Nitrosamine impurities in medications: Overview
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What's new
March 28, 2024: An updated version of the list of established acceptable intake limits (Appendix 1 of Health Canada's Guidance on nitrosamine impurities in medications) has been posted online to include eight (8) additional nitrosamines and their corresponding AI limits.
March 27, 2024: An information update on nitrosamines impurities was distributed to all Market Authorization Holders (MAHs). This information update includes (i) details on certain nitrosamine impurities that have been confirmed to be present in the related drug product to ensure that these impurities have been adequately considered by MAHs in their risk assessments for nitrosamine presence, and (ii) summaries of notable updates to Health Canada’s Guidance on nitrosamine impurities in medications. A copy of the information update letter can be requested by contacting bpsenquiries@hc-sc.gc.ca.
March 15, 2024: An updated version of the Guidance on nitrosamine impurities in medications has been posted online.
Several updates to General and Quality-related topics have been incorporated into the guidance document, including:
- when the submission of confirmatory testing results is not expected (i.e., for nitrosamine impurities in Appendix 1 (formerly Appendix 2) that are classified as non-mutagenic) (number 3),
- managing and submitting Step 3 changes to the market authorization relating to risk mitigation measures, including several additional changes that can be implemented as Level III - Annual Notifications (number 13 and Appendix 2 (formerly Appendix 1)), and
- acceptable limits of quantitation for analytical procedures (number 33).
Those sections that have updated from the previous version are identified with the descriptor "updated".
Of note, Health Canada's table of established Acceptable Intake (AI) limits (formerly Appendix 2) has been renumbered to Appendix 1, removed from the guidance document and placed in a tab on Health Canada's nitrosamines webpage. These changes are to enable a more timely update to the listing of established AI limits. In addition, to facilitate searching an AI limit for a N-nitrosamine impurity, the tab contains a table that can be filtered and a spreadsheet that can be downloaded. Additional AI limits for several nitrosamines that are considered acceptable to Health Canada are included in the update. The AI list can be filtered by date to identify the most recent additions.
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:
- 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 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:
- 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.
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 and confirmed 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 minimize or 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
- Brazil's Health Regulatory Agency (Anvisa)
- World Health Organization
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
We regularly communicate information on health risks, test results, recalls and other actions taken. Some of these key actions and communications include:
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Letter to all manufacturers (October 2, 2019): and follow-up on risk assessments (April 14, 2021): 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 bpsenquiries@hc-sc.gc.ca
On April 14, 2021, Health Canada sent a letter to all affected market authorization holders to request information on the completion status of risk assessments and a high level summary of any risk identified. An extension letter was sent on May 26, 2021. A copy can be requested by contacting bpsenquiries@hc-sc.gc.ca
- Nitrosamine impurities in medications guidance (previously a Questions and Answers (Q&A) document): Health Canada issued a guidance document on issues relating to the control of nitrosamines in medicines. This document is sent to all DIN, DEL and Master Files (MF) Types I and IV holders and will be updated periodically as new information becomes available.
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Webinar on nitrosamines (January 31, 2020, February 10, 2021 and October 20, 2021): The purpose of the January 31, 2020 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.
The Feb 10, 2021 stakeholder webinar had similar objectives and provided stakeholders with an update on ongoing and emerging nitrosamine activities and developments. Feedback gathered and responses to questions received will be used to help update our nitrosamines questions and answers document.
The Oct 20, 2021 session focused on scientific and technical developments by industry and featured seven presentations from Innovative Medicines Canada and the Canadian Generic Pharmaceutical Association. The presentations highlighted industry advances and progress on safety and quality topics that are presently at the forefront of the nitrosamines issue. Presentations were followed by a discussion between Health Canada's scientific experts and industry presenters. Several key stakeholders attended as observers along with representatives from international regulatory partners.
- Timeline extension letters (March 26, 2020, August 10, 2020 and July 22, 2022): Health Canada issued extensions for completion of risk assessments, conducting confirmatory testing and/or filing changes to the market authorization. Letters were sent to all DIN and DEL holders. A copy of these letters can be requested by contacting bpsenquiries@hc-sc.gc.ca
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Letter to all manufacturers of biological and radiopharmaceutical products (December 15, 2020) and follow- up on risk assessments (February 25, 2022): 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 brdd.ora@hc-sc.gc.ca
On February 25, 2022, Health Canada sent a letter to all market authorization holders of biological and radiopharmaceutical products to request information on the completion status of risk assessments and a high- level summary of any risk identified. A copy can be requested by contacting brdd.nitrosamines.dmbr@hc-sc.gc.ca.
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Pre-market submission filing expectations (April 1, 2021): As previously communicated in the nitrosamines questions and answers guidance, as of April 1, 2021, all NDSs, ANDSs and Supplements (for quality changes that may impact the potential presence of nitrosamines in the drug substance or drug product) for human pharmaceutical products containing chemically synthesized APIs should include a summary of risk assessments for the potential formation/introduction of nitrosamines in the API and drug product. The risk assessment should be placed in section 3.2.P.2, and confirmatory testing results and updated control strategy (where warranted) should also be included in the drug application (for example, under sections 3.2.S.2, 3.2.S.4, 3.2.S.7, 3.2.P.3, 3.2.P.4, 3.2.P.5, 3.2.P.8). Applicants should complete and include a discussion on the risk assessments as well as any supporting information. The respective section(s) of the Quality Overall Summary (QOS) should also be updated. Failure to include this information could result in requests for additional information, delays in the review process, and potentially the issuance of negative decisions. If the risk assessment cannot be located during screening, you may receive a screening clarification request or a screening deficiency notice.
This expectation also extends to DINAs with a chemistry and manufacturing component, including post-DIN applications for quality changes that may impact the potential presence of nitrosamines in the drug substance or drug product, for human pharmaceutical products containing chemically synthesized APIs.
We will continue to update Canadians if a product is being recalled.
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