Hsiao-Wu Hsieh*, Daniel J. Griffin*, Anirudh M. K. Nambiar, Nandini Sarkar, Hamza Youssef Ismail, Kartik Saigal, Dongying Erin Shen, Nicole Goudas-Salomon, Rasangi Wimalasinghe, Alicia Zeng, Oliver R. Thiel and Matthew G. Beaver,
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引用次数: 0
Abstract
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.
在此之前,我们曾报道过用于合成 Otezla 药物阿普司特倒数第二步的集成连续制造(CM)工艺的开发和特性分析。在此,我们以案例研究的形式报告了闭环控制在该 CM 过程中的应用。我们开发了一种基于 Python 的前馈闭环控制器,它使用红外(IR)过程分析技术(PAT)来监控进料浓度,然后自动调整下游进料流速以应对干扰,从而在连续操作中保持接近最佳的产品产量。闭环控制器是在实验室系统上开发和演示的,该系统复制了阿普司特生产的连续生产橇。在报告该演示时,我们的目的是:(1) 举例说明如何将基于 PAT 的闭环控制有益地应用于药物 CM 工艺;(2) 强调我们认为需要进一步提高技术的领域,以便在生产环境中成功部署这种闭环控制。
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.