Regulatory Rationale for Restricting LTL Application to Nitrosamines

[Thamara]

I would like to revisit a point that has already been discussed previously in the forum regarding the application of the LTL (Less Than Lifetime) concept to nitrosamines. I apologize if I am returning to a topic that has already been addressed, but I still have some conceptual doubts about the regulatory rationale for not applying this approach to nitrosamines in certain situations.

My question arises particularly in scenarios involving potential drug shortages, for example when an API is contaminated with a nitrosamine and there is no immediate alternative supplier or therapeutic replacement available. In these situations, considering that the LTL concept was developed precisely to allow flexibility based on duration of exposure, what would be the main technical/toxicological rationale for restricting its application to nitrosamines?

I understand that nitrosamines are considered compounds of very high toxicological concern, especially due to their carcinogenic potential, but I would appreciate a better understanding of how regulatory agencies assess the risk-benefit balance in situations involving supply shortages and treatment continuity.

Thank you in advance for your attention and for the always insightful discussions in this forum.

[shuhui.gu]

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

[Thamara]

Dear,

Thank you very much for your clarification and for taking the time to address my question.

Best regards,

[ASrinivasan]

While ICH M7 called nitrosamines as “cohort of concern” they were not thinking of large API like nitrosamines that the FDA calls NDSRIs. This term was mostly thought about related to smaller and potent nitrosamines like NDMA, NDEA etc. Also, for most nitrosamies, the less than lifetime approach is applicable. The sad part is the the agencies and industries took this term “cohort of concern” and ran with it, throwing everything else out of the window. As somebody who was immersed in nitrosamines for many, many years, I can tell you that it was well known in the nitrosamine community (most of the stalwarts are dead or very old) that larger nitrosamines are not a cohort of concern and LTL can be applied to them (read Joel Bercu’s paper from 2021), alpha-carboxyl substituted nitrosamine like nitroso-proline are non-carcinogenic. Sadly, we are reinventing the wheel and looks like it is a square wheel.

[Naiffer_Host]

The topic of LTL is advancing, despite the fact that it doesn’t feel that way!!

We have a powerhouse in Dr. Joel Bercu (@jbercu) and Dr. Susan Felter (@SusanFelter), driving insightful engagements and leading a series of research to move the needle. Remember, this is one of the deliverables from the M7 revision working group. For now check the number of discussions related to Dr. Felter’s publications:

LTL or not LTL that's the question?

@SusanFelter Once again thank you for becoming part of our community. I had opportunity to read some of your published work (‘A proposed framework for assessing risk from less-than-lifetime exposure to carcinogens’. ICH M7(R1) defined a sub-class of MIs described as the Cohort of Concern (CoC), including N-nitroso compounds. However, there is still debate about the use or not of LTL for this family of compounds when defining acceptable limits. Do you think there is even room for debate on this?

Use of the TD50 99 % CI for single dose rodent carcinogenicity studies -Pub

The TD50 (tumor dose 50%) value is a crucial parameter in determining the acceptable intake limits (AIs) for nitrosamine impurities in pharmaceutical products. It represents the estimated daily dose of a substance that is expected to induce tumors in 50% of the exposed animal population over their lifetime. The TD50 value is primarily used in two approaches to calculate nitrosamine impurity AIs: Class-Specific Threshold of Toxicological Concern (TTC): For nitrosamines with limited or no avai…

Lifetime Cumulative Dose and Less Than Lifetime Approach

This was published just last week. I don’t have the full version to read yet but will purchase shortly. Evaluating the Lifetime Cumulative Dose as a Basis for Carcinogenic Potency of Nitrosamines – a Key Tenet Underpinning Less-than-Lifetime Approaches for Establishing Acceptable Intake limits - ScienceDirect [image] @David - thank you to you and all your colleagues for this. Something many of us have been waiting for.