(471c) Dynamic Simulation and Process Assessment of Cultivation Modes in Monoclonal Antibody Production Using Pilot-Scale Experimental Data

The market size of biopharmaceuticals has been expanding, especially, for monoclonal antibodies (mAbs). In the cultivation step of the production, host cells such as Chinese Hamster Ovary (CHO) produce mAb. There are mainly three established cultivation modes, Batch, Fed-batch, and Perfusion. Recent advancements in cell design include the development of host cells which can tolerate high cell density cultivation. Development of continuous operation of the downstream processes following cell cultivation is ongoing to improve the overall process productivity. Such developments enable the connection of the output of cultivation units run in perfusion mode, where continuous feeding and removal of mAb are conducted, can be connected to the continuously run downstream processes. The number of process options is expanding in lieu with developments in the cell performance, however process assessment efforts have been using fixed expected cell performance results, e.g. output titers without considering recent developments or fully exploring the potential range of design options.

The purpose of this work is to integrate recent experimental cell developments with the developed cultivation models to map out preferential production modes through dynamic simulation and process assessment with respect to productivity and economic aspects. The work also explores the impact of potential future developments in the cell design on the process performance. The approach consists of three steps: (I), Based on the previous work [2][3], the mathematical cultivation model for each mode was developed. Model parameters were fitted using experimental data from a pilot-scale research facility; (II), dynamic simulation was conducted using the developed models to explore the impact of process parameters, e.g. production scale and size and the produced mAb titer on the process performance and preferential production mode. (III) As the final step, a map was created for the mode minimizing the cultivation time and operating cost.

The results showed that the perfusion-favorable operating range was larger than batch and fed-batch especially at larger production scales, however the fed-batch favorable operating area widened for processes employing cells with higher doubling rate. Results were validated with experimental data from the pilot-scale facility. Similar analysis is conducted for further cell parameters.

[1] Bunnak, P., Allmendinger, R., Ramasamy, S. V., Lettieri, P., & Titchener-Hooker, N. J. (2016). Life-cycle and cost of goods assessment of fed-batch and perfusion-based manufacturing processes for mAbs. Biotechnology Progress, 32(5), 1324–1335. https://doi.org/10.1002/btpr.2323

[2] Xing, Z., Bishop, N., Leister, K., & Li, Z. J. (2010). Modeling kinetics of a large-scale fed-batch CHO cell culture by markov chain monte carlo method. Biotechnology Progress, 26(1), 208–219. https://doi.org/10.1002/btpr.284

[3] Kornecki, M., & Strube, J. (2018). Process Analytical Technology for Advanced Process Control in Biologics Manufacturing with the Aid of Macroscopic Kinetic Modeling. Bioengineering, 5(1), 25. https://doi.org/10.3390/bioengineering5010025