Sitagliptin NTTP nitrosamine impurity maximum active intake level 37ng to 246.7 ng/per day

Risk Assessment Strategy / Tools & Technology
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Dear Experts

Is it possible to relax the Sitagliptin NTTP nitrosamine impurity maximum active intake level from 37ng to 246.7 ng/per day as per below mentioned USFDA Statement by upcoming revisions of USFDA and EMA guidelines?

Kindly suggest.

FDA works to avoid shortage of sitagliptin following detection of nitrosamine impurity | FDA

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The latest FDA guidance removes previous temporary limits but speaks to communication with the Drug Shortages Staff to implement temporary limits on a case-by-case basis.

Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities | FDA

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Dear @Saravanan1985 ,

According to the Guidance: “The Agency recognizes that the science is evolving in the prediction of mutagenic potential and carcinogenic potency based on SAR concepts. Therefore, the predicted carcinogenic potency categorization method is a conservative approach that represents the best available science at this time and is expected to be further refined and expanded as new data become available. Additionally, as with all guidance documents, manufacturers and applicants can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations”.

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It should be noted that both EMA and USFDA still adhere to an AI of 37 ng/day for NTTP, please refer table 2 of FDA guidance.

Table 2: FDA Recommended AI Limits for Certain NDSRIs

Based on Compound-Specific Data or Read-Across Analysis from a Surrogate

(last updated 8/4/2023)

NDSRI Name Source Recommended AI Limit (ng/day) Surrogate Date Added to Table
7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (NTTP) Sitagliptin 37 N-nitroso-1,2,3,6-tetrahydropyridine (NTHP) 8/4/2023*
Updated Information | Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs) | FDA

More excerpts from the USFDA guidance which I would leave for your interpretation,

If FDA recommends an interim AI limit, it generally does not intend to object, for example based on applicable underlying CGMP violations, to distribution of such drug product batches that contain NDSRI levels at or below the recommended interim AI limit during the specified period under certain circumstances on a case-by-case basis. In certain cases where FDA does not intend to object to the distribution of drug products from multiple drug manufacturers that contain NDSRI levels at or below the recommended interim AI limit, FDA intends to post such recommended interim AI limits on this website.

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Dear Lucas10mauriz

Thank you very much for valuable input.

Agency might accept for relaxation of Sitagliptin NTTP impurity AI interim limit, If we are going with enhanced AMES test results for Sitagliptin NTTP Impurity showing Cut off limit more than 37ng/per day as per EMA, Rev 17 guidelines.

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Dear Muzaffar

Thank you very much for valuable input.

Agency might accept for relaxation of Sitagliptin NTTP impurity AI interim limit, If we are going with enhanced AMES test results for Sitagliptin NTTP Impurity showing Cut off limit more than 37ng/per day as per EMA, Rev 17 guidelines.

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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.

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Dear Muzaffar

Thank you very much and it helps me lot.

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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.

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I posted the risk assessment results of NTTP in Sitagliptin in Japan in the following thread.

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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.

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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.

Risk assessment of sitagliptin english.pdf (7.4 MB)

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Thanks a lot Yosukemino, the translation is actually very accurate :wink:

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Thanks alot dear! Have they published any information regarding the immediate release combination of sitagliptin and metformin?

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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.

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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.

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@Yosukemino can you share me the English version of this document

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I am sorry, I can’t find the English version on the official page.

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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.

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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)

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