Nitrosamine impurities in medications: Overview
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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 - Risk assessment follow up letter was sent to all affected market authorization holders. A copy can be requested by contacting firstname.lastname@example.org
April 1, 2021 – Increased expectations for nitrosamine data in certain premarket 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. 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): 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 firstname.lastname@example.org
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 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
Webinar on Nitrosamines (January 31, 2020 and February 10, 2021): The purpose of the Jan 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 & Answers document.
- 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
- 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 firstname.lastname@example.org
Premarket submission filing expectations (April 1, 2021): As previously communicated in Nitrosamines Q&A 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 (e.g., 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, etc.). Applicants should complete and should 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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