A novel direct injection gas chromatography method coupled with selective ion monitoring mass spectrometry (GC/SIM-MS) was developed for quantitation of trace levels of high boiling point (HBP) epoxide genotoxic impurity (GTI) in drug substance. The injector temperature was optimized with the aims to minimize matrix effects and enhance SIM signal response. The final injector temperature 160 °C was selected after balancing between these two factors. The column screening was conducted as well and MN OPTIMA delta-3 silica capillary column was selected since it showed good peak symmetry without column bleeding. The good linearity was established for the concentration in the range from 0.0045 μg/mL to 0.5 μg/mL with a R2 = 0.9999. The limit of detection (LOD) and the limit of quantitation (LOQ) were 0.0014 μg/mL and 0.0045 μg/mL, respectively. The recovery which ranged from 95.0% to 112.5% could meet the ICH acceptance criteria. The validation results demonstrated the good linearity, precision and accuracy of the method which can be further adopted as an adequate quality control tool for quantitation of epoxide impurity at trace levels in drug substance and drug product.