Saravanan,
To my knowledge, NTTP is a known mutagen in the regular Ames assay. As per the current guidelines, for such compounds there is no point in performing an EAT.
“If a standard Ames assay is conducted and produces a positive result, there is no need to conduct an additional assay using enhanced testing conditions.”
So I am afraid, you have to control this impurity with an AI of 37 ng/day unless you negotiate with the health authority directly and reach a consensus.
Hope this helps.
Dear Muzaffar
Thank you very much and it helps me lot.
We saw that FDA and EMA did not change some of the older values they have. However, they are aware that many are seeing nitrosamine in sitagliptin at levels far above 37 ng/day. My recommendation like some of the others here is to go to drug shortage and propose an interim limit based on the CAPA principles that EMA has proposed (you have to limit the CAPA to 2 years possibly). But this level should be shared with the review division too.
I posted the risk assessment results of NTTP in Sitagliptin in Japan in the following thread.
Hi Yosukemino,
That is a very interesting investigation report! Thanks a lot! I would like to highlight the use of TGRs to infer potency and argue that patient safety with higher proposed limits is not impacted, and something has been used for a regulatory submission if I understood correctly.
Also, that the change of high % compounds with known nitrite to low nitrite versions is a pragmatic solution as well something that was known but really a lot effort to do, to add a nitrosamine inhibitor to be able to pragmatically comply with limits close to dozens of ng/day.
By any chance is there any English version of the document? I am trying to use Deeple.com but not as acurrate as I would like to.
Interesting thing apart that Sitagliptin is a billions dollars molecule. Therefore, for low margin compounds such a big investigation report is a real challenge.
Thank you for responding, @Diego_HM. Though the pharmaceutical companies evaluated the risk of nitrosamine contamination from several points, the limit has stayed conservatism, 37 ng/day. If CPCA is available, they may provide different control strategies…
As far as I know, there is no document translated into English. I translated it with AI translation, but I am not sure of the correctness.
Thanks a lot Yosukemino, the translation is actually very accurate 
Thanks alot dear! Have they published any information regarding the immediate release combination of sitagliptin and metformin?
Thanks for this data.
It is very interesting to see that the BMDL50 for NTTP was calculated to be 9.17 mg/kg/day which is 150-times less potent than NDMA and 83-times less potent that NDEA, based on their respective BMDL50s reported in the this report. This definitely supports NTTP not being in the cohort of concern potency range. What is left for us to do is to convince the health authorities that such BMD comparisons can be done and that there is a direct correlation between in vivo mutagenicity potency and carcinogenicity potency.
Hi, @conudel,
I agree with you. The way is what you explained in your presentation. Though the data is used to justify the safety of the patients, suggested AI is the same as the conservative 37ng/day. I guess now the authority does not accept higher AIs than read across or CPCA even though the safety data justify the higher values except for negative results in the TGR assay. Further time and data are required to discuss this issue.
I am sorry, I can’t find the English version on the official page.
TGA extends transition to nitrosamine restriction to avoid shortages of diabetes medicines
https://www.raps.org/news-and-articles/news-articles/2023/12/asia-pacific-roundup-cdsco-advises-drugmakers-to-o
TGA is allowing manufacturers to continue supplying sitagliptin medicines contaminated with levels of a nitrosamine impurity above the acceptable intake (AI) limit for longer than originally planned. The change in the enforcement timeline is intended to prevent a shortage of the diabetes medicines.
Reformulated Januvia includes propyl gallate as anti oxicidant. I could not find the English document, so I attached the translated one from Japanese.
januvia_20240209 (AI translation).pdf (118.6 KB)
Yes dear, this change is approved in EMA and FDA as well.
Hi Alaaelkazak
Can you kindly share EMA and FDA approved NTTP AI limit from 37 ng to 246.7 ng approved letter or any kind of communication?
Interesting choice to use.
Propyl gallate is not without its issues from a formulation and analytical perspective.
Also, it was included in one of the original papers looking at the capability of scavengers, but didn’t progress very far in the paper, as in the systems and molecules that were being looked at I don’t remember it having much scavenging activity.
Scavengers do seem to be very nitrosamine specific! What works for one molecule may not work for another.
Is the decrease in shelf life because there isn’t enough data to support maintaining three years, and as real-time later stability time points become available it will be extended again, or because, even with the propyl gallate, the nitrosamine goes above the permitted level after 2 years?
Hi MarkS,
It’s a good point. The reason why they selected propyl gallate for their products is not described in the document.
As I wrote in the previous post, their policy is to keep the amount of NTTP less than 37 ng/day. The AI was published in May 2022 in EMA and the change application was scheduled in October 2023. Their data might only cover two years from one-year stability tests, despite the original being three years.
Most likely it was left out of the paper on purpose, to avoid giving tips to the competitors, or even maybe if they wanted to patent the new formulation? I would not have expected MSD to publish their mitigation action prior to it being 100% implemented
Already Sita+ Met ER tablets have propyl gallate in Sitagliptin portion which is drug layering approach on metformin matrix tablets.