Information on Nitrosamine Impurity
Author: Preetha Prabhu
In July 2018 Health Canada first became aware of the presence of nitrosamine impurity, N-nitrosodimethylamine (NDMA) in certain “sartan” angiotensin receptor blocker (ARB) blood pressure medications and has been working to address the issue. Similar nitrosamine impurities including N-nitrosodiethylamine (NDEA), N-Nitrosodiisopropylamine (NDIPA) and N-Nitrosomethyl-n-butylamine (NMBA), were subsequently found in other medications.
Nitrosamines refer to any molecule containing the nitroso functional group. Nitrosamine impurities are classified as a probable human carcinogen and hence are of concern. Although these are also present in some foods (such as smoked and cured meats, dairy products and vegetables) and drinking water supplies, their presence in medicines is nonetheless considered unacceptable.
The formation of nitrosamines is generally only possible when secondary or tertiary amines react with nitrous acid. Nitrous acid itself is unstable but can be formed in situ from nitrites under acidic conditions. However, on-going investigations concluded that the possibility for nitrosamine impurity content was broader than simply the concurrent presence of nitrites and amines in the synthesis of the active pharmaceutical ingredient (API). Possible sources of nitrosamine impurities are:
- Use of sodium nitrite, or other nitrosating agents, in combination with reagents, solvents and catalysts, which are susceptible to degradation to secondary or tertiary amines.
- Use of recovered materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who carry out recovery process in non-dedicated equipment
- Contaminated raw materials in the API manufacturing process.
- Cross-contaminations due to different processes run on the same line.
- Use of certain packaging materials. It has been hypothesized that the lidding foil containing nitrocellulose printing primer may react with amines in printing ink to generate nitrosamines, which would be transferred to the product.
Health Canada has expanded its efforts to evaluate the potential for nitrosamines in drugs other than sartans and ranitidine, along with measures to address and prevent the impurities. Health Canada has requested that companies:
- Review their products and manufacturing processes for the possible presence of nitrosamines
- Take any necessary measures to ensure that their products do not contain nitrosamines at levels exceeding the accepted limit
- Test products if a risk of nitrosamines is identified; and
- Immediately report to Health Canada if nitrosamines are detected.
In addition to testing by companies, the Department has conducted its own testing of certain sartan and ranitidine drugs, and has developed laboratory test methods to provide validated testing options for use by industry and other regulators. The Department has also been working in collaboration with its international partners, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency. Health Canada continues to work with companies and international partners to understand the root causes of nitrosamines in drugs. The Department will take action if a risk to Canadians is identified and will be vigilant in informing the public of any new safety information.
Health Canada updates Canadians on its ongoing assessment of nitrosamine impurities in certain drugs (dated Dec. 3, 2019) https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/71770a-eng.php
Information Note Nitrosamine impurities (dated. Nov. 20, 2019) https://www.who.int/medicines/publications/drugalerts/InformationNote_Nitrosamine-impurities/en/
Questions and answers on “Information on nitrosamines for marketing authorisation holders” (dated Dec. 20, 2019) https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation_en.pdf