Integrated Synthesis, Crystallization, Filtration, and Drying of Active Pharmaceutical Ingredients: A Model-Based Digital Design Framework for Process Optimization and Control

Over the past two decades, pharmaceutical manufacturing has seen significant modernization due to the digitalization of manufacturing as more manufacturers adopt Industry 4.0 standards. The FDA launched the quality-by-design and quality-by-control initiatives as steps to ensure this digitalization in pharmaceutical manufacturing may proceed alongside regulatory guidelines for the transition from traditional batchwise manufacturing to end-to-end continuous or hybrid batch-continuous manufacturing schemes. Adoption of a process digital twin is a pivotal step in providing quantitative justification for updating or designing new processing routes for pharmaceutical materials, especially when implementing online process control. This article presents a framework for the integrated design of continuous and hybrid systems for the synthesis-crystallization and filtration-drying steps of paracetamol using digital twins to simulate process operation and control.