Lhasa TD50 or Gold TD50 to set AI limit?

[sushantkamath]

Hi All,

Are there any examples of health authorities setting AI limits based on Lhasa TD50 values? As far as i know only Gold TD50 value is used to set AI limits, even though Lhasa TD50 values are more robust and relevant. Does anybody have any insight on future acceptance of Lhasa TD50 values to set AI limits by health authorities?

[elenipoliti]

Hi.
perhaps you can refer the article from Dobo et al., 2022

Practical and Science-Based Strategy for Establishing Acceptable Intakes for Drug Product N-Nitrosamine Impurities

doi: 10.1021/acs.chemrestox.1c00369

Moreover, based on my little experience, Authorities tend to accept also Lhasa TD50 under a well documented justification (Number of animals, exposure time, number of doses); and even better when Lhasa TD50 are lower than Gold TD50 resulting in stricter AI.

Hope it helps you

BR,
Eleni

[sushantkamath]

Hi Eleni,

Thank you. My query was related to current regulatory stand on TD50 values. I guess conservative approach is the option (Gold TD50) as you mentioned even if Lhasa TD50 is robust.

Regards

Sushant

[Pradpharma]

@sushantkamath

there any examples of health authorities setting AI limits based on Lhasa TD50 values? As far as i know only Gold TD50 value is used to set AI limits, even though Lhasa TD50 values are more robust and relevant. Does anybody have any insight on future acceptance of Lhasa TD50 values to set AI limits by health authorities?

Hi @sushantkamath - You are correct mostly Gold TD50 chosen being conservative. But agencies do accept Lhasa TD50 wherever they feel relevant.

Below is one of the communication i had with EMA way back in 2022.

"Dear Mr Dadisetti

Thank you for your question

NDMA and NDEA were the first nitrosamines to be detected in sartan medicines. At that time it was not anticipated that many other nitrosamines would be detected in other medicines. The EMA and many other international regulators agreed to harmonise the AI, and because there were many studies for these two nitrosamines, the harmonic means of the TD50 values in the CPDB database were used as points of departure for establishing the AI. Additionally, the Lhasa TD50 database is now generally used by EMA rather than CPDB TD50 as the criteria used for determining the robustness of the carcinogenicity data are similar to those established by the Non clinical working party.

Best regards

European Medicines Agency

[sushantkamath]

Hi Pradeep,

Thank you for sharing your insights regarding the acceptance of Lhasa TD50 by agencies. I appreciate the context provided from your previous communication with EMA.

Your explanation aligns with my understanding that while a conservative approach often leads to the choice of Gold TD50, the Lhasa TD50 values are indeed recognized and utilized by regulatory agencies when deemed relevant.

It is good to see a communique from EMA shifting towards Lhasa TD50, given its robust carcinogenicity data criteria. This information is valuable and helps to clarify the current practices. Thank you once again for providing this context.

Best Regards

Sushant

[Yosukemino]

Dear @sushantkamath and @Pradpharma ,

Though you may have solved this problem, I want to add the previous post by @David.

NDEA AI Limit 26.5ng/day?

A few thoughts on these discussions: The TD50s used for limit setting are typically the rodent TD50s, firstly since that is the standardised carcinogenicity assay (thus that exceptionally potent primate result for NDEA is ignored from the dataset), and secondly since rodent TD50s were used for the TTC and CoC initial development by Kroes, Cheeseman and co-workers. Additionally, a primate assay is less likely to be lifetime, due to longer lifespans, would use fewer animals for cost and ethics …

Do you have additional information, David?

[David]

Only one observation - in some of the discussion above Gold TD50s are referred to as ‘conservative’; in terms of their actual limits, sometimes the Gold TD50 is actually higher! It’s worth clarifying that the ‘conservatism’ therefore is in the choice of data to submit rather than the limit actually requested.

[Pradpharma]

@David

in some of the discussion above Gold TD50s are referred to as ‘conservative’; in terms of their actual limits, sometimes the Gold TD50 is actually higher! It’s worth clarifying that the ‘conservatism’ therefore is in the choice of data to submit rather than the limit actually requested.

Agree- all Gold TD50s are not conservative.

[Yosukemino]

Thank you for the additional information, David. Yes, you are right.