Direct control of recombinant protein production rates in E. coli fed-batch processes by nonlinear feedback linearization

Biotechnological cultivation processes aim for high and long lasting productivities. In this paper, a method to directly control the productivity of a recombinantly produced protein in an E. coli fed-batch process is introduced. After modeling the process using a nonlinear kinetic model, which includes the degeneration of the product formation capacities, a controller was derived by feedback linearization. The derived control law presents an improved and novel approach to directly influence the process parameter associated with the biomass specific product formation rate. In order to deal with observed model-plant mismatches a Two-Degrees-of-Freedom controller was implemented. A simulation study using different model parameters derived from calibration and validation data sets and two realistic measurement scenarios was carried out to demonstrate the potential of the presented method in comparison to a constant substrate addition. Compared to optimized, constant glycerol feed rates the simulations with controlled productivities led to significantly higher specific titers with the same amount of fed glycerol. The feeding rates given by the developed controller minimize the metabolic load as well as product release and therefore stabilizes the productivity for a prolonged, potentially continuous, production process.