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 pro®led to compensate for enzyme inactivation maintaining substrate conversion constant. Throughput can be maintained within speci®ed 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 ®rst-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 ®rst-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. List of symbolsA m 2 cross sectional area of reactor a kat/kg speci®c activity of catalyst D m reactor diameter d s total operation time for each reactor cycle E kat enzyme activity e kat/m 3 volumetric enzyme activity F m 3 /s total process¯ow rate F 0i m 3 /s initial feed¯ow-rate to each reactor H number of enzyme half-lives used in the reactor H b m catalyst bed height H R m reactor height K eq kg-mole/m 3 equilibrium constant of glucose isomerization to fructose ( V G K F aV F K G ) K F kg-mole/m 3 IGI Michaelis constant for fructose K G kg-mole/m 3 IGI Michaelis constant for glucose K L kg-mole/m 3 CIL Michaelis constant for lactose K P kg-mole/m 3 CIL competitive inhibition constant for galactose k cat catalytic rate constant for lactose hydrolysis k H cat catalytic rate constant for glucose isomerization k D s À1 ®rst-order inactivation rate constant under no modulation k DJ s À1 ®rst-order inactivation rate constant under modulation by J M kg catalyst mass N 1 ± CIL global modulation factor N 2 ± IGI global modulation factor N R ± number of reactors n L ± CIL modulation factor by lactose n P ± CIL modulation factor by galactose n G ± IGI modulation factor by glucose n F ± IGI modulation factor by fructose R F ± ratio of minimum to maximum ow rate s 0 kg-mole/m 3 feed lactose concentration t s time of operation t s s time interval between e...