Inherently Safer Design (ISD) describes a strategy that reduces and even eliminates inherent hazards in processes. However, ISD principles improving inherent safety always involves tradeoffs between these two competing factors: safety and costs. In inherent safety aspects, process intensification (PI), one of the methodologies in ISD, aims to eliminate units and simplify the process. Therefore, synchronous promotion of cost-efficiency and safety is achieved. Nevertheless, applying PI strategies in the design stage may result in adverse safety effects, and eliminating units may cause risk transfer and risk accumulation, which could lead to serious consequences when accidents occur. In this study, we introduced a novel methodology involved in a better-suited indicator, Advanced Comprehensive Inherent Safety Index (ACISI), along with Quantitative Risk Analysis (QRA) to evaluate the safety performance of PI designs in the early stage. To further illustrate, a case study of C-3-alkyne selective hydrogenation distillation process is selected to analyze safety and economic impacts on four intensified designs (reactive distillation, thermally coupled distillation of a side-rectifying section, thermally coupled distillation of a side-stripping section, and fully thermally coupled distillation) using the proposed methodology. Moreover, the safety performance of individual units in each process is explored. Investigation of the case study found that potential root causes for risk transfer are related to the vapor-liquid flow profiles in the column. Considering PI features and risk transfer, this study provides a generally effective framework to evaluate process safety quantitatively and to explore safety characteristics comprehensively for different intensified processes, thus better assisting the achievement of ISD through PI.