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

项目摘要/摘要 在过去的五年里，普渡大学的这个团队一直在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 固体口服剂量产品。这项工作是在NSF支持的中心下进行的十年研究的基础上进行的 结构化有机颗粒系统。同时，PI和普渡的同事也对CM进行了调查 小分子原料药的中微规模生产方法。这项工作证明了 过程建模、过程分析技术、主动过程控制、智能过程的基本作用 监控、材料跟踪和实时风险评估。此外，目前的研究表明，这些 组件必须通过集成的数据管理和信息基础设施进行链接，以便 实现所需的Industry 4.0功能。 虽然CM是制药业的一个重要发展，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制造需求：通常是混合批处理-连续批处理或全批处理 模式可能是有利的。此外，鉴于对通用汽车现有批处理设施的主要投资 \制造业，为这些制造商带来工业4.0功能的需求尚未得到满足 从而显著提高药品质量，降低药品成本。这项提议的目标是扩大 研究CM以开发和演示间歇式和混合式小型汽车的设计和运营框架 分子制造系统。这将通过五个目标来实现： 目标1：小分子药物模型库的开发及口服药物制品的研制 目标2：以小分子为基础的原料药和产品的最佳合成工艺的一般框架 制造，涵盖从批量到完全连续的过程 目标3：开发工业4.0实时过程管理框架(RTPM)。 目标4：使用几个案例研究来演示这些技术，包括高成本/低数量和高成本 三种不同规模的批量/低成本仿制药(实验室、中试和工业) 目标5：开发教学模块，为FDA工作人员和行业开展培训方案 以及通过PharmaHub以网络方式访问工具和案例研究。 这项工作将导致开发实施整个行业4.0所需的工具集 医药部门以及系统设计和运作框架的示范 几种特定药物的加工过程，包括规模效应。案例研究将有助于提供信息和 在众多间歇和混合间歇-连续设施中促进创新的制造实践 存在于世界各地。此外，通过补充在CM方面取得的进展，它将使FDA能够开发 关于在整个行业应用行业4.0功能的有效指南。

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.