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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