Use of the reversed-phase HSS T3 Column provided excellent retentivity for nitrosamine impurities, particularly the most polar nitrosamine, NDMA, while also providing separation from ranitidine API. Detection using a tandem quadrupole MS system with MRM analysis using atmospheric pressure chemical ionization (APCI), provided a 10X fold sensitivity improvement compared to electrospray ionization (ESI) for the nitrosamines. With this developed assay, LLOQs 0.025–0.1 ng/mL (<3 pg/mL on-column), for the various nitrosamine impurities were achieved for neat standard solutions, DS, and DP, with recoveries between 85–115% for the calibration points. The specificity, sensitivity, and broad linear dynamic range of this developed assay easily detected 0.1 ng/mL (0.0033 ppm, relative to 30 mg/mL DP or DS) of the nitrosamines in ranitidine drug product. Using this method, endogenous levels of NDMA from a prepared ranitidine drug tablet were detected and calculated to be 28 ng/mL (~1 ppm). The performance of this developed assay demonstrates a highly sensitive, accurate, and robust method for simultaneous nitrosamine impurity detection and quantitation, easily achieving regulatory guidance threshold values for these nitrosamine impurities in drug substance and drug product.