In this research evaluation, the catalytic synthesis off-gas was investigated through a safety assessment approach. Though operation safety measures are of utmost importance in the industrial processes, they are difficult to maintain when variable components are dealt with. Four different scenarios based on various process phases and off-gas compositions were experimentally evaluated. The results exhibited significant differences in explosion pressure values, revealing the most severe consequences during the start-up phase, when H₂ is abundant, and during the advanced process (over 30 h of operation), when CO is abundant in the off-gas composition. The first case possessed 200 MPa/s explosion pressure change, while the latter was equal to 152 MPa/s. These findings have provided a significant guideline for progressive industrial applications with complex material mass balance.