A large number of optimization strategies have been developed for semi-batch reactors (SBR) with a fixed or free terminal time, with or without considering various sources of uncertainty. Such strategies account for safety constraints rather empirically determined in the form of parameter thresholds, while safety indices are seldom integrated in the optimization objective function. The present work illustrates how the runaway boundaries, and their confidence region associated to the parameter uncertainty, can be evaluated using the process model and a generalized sensitivity criterion, and how they can be included in the SBR optimization. A concrete example is provided for the SBR used for the acetoacetylation of pyrrole with diketene in homogeneous catalysis, a process known to be of high risk due to the very exothermic side-reactions. While previous studies approached the isothermal SBR, the present work is focused on optimizing the non-isothermal SBR operation. (C) 2010 Elsevier Ltd. All rights reserved.