Comparative Evaluation of Nitrosamine Impurity Control Strategies in USFDA, EMA, and WHO Pharmaceutical Submissions
Abstract
Nitrosamine impurities are of significant concern to the pharmaceutical industry because of their genotoxic and carcinogenic effects. They are formed during the manufacturing, storage, and/or packaging of APIs and/or drug products owing to the nitrosation reactions of amines with nitrosating reagents. The detection of nitrosamine impurities, such as N-nitrosodimethylamine and N-nitrosodiethylamine in medicinal products, including angiotensin II receptor blockers, ranitidine, and metformin, has raised significant concerns in the industry. Regulatory agencies have developed guidelines for controlling nitrosamine impurities. This review aims to evaluate the guidelines developed by the United States Food and Drug Administration, European Medicines Agency, and World Health Organization for controlling nitrosamine impurities and to identify the similarities and differences in the guidelines developed by the above agencies and the literature for risk evaluation, testing, and limits of intake, detection, and control of nitrosamine impurities. The review highlights the importance of strengthening international cooperation and developing standardised control strategies for the control of nitrosamine impurities in medicinal products, which is of significant importance for the quality and safety of medicinal products worldwide.
Conclusion: Effective control of nitrosamine impurities requires harmonized global guidelines, robust risk assessment, and advanced detection strategies to ensure the safety and quality of pharmaceutical products. Strengthening international collaboration is essential for developing consistent and reliable control measures worldwide.
Keywords:
Nitrosamine impurities, Regulatory Affairs, acceptable intake limits, pharmaceutical contamination, USFDA, EMA, WHO, genotoxic impurities
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References
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https://doi.org/10.1093/carcin/5.11.1381
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https://doi.org/10.3181/00379727-216-44168
16. Lin JK. Nitrosamines as potential environmental carcinogens in man. Clin Biochem [Internet]. 1990 [cited 2026 May 8]; 23:67–71. Available from:
https://doi.org/10.1016/0009-9120(90)90489-h
17. Tricker AR, Preussmann R. Carcinogenic N-nitrosamines in the diet: occurrence, formation, mechanisms and carcinogenic potential. Mutat Res [Internet]. 1991 [cited 2026 May 8]; 259:277–89. Available from:
https://doi.org/10.1016/0165-1218(91)90123-4
18. Snodin DJ, Trejo-Martin A, Ponting DJ, Smith GF, Czich A, Cross K, et al. Mechanisms of nitrosamine mutagenicity and their relationship to rodent carcinogenic potency. Chem Res Toxicol [Internet]. 2024 [cited 2026 May 8]; 37:181–98. Available from:
https://doi.org/10.1021/acs.chemrestox.3c00327
19. Thresher A, Foster R, Ponting DJ, Stalford SA, Tennant RE, Thomas R. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Regul Toxicol Pharmacol [Internet]. 2020 [cited 2026 May 8]; 116:104749. Available from:
https://doi.org/10.1016/j.yrtph.2020.104749
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https://www.fda.gov
21. Acceptable intake limits (NDMA 96 ng/day; NDEA 26.5 ng/day) – derivation and conversion notes [Internet]. US: US FDA; 2013 Aug [cited 2026 May 8]. Available from:
https://www.fda.gov/media/170794/download
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https://doi.org/10.1016/j.jpha.2023.12.009
25. Pardeshi N, Satapara V, Patel K. Nitrosamine contamination in pharmaceuticals: Regulatory perspectives and control strategies of USFDA, EMA & HC. Int J Drug Regul Aff [Internet]. 2024 [cited 2026 May 8]; 12:1–8. Available from:
https://doi.org/10.22270/ijdra.v12i1.624
26. Diab S, Dominey AP, Ferrini P, Hayler J, Hermitage S, Urquhart MW, et al. Formation of N-nitrosamines by reaction of secondary dialkylamines with trace levels of nitrite in aqueous solution: An automated experimental and kinetic modeling study using di-n-butylamine. Org Process Res Dev [Internet]. 2024 [cited 2026 May 8]; 28:293–304. Available from:
https://doi.org/10.1021/acs.oprd.3c00404
27. Dobariya U, Chauhan N, Patel H, Pardeshi N. Nitrosamine impurities: Origin, control and regulatory recommendations. Int J Drug Regul Aff [Internet]. 2021 [cited 2026 May 8]; 9:77–80. Available from:
https://doi.org/10.22270/ijdra.v9i2.472
28. Wichitnithad W, Sudtanon O, Srisunak P, Cheewatanakornkool K, Nantaphol S, Rojsitthisak P. Development of a sensitive headspace gas chromatography–mass spectrometry method for the simultaneous determination of nitrosamines in losartan active pharmaceutical ingredients. ACS Omega [Internet]. 2021 [cited 2026 May 8]; 6:11048–58. Available from:
https://doi.org/10.1021/acsomega.1c00982
29. Kumar S, Pawar AS. Formation of nitrosamine impurities: Discussion and advanced method development and validation using LC-MS/MS for their detection. World J Bio Pharm Health Sci [Internet]. 2024 [cited 2026 May 8]; 20:385–9. Available from:
https://doi.org/10.30574/wjbphs.2024.20.3.1016
30. Berardi A, Jaspers M, Dickhoff BHJ. Modeling the impact of excipients selection on nitrosamine formation towards risk mitigation. Pharmaceutics [Internet]. 2023 [cited 2026 May 8]; 15:2015. Available from:
https://doi.org/10.3390/pharmaceutics15082015
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K S, Vaz ISS, S R. Comparative Evaluation of Nitrosamine Impurity Control Strategies in USFDA, EMA, and WHO Pharmaceutical Submissions. Int J Drug Reg Affairs [Internet]. 2026Sep.17 [cited 2026Oct.2];14(3):77-1. Available from: https://www.ijdra.com/index.php/journal/article/view/905
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