A Systematic Framework for Process Control Design and Risk Analysis in Continuous Pharmaceutical Solid-Dosage Manufacturing

The paradigm shift in the pharmaceutical industry to continuous manufacturing, which has recently progressed from conceptual demonstration to pilot production, has stimulated the development and application of process systems engineering (PSE) tools for implementing efficient and robust control strategies. In this study, a systematic framework for process control design and risk analysis for continuous pharmaceutical solid-dosage manufacturing is proposed, consisting of system identification with state-space models; control design and analysis metrics; hierarchical three-layer control structures; risk mapping, assessment and planning (Risk MAP) strategies; and control performance indicators. The framework is applied to a feeding-blending system, wherein the major source of variance in the product quality arises. It can be demonstrated that the variance in the feeding-blending system can be mitigated and managed through the proposed systematic framework for control design and risk analysis. The process analytical technology (PAT) tool for mass fraction measurement of active pharmaceutical ingredient (API) and its relative standard deviation (RSD) were indispensable to achieve an efficient control design at the advanced layers. Specifically, the improvements in control performance by implementing advanced model-based control strategy are found to be limited by model-plant mismatch and the sampling time of the PAT tools.

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