Risk-based process synthesis and Industry 4.0 framework for pharmaceutical manufacturing processes

项目总结/摘要 在过去的五年里，普渡大学的这个团队一直与罗格斯大学的同事合作 大学研究连续制造（CM）的计算和实验基础设施 固体口服剂型产品。这项工作是建立在NSF支持的中心十年的研究基础上的， 结构化有机颗粒系统。与此同时，PI和普渡大学的同事也对CM进行了调查 小分子API生产的方法在微观和中等规模。这项工作表明， 过程建模、过程分析技术、主动过程控制、智能过程 监测、材料跟踪和真实的时间风险评估。此外，目前的工作表明， 各组成部分必须通过综合数据管理和信息基础设施联系起来， 实现所需的工业4.0功能。 虽然CM是制药行业的一个重要发展，但它并不是一个通用的解决方案， 在技术上或经济上满足所有生产需求：通常是混合分批-连续或完全分批 模式可以是有利的。此外，鉴于对通用制药厂现有批处理设施的重大投资， \制造业，有一个未满足的需求，使工业4.0的功能，这些制造商和 从而显著提高药品质量，降低药品成本。该提案的目标是扩大 研究CM开发和演示一个框架的设计和操作的批量和混合小 分子制造系统。这将通过五个目标实现： 目的1：开发用于小分子和口服制剂生产的药物模型库 目的2：小分子API和产品最佳合成工艺的一般框架 生产，包括从批量到完全连续的过程 目标3：开发工业4.0实时流程管理框架（RTPM）。 目标4：利用若干案例研究示范这些技术，包括高成本/低产量和高 三种不同规模（实验室、试点和工业）的批量/低成本仿制药 目标5：为FDA工作人员和行业开发培训项目的教学模块 以及通过pharmaHUB访问基于网络的工具和案例研究。 这项工作将导致开发在全球范围内实施工业4.0所需的工具集。 制药部门以及系统设计和运作的框架示范 几种特定药物的生产过程，包括规模效应。这些案例研究将有助于提供信息， 在众多的间歇式和混合间歇式连续生产设施中推广创新的生产实践 存在于世界各地。此外，通过补充CM取得的进展，它将使FDA能够开发 在整个行业中应用工业4.0功能的有效指导方针。

Project Summary / Abstract Over the past five years, this Purdue University team has been collaborating with colleagues at Rutgers University to investigate the computational and experimental infrastructure for continuous manufacturing (CM) of solid oral dosage products. This work has built on a decade of research under the NSF supported Center for Structured Organic Particulate Systems. In parallel, the PI and Purdue co-workers have investigated CM approaches to small molecule API manufacture at micro and intermediate scales. This work has demonstrated the essential roles of process modeling, process analytical technology, active process control, intelligent process monitoring, material tracking and real time risk assessment. Moreover, current work is showing how these components must be linked through an integrated data management and informatics infrastructure in order to achieve the desired Industry 4.0 functionalities. While CM is an important development for the pharmaceutical industry, it is not a universal solution that meets all manufacturing needs, either technically or economically: often hybrid batch-continuous or fully batch modes can be advantageous. Moreover, given the major investment in existing batch facilities in the generic \manufacturing sector, there is an unmet need to bring Industry 4.0 functionalities to those manufacturers and thus significantly improve quality and reduce cost of medicines. The goal of this proposal is to expand the research on CM to develop and demonstrate a framework for the design and operation of batch and hybrid small molecule manufacturing systems. This will be achieved through five aims: Aim 1: Development of Pharmaceutical Model Library for small molecule and oral drug product manufacture Aim 2: General framework for the optimal synthesis of processes for small molecule-based API and product manufacture, encompassing the spectrum from batch to fully continuous processes Aim 3: Development of an Industry 4.0 real-time process management framework (RTPM). Aim 4: Demonstration of these technologies using several case-studies including high cost/low volume and high volume/low cost generic drugs at three different scales (lab, pilot and industrial) Aim 5: Development of instructional modules for conducting training programs for both FDA staff and industry as well as web-based access to tools and cases studies via pharmaHUB. This work will result in the development of the tool set necessary to implement Industry 4.0 across the pharmaceutical sector as well as the demonstration of the framework for systematic design and operation of processes for several specific drugs, including the effects of scale. The case studies will serve to inform and promote innovative manufacturing practices across the numerous batch and hybrid batch-continuous facilities existing worldwide. Moreover, by complementing the progress made in CM, it will enable the FDA to develop effective guidelines on the application of Industry 4.0 functionalities across the industry.