Dear Thamara,
I would like to share with you a discussion thread from the USP Nitrosamines Exchange regarding the Less‑Than‑Lifetime (LTL) approach for nitrosamine risk assessment, specifically in the context of new generic product registrations. You can access the discussion here:
https://nitrosamines.usp.org/t/ltl-approach-for-new-generic-registrations/14337?u=shuhui.gu
Based on the discussion and current regulatory positions, I have summarised the key takeaways as follows:
1. Fundamental Restriction Reason
Nitrosamines are classified as ICH M7 Cohort of Concern (CoC) high‑potency carcinogens. Consequently, regulators generally apply conservative, uniform standards and do not routinely permit LTL adjustments. In fact, the discussion indicates that while ICH M7 does not explicitly preclude LTL for CoC impurities, FDA currently does not accept the LTL approach for nitrosamine limits.
2. Mechanistic Consideration
The potent DNA‑alkylating capacity of nitrosamines may saturate repair mechanisms; therefore, the risk equivalence assumption underlying LTL (i.e., that lifetime cumulative dose determines overall cancer risk) may not automatically hold for this class of compounds. This is a key reason why many agencies remain cautious about applying LTL adjustments to nitrosamines.
3. Flexibility in Shortage Scenarios (EMA)
EMA permits LTL only as a temporary/interim measure under exceptional shortage circumstances, accompanied by a CAPA (Corrective and Preventive Action) plan that must be completed within a defined timeframe. Market authorisation holders (MAHs) are required to implement CAPAs promptly with a clear plan to ultimately meet the lifetime Acceptable Intake (AI) limits.
I hope this summary is helpful. Please feel free to let me know if you would like to discuss any of these points in more detail.
Best regards,
Shuhui