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

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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.