This work details development of a system/process model and usage of Computer Experiments methodology for continuous manufacturing of Active Pharmaceutical Ingredients (API). The process of interest has three interconnected continuous unit operations, with the first two being reactors and the last being an evaporator. The overall workflow detailed can be summarized as follows: a) develop mechanistic process models, b) verify/validate the model, c) convert model parameters to process parameters d) design computational grid to simulate the model – Latin hypercube design in this case, e) perform simulations, f) fit meta-model (surrogate model) to the output parameter/attribute of interest, g) analyze the meta-model using global sensitivity analysis, and h) slice and dice the model, e.g., study response surfaces of interest, for further analysis. This workflow has several practical advantages in process development, optimization, and troubleshooting, especially when the number of process inputs and/or parameters are large and/or output response surfaces are potentially complex. Phenomenological model development is detailed for biphasic reaction with large solvent volume change.

这项工作详细介绍了系统/过程模型的开发以及计算机实验的用法连续生产活性药物成分（API）的方法学。感兴趣的过程具有三个相互连接的连续单元操作，前两个是反应器，最后一个是蒸发器。详细的总体工作流程可总结如下：a）开发机械过程模型，b）验证/验证模型，c）将模型参数转换为过程参数d）设计计算网格以模拟模型–在这种情况下为拉丁超立方体设计， e）执行仿真，f）使元模型（代理模型）适合目标输出参数/属性，g）使用全局灵敏度分析来分析元模型，以及h）对模型进行切片和切块，例如研究响应面感兴趣，以供进一步分析。此工作流程在流程开发，优化，和故障排除，特别是当过程输入和/或参数的数量很大和/或输出响应面可能很复杂时。对于溶剂体积变化较大的双相反应，详细建立了现象学模型。