Safe operating conditions, for strongly exothermic chemical systems involving multiple reactions, are particularly critical to be obtained, because of the complex interactions between selectivity and safety constraints. In this work, new criteria, which are useful for isoperibolic semibatch processes involving consecutive reactions and based on the topology of a particular phase space, are presented. Such criteria are able to detect both the runaway boundary and the so-called "quick onset, fair conversion, smooth temperature profile" (QFS) operating region by performing a topological analysis of the phase space of the system of ordinary differential equations (ODEs) that describe the analyzed process. Moreover, a safe optimization procedure, the objective of which is to obtain the optimum values both of the dosing time of the dosed reactant and the initial reactor temperature, based on such criteria, has been developed. Finally, such a set of optimum operating parameters has been validated through a comparison with experimental data from published literature.