Hello Tobias,
I'll try to address your two questions based on my experience with small molecules. For full disclosure, I am not a toxicology expert; therefore, my understanding of ICH M3 is not much different from yours.
1) ICH M3 is about the drug (as finished product and API), not the impurities. Drugs intended to be administered at low dose are not exempted from nonclinical studies to ascertain their safety and tolerability before they are given to humans. As you can see from the details of Table 3, a variety of approaches are possible-the extent of the possible studies therein listed is more limited than what would be required for drugs at higher doses.
2) the LTL principle typically only applies within the context of ICH M7. With the possible exception of drugs introduced in Phase 1, for which a justification for thresholds higher than those indicated in ICH Q3A and Q3B is being accepted by regulators worldwide nowadays (see the 2017 Harvey paper).
As a general principle, please keep in mind that an impurity by its own definition does not bring any benefit, only risk. That is why there is an expectations that impurities are controlled at limits that are considered generally safe, in the absence of qualifying toxicological studies.
I have a question for you: if you intend to include this now identified impurity in the specification of the drug substance, in the absence of toxicological qualification the highest limit you could claim is not more than 0.15%. If you specify it at 0.1%, do you mean that at 0.14% a batch would still pass?
Have you monitored this impurity on stability? Does the limit takes into account the possibility that it may grow on storage? In other words, is it a drug substance degradation product?
Finally, what about the drug product? Does it grow on storage, could it be considered a degradation product?
Hope this hleps,
Maurizio
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Maurizio Franzini
Regulatory Affairs CMC, Associate Director
San Francisco CA
United States
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Original Message:
Sent: 08-Dec-2021 09:41
From: Anonymous Member
Subject: TDI for process impurities, ICH Q3A/M3
This message was posted by a user wishing to remain anonymous
Hi RAPS community,
I work on biologics, and small molecule CMC is certainly not my area of expertise, but I have a question on some apparent inconsistencies (to me as a layman) among ICH guidelines.
Say hypothetically, I am trying to develop a generic version of a hypertension drug that the patient needs to take for life. The RLD has a dose of 800 mg/day. I have a process impurity at 0.07% that is not present in the RLD. There is no obligation of identifying this impurity as it is below the identification threshold, but I performed the identification out of an abundance of caution. The impurity is predicted to be negative for bacterial mutagenicity. I propose an acceptance limit of 0.1%. If this is agreeable to the agency, it would mean that from a regulatory standpoint, 0.8 mg TDI for chronic dosing is acceptable.
1) If 0.8 mg TDI lifetime exposure is an acceptable risk for an unqualified impurity, why does ICH M3 require a 14-day tox study for microdose trials (single dose of 0.1 mg or lower) ?
2) Applying the approach of Less-than-Lifetime exposure, a single dose of 50 mg of this impurity (neat) should be considered safe in humans (1.5 ug of lifetime exposure is similar to 120 ug of short-term exposure less than a month, as most toxicities depend on both dose and duration, ICH M7) ?
Thank you very much for insights
Tobias