In this paper, we investigate the continuous production of high-fructose corn syrup in a reactive simulated moving bed (RSMB) process which combines a quasi-continuous chromatographic separation with the enzymatic biochemical conversion of glucose to fructose. Such an integration of reaction and separation in one unit operation is advantageous for the equilibrium limited glucose isomerization. However, it complicates process design and process control. The continuous operating parameters and the discrete distribution of the columns over the different zones of the RSMB process are determined using a rigorous model-based optimization strategy. In order to maintain the product purity in the presence of disturbances while injecting a minimal additional amount of eluent, a nonlinear model predictive controller was developed which can deal with the complex hybrid (continuous/discrete) dynamics of the RSMB plant and takes hard process constraints (e.g. the maximal allowable pressure drop) into account. The efficiency of the control concept is proven in experimental studies using a 6-column RSMB plant of pharmaceutical scale. (C) 2004 Elsevier Ltd. All rights reserved.