Quantification of Genotoxic Impurities (GTIs) in Active Pharmaceutical Ingredient (API) Using Gas Chromatography/ Mass Spectrometry (GC/MS) Selected Ion Monitoring (SIM) Method

Liron Sulimani, Discovery & Product development, TEVA Pharmaceutical, Netanya, Israel
Tatiana Molotsky, Discovery & Product Development, Teva Pharmaceutical, Netanya, Israel
Juergen Kettenring, Discovery & Product Development, Teva Pharmaceutical, Netanya, Israel
Ofir Barel, Discovery & Product Development, Teva Pharmaceutical, Netanya, Israel

GTIs in pharmaceuticals are of emerging and increasing concern for both the pharmaceutical industry and regulatory agencies due to their potential toxicological consequences. It is necessary to develop analytical methods to measure ppm levels of GTIs in API. Determination of GTIs at ppm levels requires highly sensitive and selective analytical methodologies. The common methods for GTIs at ppm levels are based on Liquid Chromatography-Mass Spectrometry/Mass Spectrometry (LC-MS/MS) technique utilizing Multiple Reaction Monitoring mode (MRM). This presentation describes a GC/MS-SIM method for the quantitative determination of residual amounts of 4-Chloro-1-butanol and 1-Bromohexane in synthetic intermediates and final API. Good resolution between 4-Chloro-1- butanol and 1-Bromohexane was achieved with column, Agilent Sand W GC, DB 1701, 30 m × 0.25 mm ID, 0.25mm film. The results of linearity, repeatability and selectivity support the suitability of this method for determination of 1-Bromohexane and of 4-Chloro-1-butanol in the concentration range of 1-100ppm in a preparation of 10mg/ml of API. Quantitation limit (QL) level is 1ppm for 1-Bromohexane and 2ppm for 4-Chloro -1-butanol. The recovery results demonstrated that impurity 4-Chloro-1-butanol in the intermediates and final API can be reliably estimated taking into account the matrix effect. The method was successfully applied to intermediates and final API. 1-Bromohexane and 4-Chloro -1-butanol were detected in the intermediates, but not detected in all final API.