This paper elaborates three novel contributions in the field of chemical process safety. The first contribution is the identification and classification of chemical system variabilities into seven broad categories, namely, media, equipment, component, operator, procedural, management, and external (MECOPME). The identified variabilities lead to epistemic and aleatory types of uncertainties in the probabilistic safety analysis. To deal with the uncertainties caused due to the variabilities, a concept of the flexible node is proposed, which demands a failure probability in the flexible range of a lower level to a higher level instead of a fixed static probability. Since the existing techniques are not robust enough to handle the probability range, the classical fault tree is mapped into a statistically more reliable approach of the response surface method (RSM). The unique idea of using RSM in the failure analysis is demonstrated over the fault tree of an overtemperature scenario in a semipilot scale setup for the hydrogenation process and successfully evaluated over an industrial accident of the release prevention barrier scenario. The contour and surface plots of RSM reveal more information than the traditional approach of minimal cut sets. The statistical markers of RSM are a better substitute for the improvement index for sensitivity analysis. The proposed approach deals with chemical system variabilities and the lack of knowledge of exact occurrence probabilities more effectively.