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

Risk Assessment Strategy / Tools & Technology
21

Yes dear, this change is approved in EMA and FDA as well.

2 Likes
22

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?

1 Like
23

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 didnā€™t progress very far in the paper, as in the systems and molecules that were being looked at I donā€™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 isnā€™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?

3 Likes
24

Hi MarkS,

Itā€™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.

25

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

26

Already Sita+ Met ER tablets have propyl gallate in Sitagliptin portion which is drug layering approach on metformin matrix tablets.

2 Likes
27

Dears,

PFA : Science direct article which refer use of antioxidant to reduce Nitrosamine impurity level.

N-nitrosamine Mitigation with Nitrite Scavengers in Oral Pharmaceutical Drug Products

Regards,
JIGAR SHAH
Science Direct Nitrosamine.pdf (638.8 KB)

28
  • On May 31, 2024, Health Canada released an updated version of its Guidance on nitrosamine impurities in medications.
  • This update includes additional guidance for establishing acceptable limits based on a structure-activity relationship (SAR) assessment and read-across to a surrogate with sufficient compound-specific data.
  • The list of established Acceptable Intake (AI) limits (Appendix 1) has also been updated:
    AI limit is revised For NTTP i.e.100ng/day instead of 37ng/day.
    Do other agencies follow the suitā€¦ what will be the timelines, if any one have idea on this.
4 Likes
29

This paper is now also out, in the context of NTTP AI setting and potency ranking:
N-Nitrosamine Impurity Risk Assessment in Pharmaceuticals: Utilizing In Vivo Mutation Relative Potency Comparison to Establish an Acceptable Intake for NTTP - ScienceDirect

  • Practical strategies are needed to establish exposure limits for N-nitrosamines
  • In vivo TGR mutation study provides compound specific data for novel N-nitrosamines
  • Relative potency comparison of in vivo TGR data provides basis for exposure limit
  • NPIP in vivo TGR data adds to the database of well-studied, model N-nitrosamines
  • Relative potency comparison supports the safety of NTTP exposures ā‰„ 1500 ng/day

The resulting database of in vivo mutation data and carcinogenicity data for NDEA, NDMA, and NPIP can serve as basis for comparison to novel N-nitrosamines. Using the relative potency comparison approach, we have demonstrated the safety of NTTP exposures at or above levels of 1500 ng/day.

1 Like