πŸ‡¦πŸ‡Ί TGA - Latest Update to Nitrosamine Limits

Limits of Nitrosamines
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The TGA in Australia :australia: have updated their list of nitrosamine limits again last week - see the link below.

Appendix 1 - Established acceptable intake for nitrosamines in medicines | Therapeutic Goods Administration (TGA)

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Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies | Organic Process Research & Development (acs.org)

A paper by Răzvan C. Cioc et al (EMA) provides a good consolidation of current information on possible risk factors

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**Just in case useful :wink: **

Nitrosamine structures added to the table.

New (x14) or updated (x1):

N-Nitroso-apixaban impurity B / 5-[4-[3-carbamoyl-1-(4-methoxyphenyl)-7-oxo-4,5-dihydropyrazolo[3,4-c]pyridine-6-yl]-N-nitrosoanilino]pentanoic acid / (source Apixaban) οƒ  AI 1500 ng/day, CPCA Category 4

N-Nitroso-clozapine / 8-chloro-11-(4-methylpiperazin-1-yl)-5-nitroso-5H-dibenzo[b,e][1,4]diazepine (156632-03-0) / (source Clozapine) οƒ  AI 1500 ng/day, CPCA Category 5

N-Nitroso-clozapine EP Impurity C / 8-chloro-11-(4-nitrosopiperazin-1-yl)-5Hdibenzo[b, e][1, 4]diazepine / (source Clozapine) οƒ  AI 400 ng/day, CPCA Category 3

2,2,5-Trimethyl-3-nitroso-1,3-oxazolidine (77400-46-5, TMNO) / (source Cyanocobalamine) οƒ  AI 1500 ng/day, CPCA Category 4

Only structure added for N-nitroso-dabigatran (rest remains the same, however date for update changed from β€œ31 Jan 2024” to β€œ23 Apr 2024”) i.e. really not a change to consider

N-Nitrosodiisopropanolamine / 1, 1’-(nitrosoimino)bis-2-propanol (53609-64-6) οƒ  AI 400 ng/day, CPCA Category 3

N-Nitroso-flecainide / N-((1-nitrosopiperidin-2-yl)methyl)-2, 5-bis(2, 2, 2-trifluoroethoxy)benzamide (2901109-58-6) / (source Flecainide) οƒ  AI 1500 ng/day, CPCA Category 4

N-Nitroso-masitinib / 4-[(4-nitrosopiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)benzamide / (source Masitinib) οƒ  AI 400 ng/day, CPCA Category 3

N-Nitroso-meropenem / (4R, 5S, 6S)-3-(((3S, 5S)-5-(dimethylcarbamoyl)-1-nitrosopyrrolidin3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid / (source / (source Meropenem) οƒ  AI 1500 ng/day, CPCA Category 4

N-Nitroso-ritalinic acid / 2-(1-nitrosopiperidin-2-yl)-2-phenylacetic acid / (source Methylphenidate) οƒ  AI 1500 ng/day, CPCA Category 4

N-Nitroso-N-methyl-valacyclovir (source Valacyclovir) οƒ  AI 400 ng/day, CPCA Category 3

N-Nitroso-silodosin / 1-(3-hydroxypropyl)-5-[(2R)-2-[nitroso-[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-2,3-dihydroindole-7-carboxamide / (source Silodosin) οƒ  1500 ng/day, CPCA Category 4

N-Nitroso-desmethyl-tamoxifen / (Z)-N-(2-(4-(1, 2-diphenylbut-1-en-1-yl)phenoxy)ethyl)-N-methylnitrous amide / (source Tamoxifen) οƒ  AI 18 ng/day, CPCA Category 1

N-Nitroso terazosin impurity C / N-nitroso 6,7-dimethoxy-2-(1-piperazinyl)-4-quinazolinamine / N-nitroso 2-(1-piperazinyl)-4-amino-6, 7-dimethoxyquinazoline / (source Terazosin) οƒ  AI 400 ng/day, CPCA Category 3

N-Nitroso terazosin impurity N / (4-nitrosopiperazin-1-yl)(tetrahydrofuran2-yl)methanone (2470438-57-2) / (source Terazosin) οƒ  AI 400 ng/day, CPCA Category 3

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TGA list has been updated 29 July 2024:
Appendix 1 - Established acceptable intake for nitrosamines in medicines | Therapeutic Goods Administration (TGA)

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thank you Wybon,
as a first note, the AI for N-nitrososertraline remains as 1500ng/day

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Hello everyone, what an update Β‘! in case useful :wink:

New (x 29):

  • 3-((Ethyl(nitroso)amino)methyl) benzenesulfonate (N-M8) οƒ  AI 18 ng/day, CPCA 1

  • N-Nitroso-N-ethyl-benzylamine / N-benzyl-N-ethylnitrous amide (20689-96-7, NBEA) οƒ  AI 18 ng/day, CPCA 1

  • N-Nitroso-2-(7-methoxy-1-naphthyl)-N-[2-(7-methoxy-1-naphthyl)ethyl]ethylamine (source Agomelatine) οƒ  AI 100ng/day, CPCA 2

  • N-Nitroso-articaine / methyl 4-methyl-3-(2-(nitroso(propyl)amino)propanamido)thio phene-2-carboxylate (source Articaine) οƒ  AI 1500 ng/day, CPCA 4

  • 3-(Dimethylamino)propyl 2-[benzyl(nitroso)amino]benzoate (source Benzydamine) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-bilastine impurity 2 / 1-(2-ethoxyethyl)-2-(1-nitrosopiperidin-4-yl)-1H-benzo[d]imidazole (source Bilastine) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-caspofungin / (10R,12S)-N ((2R,9S,11R,12S,14aS,15S,20S,25aS)-20 ((R)-3-amino-1-hydroxypropyl)-12-((2 aminoethyl)(nitroso)amino)-23-((1S,2S) 1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl) 2,11,15-trihydroxy-6-((R)-1-hydroxyethyl) 5,8,14,19,22,25-hexaoxotetracosahydro 1H-dipyrrolo[2,1-c:2’,1’ l][1,4,7,10,13,16]hexaazacyclohenicosin-9 yl)-10,12-dimethyltetradecanamide (source Caspofunfin) οƒ  AI 1500 ng/day, CPCA 4

  • 1-(Diphenylmethyl)-4-nitrosopiperazine / 1-benzhydryl-4-nitrosopiperazine (1698-25-5) (source Cinnarizine) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-N-desmethyl-clarithromycin / N-[(2S,3R,4S,6R)-2 [[(3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-14 ethyl-12,13-dihydroxy-4-[(2R,4R,5S,6S)-5 hydroxy-4-methoxy-4,6-dimethyloxan-2 yl]oxy-7-methoxy-3,5,7,9,11,13 hexamethyl-2,10-dioxo-oxacyclotetradec 6-yl]oxy]-3-hydroxy-6-methyloxan-4-yl] N-methylnitrous amide (source Clarithromycin) οƒ  NMI

  • N-Nitroso-N-desmethyl dextromethorphan/ (4bS,8aS,9S)-3-methoxy-11-nitroso 6,7,8,8a,9,10-hexahydro-5H-9,4b (epiminoethano)phenanthrene (N-DEX) (source Dextromethorphan) οƒ  AI 1500 ng/day, CPCA 4

  • N-Nitroso-desmethyl-edoxaban / N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S) 4-(dimethylcarbamoyl)-2-(5-nitroso 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2-carboxamido)cyclohexyl)oxalamide 4 methylbenzenesulfonate (source Edoxaban) οƒ  AI 100 ng/day, CPCA 2

  • N-Nitroso-trientine Impurity 1 / N-(2-aminoethyl)-N-(2-((2 aminoethyl)amino)ethyl)nitrous amide (2817316-41-7) (source Treintine) οƒ  AI 18 ng/day, CPCA 1

  • N-Nitroso-N-desmethyl diphenhydramine / N-(2-benzhydryloxyethyl)-N methylnitrous amide (55855-43-1) (source Diphenhydramine / Dimenhydrinate) οƒ  AI 18 ng/day, CPCA 1

  • N-Nitroso-fenfluramine / N-ethyl-N-[1-[3 (trifluoromethyl)phenyl]propan-2 yl]nitrous amide (19023-40-6) (source Fenfluramine) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-furosemide / 4-chloro-2-[furan-2 ylmethyl(nitroso)amino]-5 sulfamoylbenzoic acid (2708280-93-5) (source Furosemide) οƒ  AI 1500 ng/day

  • N-(2-Hydroxy-2-phenylethyl)-N-(4 nitrophenethyl)nitrous amide / (R)-N-(2-hydroxy-2-phenylethyl)-N-(4 nitrophenethyl)nitrous amide (MBL-2-NO) (source Mirabegron) οƒ  AI 400 ng/day, CPCA 3

  • N-(4-Aminophenethyl)-N-(2-hydroxy-2 phenylethyl)nitrous amide / (R)-N-(4-aminophenethyl)-N-(2-hydroxy 2-phenylethyl)nitrous amide (MBL-3-NO) (source Mirabegron) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-posaconazole Impurity 1 / 1-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1 yl)methyl)-5-(2,4 difluorophenyl)tetrahydrofuran-3 yl)methoxy)phenyl)-4-nitrosopiperazine (source Posaconazole) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-vibegron (S)-N-(4-(((2R,5S)-5-((R) hydroxy(phenyl)methyl)-1 nitrosopyrrolidin-2-yl)methyl)phenyl)-4 oxo-4,6,7,8-tetrahydropyrrolo[1,2 a]pyrimidine-6-carboxamide (source Vibegron) οƒ  AI 1500 ng/day, CPCA 5

  • 4-Nitroso-methyl piperazine-1 carboxylate (N-nitroso PMEC) (source Omecamtiv mecarbil) οƒ  AI 400 ng/day, CPCA 3

  • 2-(4-Nitrosopiperazin-1-yl)ethanol (48121-20-6) (source Opipramol) οƒ  AI 400 ng/day, CPCA 3

  • N-Nitroso-desformyl-riociguat / N-(4,6-diamino-2-(1-(2-fluorobenzyl)-1H pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5 yl)-N-methylnitrous (source Riociguat) οƒ  AI 100 ng/day, CPCA 2

  • Rivaroxaban Nitroso Impurity 1 / N-(2-hydroxyethyl)-N-phenyl-nitrous amide
    (25413-76-7, N-Nitroso KCR-1) (source Rivaroxaban) οƒ  AI 1500 ng/day, CPCA 4

  • Rivaroxaban Nitroso Impurity 2 / N-(3-(1,3-dioxoisoindolin-2-yl)-2 hydroxypropyl)-N-(4-(3-oxomorpholino) phenyl)nitrous amide(source Rivaroxaban) οƒ  AI 1500 ng/day, CPCA 4

  • Rivaroxaban Nitroso Impurity 5 / N-(3-chloro-2-hydroxypropyl)-N-(4-(3 oxomorpholino)phenyl)nitrous amide (N-Nitroso RVR-A) N-(3-(1,3-dioxoisoindolin-2-yl)-2 hydroxypropyl)-N-(4-(3-oxomorpholino) phenyl)nitrous amide (N-Nitroso RVR-A) (source Rivaroxaban) οƒ  AI 1500 ng/day, CPCA 4

  • N-Nitroso-tigecycline / (4S, 4aS, 5aR, 12aS)-9-(2-(tert butyl(nitroso)amino)acetamido)-4, 7 bis(dimethylamino)-3, 10, 12, 12a tetrahydroxy-1, 11-dioxo-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydrotetracene-2 carboxamide (source Tigecycline) οƒ  NMI

  • N-Nitroso-desmethyl-tramadol / N-[[(1R,2R)-2-hydroxy-2-(3 methoxyphenyl)cyclohexyl]methyl]-N methylnitrous amide (source Tramadol) οƒ  AI 18 ng/day, CPCA 1

  • N-Nitroso-trandolapril / (2S,3aR,7aS)-1-(N-((S)-1-ethoxy-1-oxo-4 phenylbutan-2-yl)-N-nitroso-L alanyl)octahydro-1H-indole-2-carboxylic acid (source Trandolapril) οƒ  AI 1500 ng/day, CPCA 5

  • N-Nitroso-desvaleryl-valsartan / (S)-2-(((2’-(1H-tetrazol-5-yl)- [1,1β€² biphenyl]-4-yl) methyl)(nitroso)amino)- 3 methylbutanoic acid (2254485-68-0) (source Valsartan) οƒ  NMI

Updated (x7):

  • 7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine (2892260-32-9, NTTP) (source Sitagliptin) οƒ  AI from 37.0 to 100 ng/day, CPCA 2

  • N-Nitroso-desmethyl-citalopram / N-(3-(5-cyano-1-(4-fluorophenyl)-1, 3 dihydroisobenzofuran-1-yl)propyl)-N methylnitrous amide (source Citalopram) οƒ  AI from 18 to 100 ng/day, CPCA from 1 to none

  • N-Nitroso-diisopropylamine / N,N-di(propan-2-yl)nitrous amide (601-77-4, DIPNA/NDIPA) οƒ  AI from 26.5 to 1500 ng/day, CPCA 5

  • N-Nitroso-ethylisopropylamine / N-ethyl-N-propan-2-ylnitrous amide (16339-04-1, EIPNA/NEIPA) οƒ  AI from 26.5 to 400 ng/day, CPCA 3

  • N-Nitroso-folic acid / 2-[[4-[(2-amino-4-oxo-3H-pteridin-6 yl)methyl-nitrosoamino] benzoyl]amino]pentanedioic acid (26360-21-4, NFA) (source Folic acid) οƒ  AI 1500 ng/day, CPCA 4

  • N-Nitroso-lisinopril / N2-((S)-1-carboxy-3-phenylpropyl)-N2 nitroso-L-lysyl-L-proline (519175-80-5, NLP) (source Lisinopril) οƒ  from AI 1500 ng/day, CPCA 5 to NMI

  • N-Nitroso-N-methyl-4-aminobutyric acid / 4-[methyl(nitroso)amino]butanoic acid (61445-55-4, NMBA) οƒ  AI from 96 to 1500 ng/day, CPCA 4

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