(545b) Multi-Scale Modelling of Chinese Hamster Ovary Cell Cultures

Recombinant DNA technology has made possible the generation of high-valued proteins with therapeutic potentials. Sales of US$ 16 billion are expected for monoclonal antibodies alone in 2010. The complex structural nature of these therapeutic proteins and their requirement for post-translational modifications make mammalian cells a good host for complete expression of the proteins.

Mammalian cell culture reproducibility and optimal operation depends on various environmental and physiological factors; fragile and susceptible to shear stresses, inhibition of growth rate by several products of cell metabolism, sensitivity to process parameter (pH, temperature and dissolved oxygen tension) changes on cell metabolism, apoptosis, and variable nutrient consumption and energy requirements. Heterogeneous nature of the culture system due to the apportioning of cell cycle phases, further worsen this problem.

At this juncture, models of mammalian cell culture systems have a wide range of potential applications, such as analysis and prediction of experimental results, optimization of culture conditions, and perhaps most importantly, the investigation of fundamental metabolic processes and their subsequent elucidation, which will result in the design of more efficient mammalian cell culture systems both from a genetic engineering and process control perspective.

In this work, most of the predominant physiological phenomena that determines the intrinsic state of Chinese Hamster Ovary cells are modeled in an effort to unify them to estimate the onset of metabolism shift from available on-line and off-line measurements which may be noisy. Multi-level modeling is adapted to characterize the intra-cellular and inter-cellular processes in mammalian cell cultures. A hybrid single cell model is developed to quantify cell growth, death, lysis, nutrient uptake, metabolite and protein production and their dependency on various environmental and physiological factors. Population balance models are combined with this hybrid model to characterize various phases in the cell cycle and in turn account for the heterogeneity in the cell populations.