Nitrosamine impurities in medications: Overview
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December 15, 2020 – Nitrosamines Questions and Answers guidance document has been updated. A copy can be requested by contacting email@example.com
December 15, 2020 – Scope of nitrosamine evaluations expands to companies marketing biological and radiopharmaceutical products. A letter was sent to all manufacturers.
In the summer of 2018, several medications containing the active ingredient Valsartan were recalled in Canada and elsewhere in the world. This was because the nitrosamine impurity, N-nitrosodimethylamine (NDMA), was found in the active pharmaceutical ingredient (API). APIs are the substances in pharmaceutical medications that are responsible for the beneficial health effects experienced by patients or consumers.
Since then, some other medications made by different manufacturers have been found to contain NDMA or other similar nitrosamine impurities, such as:
- N-nitrosodiethylamine (NDEA)
- N-nitrosodiisopropylamine (NDIPA)
- N-nitroso-N-methyl-4-aminobutanoic acid (NMBA)
- 1-methyl-4-nitrosopiperazine (MNP)
- N-nitrosoethylisopropylamine (NEIPA)
- N-nitrosodibutylamine (NDBA)
For the current list of nitrosamines assessed by Health Canada along with acceptable limits, consult the latest version of the Questions and Answers (Q&A) document.
About nitrosamine impurities
Based primarily on animal studies, nitrosamine impurities are probable human carcinogens. This means that long-term exposure to a level above what is considered safe may increase the risk of cancer.
There is no immediate health risk associated with the use of medications containing low levels of a nitrosamine impurity. Foods such as meats, dairy products and vegetables as well as drinking water may also contain low levels of nitrosamines.
We don’t expect that a nitrosamine impurity will cause harm when exposure is at or below the acceptable level. For example, no increase in the risk of cancer is expected if exposure to the nitrosamine impurity below the acceptable level occurs every day for 70 years.
The actual health risk varies from person to person. The risk depends on several factors, such as:
- the daily dose of the medication
- how long the medication is taken
- the level of the nitrosamine impurity in the finished product
Patients should always talk to their health care provider before stopping a prescribed medication. Not treating a condition may pose a greater health risk than the potential exposure to a nitrosamine impurity.
What we're doing
Health Canada recognizes that the nitrosamine impurity issue may cause concern for Canadians. Your health and safety is our top priority and we will continue to take action to address risks and inform you of new safety information.
We have created a list of all medications currently known to contain nitrosamine impurities. We will continue to update it, as needed, as more information becomes available.
As we continue to hold companies accountable for determining the root causes, we’re learning more about how nitrosamine impurities may have formed or be present in medications. In the meantime, we will continue to take action to address and prevent the presence of unacceptable levels of these impurities.
These actions may include:
- assess the manufacturing processes of companies
- determine the risk to Canadians and the impact on the Canadian market
- test samples of drug products on the market or soon to be released to the market for NDMA and other nitrosamine impurities
- ask companies to stop distribution as an interim precautionary measure while we gather more information
- make information available to health care professionals and to patients to enable informed decisions regarding the medications that we take
As the federal regulator of health products in Canada, we also:
- request, confirm and monitor the effectiveness of recalls by companies as necessary
- conduct our own laboratory tests, where necessary, and assess if the results present a health risk to humans
- conduct inspections of domestic and foreign sites and restrict certain products from being on the market when problems are identified
We share information on potential root causes of nitrosamines identified to date in medications with Canadian drug companies. We also ask the companies to:
- review their manufacturing processes and controls
- take action to avoid nitrosamine impurities in all medications, as necessary
- test any products that could potentially contain nitrosamine impurities
- report their findings to Health Canada
To better understand this global issue, we are collaborating and sharing information with international regulators, such as:
- U.S. Food and Drug Administration
- European Medicines Agency and the European Directorate for the Quality of Medicines & HealthCare
- Australia’s Therapeutic Goods Administration
- Japan’s Ministry of Health, Labour and Welfare and Pharmaceuticals and Medical Devices Agency
- Switzerland’s Swissmedic
- Singapore’s Health Sciences Authority
We continue to work with companies and our international regulatory partners to:
- determine the root causes of the issue
- verify that appropriate actions are taken to minimize or avoid the presence of nitrosamine impurities
- Letter to all manufacturers (October 2, 2019): Health Canada issued a key communication to all companies marketing human prescription and non-prescription medications requesting companies marketing products with chemically synthesized active pharmaceutical ingredients to conduct detailed evaluations of their manufacturing procedures and controls for the potential presence of nitrosamines. The letter outlined examples of potential root causes for the presence of nitrosamines and included a request for a stepwise approach to conduct these risk assessments and expectations for any necessary subsequent actions. The letter was sent to all DIN and DEL holders. A copy can be requested by contacting firstname.lastname@example.org
- Webinar on Nitrosamines (January 31, 2020): The purpose of this session was to provide an opportunity for a discussion between Health Canada and stakeholders. Health Canada provided overviews of the situation relating to nitrosamine impurities in pharmaceuticals and stakeholders had the opportunity to share their experiences, successes and challenges in addressing the issue of nitrosamine contamination. The on-line webinar was well attended, with approximately 500 participants from over 18 countries, and provided valuable information to respond to this global issue.
- Timeline Extension Letters (March 26, 2020, and August 10, 2020): Health Canada issued extensions for risk assessments and any confirmatory testing and changes to the market authorization. Letters were sent to all DIN and DEL holders. A copy of these letters can be requested by contacting email@example.com
- Nitrosamines Questions and Answers (Q&A) document (November 26, 2019, updated June 12, 2020 and December 15, 2020): Health Canada issued a Q&A document on issues relating to the control of nitrosamines in medicines. This Q&A document will be updated periodically as new information becomes available. This document was sent to all DIN, DEL, and MF Types I and IV holders. A copy of the latest version can be requested by contacting firstname.lastname@example.org
- Letter to all manufacturers (December 15, 2020): Health Canada issued a key communication requesting companies marketing human biological and radiopharmaceutical products (previously exempt from the October 2, 2019, letter) to conduct detailed evaluations of their manufacturing procedures and controls for the potential presence of nitrosamines. The letter outlined examples of potential root causes for the presence of nitrosamines and included a request for a stepwise approach to conduct these risk assessments and expectations for any necessary subsequent actions. The letter was sent to all DIN and DEL holders. A copy can be requested by contacting email@example.com
We will continue to update Canadians if a product is being recalled.
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