With the ever increasing complexity of active pharmaceutical ingredient (API) preparations, more potential genotoxic impurities (PGI’s) are being observed. It is thus necessary to determine if these PGI’s are present in the final API’s, and if they are present, to ensure the levels are acceptable for any clinical uses. For PGI’s that have authentic standards available, quantitation can be accomplished in a straightforward manner. However, for PGI’s that are expected to form through rearrangements or side reactions, authentic standards may not be readily available, significantly complicating the analysis. In this study we describe a surrogate standard approach for quantifying PGI’s that allows for relative response factor calculations of PGI species utilizing both gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS).