Kinetic modeling: A tool for temperature shift and feeding optimization in cell culture process development

Mammalian cells have dominated the biopharmaceutical industry for biotherapeutic protein production and tremendous efforts have been devoted to enhancing productivity during the cell culture process development. However, determining the optimal process conditions is still a huge challenge. Constrained by the limited resources and timeline, usually it is impossible to fully explore the optimal range of all process parameters (temperature, pH, dissolved oxygen, basal and feeding medium, additives, etc.). Kinetic modeling, which finds out the global optimum by systematically screening all potential conditions for cell culture process, provides a solution to this dilemma. However, studies on optimizing temperature shift and feeding strategies simultaneously using this approach have not been reported. In this study, we built up a kinetic model of fed-batch culture process for simultaneous optimization of temperature shift and feeding strategies. The fitting results showed high accuracy and demonstrated that the kinetic model can be used to describe the mammalian cell culture performance. In addition, five more fed-batch experiments were conducted to test this model's predicting power on different temperature shift and feeding strategies. It turned out that the predicted data matched well with experimental ones on viable cell density (VCD), metabolites, and titer for the entire culture duration and allowed selecting the same best condition with the experimental results. Therefore, adopting this approach can potentially reduce the number of experiments required for culture process optimization.