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

项目总结/摘要 该提案的主要目标是推进监管科学，以支持实施 连续固体剂量生产系统，配备有能够处理原料的控制系统， 材料可变性和真实的时间保证产品质量。这一目标将通过以下方式实现： 具体目标如下： 1.材料和工艺表征：建立基于机理的预测框架 材料性能、工艺参数和产品性能之间的多元关系 美德.先知-愿 2.感知策略：实施各种PAT工具，由基于模型的验证支持， 传感配置，将其集成到有效的测量预测系统中，实现真实的时间 质量合规性，从而促进真实的时间发布 3.基于风险的监测和控制：确定不同传感配置的风险水平 评估并使用它们来实现能够确保产品质量的控制系统。 4.系统稳健性和验证：系统地检查不确定性和可变性的来源 并确定策略，以实现质量性能的持续验证，并实现真实的时间 产品发布。 经过50年的近乎停滞，制药业正在经历前所未有的科学化 和技术创新。在过去的三年里，制药行业及其技术供应商 已经接受了从批量生产到连续生产的全球性转变。公司都在积极 实施API和固体制剂生产的连续工艺，并开始开发 用于生物制品和液体产品的系统。兴趣已经扩大到仿制药公司，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。 拟议的项目将开发、实施和演示设计的系统方法 和实施连续固体剂量生产工艺，包括广泛的和预测性的 原材料特性的表征，传感和测量的最佳实施和严格验证， 控制方法和故障模式的系统分析，具体目标是实现真实的时间 质量保证（和真实的时间产品发布）。该项目的意义有两个方面：这些工具将 两者都能实现强大而可靠的制造工艺，并将促进科学- 基于监管评估和连续生产应用的评估。

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.