPLC在线监测的商用仪器，但它们在许多关键领域存在不足。有些仪器无法实现取样和分析的一体化，而另一些在样品制备方面的灵活性有限。目前的产品提供的用于样品处理的单元操作数量有限，且没有工作流程可定制性选项。这项工作描述了一种微流控自动化程序（MAP）的开发，该程序可完全自动化样品提取、处理及在线液相色谱分析。这个灵活的系统通过基于直观的Microsoft Excel的用户界面进行控制。该自主系统能够进行无人值守的反应监测，允许灵活的单元操作和工作流程定制，以实现复杂操作和在线样品制备。结果表明，该自动化系统在关键领域比手动方法具有优势，同时能提供一致且可重复的过程数据。
