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Identification and Control of Impurities for Drug Substance Development using LC/MS and GC/MS

Abstract Identification and control of impurities for drug substances is a critical task in pharmaceutical process development for quality and safety. The most commonly used analytical technique for impurity analysis in drug substances and drug products is undoubtedly a chromatographic method, namely high performance liquid chromatography (HPLC). Impurity profiling is typically performed by HPLC and impurities are further tested for identification and confirmation by other techniques. Several case studies are presented in this paper to report the identification of unknown impurities employing chromatographic techniques interfaced with mass spectrometry. The task of unknown identification was facilitated by complementary methodologies including tandem mass spectrometry (MS/MS), high resolution mass spectrometry (HRMS), preparative HPLC and NMR. Upon identification of the impurity, the impurity formation was monitored and controlled throughout the synthesis. Three case studies are described where unknown process impurities were analyzed for identification using LC/MS and GC/MS methodologies. It is demonstrated that identification of the unknown impurity enabled chemists to pinpoint the chemical step of impurity generation, aiding the effort to reduce or even eliminate the impurity in the drug substances.