Oxygen Uptake Rate (OUR) Estimation in High Density Mammalian Cell Perfusion Cultures

Mammalian cells are being widely used for the production of therapeutic proteins given their ability to correctly fold and glycosylate large molecules. However, productivities from a typical mammalian cell reactor are low and one approach to increase productivity is using perfusion systems for high cell density cell cultivations. Perfusion bioreactors are characterized by a high degree of complexity and require considerable effort to maintain. Due to the long duration of this type of process, disturbances in bioreactor operation can directly affect cellular metabolism and productivity. One parameter which has been shown to correlate to these metabolic shifts is the oxygen uptake rate (OUR). We present a method for real-time estimation of OUR in high density mammalian cell perfusion cultures. These computations are based on a global mass balance which does not require k(L)a data or reactor perturbations. The applicability of this approach was tested in a long-term BHK cell cultivation. Furthermore, real-time OUR data enables real-time metabolic flux estimation and cell physiological state monitoring.