Nitrosamines Published Limits -reference

Limits of Nitrosamines
49

Hi Rafa…

Thanks you very much sharing this information, so far i gone through revision 9, in that N-Nitroso Dabigatran not there…
They might have used default option 18ng/day as per LCDB, correct me if I am wrong…

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@ Yosukemino
Thanks for technical inputs & information…

@ Naiffer sir…
Could you please share this complied AI Limit in PDF format, instead image one?

Complied AI Limit in PDF format will cover all Nitrosamine AI limit with respect to all Regulatory agency (FDA, EMA, ANVISA, Health Canada, NPMA & other Agency)
You have already covered all Nitrosamine AI limit, except N-nitrosodabigatran.

Thanks
Nilesh

51

New NDSRI included in TGA. @Naiffer_Host
Date: 20 July 2022.

N -nitroso-tamsulosin AI 18.0 ng.day.
Nitrosamine impurities in medicines - Information for sponsors and manufacturers | Therapeutic Goods Administration (TGA)

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52

@Sarada.jena
Thanks for sharing this information…
It’s really great to update/share the Nitrosamine limit…

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53

@Naiffer_Host @Yosukemino @Sarada.jena @AmandaGuiraldelli

Dear Team,
What is the Default class specific TTC for nitrosamine, as per Health Canada & ANVISA guidance’s?

However, as per USFDA is 26.5ng/day and EMA & TGA is 18.0ng/day

Thanks
Nilesh

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54

Hi, @Nilesh.

You can find the links to the guidelines in the following post. HC and ANVISA allow 18.0ng/day to use. And details in those guidelines are helpful to understand their policies.

55

@Yosukemino
Great…
Thanks for providing all useful references…

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56

@Yosukemino @Naiffer_Host @Sarada.jena @AmandaGuiraldelli @jxl

I am just sharing one more reference, China NMPA CDE published a guidance on May 08, 2020 in continuation with above references

https://www.cde.org.cn/main/news/viewInfoCommon/776b663787ec5a60ac744071c3714d5a

Note: China NMPA CDE published a guidance is shared by @jxl . Thanks to him.

57

Hi, @Nilesh.

Thank you for sharing the information. I share the translated document by Google. It does not include a class-specific limit.

化学药物中亚硝胺类杂质研究技术指导原则（试行）(2).pdf (135.9 KB)

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Thanks @Yosukemino
Yes, It does not include a class-specific limit.

59

No, it does not. ICH M7 is referenced to calculate the limit.

60

@Naiffer_Host Please add N-nitroso-tamsulosin to the table

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62

@Naiffer_Host Please add 4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK) AI 100 ng/day from Health Canada Guidance update from -01 September 2022 at https://www.canada.ca/content/dam/hc-sc/documents/services/drugs-health-products/compliance-enforcement/information-health-product/drugs/nitrosamine-impurities/medications-guidance/guidance-nitrosamine-impurities-medications-eng.pdf

2 Likes
63

@pragnesh
Thanks for sharing this information

@Naiffer_Host @pragnesh @Yosukemino @jxl @Sarada.jena @Rafa
Dear Team,
Moreover, as per recent updated guidance’s regarding Nitrosamine impurities, 3 new Nitrosamine AI limit has been published.

  1. 4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK) - 100ng/day
  2. N-nitroso-dabigatran- 18.0 ng/day
  3. N-nitroso-tamsulosin- 18.0 ng/day

guidance-nitrosamine-impurities-medications-eng.pdf (canada.ca)

However, 4-(methylnitrosamino)-1-(3-pyridyl)-1-(butanone) (NNK) is new Nitrosamine Impurity AI limit is published in Health Canada guidance’s only.

N-nitroso-dabigatran impurity AI limit is published in EMA & Health Canada guidance’s only, having same 18.0 ng/day AI limit.

N-nitroso-tamsulosin AI limit is published in TGA & Health Canada guidance’s only, having same 18.0 ng/day AI limit.

Thanks
Nilesh

3 Likes
64

Sir, US FDA used lowest TD50 value of 0.0374 mg/kg/day from N-Nitroso-1,2,3,6-tetrahydropyridine.

67

Dear all,

Yesterday EMA published Rev 12 of the Q&A nitrosamines guideline. In particular:

Newly added to Q&As 10 and the list of potential N-nitrosamines is
 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) with a limit of 100 ng/day and
 N-nitrosoduloxetine using a limit of 100 ng/day.

Furthermore, the footnotes for N-nitrosoduloxetine was added clarifying that the limit derived using structure-activity-relationship (SAR) /read-across approach using the TD50 of NNK as point of departure.

Nitrosamines EMEA-H-A5(3)-1490 - QA Art. 5(3) Implementation_ for October PROM (QA10 and 21) (europa.eu)

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68

@Yosukemino @Naiffer_Host

Additionally, provision has been incorporated to allow the marketed products with a limit of 178ng/day whose AI is not yet established and the levels are found above 18ng/day. This means if the level of the nitrosamines found above 18ng/day, agency will not trigger any market action (product recall) for the period of 12 months or until the AI is established, whichever is earlier.

I am assuming that it is not applicable to product under development or during on-going MAA applications. For such cases, still Q&A 10 should apply.

Your thoughts are welcome.

1 Like