A structured approach to safety assessment of a newly identified leachable using chemical identity, exposure, mutagenicity, existing limits, read-across and general toxicity information.
Identification of a new leachable is only the beginning of the safety assessment. The central question is whether the estimated patient exposure is acceptable in light of the compound’s toxicological profile and uncertainty.
1. Confirm the chemical identity
Safety assessment depends on correct identity. Where identity remains tentative, the uncertainty should be made explicit and the analytical plan should be designed to improve confidence.
2. Define patient exposure
The measured or estimated amount should be converted into the relevant patient exposure for the intended route, dose and treatment duration.
3. Check for established compound-specific limits
Existing PDEs, other authoritative health-based limits or relevant regulatory classifications can substantially simplify the assessment when they are applicable to the actual exposure scenario.
4. Assess mutagenicity and higher-concern endpoints
Potential DNA-reactive mutagenicity requires specific consideration under ICH M7. Other high-concern features may also require a compound-specific approach rather than a generic threshold.
5. Evaluate non-mutagenic toxicity
When necessary, general toxicity, target-organ effects, local toxicity, sensitization and other relevant endpoints should be assessed using available experimental evidence and scientifically justified alternative methods.
6. Use read-across when appropriate
Read-across can help when direct data are limited, provided the analogue is scientifically justified and the comparison addresses the properties relevant to the endpoint and exposure scenario.
7. Document uncertainty and conclusion
The final safety conclusion should explain the evidence, limitations and rationale for the applicable safety limit or acceptable exposure.
Frequently asked questions
Does every new leachable require new animal testing?
No. Existing data, read-across, in silico and other scientifically justified approaches can contribute to qualification.
What should be done first after identifying a new leachable?
Confirm the identity and determine the relevant patient exposure.
When is ICH M7 relevant?
When the compound presents a potential DNA-reactive mutagenic concern.
Can read-across be used for leachables?
Yes, when analogue selection and endpoint relevance are scientifically justified.
Why are compound-specific limits important?
They can provide a more appropriate safety basis than a generic threshold for compounds with established toxicology or higher-concern profiles.
