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Challenge
A pharmaceutical sponsor implemented a packaging change for a solid oral drug product, switching to a new polymeric blister film for improved shelf-life and mechanical integrity. During chemical characterization of the new packaging system, extractables data revealed trace-level impurities not previously associated with the original configuration.
While these compounds were present at extremely low levels, some were structurally unfamiliar and lacked publicly available toxicological data. To remain compliant with ICH M7 (Assessment and Control of DNA Reactive Impurities), the sponsor needed to determine whether the detected compounds posed genotoxic risks, without triggering additional in vitro genotoxicity studies or submission delays.
Chemva’s Solution
Chemva performed a tiered in-silico genotoxicity assessment using (Q)SAR tools and expert toxicological interpretation to classify the packaging-derived impurities per ICH M7 guidelines.
Our approach included:
- Impurity Structuring and Standardization:
- Assigned SMILES/InChI structures to all impurities using cheminformatics tools.
- Cleaned and standardized the chemical representations to avoid misclassification in the predictive models.
- Dual-Platform (Q)SAR Evaluation:
- Conducted genotoxicity predictions using two complementary ICH M7-compliant software platforms:
- Expert rule-based model
- Statistical/machine learning model
- Classified each impurity into ICH M7 Classes 1–5, based on predicted mutagenic potential.
- Conducted genotoxicity predictions using two complementary ICH M7-compliant software platforms:
- Expert Toxicologist Review & Justification:
- For any conflicting predictions, Chemva performed expert rule-based evaluation, considering:
- Functional group reactivity
- Structural analogs with known genotoxicity data
- Compound-specific metabolism or potential for detoxification
- All assessed impurities were ultimately assigned to ICH M7 Class 5, indicating no structural alerts.
- For any conflicting predictions, Chemva performed expert rule-based evaluation, considering:
- Regulatory Documentation:
- Prepared a full ICH M7 assessment report detailing methodology, prediction outcomes and classification rationale.
Impact Delivered
Chemva’s in-silico genotoxicity assessment:
- Delivered a regulator-ready justification aligned with ICH M7 and widely accepted around the world.
- Helped the sponsor maintain submission timelines and proceed with the packaging change without triggering a requalification of the drug product’s safety profile.
- Eliminated the need for laboratory genotoxicity testing, saving 8–10 weeks and ~$100K in study costs.
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