New guidance for evaluating and managing the risks of N-nitrosamine impurities in products
Drug Establishment Licensing Bulletin 133, April 7, 2022
On this page
About the new guidance
Health Canada has released a new guidance document for evaluating and managing the risks of N-nitrosamine impurities in human pharmaceutical, biological and radiopharmaceutical products.
This guidance document contains recommendations on issues related to N-nitrosamine impurities (nitrosamine impurities or nitrosamines). The document represents our current thinking on this subject, such as the risks associated with nitrosamines. It also reflects discussions we held with our international regulatory partners and feedback we received from stakeholders, including industry and industry associations.
We may update this new document as new information becomes available and if applicants and market authorization holders (MAHs) require further guidance.
We originally issued a questions-and-answers (Q&A) document on nitrosamines on November 26, 2019. We updated this document twice since then:
- update 1 on June 12, 2020
- update 2 on December 15, 2020
Details on the new changes
The new document is formatted like a 'true' guidance document, with information grouped under general headings (for example, General, Safety and Quality). As a result, the numbering in this guidance document may differ from that in update 2. Editorial changes make the content more readable and understandable.
We have also added more information for active pharmaceutical ingredient (API) manufacturers, drug product manufacturers, MAHs and importers of APIs and drug products.
Changes to the content since update 2 are identified by "new" or "updated".
Notable new or updated information includes the following:
- under General:
- considerations relating to the filing of certain applications when risks of nitrosamines have been identified (for example, for supplements and notifiable changes, clinical trial applications)
- under Safety:
- 10 nitrosamines now included in list of established acceptable intake (AI) limits
- applying the class-specific threshold of toxicological concern (TTC) of 18 ng/day for nitrosamines as a default limit when there's now established AI
- new guidance on AI limits for nitrosamines in drug products that fall within the scope of ICH's S9 guideline or where the API is genotoxic
- updated guidance on AI limits when multiple nitrosamines are found in an API or drug product
- under Quality:
- potential root causes for presence of nitrosamines
- details on control strategy options when there are nitrosamines
- recommendations on testing a representative number of batches when a risk issue has been identified and the root cause is known
Contact us
For questions about nitrosamines:
- for drug products containing chemically synthesized or semi-synthetic APIs:
- for biological and radiopharmaceutical products:
For questions about this guidance document, send an email to bpsenquiries@hc-sc.gc.ca.