AAPS PharmSciTech

, 20:166 | Cite as

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities

  • Naseem Ahmad Charoo
  • Areeg Anwer Ali
  • Shailesh Kumar Buha
  • Ziyaur RahmanEmail author
Review Article Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model
Part of the following topical collections:
  1. Theme: Team Science and Education for Pharmaceuticals: the NIPTE Model


The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer’s and FDA’s attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Key Words

N-nitrosodimethylamine N-nitrosodiethylamine valsartan losartan irbesartan product recall carcinogenic FDA ICH 



This article reflects the scientific opinion of the authors and not necessarily the policies of the Zeino Pharma FZ LLC and Neopharma LLC.


  1. 1.
    FDA (2019) FDA updates on angiotensin II receptor blocker (ARB) recalls including valsartan, losartan and irbesartan. Accessed 21 Jan 2019.
  2. 2.
    EMA (2018) EU authorities take further action in ongoing review of sartans: Zheijiang Huahai placed under increased supervision; Aurobindo Pharma stopped from supplying irbesartan to the EU. Accessed 21 Jan 2019.
  3. 3.
    Shanley A. After Valsartan Recalls, Regulators grapple with nitrosamine contamination in APIs. Pharma Tech 2018. Accessed 21 Jan 2019.
  4. 4.
    EMA (2018b) Press release on 13th September. Update on review of valsartan medicines: risk from NDMA remains low, a related substance NDEA also being investigated. Accessed 21 Jan 2019.
  5. 5.
    Pottegard A, Kristensen K, Ernst MT, Johansen NB, Quartorolo P, Hallas J. Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study. Br Med J. 2018;362:k3851.CrossRefGoogle Scholar
  6. 6.
    IARC (1978) Some N-nitroso Compounds: IARC monographs on the evaluation of carcinogenic risk of chemicals to humans. International Agency for Research on Cancer, Lyon, France.Google Scholar
  7. 7.
    González CA, Riboli E, Badosa J, Batiste E, Cardona T, Pita S, et al. Nutritional factors and gastric cancer in Spain. Am J Epidemiol. 1994;139:466–73.CrossRefGoogle Scholar
  8. 8.
    La Vecchia C, D’Avanzo B, Airoldi L, Braga C, Decarli A. Nitrosamine intake and gastric cancer. Eur J Cancer Prev. 1995;4:469–74.CrossRefGoogle Scholar
  9. 9.
    Pobel D, Riboli E, Cornée J, Hémon B, Guyader M. Nitrosamine, nitrate and nitrite in relation to gastric cancer: a case–control study in Marseille, France. Eur J Epidemiol. 1995;11:67–73.CrossRefGoogle Scholar
  10. 10.
    Goodman MT, Hankin JH, Wilkens LR, Kolonel LN. High fat foods and the risk of lung cancer. Epidemiology. 1992;3:288–99.CrossRefGoogle Scholar
  11. 11.
    De Stefani E, Deneo-Pellegrini H, Carzoglio JC, Ronco A, Mendilaharsu M. Dietary nitrosodimethylamine and the risk of lung cancer: a case–control study from Uruguay. Cancer Epidemiol Biomarkers Prev. 1196(5):679–82.Google Scholar
  12. 12.
    Knekt P, Järvinen R, Dich J, Hakulinen T. Risk of colorectal and other gastro-intestinal cancers after exposure to nitrate, nitrite and N-nitroso compounds: a follow-up study. Int J Cancer. 1999;80:852–6.CrossRefGoogle Scholar
  13. 13.
    Archer MC. Mechanisms of action of N-nitroso compounds. Cancer Surv. 1989;2:241–50.Google Scholar
  14. 14.
    Nakae D, Kobayashi Y, Akai H. Involvement of 8-hydroxyguanine formation in the initiation of rat liver carcinogenesis by low dose levels of N-nitrosodiethylamine. Cancer Res. 1997;57(7):1281–7.PubMedGoogle Scholar
  15. 15.
    Dragan YP, Hully JR, Nakamura J, Mass MJ, Swenberg JA, Pitot HC. Biochemical events during initiation of rat hepatocarcinogenesis. Carcinogenesis. 1994;15(7):1451–8.CrossRefGoogle Scholar
  16. 16.
    EPA Integrated Risk Information System (IRIS). “N-nitrosodimethylamine; CASRN 1993; 62–75-9.” Accessed 21 Jan 2019.
  17. 17.
    WHO (2008). N-nitrosodimethylamine in drinking-water. Background document for preparation of WHO Guidelines for drinking-water quality. Geneva, World Health Organization (WHO/HSE/AMR/08.03/8). Accessed 21 Jan 2019.
  18. 18.
    FDA (1996) FDA compliance policy guides manual: sec. 510.600 dimethylnitrosamine in malt beverages. US Food and Drug Administration, Washington, DC.Google Scholar
  19. 19.
    FDA (1995) FDA compliance policy guides manual: sec. 578.500 dimethylnitrosamine in barley malt. US Food and Drug Administration, Washington, DC.Google Scholar
  20. 20.
    ICH (2006) IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2). Accessed 21 Jan 2019.
  21. 21.
    Krasner SW, Mitch WA, McCurry DL, Hanigan D, Westerhoff P. Formation, precursors, control, and occurrence of nitrosamines in drinking water: a review. Water Res. 2013;47(13):4433–50.CrossRefGoogle Scholar
  22. 22.
    Mitch WA, Sedlak DL. Characterization and fate of N-nitrosodimethylamine precursors in municipal wastewater treatment plants. Environ Sci Technol. 2004;38(5):1445–54.CrossRefGoogle Scholar
  23. 23.
    FDA (2008) Genotoxic and carcinogenic impurities in drug substances and products: recommended approaches. Draft guidance. Accessed 21 Jan 2019.
  24. 24.
    EMA (2006) Guideline on the limits of genotoxic impurities. Accessed on Jan 21, 2019.
  25. 25.
    FDA (2019) Combined N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurity assay by GC/MS-headspace. Available at: (Accessed 6th March 2019).
  26. 26.
    EDQM (2018) OMCLs release three methods for determination of NDMA in sartans. Available at: . (Accessed 6 th March 2019).
  27. 27.
    Looker AR, Ryan MP, Neubert-Langille BJ, Naji R. Risk assessment of potentially genotoxic impurities within the framework of quality by design. Org Process Res Dev. 2010;14:1032–6.CrossRefGoogle Scholar
  28. 28.
    Cimarosti Z, Bravo F, Stonestreet P, Tinazzi F, Vecchi O, Camurri G. Application of quality by design principles to support development of a control strategy for the control of genotoxic impurities in the manufacturing process of a drug substance. Org Process Res Dev. 2010;14:993–8.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Naseem Ahmad Charoo
    • 1
  • Areeg Anwer Ali
    • 2
  • Shailesh Kumar Buha
    • 3
  • Ziyaur Rahman
    • 4
    Email author
  1. 1.Zeino Pharma FZ LLC, 703-HQ Complex-North TowerDubai Science ParkDubaiUAE
  2. 2.RAK College of Pharmaceutical SciencesRAK Medical and Health Sciences UniversityRas Al KhaimahUAE
  3. 3.Neopharma LLC, Industrial City of Abu Dhabi (ICAD)Abu DhabiUAE
  4. 4.Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science CenterTexas A&M UniversityCollege StationUSA

Personalised recommendations