Nitrosamine Impurities: Origin, Control and Regulatory Recommendations

  • Umesh Dobariya Regulatory and Compliance Specialist
  • Narendra Chauhan
  • Himani Patel
  • Nidhi Pardeshi

Abstract

The unexpected finding of presence of nitrosamine impurities, by USFDA and EMA in year 2018, in drugs such as Angiotensin-II Receptor Blockers (ARBs), Ranitidine, Nizatidine and Metformin, has triggered the need for a risk assessment strategy for evaluation and control of these probable human carcinogen - nitrosamine in pharmaceutical product that are at risk. This finding leads to voluntarily recall of products worldwide. The finding of nitrosamines in some types of drug products led FDA and other international regulators to conduct a detailed risk assessment of these impurities in APIs and drug products. Although nitrosamine impurities have been found in only some drug products, regulatory agencies recommended to extend risk analysis in other chemically synthesized APIs and drug products also.

Keywords: Nitrosamine, Risk Assessment, USFDA, EMA, EDQM, Amines, Nitrous Acid, Azide

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References

1. USFDA Guidance for Industry: Control of Nitrosamine Impurities in Human Drugs, Revision 1, February 2021. Available from: https://www.fda.gov/media/141720/download
2. EMA Assessment report Nitrosamine impurities in human medicinal products, EMA/369136/2020, 25 June 2020. Available from: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf
3. The EDQM’s Response to Nitrosamine Contamination. Available from: https://www.edqm.eu/en/edqms-response-nitrosamine-contamination
4. WHO’s Information Note Nitrosamine impurities. Available from: https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en/
5. ICH Harmonized Guideline M7(R1): Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Step 4 Version, 31 March 2017. Available from: https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf
6. Active Pharmaceutical Ingredients Committee (APIC) Guideline: Additional guidance on the assessment on the risk assessment for presence of N-nitrosamines in APIs. Available from: https://www.apic.cefic.org/pub/APIC_Guidance_on_Nitrosamines_Risk_Assessment-final-18Feb2020.pdf
7. Health Canada Guideline: Nitrosamine impurities in medications: Overview. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities.html
8. Swissmedic Guideline: Evaluation of potential nitrosamines in connection with new authorisations, 21 April 2020. Available from: https://www.swissmedic.ch/swissmedic/en/home/humanarzneimittel/authorisations/information/bewertung_potentieller_nitrosamine_nas.html
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How to Cite
Dobariya, U., N. Chauhan, H. Patel, and N. Pardeshi. “Nitrosamine Impurities: Origin, Control and Regulatory Recommendations”. International Journal of Drug Regulatory Affairs, Vol. 9, no. 2, June 2021, pp. 77-80, doi:10.22270/ijdra.v9i2.472.