Real Time Release in Continuous Solid Dose Manufacturing: Systematic Characterization of Material Properties, and Optimal Design of Sensing and Control Methods

项目摘要/摘要 这项提案的主要目标是推进监管科学，以支持实施 连续固体剂量制造系统，配备能够处理原料的控制系统 材料变化性，实时保证产品质量。这一目标将通过关注 以下是具体目标： 1.材料和工艺表征：建立基于机械论的预测框架 材料性能、工艺参数和产品性能之间的多元关系 属性。 2.感知策略：实现多种PAT工具，支持基于模型的验证 感测配置，将其集成到有效的测量预测系统中，实现实时 质量合规性，从而促进实时发布 3.基于风险的监控：根据不同的感知配置确定风险级别 评估并使用它们来启用能够确保产品质量的控制系统。 4.系统的稳健性和验证：系统地检查不确定性和可变性的来源 并确定实现质量性能持续验证和实时的策略 产品版本。 在经历了50年的近乎停滞之后，制药制造业正在经历前所未有的科学 和技术创新。在过去的三年里，制药业及其技术供应商 已经在全球范围内实现了从批量生产到连续生产的转变。公司正在积极地 实施原料药和固体剂量制造的连续工艺，并开始开发 生物制品和液体产品的系统。人们的兴趣也已经扩展到仿制药公司，以及 合同制造商和技术供应商正在积极开发一系列工艺和分析 能够进行连续加工的设备。 拟议的项目将为设计开发、实施和演示系统的方法 和实施连续固体剂量制造工艺，包括广泛的和可预测的 原材料特性的表征、传感和严格验证的最佳实施和严格验证 控制方法和故障模式的系统分析，其具体目标是实现实时 质量保证(和实时产品发布)。该项目的意义是双重的：这些工具将 两者都能够实施稳健和可靠的制造工艺，并将促进科学- 基于连续制造应用的法规评估和评估。

Project Summary/Abstract The main goal of this proposal is to advance regulatory science to support the implementation of continuous solid dose manufacturing systems, equipped with control systems that are capable of handling raw material variability and assuring product quality in real time. This goal will be realized by focusing on the following specific aims: 1. Material and Process Characterization: Establish a predictive framework based on mechanistic multivariate relationships between material properties, process parameters, and product performance attributes. 2. Sensing Strategy: Implement a variety of PAT tools, supported by model-based verification of sensing configurations, integrating them into effective measure-predictive systems, enabling real time quality compliance, thus facilitating Real Time Release 3. Risk-Based Monitoring and Control: Determine risk levels from the different sensing configurations evaluated and use them to enable control systems capable of assuring product quality. 4. Systems Robustness and Verification: Systematically examine sources of uncertainty and variability and determine strategies to enable continuous verification of quality performance and enable Real Time Product Release. After 50 years of near-stagnation, pharmaceutical manufacturing is experiencing unprecedented scientific and technological innovation. In the last three years, the pharmaceutical industry and its technology suppliers have embraced a world-wide transformation from batch to continuous manufacturing. Companies are actively implementing continuous processes for API and solid dose manufacturing, and are beginning to develop systems for biologicals and liquid products. Interest has already expanded to generic companies as well, as contract manufacturers, and technology suppliers are actively developing a range of process and analytical equipment to enable continuous processing. The proposed project will develop, implement, and demonstrate systematic methodologies for the design and implementation of continuous solid dose manufacturing processes, including the extensive and predictive characterization of raw material properties, the optimal implementation and rigorous verification of sensing and control methods, and the systematic analysis of failure modes, with the specific objective of enabling real time quality assurance (and real time product release). The significance of the project is two-fold: these tools will both enable the implementation of robust and reliable manufacturing processes, and will facilitate science- based regulatory assessment and evaluation of continuous manufacturing applications.