Digital design and optimization of an integrated reaction-extraction-crystallization-filtration continuous pharmaceutical process

This work investigates the digital design of a continuous pharmaceutical plant comprising a continuous three stage reaction, liquid-liquid extraction, multistage cooling and antisolvent crystallization, and wash-filtration. Firstly, the mathematical models were developed and validated in conjunction with the available experimental data obtained from the literature and research partners. The resulting digital twin was used for steady state optimization to deliver optimal options for plant design and operation, including process capacities and number of crystallization stages. After the identification of the optimal design and optimal steady state operation, the digital twin was used to perform uncertainty propagation and global sensitivity analysis to identify the Critical Process Parameters (CPP) and Critical Material Attributes (CMA) and deliver robust and cost-effective methods for a systematic implementation of Quality-by-Design (QbD). This approach is aimed at demonstrating that the plant can be operated within the robust quality bounds which provide a built-in quality assurance for the final product. Several Critical Quality Attributes (CQA) which impact drug safety and efficacy were considered which includes the average crystal size, crystal size distribution, coefficient of variation and product purity were considered as the CQA.