Design of Integrated Monoclonal Antibody Production Processes: Modelling, Data, and Process Challenges

Monoclonal antibodies (mAb)s are therapeutic proteins used for the treatment of cancer and autoimmune diseases. Designing optimal biopharmaceutical production processes can help meet the rapidly rising demand for these drugs and overcome competition from emerging biosimilars. The mAb production process involves upstream cultivation activities and downstream purification processes. Approaches to improve process efficiency and productivity include adjustments to cell cultures and cell lines, in addition to optimizing process conditions and operating modes. Moving from traditional batch operations to continuous modes promises a greater productivity boost. This work offers a mechanistic modelling approach for key upstream and downstream processes, e.g. chromatography units. The models are developed and verified using data from a pilot-scale facility in Japan. The higher resolution cultivation model employed in this work takes into account host cell proteins (HCP)s and DNA, in addition to, key nutrients and metabolites in the system. Kinetic models developed in this work are applied to the dynamic simulation of various production scenarios. Cultivation conditions can greatly influence the performance of downstream processes. Process failures at different unit operations are investigated and the propagation of impacts downstream are explored. Appropriate mitigating actions are accordingly suggested. A comprehensive assessment framework is presented. Additionally, preferential conditions and modes are mapped out according to various production scenarios in terms of economic performance and process robustness. The higher resolution gained by these models offers deeper insights into cell behavior and product quality issues. Current global events can only emphasize the need for efficient and robust pharmaceutical manufacturing processes. The integrated design approach is thus critical to avoid introducing further complexities in downstream operations and can lead to faster commercialization of new applications.