Previously, we reported the development and characterization of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance of Otezla. Herein, we report the application of closed-loop control to this CM process as a case study. A Python-based feedforward closed-loop controller is developed that uses infrared (IR) process analytical technology (PAT) to monitor incoming feed concentrations and then automatically adjusts the downstream feed flow rates in response to disturbances such that near optimal product yield is maintained through the continuous operation. The closed-loop controller was developed and demonstrated on a lab system that replicates the continuous manufacturing skid for apremilast production. In reporting this demonstration, we aim to (1) provide an example of how PAT-based closed-loop control could be beneficially applied to a drug substance CM process and (2) highlight areas where we believe further technical advancement is required to enable such closed-loop control to be successfully deployed in a manufacturing setting.

中文翻译：

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支持 PAT 的自动前馈控制：阿普斯特连续生产的应用


此前，我们报道了 Otezla 原料药阿普斯特合成倒数第二步的集成连续制造 (CM) 工艺的开发和表征。在此，我们报告了闭环控制在此 CM 过程中的应用作为案例研究。开发了基于 Python 的前馈闭环控制器，该控制器使用红外 (IR) 过程分析技术 (PAT) 来监测进入的进料浓度，然后自动调整下游进料流量以响应干扰，从而通过以下方式保持接近最佳的产品产量：连续运行。闭环控制器是在实验室系统上开发和演示的，该系统复制了阿普斯特生产的连续制造橇。在报告这一演示时，我们的目标是 (1) 提供一个示例，说明如何将基于 PAT 的闭环控制有益地应用于原料药 CM 工艺，以及 (2) 重点介绍我们认为需要进一步技术进步才能实现这一目标的领域。闭环控制成功部署在制造环境中。