A sequential fashion experimental design algorithm for the optimal pH profile search in the asymmetric reduction of ethyl 4-chloro-3-oxobutyrate catalyzed by Saccharomyces cerevisiae was addressed. Ethyl S-4-chloro-3-hydroxybutyrate was produced to reach two important quality indices: reaction yield and product's optical purity. Instead of the traditional strategies with the fixed pH or the uncontrolled pH values during the reaction, a novel strategy for designing the optimal time-varying operating pH profile was developed based on the methodology of the data-driven method. The proposed design technique composed of the hybrid function approximation and the Taguchi's orthogonal array was used to determine the new design profiles in the next run. The hybrid type of the function approximation allows the global and local approximations to construct the profiles in the whole design space and some local regions, respectively. The optimal profile can be obtained if the location of the function coefficients is properly adjusted in the functional space. The Taguchi's approach is used to design experiments and analyze the outcomes of each experimental design to improve the optimal objective (quality) function. Without the prior knowledge of the system, the proposed method using information from the previous experiments can update and modify the profiles that would be applied to the subsequent experiments. In comparison with traditional methods, the product's ee could be significantly enhanced (from 83.8% to 91.3%) without decreasing the reaction yield. (c) 2005 Elsevier Inc. All rights reserved.