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An alkylating agent, 4-chloro-1-butanol, is a genotoxic impurity (GTI); it may be generated during the synthesis of active pharmaceutical ingredients (APIs). For the trace-level detection of GTIs in APIs, usually, gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS) is employed. In this study, a novel LC-inductively coupled plasma (ICP)-MS method was developed and validated. Linearity was observed over the 0.5 -50 ppm (μg/g API) range, with an R 2 value of 0.9994. The detection limit (DL) and quantitation limit (QL) were 0.2 and 0.5 ppm, respectively. The DL and QL values are well over the thresholds specified in the guidelines. The accuracy was 95.1 -114.7% for concentrations of 1 -50 ppm, and the relative standard deviation of the spiked recovery test's repeatability was 6.2%. In addition, six lots of an API were analyzed, and all results were lower than the reported threshold (1 ppm).

The analysis of genotoxic impurities (GTIs) in active pharmaceutical ingredients (APIs) is a challenging task. The target detection limit (DL) in an API is typically around 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis. 4-Chloro-1-butanol, an alkylating agent, is one of the GTIs. It is generated when tetrahydrofuran and hydrochloric acid are used during the synthesis of the APIs. In this study, a sensitive and robust gas chromatography-mass spectrometry (GC-MS) method was developed and validated for the identification of 4-chloro-1-butanol in APIs. In the GC-MS method, 3-chloro-1-butanol was employed as an internal standard to ensure accuracy and precision. Linearity was observed over the range 0. Key words 4-chloro-1-butanol; GC-MS; genotoxic impurity; active pharmaceutical ingredient; trace analysisThe analysis of genotoxic impurities (GTIs) in trace amounts is of increasing interest to pharmaceutical industries owing to its potential application in the detection of human carcinogenesis and in regulatory aspects. The assessment of GTIs during clinical development is a major liability.1-5) Since GTIs are expected to be present in active pharmaceutical ingredients (APIs), a method for the sensitive and selective analysis of GTIs is required. The allowable limits of GTIs in new commercial drugs are regulated by government agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), [6][7][8][9] although the toxicological assessment of GTIs is not addressed sufficiently in the International Conference on Harmonisation (ICH) guidelines. The present ICH Q3A and Q3B guidelines only describe the limits of conventional impurities and related substances, where typical levels are above 0.05%. Therefore, the ICH has been discussing about GTIs as part of the ICH M7 guideline. The allowable limits of GTIs are decided by the U.S. FDA and the EMA depending on the duration and the daily dose of exposure during the clinical development. A toxicological threshold of 1.5 µg/d is suggested. Typically, the target detection limit (DL) in an API is 1 ppm (1 µg/g API). Therefore, a sensitive and selective analytical method is required for their analysis.4-Chloro-1-butanol, an alkylating agent, is one of the GTIs, which is generated when tetrahydrofuran (THF) and hydrochloric acid (HCl) are used during the synthesis of APIs. The interaction of THF with HCl leads to the generation of 4-chloro-1-butanol (Fig. 1). THF and HCl are frequently used in the synthesis of APIs. Hence, it is necessary to confirm the fate of 4-chloro-1-butanol, to develop the process control for APIs and ensure their quality. The quantitation limit (QL), as per the analytical method, should be at low ppm levels, considering the protocols (the daily dose and the duration of exposure) of the clinical studies.As part of the analytical method, conventional analytical instrumentations such as the HPLC with UV detection (for nonvolatile GTIs) or the GC with flame ioniza...