A headspace GC-MS method to quantify nitrosamine impurities and precursors in drug products: Method validation and product testing

Susan Daniela Selaya; Nicolas Abrigo; Dustin G Brown; Saaniya Desai; Christopher Beekman; Patrick Faustino; Diaa Shakleya

doi:10.1002/bmc.6040

A headspace GC-MS method to quantify nitrosamine impurities and precursors in drug products: Method validation and product testing

Biomed Chromatogr. 2024 Nov 7:e6040. doi: 10.1002/bmc.6040. Online ahead of print.

Authors

Susan Daniela Selaya^{1

2}, Nicolas Abrigo^{1

2}, Dustin G Brown¹, Saaniya Desai¹, Christopher Beekman^{1

3}, Patrick Faustino¹, Diaa Shakleya¹

Affiliations

¹ Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, USA.
² Office of Product Quality Assessment, Center for Drug Evaluation and Research Food and Drug Administration, Silver Spring, Maryland, USA.
³ Office of Regulatory Science, Center for Food Safety and Applied Nutrition, College Park, Maryland, USA.

PMID: 39510975
DOI: 10.1002/bmc.6040

Abstract

Pharmaceutical manufacturers are working to mitigate the formation of nitrosamine impurities in drug products. The work herein describes the development and validation of a headspace GC-MS method according to ICH Q2(R1) guidelines for the detection and quantification of NDMA, NDEA, NDIPA, and NEIPA in drug products. The analytical procedure was further modified to include detection and quantitation of DMF due to the potential decomposition pathway of DMF to form dimethylamine, a known precursor for NDMA formation. The NDMA impurity was detected in the "sartan" class of drug products between 0.1 and 113 ppm. The validated analytical procedure was applied in an investigation of approaches to mitigate nitrosamine formation in metformin drug products. The developed analytical procedures provide another tool for pharmaceutical manufacturers to evaluate drug products for nitrosamine impurities.

Keywords: angiotensin receptor blockers; carcinogens; headspace GC–MS; impurities; mitigation; nitrosamines; pharmaceutical drug products; validation.

Abstract

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