Modeling of cell culture damage and recovery leads to increased antibody and biomass productivity in CHO cell cultures

• Published in: Biotechnology journal 2014-09, Vol.9 (9), p.1152-1163
• Main Authors: Naderi, Saeideh, Nikdel, Ali, Meshram, Mukesh, McConkey, Brendan, Ingalls, Brian, Budman, Hector, Scharer, Jeno
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - metabolism; Biomass; Cell Culture Techniques - methods; CHO cell culture; CHO Cells; Cricetulus; Culture Media - metabolism; Intermittent harvesting; Mathematical modeling; Model-based minimization of cell culture damage; Models, Theoretical; Tessier equation
• ISSN: 1860-6768; 1860-7314
• DOI: 10.1002/biot.201300287

The development of an efficient and productive cell‐culture process requires a deep understanding of intracellular mechanisms and extracellular conditions for optimal product synthesis. Mathematical modeling provides an effective strategy to predict, control, and optimize cell performance under a range of culture conditions. In this study, a mathematical model is proposed for the investigation of cell damage of a Chinese hamster ovary cell culture secreting recombinant anti‐RhD monoclonal antibody (mAb). Irreversible cell damage was found to be correlated with a reduction in pH. This irreversible damage to cellular function is described mathematically by a Tessier‐based model, in which the actively growing fraction of cells is dependent on an intracellular metabolic product acting as a growth inhibitor. To further verify the model, an offline model‐based optimization of mAb production in the cell culture was carried out, with the goal of minimizing cell damage and thereby enhancing productivity through intermittent refreshment of the culture medium. An experimental implementation of this model‐based strategy resulted in a doubling of the yield as compared to the batch operation and the resulting biomass and productivity profiles agreed with the model predictions. Continued optimization of cell culture systems is needed to meet the production needs of biological products such as monoclonal antibodies (Mabs). In this manuscript, a mathematical model is proposed to describe cell damage and recovery following exposure to stressful pH conditions and optimization is performed based on this model to predict perfusion steps to maximize productivity. The three‐step perfusion operation predicted resulted in near doubling of mAb productivity, compared with a conventional batch operation.