Nitrosamine impurities in medications: Overview

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What's new

October 20, 2023: An updated version of the Guidance on nitrosamine impurities in medications has been posted online.

The guidance document has been updated to indicate that the timeline for completing Changes to the Market Authorization (Step 3 of Health Canada's call for review) has been extended to August 1, 2025 for drug products containing chemically synthesized and semi-synthetic active pharmaceutical ingredients and for biological and radiopharmaceutical drug products.

Updates to some General, Safety (Appendix 2) and Quality-related topics (including Appendix 1) are also included. For example, the updated guidance document includes additional recommendations for managing and submitting Step 3 changes to the market authorization relating to risk mitigation measures (section 13), updates to the thresholds for reporting to Health Canada on the presence of nitrosamine impurities in drug products (numbers 3 and 15), established Acceptable Intakes (AI) for 3 additional nitrosamine impurities and revisions to the AI limits for 2 nitrosamine impurities.

Those sections that have updated from the previous version are identified with the descriptor "updated".

October 20, 2023: Lots of Amitriptyline Tablets (32 lots) and Acyclovir Tablets (7 lots) were recalled in August 2023 due to the presence of nitrosamine impurities.

July 24, 2023: An updated version of Health Canada’s Guidance on nitrosamine impurities in medications has been posted online. The updates include two significant approaches recently finalized by the Nitrosamines International Technical Working Group (NITWG) that will assist industry and regulators in setting Acceptable Intake (AI) limits for nitrosamines in drug products, namely the Enhanced Ames Test (EAT) conditions and the Carcinogenic Potency Categorization Approach (CPCA). The updates to the guidance document include the addition of AI limits for several nitrosamines that are considered acceptable to Health Canada.  The application of the CPCA has revised already established AIs for various nitrosamines, these include N-nitroso-dabigatran, N-nitroso-tamsulosin, N-nitroso-rasagiline and 1-methyl-4-nitrosopiperazine (MNP).

Updates to several General and Quality-related topics are also included, such as when Health Canada is to be advised of the presence of nitrosamine impurities following the completion of confirmatory testing of the drug product, when risk assessments for nitrosamine impurities are expected in drug submissions for post-authorization changes, a threshold below which a nitrosamine impurity is not expected to be included in routine testing specifications, testing approaches where more than one strength of a dosage form is concerned, and expectations when a nitrosamine impurity cannot be synthesized or isolated and purified.

April 17, 2023: An updated version of the Guidance on nitrosamine impurities in medications has been posted online. The updated guidance document includes established Acceptable Intakes for 5 additional nitrosamine impurities and further guidance on general and quality related information. Those sections that have updated from the previous version are identified with the descriptor "updated".

December 17, 2022: Health Canada published the Quality (chemistry and manufacturing) draft guidance: New Drug Submissions and Abbreviated New Drug Submissions document for consultation, which includes reference to the Guidance on nitrosamine impurities in medications and several other recommendations for information relating to nitrosamines (e.g., on where information should be included in these drug submissions).

September 1, 2022: An updated nitrosamines guidance has been posted online. The updates are limited to Sections 2, 19, 24, and 34.

July 22, 2022: Health Canada issued an extension to file changes to the market authorization. Letters were sent to all DIN and DEL holders.

May 27, 2022: An updated nitrosamines guidance has been posted online. The updates are limited to Section 24.

April 5, 2022: An updated nitrosamines guidance (formerly the nitrosamines Q&A document) has been posted online. It has been distributed to all drug identification number (DIN) and drug establishment licence (DEL) holders.

February 25, 2022: A risk assessment follow- up letter was sent to all market authorization holders of biological and radiopharmaceutical products. A copy can be requested by contacting brdd.nitrosamines.dmbr@hc-sc.gc.ca.

November 17, 2021: A brief summary of the October 20, 2021 scientific and technical webinar is available below

July 28, 2021: An additional test method for metformin products has been developed by Health Canada

July 28, 2021 - A summary of the February 10, 2021 stakeholder webinar is now available

April 14, 2021: A risk assessment follow- up letter was sent to all affected market authorization holders. A copy can be requested by contacting bpsenquiries@hc-sc.gc.ca.

April 1, 2021: Increased expectations for nitrosamine data in certain pre-market submissions as per Q17 and Q18 of the December 15, 2020, nitrosamines questions and answers guidance document.

December 15, 2020: Nitrosamines questions and answers guidance document has been updated.

December 15, 2020: Scope of nitrosamine evaluations expands to companies marketing biological and radiopharmaceutical products. A letter was sent to all manufacturers.

Background

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:

For the current list of nitrosamines assessed by Health Canada along with acceptable limits, consult the latest version of the nitrosamines guidance 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:

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:

As the federal regulator of health products in Canada, we also:

We share information on potential and confirmed root causes of nitrosamines identified to date in medications with Canadian drug companies. We also ask the companies to:

To better understand this global issue, we are collaborating and sharing information with international regulators, such as:

We continue to work with companies and our international regulatory partners to:

We regularly communicate information on health risks, test results, recalls and other actions taken. Some of these key actions and communications include:

We will continue to update Canadians if a product is being recalled.

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