Nitrosamines and ICH M7: Practical Questions After an Initial Assessment

Nitrosamine risk assessment is not a one-time checkbox. Changes in synthesis, raw materials, suppliers, processes, formulations, or other product characteristics can create a need to revisit assumptions and determine whether a reassessment is appropriate.

ICH M7 provides a framework for the assessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals, with the objective of limiting potential carcinogenic risk. ICH materials also describe an ongoing maintenance process for M7 as new scientific and technical information becomes available. Source

The central question: did something relevant change?

A practical reassessment starts by identifying the change and asking whether it could introduce a new mutagenic impurity, increase an existing risk, or materially alter the basis for the prior assessment.

Potential triggers can include:

• changes to synthetic routes or reagents;
• changes in raw materials or suppliers;
• changes to process parameters or scale;
• changes in formulation or composition;
• new degradation pathways or impurities;
• new scientific information that changes the assessment basis.

A disciplined reassessment sequence

1. 1Map the change. Describe exactly what changed from the previously assessed state.
2. 2Identify affected impurities. Determine which impurities could plausibly be introduced, increased, or changed in relevance.
3. 3Apply the applicable framework. Use the relevant ICH and regional regulatory expectations for assessment, classification, and control.
4. 4Document the rationale. Record the evidence, assumptions, scientific reasoning, and resulting control strategy.
5. 5Revisit the control strategy when conditions change. A prior conclusion should remain traceable to the assumptions and data supporting it.

Why change management matters

Nitrosamine reassessment sits at the intersection of impurity science, process knowledge, regulatory expectations, and change control. Treating the exercise as a purely analytical task can miss the upstream question: what changed in the product or process that altered the impurity risk?

Questions teams should ask

• What changed since the previous assessment?
• Which impurity pathways became newly plausible?
• Do current analytical methods provide adequate sensitivity for the question being asked?
• Which assumptions from the prior assessment still hold?
• Has new scientific or regulatory information emerged?
• Is the control strategy still appropriate for the current risk?