DescriptionBiopharmaceutical manufacturing mainly produces large molecule-based products and is becoming increasingly important in the last few years, leading to high market demand. Two approaches are investigated in this dissertation to satisfy the high market demand, including the selection of high-performance process operating mode and improvement of operating strategies. Continuous processing shows a significant benefit in increasing productivity, reducing the footprint, and cost-effectiveness over conventional operations. Quantitative evaluation of the overall process performance is critical to decide the preferred mode of operation (batch or continuous). At the same time, enhancing the understanding of conventional unit operations is also essential to improve productivity while maintaining the product quality for current manufacturing setups.
In this dissertation, different simulation methods, including flowsheet modeling and mathematical modeling, are explored to accurately predict and evaluate large molecule-based drug production. Flowsheet modeling is implemented to design and construct fully integrated frameworks for continuous monoclonal antibody and gene therapy drug productions and compare their performance with the batch processes using techno-economic analysis. Scenario studies are used to evaluate process cost-effectiveness under varied production scales and upstream/downstream parameters. Under the guidance of quality by design (QbD), mechanistic and surrogate models are built to capture the nonlinear bioprocess dynamics between operating conditions and output variables, aiming to improve productivity while maintaining critical quality attributes of the products. Furthermore, feasibility analysis has been used to determine the design space for protein production based on the requirement of commercial product quality attributes. This dissertation provides a framework covering process design and decision-making in biopharmaceutical manufacturing, paving the way for cost-effective manufacturing and high-quality biological drug production.