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(763g) Design of Integrated Monoclonal Antibody Production: Opportunities for Continuous Manufacturing

Authors: 
Badr, S., The University of Tokyo
Okamura, K., The University of Tokyo
Takahashi, N., The University of Tokyo
Shirahata, H., The University of Tokyo
Sugiyama, H., The University of Tokyo
Monoclonal antibodies (mAb)s are prominent examples of therapeutic proteins. They represent a growing fraction of the biopharmaceutical market in a trend that is expected to continue over the next five years. As the market for mAbs continues to expand, production facilities remain rather constant and therefore there is increasing pressure to optimize manufacturing practices to keep up with the increasing demand. Continuous production modes can provide valuable opportunities for improving process efficiency and flexibility. Continuous operation of different process units has been previously experimentally established in upstream production units, e.g. cell cultivation and in downstream purification units, e.g. protein A chromatography processes. Stability of end-to-end integrated continuous operations has also been experimentally demonstrated. This work aims to provide a framework for the generation and evaluation of batch, continuous and hybrid production modes as well as mapping out favorable production ranges for batch and continuous operation at different production scales.

Pilot-scale production data has been obtained from a research facility for the production of mAbs from Chinese Hamster Ovary (CHO) cells. Models for different upstream and downstream units have been developed and fitted against the available data for validation. The developed models were used to compare the effect of different operating modes for the cultivation units: batch, fed-batch, and perfusion; and for the chromatography units: batch vs. continuous operation through simulated moving bed (SMB), or multi-column periodic counter-current chromatography (PCC). An economic assessment was conducted to compare the results of the generated scenarios. A complementary performance analysis in terms of productivity enhancement was also conducted.

A sensitivity analysis was further carried out and the results show a strong dependence of the process performance and favorable operating modes on the required production size and scale as well as other cell performance parameters. Recent developments in cell performance and tolerance is shown to be a strong factor affecting preferential process operation modes. The results of this analysis can be used to set guidelines for further cell development efforts. The interdependence of the process performance on the different aspects of cell design and product properties highlights the need for the integrated and simultaneous design of cell, product, and process parameters.