Chromatographic considerations in the standardization of liquid chromatographic methods used for extractables screening

Abstract

ABSTRACTOrganic extractables and leachables (E&L) from drug product packaging, manufacturing components, and delivery devices are of concern as they could impact product quality and/or user safety. Proper E&L assessment involves chromatographic profiling of a drug product or extraction solvent, including liquid chromatography with UV absorption and mass spectrometric detection (LC/UV/MS), to uncover these substances and establish their identities and concentrations. Relative retention time (RRT) could be used as one parameter for identifying E&L and relative response factors (RRFs) could be used for quantifying extractables if (a) RRT and RRFs were consistent across various LC/UV/MS methods and instrument systems used for profiling and (b) a database existed for RRT and RRFs. This manuscript addresses (a) by examining the variation in RRT and RRF for model extractables across variations to a specified LC/UV/MS method. Creating and populating a database of relative retention and response data (b) is beyond the manuscript’s scope. Studies which examined small, and more controlled, variations to the method and larger, and less controlled, variations were performed. These assessments support the conclusions that if the operational parameters of the LC/UV/MS are specified and if only relatively minor deviations from these parameters are allowed, then RRTs are sufficiently reproducible that they are an effective means of securing tentative extractable’s identities and UV RRFs are sufficiently reproducible that they provide accurate extractable’s concentrations. MS RRFs are less reproducible and only estimate concentration.