Fed-batch fermentation processes are common methods for producing recombinant biological products from different microorganisms. Model-based control of bioprocess is a difficult task due to the challenges associated with bioprocess modeling and the lack of on-line measurements. In this paper a new hybrid adaptive feeding control strategy for fed-batch cultivation of high cell density Escherichia coli (E. coli) is designed which is capable of maintaining the growth of the cells in optimal critical value despite disturbances and modeling uncertainties. For this purpose first an optimal controller is suggested that fosters the growth rate to the optimal critical value and then a sliding mode controller is applied which powerfully strengthens the optimal controller against disturbances and uncertainties. The combined controller is capable of achieving the maximum amount of biomass and recombinant protein production despite a large number of uncertainties and disturbances. The process considered in this study is fed-batch cultivation of E. coli BL21 (DE3) [pET3a-ifn gamma] under maximum attainable specific growth rate for producing gamma-interferon protein. (C) 2009 Elsevier Ltd. All rights reserved