NDMA: a recall trigger for the drug development industry

N-nitrosodimethylamine (NDMA) is one of the main compounds responsible for pharmaceutical product recalls. This year, 12 US Food and Drug Administration (FDA)-regulated drug products have already been recalled¹ and, according to the administration’s records, 1,159 lots of these particular drugs have been affected by an FDA recall due to dangerous levels of nitrosamides such as NDMA.² The FDA is not the only regulatory agency that has shown concern for nitrosamide contamination. The US Environmental Protection Agency (EPA) has regarded NDMA as a priority pollutant and last September the European Medicines Agency (EMA) initiated a review to advise marketing authorisation holders on how to prevent contamination by these agents.³

NDMA is a semi-volatile organic compound that appears as a by-product of different industrial and natural processes. It is a member of the N-nitrosamines – a family of molecules known for their carcinogenic potential – and is classified as a B2 carcinogen. Exposure to high concentrations of NDMA is also related to significant liver damage and accidental ingestion is known to produce fever, nausea, vomiting and jaundice.⁴

Sources of nitrosamide contamination can vary; it can be found in both soil and water. In March 2011, for example, out of 17,900 water samples collected by the EPA, 10 percent were found to be contaminated by NDMA.⁴ Some researchers believe that the source of water contamination by NDMA is likely to be dimethylhydrazine, used for rocket fuel. However, in most cases of drug manufacturing, pharmaceutical contamination is more likely to result from a side reaction rather than external contamination. In some cases, active pharmaceutical ingredient (API) manufacturers contaminate their own products during the production process. The companies that deal with drug formulation and dosage forms will then use these contaminated APIs to develop the final drug product.⁵

As mentioned earlier, NDMA contamination has triggered a significant number of recalls and valsartan, a heart failure drug, has been one of the most affected products. Last year, Pfizer Japan recalled more than 700,000 tablets of Amvalo⁶ – their own brand of valsartan – and in 2018, Camber Pharmaceuticals⁷ and Major Pharmaceuticals⁸ issued recalls for valsartan batches. Other angiotensin II receptor blockers like losartan and irbesartan are also prone to NDMA contamination. Of note, other types of drugs have also been the subject of NDMA-related recalls. For example, high NDMA levels in ranitidine, used for gastric ulcer treatment, have led 14 companies to issue recalls in the last 12 months and six companies have issued NDMA-related recalls for metformin hydrochloride tablets, used to treat type 2 diabetes, since January this year.¹

Considering the magnitude of the problem, it is important that companies know how to detect nitrosamide impurities in drug products, especially those that are more likely to be contaminated by side reactions. Although it will depend on the expected source of contamination, gas chromatography and mass spectroscopy are both typically used to detect the presence of nitrosamides; however, liquid chromatography and solid phase extraction are also used in some samples.^4,9 While NDMA detection is not particularly hard, and elimination is not that complicated compared to other pharmaceutical contaminants (eg, biofilm forming bacteria), routine controls must be established to avoid any major problems. Photolytic reactions can be used to degrade NDMA and ultraviolet radiation can be used to effectively remove NDMA from water sources. Monoxygenases have also proved to be efficient for NDMA treatment, according to different studies.^10,11

However, with some of the aforementioned drugs, the problem extends further than recalling, increasing nitrosamide detection, retiring one batch and then returning with an improved method. For ranitidine, NDMA impurities have contributed to the product’s demise, at least in the US market. Several laboratory tests revealed to the FDA that NDMA levels in ranitidine may increase over time, especially if the drug is exposed to higher temperatures.¹² While the FDA stated that they might consider the product back on the market if any company showed evidence of NDMA levels not increasing to an unsafe level for consumers – currently set at 96ng/day – it is yet to be seen if this can be accomplished anytime soon. In fact, the contrary appears to be true; last April, the FDA announced the recall of all forms of nizatidine for the above reasons.¹³

The case of ranitidine highlights the importance of checking for possible NDMA impurities in drug products, even before they are commercialised, to avoid major health and economical pitfalls in the future. This is crucial for companies that rely on these pharmaceutical products, since the economic drawbacks are huge for companies that depend on products that might not return to the market. The drug development process is extremely long and expensive – involving an investment of more than €2,000,000,000 over a period of 10 to 12 years.¹⁴ Therefore, a recall that knocks a product out of the market might imply bankruptcy for smaller pharmaceutical companies that cannot buffer such a set-back. For this reason, NDMA contamination should not only be considered during production, but also before and during the strategic planning of new drug product development.

References

1. S. Food and Drug Administration. 2020. Recalls, Market Withdrawals, & Safety Alerts. [online] Available at: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts [Accessed 27 July 2020].
2. S. Food and Drug Administration. 2020. Search List Of Recalled Arbs: Valsartan, Losartan And Irbesartan. [online] Available at: https://www.fda.gov/drugs/drug-safety-and-availability/search-list-recalled-angiotensin-ii-receptor-blockers-arbs-including-valsartan-losartan-and [Accessed 27 July 2020].
3. Information on nitrosamines for marketing authorisation holders [Internet]. European Medicines Agency; 2019 [cited 27 July 2020]. Available from: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf
4. Technical Fact Sheet – N-Nitroso-dimethylamine (NDMA) [Internet]. United States Environmental Protection Agency; 2014 [cited 27 July 2020]. Available from: https://www.epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_contaminant_ndma_january2014_final.pdf
5. A side reaction may have led to impurities found in valsartan heart drugs [Internet]. Chemical & Engineering News. 2020 [cited 27 July 2020]. Available from: https://cen.acs.org/pharmaceuticals/process-chemistry/side-reaction-led-impurities-found/97/web/2019/02
6. Pfizer Japan recalls high blood pressure drug over cancer-causing impurity [Internet]. U.S. 2020 [cited 27 July 2020]. Available from: https://www.reuters.com/article/us-pfizer-japan-recall-idUSKCN1PX19R
7. Camber Pharmaceuticals, Inc. Issues Voluntary Nationwide Recall of Valsartan Tablets, USP, 40mg, 80mg, 160mg and 320mg Due to The Detection of Trace Amounts of N-Nitrosodimethylamine (NDMA) Impurity, Found in an Active Pharmaceutical Ingredient (API) [Internet]. U.S. Food and Drug Administration. 2020 [cited 27 July 2020]. Available from: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/camber-pharmaceuticals-inc-issues-voluntary-nationwide-recall-valsartan-tablets-usp-40mg-80mg-160mg
8. Major Pharmaceuticals Issues Voluntary Nationwide Recall of Valsartan Due to The Potential Presence of a Probable Carcinogen (NDMA) [Internet]. U.S. Food and Drug Administration. 2020 [cited 27 July 2020]. Available from: https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/major-pharmaceuticals-issues-voluntary-nationwide-recall-valsartan-due-potential-presence-probable
9. Guidelines for Drinking-Water Quality [Internet]. 3rd ed. World Health Organization; 2020 [cited 27 July 2020]. Available from: https://www.who.int/water_sanitation_health/dwq/chemicals/ndmasummary_2ndadd.pdf?ua=1
10. Sharp J, Wood T, Alvarez-Cohen L. Aerobic biodegradation of N-nitrosodimethylamine (NDMA) by axenic bacterial strains. Biotechnology and Bioengineering. 2005;89(5):608-618.
11. Sharp J, Sales C, LeBlanc J, Liu J, Wood T, Eltis L et al. An Inducible Propane Monooxygenase Is Responsible for N-Nitrosodimethylamine Degradation by Rhodococcus sp. Strain RHA1. Applied and Environmental Microbiology. 2007;73(21):6930-6938.
12. Q&A: NDMA impurities in ranitidine (commonly known as Zantac) [Internet]. U.S. Food and Drug Administration. 2020 [cited 27 July 2020]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/questions-and-answers-ndma-impurities-ranitidine-commonly-known-zantac
13. NDMA in Zantac (ranitidine) [Internet]. U.S. Food and Drug Administration. 2020 [cited 27 July 2020]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine
14. Wouters O, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844.