EMA Updates Nitrosamine Q&A Guidance: New Requirements for Acceptable Intake Limits and Less-Than-Lifetime Exposure
The European Medicines Agency (EMA) has revised its Questions and Answers guidance for marketing authorisation holders (MAHs) and applicants on nitrosamine impurities in human medicinal products. Revision 24, dated 3 November 2026, introduces important clarifications on acceptable intake (AI) limits, less-than-lifetime (LTL) exposure, other N-nitroso compounds and nitrosamines originating from excipients.
The update also revises existing recommendations on risk factors, control strategies and CAPA implementation under the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004.
Risk Evaluation and Identified Risk Factors
MAHs and applicants should evaluate potential sources of nitrosamine formation and contamination throughout API and finished product manufacturing.
Key risk factors include:
API manufacturing: Use of nitrites, nitrosating agents, secondary or tertiary amines and contaminated raw materials or recycled solvents.
Finished products: Reactions between vulnerable amine groups in APIs and nitrites present in excipients during manufacturing or storage.
Packaging: Potential nitrosamine contamination from nitrocellulose-containing blister packaging and polymer bags.
GMP operations: Cross-contamination, inadequate process controls and impurity carry-over.
Risk assessments should be periodically reviewed when new information or potential root causes emerge.
Risk Assessment and Confirmatory Testing
The EMA follows a three-step approach:
Step 1 – Risk Evaluation: Identify potential sources of nitrosamine formation or contamination.
Step 2 – Confirmatory Testing: Conduct appropriate testing where risks are identified.
Step 3 – Risk Mitigation: Implement necessary manufacturing and control changes.
Risk evaluations should follow ICH Q9 principles, involving MAHs, API manufacturers, finished product manufacturers and raw material suppliers.
Confirmatory testing should generally be performed on finished products. Where the risk source is well understood, testing should cover 10% of annual batches or three batches per year, whichever is higher. If fewer than three batches are manufactured annually, all batches should be tested.
Key Updates in Revision 24
1. Acceptable Intake Limits for Nitrosamines Originating from Excipients
The revised Q&A 10 introduces clarification on controlling nitrosamines originating from excipients.
The control strategy should ensure that patient exposure does not exceed the applicable AI in ng/day. Calculations should consider the maximum daily quantity of excipient consumed based on the maximum daily dose specified in the SmPC.
Limits may be established in the excipient or finished product, provided the approach is scientifically justified. A single limit should generally apply across all strengths unless otherwise justified.
2. Acceptable Intake Limits for Other N-Nitroso Compounds
New Q&A 23 clarifies the approach for other N-nitroso compounds.
The EMA recommends using compound-specific carcinogenicity data, read-across from suitable surrogate compounds and appropriate mutagenicity testing to establish acceptable intake limits.
The CPCA is specifically developed for N-nitrosamines and cannot be used to derive limits for other N-nitroso structures.
A negative Ames assay may support control at 1,500 ng/day. In the absence of a justified compound-specific AI, a TTC of 18 ng/day is considered applicable.
The same general principles for analytical requirements and control strategies should also be considered. However, LTL correction factors do not apply to other N-nitroso compounds.
3. Application of Less-Than-Lifetime (LTL) Limits to Nitrosamines
New Q&A 24 confirms that the LTL framework under ICH M7 can be applied to eligible nitrosamine impurities based on treatment duration.
The revised adjustment factors are:
Duration of administration | Adjustment factor |
≤ 1 month | 80 × AI |
More than 1–12 months | 13.3 × AI |
More than 1–10 years | 6.7 × AI |
More than 10 years to lifetime | Lifetime AI |
These adjustments apply to eligible products in clinical development, authorised medicinal products and marketing authorisation applications.
The approach considers treatment duration while maintaining the theoretical lifetime excess cancer risk of 1 in 100,000.
4. Updated Interim Limits During CAPA Implementation
The revised Q&A 22 clarifies interim limits when nitrosamine levels exceed the established lifetime AI.
For eligible authorised products intended for lifetime administration, an interim adjustment factor of 6.7 × AI may be considered during CAPA implementation, provided the implementation timeline is up to seven years from the initial publication of the AI.
Generally, the interim limit should not exceed 1.5 µg/day, subject to specified exceptions, including higher established AIs, CPCA category 5 and negative enhanced Ames test results.
MAHs must prioritise CAPA implementation. Any required changes to shelf-life and storage conditions should be introduced without delay, subject to regulatory assessment.
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