结晶
活性成分
医药制造业
过程(计算)
泥浆
蒸发器
过程开发
悬挂(拓扑)
材料科学
连续流动
化学工程
机械工程
计算机科学
工艺工程
工程类
生化工程
数学
生物
生物信息学
同伦
热交换器
操作系统
复合材料
纯数学
作者
Martin D. Johnson,Christopher L. Burcham,Scott A. May,Joel R. Calvin,Jennifer McClary Groh,Steven S. Myers,Luke P. Webster,Jeffrey C. Roberts,G. Venkata Ramana Reddy,Carla V. Luciani,Aoife P. Corrigan,Richard D. Spencer,Robert Moylan,Raymond A. Boyse,John D. Murphy,James R. Stout
标识
DOI:10.1021/acs.oprd.0c00345
摘要
Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early research scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.
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