Investigation of Potential Risk of N-Nitrosamines in Pharmaceutical Compounds with Complex Sample Matrix by Ultrasensitive Gas Chromatography-Electron Capture Detection

N-nitrosamines with potential mutagenic and carcinogenic activity resulted in multiple recalls of marketed products and they are included in the “cohort of concern” compounds listed in ICH M7 guidelines. Strict guidelines limiting their presence thus escalated worldwide regulatory authority expectations for pharmaceutical products. Based on the EMA procedure EMEA/H/A-5(3)/1490, a typical 18 ng/day limit has been utilized if no allowable daily intake is established for the target N-nitrosamine, unless a higher limit can be justified based on the structure-activity-relationship approach described in the ICH M7 guidelines. Depending on maximum daily dosage and the solubility of the drug substance, highly sensitive (e.g., ppb level sensitivity) and robust analytical methods are often needed to fulfil these requirements. Even though LC/MS could be used for the ultrasensitive detection and robust quantitation of many N-nitrosamines, the detection sensitivity for neutral compounds with poor ionization efficiency poses significant challenges for method development and validation. Herein, we report a case study of the method development and validation for halogenated N-nitrosamine in pharmaceutical compounds with complex sample matrix by ultrasensitive gas chromatography-electron capture detection. This method achieved a limit of detection of 20 ppb to meet the regulatory requirements and no detectable level of halogenated N-nitrosamine was found in these pharmaceutical compounds with complex sample matrix. This study was sponsored by AbbVie Inc. AbbVie contributed to the design, research, financial support and interpretation of data, writing, reviewing, and approving the publication. He Nan is an employee of AbbVie Inc.