(334j) Process Modeling and Optimization for Monoclonal Antibody Production

In the past five years, monoclonal antibodies (mAbs) market has been increasing rapidly, and is predicted to reach $130-200 billion in year 2022¹. There is a need to improve the overall process productivity to satisfy the increasing demands for mAb market. Two approaches to improve the process productivity include – 1) selection of high-performance process equipment, 2) application of optimum operating conditions. Continuous processing shows a significant benefit in increasing productivity, reducing the footprint, and cost-effectiveness over the conventional operations². However, quantitative evaluation of the overall process performance is critical to decide the preferred mode of operation (batch or continuous) to satisfy the increasing market demands for mAb production. In addition, it is essential to procure detailed process understanding of unit operations to enhance product quality and process productivity.

In this work, we explore different simulation methods, including flowsheet modeling and mathematical modeling, to accurately predict mAb production. We implement flowsheet modeling to design and construct a fully integrated framework for continuous mAb production and compare its performance with the batch process using techno-economic analysis³. Scenario studies are simulated to evaluate process cost-effectiveness under varied production scales and upstream/downstream parameters. As bioreactor takes the highest percentage of the operating cost, we employ kinetic modeling method to capture the nonlinear bioprocess dynamics between operating conditions and output variables, aiming to improve the process productivity while maintaining product quality for CQAs like glycan concentration. Proposed kinetic modeling approach allows to evaluate important process variables like viable cell density, glucose, lactate, ammonia concentration, protein titers, and glycosylation during the batch culture for different temperature and pH values. Following this, we develop a surrogate model to investigate the optimum operating conditions for bioreactor. This is further integrated within the flowsheet model to capture corresponding effect on the mass balance, process scheduling, and critical quality attributes of the overall process. Thus, in conclusion, we propose applications of system engineering tools like process modeling and optimization for biopharmaceutical manufacturing, focusing on comparison of operation modes – batch and continuous, bioreactor modeling and mAb production, paving the way for cost-effective manufacturing and high quality biologics production.

Reference

1. Grilo, A. L. & Mantalaris, A. The Increasingly Human and Profitable Monoclonal Antibody Market. Trends Biotechnol. 37, 9–16 (2019).
2. Yang, O., Qadan, M. & Ierapetritou, M. Economic Analysis of Batch and Continuous Biopharmaceutical Antibody Production: a Review. J. Pharm. Innov. 15, 182–200 (2020).
3. Yang, O., Prabhu, S. & Ierapetritou, M. Comparison between Batch and Continuous Monoclonal Antibody Production and Economic Analysis. Ind. Eng. Chem. Res. 58, 5851–5863 (2019).