Biocatalyst inactivation is inherent to continuous operation of immobilized enzyme reactors, meaning that a strategy must exist to ensure a production of uniform quality and constant throughput. Flow rate can be profiled to compensate for enzyme inactivation maintaining substrate conversion constant. Throughput can be maintained within specified margins of variation by using several reactors operating in parallel but displaced in time. Enzyme inactivation has been usually modeled under non-reactive conditions, leaving aside the effect of substrate and products on enzyme stability. Results are presented for the design of enzyme reactors under the above operational strategy, considering first-order biocatalyst inactivation kinetics modulated by substrate and products. The continuous production of hydrolyzed-isomerized whey permeate with immobilized lactase and glucose isomerase in sequential packed-bed reactors is used as a case study. Kinetic and inactivation parameters for immobilized lactase have been determined by the authors; those for glucose isomerase were taken from the literature. Except for lactose, all other substrates and products were positive modulators of enzyme stability. Reactor design was done by iteration since it depends on enzyme inactivation kinetics. Reactor performance was determined based on a preliminary design considering non-modulated first-order inactivation kinetics and confronted to such pattern. The new pattern of inactivation was then used to redesign the reactor and the process repeated until reactor performance (considering modulation) matched the assumed pattern of inactivation. Convergence was very fast and only two iterations were needed.