This is a ready-to-use risk assessment template. Replace every <<FILL: ...>> placeholder, confirm current guidance and thresholds before use, and route through your normal technical and QA review. A filled specimen follows.
1. Methodology
This assessment classifies each actual and potential mutagenic impurity for a given drug substance under ICH M7(R2), determines the applicable acceptable intake, and justifies the chosen control option. Classification follows the M7 five-class system; control-option selection follows the four-option framework, with Option 4 (no analytical test) requiring documented purge-factor evidence rather than a general “small fraction of the acceptable intake” claim.
2. Scope
| Field | Entry |
|---|---|
| Drug substance / process | <<FILL>> |
| Route/step(s) assessed | <<FILL>> |
| Assessment date and author | <<FILL>> |
3. Impurity enumeration and classification
| Impurity | Structural alert? | Present in API? | Experimental mutagenicity data? | (Q)SAR result (2 methodologies) | Assigned class (1-5) |
|---|---|---|---|---|---|
<<FILL>> | <<FILL: Y/N>> | <<FILL: Y/N>> | <<FILL: Y/N, source>> | <<FILL: both negative / positive / equivocal>> | <<FILL: 1-5>> |
Classification logic: Class 1, both mutagenic and carcinogenic (compound-specific limit). Class 2, mutagenic with carcinogenicity not established (default to TTC, 1.5 microgram/day, unless compound-specific data justify otherwise). Class 3, structural alert with no data of its own (default to TTC or run an Ames test to reclassify). Class 4, alert also present in a non-mutagenic API (handle as non-mutagenic). Class 5, no structural alert (handle as non-mutagenic).
4. (Q)SAR assessment detail (for impurities without experimental data)
| Field | Entry |
|---|---|
| Methodology 1 (expert rule-based) result | <<FILL>> |
| Methodology 2 (statistics-based) result | <<FILL>> |
| Concordant? | <<FILL: Y/N>> |
| If discordant: expert review conclusion and rationale | <<FILL: signed, dated, reasoned review, not a verbal opinion>> |
5. Acceptable intake
| Field | Entry |
|---|---|
| TTC (default, if applicable) | 1.5 microgram/day |
| Compound-specific AI (if available) | <<FILL: value and source>> |
| Less-than-lifetime adjustment applied? | <<FILL: Y/N, treatment duration and basis>> |
| Multiple mutagenic impurities on spec? If 2 or more Class 2/3 impurities are specified, is the combined lifetime limit (5 microgram/day, adjusted for LTL) respected? | <<FILL>> |
6. Control option selection and justification
| Field | Entry |
|---|---|
| Chosen option (1, 2, 3, or 4) | <<FILL>> |
| Option 1/2: specification and test method | <<FILL: spec limit, method ID, LOQ vs. AI-derived concentration>> |
| Option 3: skip-testing justification | <<FILL: process understanding basis, periodic verification frequency>> |
| Option 4: purge factor evidence | See section 7 |
7. Option 4 purge-factor evidence (complete only if Option 4 is selected)
| Field | Entry |
|---|---|
| Step where impurity is introduced or forms | <<FILL>> |
| Downstream steps contributing purge | <<FILL: list each step>> |
| Purge factor per step (reactivity, solubility, volatility, ionizability basis) | <<FILL: factor and basis for each step>> |
| Cumulative purge factor (product of per-step factors) | <<FILL>> |
| Worst-case input level | <<FILL>> |
| Predicted level after purge (input / cumulative purge factor) | <<FILL>> |
| Margin vs. acceptable intake | <<FILL: predicted level should sit orders of magnitude below the AI, not merely "under a low percentage of it">> |
| Spiking study confirming predicted purge | <<FILL: study reference, spiked level, recovery/purge confirmed>> |
A purge argument built only on “the level is consistently under X% of the AI” does not satisfy Option 4 on its own; ICH M7’s own Q&A is explicit on this point. The justification must rest on demonstrated purge capability tied to process understanding, evidenced by the spiking study above.
8. Conclusion and approval
| Field | Entry |
|---|---|
| Overall conclusion | <<FILL>> |
| Analytical/process chemistry approval | <<FILL: name, date>> |
| Toxicology approval | <<FILL: name, date>> |
| QA approval | <<FILL: name, date>> |
Filled specimen
Scope. Drug substance Example-API, step 4 chlorination intermediate. Assessed 15 August 2026 by M. Okafor (Process Chemistry).
Enumeration. Impurity “Int-4-Cl”: structural alert present (alkyl chloride, potential SN2 electrophile), not present in the API, no experimental mutagenicity data. (Q)SAR: both expert rule-based and statistical methodologies predict negative, concordant. Assigned class: 3 (default negative, but no experimental confirmation on file).
(Q)SAR detail. Methodology 1: negative. Methodology 2: negative. Concordant, no expert review escalation needed; documented as a standard concordant-negative call.
Acceptable intake. TTC applies as the default for Class 3: 1.5 microgram/day. No compound-specific data exist. Chronic treatment, no LTL adjustment. Only one Class 3 impurity on this specification, so the multiple-impurity cap does not apply.
Control option. Option 4 selected, no routine analytical test.
Purge evidence. Int-4-Cl forms at step 4. Three downstream steps (aqueous wash, recrystallization, final wash) each carry a purge factor of approximately 80 to 120-fold based on the impurity’s high aqueous solubility relative to the API and its reactivity under the recrystallization conditions. Cumulative purge factor: approximately 900,000-fold. Worst-case input level at step 4: 0.5% (w/w). Predicted level after purge: roughly 0.5% / 900,000, several orders of magnitude below the 1.5 microgram/day AI at the registered maximum daily dose. Spiking study SP-2026-019 confirmed the predicted purge at 5x the worst-case input level, recovering below the assay’s detection limit after the recrystallization step.
Conclusion. Option 4 is justified by demonstrated, spiking-confirmed purge capability with wide margin. No routine test required on the drug substance specification; the purge argument is retained as part of the control strategy and revisited on any change to the step 4 through final-wash sequence. Approved by Process Chemistry, Toxicology, and QA, 22 August 2026.
Common inspection findings this assessment prevents
- Option 4 claimed with only a percentage-of-AI statement and no purge-factor or spiking evidence.
- A Class 3 impurity’s (Q)SAR result recorded without noting whether the two methodologies were concordant.
- A discordant (Q)SAR call resolved by an undocumented verbal expert opinion rather than a signed, reasoned review.
- The multiple-impurity cap ignored when two or more Class 2/3 impurities sit on the same specification.
How to adapt this assessment
- Confirm the current TTC, multiple-impurity cap, and any compound-specific AI figures against the current ICH M7(R2) text and any addendum in force before use.
- Where your (Q)SAR software differs from the two-methodology approach described, document your platform’s equivalent and how it satisfies the “two complementary methodologies” expectation.
- Pair this assessment with the analytical method validation package when Option 1 or 2 is chosen, so the LOQ-vs-AI comparison is on file alongside the classification.