The safety in operation of a fixed-bed catalytic reactor remains a sensitive issue when a highly exothermic reaction is conducted and various process development elements such as controllability, stability, risk, and economic aspects are considered. Several model-based methods are used to estimate the safe operating region limits. Nominal conditions are set to limit the hot spot in the tubular reactor and avoid excessive thermal sensitivity to variations in the process parameters. When the catalyst or its characteristics are changed, the operating conditions have to be adjusted accordingly. The safety problem becomes more important when the production optimization requires setting the nominal operating point in the vicinity of the safety limits. This paper investigates the advantages as well as the precautions that need to be taken when using a more sophisticated model-based global sensitivity criterion (MV of Morbidelli & Varma) to routinely update the runaway critical conditions when changes in the investigated system frequently occur. A concrete example is provided for the case of an industrial fixed-bed catalytic reactor for nitrobenzene hydrogenation in vapour-phase. The analysis points out the discrepancies in predicting the runaway boundaries for complex processes between precise sensitivity-based MV-method and shortcut methods, and the importance of accounting for parameter uncertainty for both evaluation of the confidence region around the runaway boundaries and for the optimal set-point location. The close connection between the operating risk limits and the process kinetics is also highlighted even if the reactor geometry and the main flow conditions are kept unchanged. (C) 2009 Elsevier Ltd. All rights reserved.