Use of cell bleed in a high cell density perfusion culture and multivariable control of biomass and metabolite concentrations

A main problem in controlling bioprocesses is the lack of manipulated variables. Batches and fed-batches cannot be drained of the waste substances produced by the biomass. A chemostat (CSTR) may have the dilution rate as the manipulated variable, allowing a certain control over the biomass concentration with a risk, however, of washout if the dilution rate gets higher than the maximum growth rate. Perfusion processes with full biomass retention are somewhat similar to batches, as no steady state is really obtained until biomass growth is stopped by nutrient limitations. Cell bleed is often used in perfusions to improve the overall cell culture viability, and prevent accumulation of dead cells. However, use of the cell bleed stream as a manipulated variable for control has not yet received much attention. This paper's main contribution is the use of cell bleed as an additional degree of freedom in a multivariable control strategy for a perfusion culture. To add to the originality of the contribution, the control strategy used is multivariable nonlinear adaptive backstepping, which has never been used for a perfusion bioreactor. Results show a good performance of the controller, while the chosen set points actually correspond to perfusion operation. (C) 2006 Curtin University of Technology and John Wiley & Sons, Ltd.