EMA - Appendix 1 - Update

Dear all,

please let me share with you that EMA has updated Appendix 1 for Nitrosamine limits :slight_smile:

As discussed previously Nitroso-STG-19 increased to AI 100ng/day.
NEIPA, NMBA and NDIPA also revised.

NAME CAS Source CPCA Cat AI
1-diphenylmethyl-4-nitrosopiperazine 1698-25-5 Cinnarizine 3 400
3-(dimethylamino)propyl 2-[benzyl(nitroso)amino]benzoate 87453-76-7 Benzydamine 3 400
Nitroso-STG-19 2892260-32-9 Sitagliptin 2 100
N-Nitroso-bilastine impurity 2 NA Bilastine 3 400
N-nitroso-caspofungin NA Caspofungin 4 1500
N-Nitroso-desformyl-riociguat NA Riociguat 2 100
N-nitroso-desmethyl-clarithromycin NA Clarithromycin NMI
N-nitroso-desmethyl-citalopram NA Citalopram 100
N-nitroso-desmethyl-tramadol NA Tramadol 1 18
N-nitroso-desvaleryl-valsartan 2254485-68-0 Valsartan NMI
N-nitroso-diisopropylamine 601-77-4 5 1500
N-nitroso-ethylisopropylamine 16339-04-1 3 400
N-nitroso-N-desmethyl-diphenhydramine 55855-43-1 Dimenhydrinate/ Diphenhydramine 1 18
N-nitroso-N-methyl-4-aminobutyric acid 61445-55-4 4 1500
N-nitroso-tigecycline Tigecycline NMI
N-nitroso-trandolapril NA Trandolapril 5 1500
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@elenipoliti ,

Thank you for bringing this update.

In the context of classic nitrosamines (NDIPA, NEIPA and NMBA), I’d like to highlight the action taken by the EMA.

It builds upon what the Canadian authority had previously done, reflecting the knowledge gained over the years. I’m optimistic that other health authorities will consider similar actions in the near future.

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Hi,

Thanks for the update! One comment I would like to highlight, the continous increase of nitrosamines coming from dealkylated drug substances. The experimental work that say that nitrosation of tertiary amines has 1000 times lower rate of formation from secondary amines with similar properties is indeed true but 1000 times less is still enough when you end in a Category 1 or 2 or even 3.

Considering also the theoretical nitrosamine content is not only related to nitrosamine of tertiary amines but includes also already available secondary amines coming from the drug substance.

Careful evaluation is needed instead of a full risk dismiss when tertiary amines are present (I have seen that). At least until (if it happens at all) we get rid of the 18 ng/day limit.

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Exactly - frequently the dealkyated substance is listed as an impurity for the tertiary API. It may well be controlled to a limit of 0.1%, but 0.1% is more than enough to be of concern in the finished product from a nitrosamines perspective if you have very low ng/day limits, or high dosing regimes. In depth investigations into the route of synthesis, and whether it is a manufacturing impurity or a degradation product that may form over time during the shelf-life needs to be taken into consideration. API manufacturers are not going to want to, or be able to, control them to ppm or below levels.

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Thank you for sharing, @elenipoliti. I want to show the details of the updates.

New:

Name CAS RN Source CPCA Category AI (ng/day)
1-diphenylmethyl-4-nitrosopiperazine 1698-25-5 Cinnarizine 3 400
3-(dimethylamino)propyl 2-[benzyl(nitroso)amino]benzoate 87453-76-7 Benzydamine 3 400
N-Nitroso-bilastine impurity 2 NA Bilastine 3 400
N-nitroso-caspofungin NA Caspofungin 4 1500
N-Nitroso-desformyl-riociguat NA Riociguat 2 100
N-nitroso-desmethyl-clarithromycin NA Clarithromycin NMI*
N-nitroso-desmethyl-tramadol NA Tramadol 1 18
N-nitroso-desvaleryl-valsartan 2254485-68-0 Valsartan NMI**
N-nitroso-N-desmethyl-diphenhydramine 55855-43-1 Dimenhydrinate/ Diphenhydramine 1 18
N-nitroso-tigecycline Tigecycline NMI**
N-nitroso-trandolapril NA Trandolapril 5 1500

*Limit derived using structure-activity-relationship (SAR)/read-across and weight of evidence approaches using N-nitroso-desmethyl-azithromycin as a surrogate
**Substance tested negative in in vivo mutagenicity study. Can be controlled in drug product according to ICH Q3B.

Updated:

Name CAS RN Source CPCA Category AI (ng/day)
Nitroso-STG-19 2892260-32-9 Sitagliptin No value => 2 37 => 100
N-nitroso-desmethyl-citalopram NA Citalopram 1 => No value 18 => 100*
N-nitroso-diisopropylamine 601-77-4 No value => 5 26.5 => 1500
N-nitroso-ethylisopropylamine 16339-04-1 No value => 3 26.5 => 400
N-nitroso-N-methyl-4-aminobutyric acid 61445-55-4 No value => 4 96 => 1500

*Limit derived using structure-activity-relationship (SAR)/read-across approach using the TD50 of NNK as point of departure.

Correction:

Name CAS RN Source CPCA Category AI (ng/day)
1-(2,3-dichlorophenyl)-4-nitrosopiperazine 2221987-86-4 Eculizumab => Aripiprazole 3 400
N-nitroso-N-desmethyl-dextromethorphan NA Dextromethorphan 5 => 4 1500

CPCA and read-across are used effectively to set AI limits.

Negative In-vivo results of N-nitroso-desmethyl-azithromycin are used for the AI setting of N-nitroso-desmethyl-clarithromycin(=NMI). It looks reasonable.

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Valsartan中的亚硝胺杂质通过Substance tested negative in in vivo mutagenicity study,按Q3B控制,那N-nitroso-valsartan是不是也可以近Q3B控制?

I classified 161 nitrosamines in Appendix 1 with publication date(registered or updated).

2020: 4
2021: 2
2022: 12 *
July 2023(CPCA is published): 55 **
September 2023: 5
November 2023: 15 ***
December 2023: 4
January 2024: 16
February 2024: 14
May 2024: 18
July 2024: 16

*: Deadline of Step2 for products containing chemically synthesized APIs is 26th September 2022
**: Deadline of Step2 for products containing biological APIs is 1st July 2023
***: Deadline of Step3 is 1st October 2023.

The number of nitrosamines in Appendix 1 is still increasing, despite the deadline arrived. What is a deadline? :sweat_smile:

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Dear Yosukemino
Thank you for including all details and clarifications :slight_smile:
BR
Eleni

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Dear Yosukemino,
Could you please elaborate on the limits that have been corrected: 1-(2,3-dichlorophenyl)-4-nitrosopiperazine and N-nitroso-N-desmethyl-dextromethorphan? Have they also been increased?
BR
Marcin

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It is good news. But I also feel a bit frustrated on behalf of the pharmaceutical industry. It has been very difficult to manage this changing goal post of Acceptable Intakes. Some companies have started working on reformulation considering the older values and now may see that it may not be needed. And then there is FDA, who has given legal issues priority over people’s health and availability of drugs and capped everything at 1500 ng/day. I wish that this story of nitrosames teaches the Regulatory Agencies to “look before they leap” in future problems.

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Yosukemino San, you are a gem. Thanks for this update. And deadlines are what the Hindus call “Maya” and illusion. Dont attach yourself to it. :grin: :grin:

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Hi @MKublicki,

Thank you for asking questions. The source of 1-(2,3-dichlorophenyl)-4-nitrosopiperazine corrected from Eculizumab to Aripiprazole. And the CPCA category of N-nitroso-N-desmethyl-dextromethorphan corrected from 5 to 4. So AIs are the same as those in rev.4.

Dear All, I have updated the dashboard with the new EMA AI limits.

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