The carcinogen NDMA (N-nitrosodimethylamine) was identified in September 2019 as a contaminant in ranitidine, with levels as high as 3000 mcg in pills of Zantac and generics [1, 2, 3].  In July 2018 the EMA and the FDA issued a report on detection of NDMA & NDEA (N-nitrosodiethylamine) found in valsartan [4].  By February 2019, hundreds of batches of valsartan, losartan & irbesartan had been recalled [5].   Process water used to prepare pharmaceuticals could lead to contamination of other drugs by NDMA.

Safety limits need to be established for the amount of NDMA allowed in pharmaceuticals.  Since NDMA is a well-known contaminant, found for instance in foods such as processed meats, regulatory authorities may have been reluctant to pose limits.  Nonetheless, batches of ranitidine have been withdrawn in Europe.  The FDA has posted GC / MS methods to identify and quantitate NDMA [6].

Contamination of compounds by NDMA was noted for years before 2018.  For instance, in 2013 a manuscript was published on the generation of NDMA when ranitidine or sumatriptan was exposed to water similar to treated wastewater effluents [7].  In 2016 work was published showing that ingestion of ranitidine increased excretion of NDMA [8].  In 1987 a manuscript was published on the determination of NDMA in dimethylamine [9].  There are dozens of papers documenting the formation of NDMA from the chlorination of municipal water, and municipal water may pose the greatest concern overall.

There are several routes to the origin of NMDA in substances, and the most direct involves reaction of dimethylamine with a nitrosating reagent.  In the case of valsartan, Me₂NH was probably generated from decomposition of the solvent DMF used in tetrazole formation; NaNO₂ added to quench excess NaN₃ charged for tetrazole formation [10] probably led to the formation of NDMA.  Valisure, the on-line pharmacy that identified NDMA in ranitidine, suggested that NDMA generation is probably due to the inherent instability of ranitidine [11].  When Me₂NH contaminated with NDMA was combined with carboxylic acids, NDMA was found in the resulting salts [9].  In municipal water treatment plants, Me₂NH can arise from breakdown of agrichemicals or pharmaceuticals, and chlorination to disinfect the streams can generate nitrosating species [7].

The physical properties of NDMA can make detection and removal difficult.  With bp 153 ºC, GC assays for residual solvents may not detect it.  Due to its poorly basic nature (pKa 3.52) [12], treatment with conventional ion exchange resins may not remove NDMA.  Photolysis may be the best approach to decompose NDMA [13].  Perhaps potable water to be used for processing pharmaceuticals should be exposed to UV light, similar to the treatment for water for injection [14].

Process water used in the manufacture of pharmaceuticals should be considered as a source of NDMA contamination, and may put at risk the manufacture of many pharmaceuticals and agrichemicals.

Teasdale and Popkin have discussed regulatory considerations for nitrosamines [15].

1. https://www.fda.gov/safety/medical-product-safety-information/zantac-ranitidine-safety-information-ndma-found-samples-some-ranitidine-medicines
2. latimes.com/business/story/2019-09-18/carcinogen-scare-tainted-zantac
3. Cross, R. Chem. Eng. News 2019, 97(37), 13.
4. https://pharmaceuticalonline.com/doc/nitroso-impurities-in-valsartan-how-did-we-miss-them-0001
5. Nguyen, T. Chem. Eng. News 2019, 97(8), 5; Boerner, L. K., Chem. Eng. News 2020, 98(15), 27.
6. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM618053.pdf; https://www.fda.gov/downloads/Drugs/DrugSafety/UCM623578.pdf; https://www.fda.gov/downloads/Drugs/DrugSafety/UCM623198.pdf
7. Shen, R.; Andrews, S. A. Water Res. 2013, 47, 802.; see also Pellet, J., “Heroin Analog May Form Carcinogen in Drinking Water,” 29 May 2015; https://cen.acs.org/articles/93/web/2015/05/Heroin-Analog-Form-Carcinogen-Drinking.html; Kollipara, P., “Treated Sewage Solids Contain Troubling Nitrosamines,”23 April 2014; https://cen.acs.org/articles/92/web/2014/04/Treated-Sewage-Solids-Contain-Troubling.html
8. Zeng, T.; Mitch, W. A. Carcinogenesis 2016, 37, 625.
9. Wigfield, Y. Y.; McLenaghan, C. C. Pesticide Sci. 1987, 19(1), 1.
10. Madasu, S. B.; Vekariya, N. A.; Koteswaramma, Ch.; Islam, A.; Sanasi, P. D.; Korupolu, R. B. Org. Process Res. Dev. 2012, 16, 2025.
11. valisure.com/blog/uncategorized/detection-of-ndma-in-ranitidine
12. http://www.t3db.ca/toxins/T3D0199
13. Mitch, W. A.; Sharp, J. O.; Trussell, R. R.; Valentine, R. L.; Alvarez-Cohen, L.; Sedlak, D. L. Environmental Engineering Science 2003, 20, 389.
14. https://www.pharmaguideline.com/2017/07/preparation-process-for-water-for-injection.html
15. Teasdale, A.; Popkin, M. Org. Process Res. Dev. 2019, 23, 1292.