Medicines

Medsafe policy for nitrosamine impurities in medicines – information for sponsors

Medsafe is working with other international regulators and medicine sponsors to investigate and address nitrosamine impurities in medicines.

This policy includes relevant information for all medicine sponsors, including those seeking approval for new medicines.

Nitrosamines
Global regulatory action
Medsafe monitoring
Medsafe’s expectations of sponsors
Actions for sponsors
Medsafe’s nitrosamine safety communications

Nitrosamines

Nitrosamines are a group of chemical compounds which have been classified as probable human carcinogens (based on animal studies). Regulators became aware of the risk of nitrosamines in medicines in 2018.

These compounds are commonly found in low levels in a variety of foods, particularly smoked and cured meats, as well as in some drinking water and in air pollution. Long-term exposure, over decades, may increase a person’s risk of developing cancer. It is not possible to provide an accurate estimate of the level of risk associated with nitrosamine impurities based on currently available safety data.

Global regulatory action

The European Medicines Agency (EMA) required all marketing authorisation holders (sponsors) to conduct a risk evaluation to identify products at risk of nitrosamine formation by 31 March 2021 for chemical medicines and 1 July 2021 for biological medicines.

The EMA then required all marketing authorisation holders to perform confirmatory testing, and where necessary submit variations (similar to changed medicine notifications in New Zealand) by 26 September 2022 for chemical medicines and 1 July 2023 for biological medicines.

See the Nitrosamine impurities page on the EMA website for more information, including the risk evaluation process.

The EMA has published limits for certain N-nitrosamines – refer to Table 1:

Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (PDF, 578KB, 26 pages)

Medsafe monitoring

Medsafe continues to monitor global regulatory actions for nitrosamine impurities in medicines. Medsafe applies the EMA’s risk evaluation process and limits for nitrosamines, unless otherwise justified by the New Zealand sponsor. The Australian Therapeutic Goods Administration (TGA) has taken a similar approach to Medsafe.

There have been several post-market investigations in New Zealand, and Medsafe has published safety communications (listed below).

As part of new medicine applications and relevant changed medicine notifications, Medsafe requires sponsors to provide risk assessment and/or testing results to demonstrate that new medicines do not exceed nitrosamine limits specified by the EMA.

Medsafe’s expectations of sponsors

Sponsors in New Zealand are responsible for the quality, safety, and efficacy of their products. After approval, Medsafe expects sponsors to monitor the safety and efficacy of their products, as well as to inform Medsafe if they become aware of any issues. This includes monitoring for emerging global quality issues, such as nitrosamine impurities.

Sponsors should be familiar with the known and likely causes of nitrosamine impurities in their products. They should be taking active steps to determine whether their products are at risk of containing nitrosamine impurities. Sponsors should have access to relevant information from the active pharmaceutical ingredient (API) manufacturer(s) regarding the potential formation and presence of nitrosamine impurities. They should also consider other possible sources of nitrosamines such as cross-contamination, excipients, packaging, etc.

Risk assessments

For each product that is marketed in New Zealand, Medsafe expects sponsors to have available a formal nitrosamine risk assessment document. The document should align with the EMA’s guidance ICH M7(R1) guideline and demonstrate whether or not the product is at risk of nitrosamine formation or contamination.

Where a nitrosamine risk is identified, sponsors should ensure confirmatory testing of the finished products has been completed and notify Medsafe if products exceed acceptable nitrosamine levels. In some cases, a changed medicine notification will be required.

Medsafe may also contact sponsors and request a copy of the relevant risk assessments, for example, if our post-market monitoring suggests certain active ingredients or groups of products are at risk of containing nitrosamine impurities. Sponsors are responsible for ensuring that the risk assessment(s) are readily available.

Actions for sponsors

Obtain and hold on file a formal nitrosamine risk assessment document from manufacturers for each product that you market in New Zealand. The document must be readily available, if requested by Medsafe.
Where a nitrosamine risk is identified, ensure confirmatory testing of the finished products has been completed.
If products exceed acceptable nitrosamine levels, notify Medsafe at recalls@health.govt.nz, and provide the risk assessment document and the confirmatory test results.

Medsafe prefers sponsors use the nitrosamine limits defined by the EMA – see Table 1 (PDF, 578KB, 26 pages). Use of different limits should be based on the ICH M7(R1) guideline and supported by risk assessment.