10 considerations for scientifically robust and defensible nitrosamine safety risk assessments

2025 marks seven years of nitrosamine impurity focus within the pharmaceutical industry.

This period, initiated by nitrosamine impurity detection in common medicines, challenged both drug manufacturers and regulatory agencies. Whilst initially proposed low acceptable intake (AI) limits, threatened widespread drug shortages, in 2023, the Carcinogenic Potency Categorisation Approach (CPCA) brought clarity to this evolving landscape. The CPCA framework increased AI limits for many nitrosamines, based on nitrosamine risk, which significantly reduced market withdrawal risks and progressed regulatory default positions.

Within the pharmaceutical industry, challenges still exist for many drugs, especially those with CPCA AI limits at or below 400 ng/day. The CPCA guidance acknowledges its conservative nature, permitting read-across methodologies and the use of compound-specific toxicological data for more scientifically relevant AI determination.

At Consult Lhasa, we use our expertise to guide you through these complexities. Here are our 10 considerations for conducting scientifically robust and defensible nitrosamine safety risk assessments:

1. Use the CPCA, but don’t feel limited by it.

The CPCA offers a valuable baseline, when using this approach, CPCA categories are often accepted without further regulatory discussion. However, consider stepping beyond CPCA classifications when there is a need and you can scientifically justify this, particularly when using read-across.

2. Recognise the chemical space limitations of the CPCA.

The CPCA framework does not cover the entirety of nitrosamine chemical space, as its predictive methodology is primarily based on the α-hydroxylation metabolic activation pathway. This means certain classes, such as N-nitrosamides, N-nitrosoureas, and other related structures, are outside of its scope. When assessing a nitrosamine, use your chemical understanding to identify and justify deviations from CPCA classifications if the impurity falls outside its defined structural applicability or presents uncommon features not well-represented in the CPCA training set.

3. Ensure that you are accessing all relevant data.

Resources such as the Lhasa carcinogenicity database (LCDB) and Vitic – a high-quality toxicity database by Lhasa – are valuable for gathering robust nitrosamine data and study reliability assessments.

4. Prioritise carcinogenicity study relevance over perfection.

Very few carcinogenicity studies for nitrosamines fully conform to OECD test guideline 451. A study with fewer animals than guideline, for instance, but on a structurally-close analogue, is more relevant than a perfect study on a poor analogue; it might introduce slightly larger error bars but does not necessarily imply an increased risk. Confidence in both the study’s scientific rigour and relevance to your compound is key.

5. Do not overlook other toxicological data.

For example, if the best analogue demonstrates negative in vivo mutagenicity data, this can potentially align its acceptable intake with ICH Q3 limits, offering a more achievable, yet still demonstrably protective, limit.

6. Use a standardised and documented process.

Establish a consistent process for all nitrosamine assessments to ensure it is repeatability by both colleagues and regulators – document all decisions and rationales. Frameworks, such as that used within Acrostic – an in silico read-across solution by Lhasa – can provide a structured approach.

7. Avoid assessment bias.

Prioritise the assessment of structural similarity, before evaluating toxicity, to remove potential bias, influenced by pre-conceived potency values or regulatory limits. This approach helps to harmonise outcomes and ensures objectivity within assessments, regardless of whether you represent industry or regulatory perspectives.

8. Strategically address the absence of direct analogues.

In cases where a single, ideal analogue is unavailable, consider grouping compounds. No single compound may encompass all necessary features, but a strategically selected group of compounds can collectively cover the relevant structural and toxicological features, allowing for a potency assessment related to that defined group.

9. You can use less robust data if necessary.

If a suitable analogue exists but lacks sufficiently robust data, it may still be possible to use less robust data while maintaining a protective assessment. For further details on this approach, consult the recent publication by Felter et al.

10. Seek expert advice to avoid regulatory deficiencies.

When faced with complex cases or uncertainties that undermine your confidence in an assessment, proactively seek expert assistance. Contact Consult Lhasa to avoid potential deficiency letters and ensure seamless regulatory compliance.