Process Modeling and Assessment Tools for Simulation, Risk Management and Design Space Development of Integrated Pharmaceutical Manufacturing Processes

摘要 开发了集成制造过程的工艺模型和仿真系统，并对其进行了仿真 通过固体药物产品合作者的中试流程进行验证。确定性过程模型 用多变量统计过程模型进行补充和调整，以考虑过程的不确定性 帐号。有了这个仿真工具，人们可以执行关键任务，包括风险评估、控制策略 确定、确定关键材料和工艺属性，并最终了解 原材料属性和工艺参数对最终产品质量的影响关系。这个过程 将模型嵌入到蒙特卡罗模拟中，以确定设计空间，同时考虑 进程失败。利用具有失效概率的设计空间来确定最优运行范围 关键工艺参数，同时将关键质量属性(CQA)的超标(OOS)降至最低。 模拟工具将为监管科学提供显著的好处。

Summary The process model and simulation system of the integrated manufacturing process are developed and validated with pilot process of a collaborator for solid based drug products. The deterministic process models are supplemented and adjusted with multivariate statistical process models to take process uncertainties into account. With this simulation tool, one can conduct critical tasks including risk assessment, control strategy determination, identification of critical material and process attributes, and eventually understanding relationship between raw material attributes and process parameters on final product qualities. The process models are imbedded in Monte Carlo simulation to determine design space while considering probability of process failure. The design space with failure probability are used for determining optimum operating ranges of the key process parameters while minimizing Out-Of-Specification (OOS) of Critical Quality Attributes (CQA). The simulation tool will provide significant benefits for regulatory sciences.