Health Canada updated nitrosamine guidance

Limits of Nitrosamines
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Health Canada has recently updated its guidance on nitrosamine impurities, adding ten (10) additional nitrosamine impurities along with their corresponding CPCA-derived Acceptable Intake (AI) limits. Additionally, the agency has revised the AI limits for three (3) nitrosamine impurities.

Newly Added Nitrosamine Impurities:

  • Acebutolol: N-nitroso-acebutolol, AI limit: 1500 ng/day
  • Buspirone: 2-(4-nitrosopiperazine-1-yl)-pyrimidine, AI limit: 400 ng/day
  • Colesevelam: N-nitroso-didecylamine, AI limit: 100 ng/day
  • Dasatinib: N-nitroso-N-deshydroxyethyl-dasatinib, AI limit: 200 ng/day
  • Epinephrine: N-nitroso-epinephrine, AI limit: 100 ng/day
  • Galantamine: N-nitroso-N-desmethyl-galantamine, AI limit: 100 ng/day
  • Ivacaftor: N-nitroso-ivacaftor, AI limit: 1500 ng/day
  • Propafenone: N-nitroso-propafenone, AI limit: 100 ng/day
  • Ritonavir: NNTA (N-[(2-isopropylthiazol-4-yl)methyl]-N-methyl-nitrosamide), AI limit: 18 ng/day
  • Valsartan: 5-methyl-2-[[2’-cyano-[1,1’-biphenyl]-4-yl)methyl]-(nitroso)amino]-3-methylbutanoate, AI limit: 100 ng/day

Revised AI Limits for Existing Impurities:

  • Amitriptyline: N-nitroso-nortriptyline, NNORT: AI limit updated to 18 ng/day
  • Bupropion: N-nitroso-bupropion, Treat as a non-mutagenic impurity and control according to ICH’s Q3A and Q3B guidelines.
  • Diclofenac: N-nitroso-diclofenac, AI limit updated to 78,000 ng/day
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thanks a lot Haresh for your information.
I notice that N-nitrosoivacaftor has been added.
I feel that this is similar to N-nitrosoticagrelor case, where a ‘‘false’’ alarm has been set from someone who used a ‘‘fake’’ reference standard and ‘‘identify’’ N-nitrosoticagrelor in the tested sample(s) (unfortunately this ‘‘alarm’’ is still present in the AIs list of EMA).
A relevant discussion has been taken place some time ago in this forum

Apparently someone did not read this :wink:
best regards
Christos

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Thanks Haresh for update!!
Only want to highlight some corrections in AI limit as per online Appendix-1(Health canada) as below:

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Dasatinib is intended for the advance cancer indications. The scope of ICH M7 specifically states that the guidance does not apply to "drug substances intended for advanced cancer.
Hence ICH Q3 A limit can be applied for N-nitroso-N-deshydroxyethyl-dasatinib

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Dear Kapilvaja,
The one you wrote about the limit of the N-nitroso-N-deshydroxyethyl-dasatinib is right but only if the dasatinib has indication only for advanced cancer. If a second indication is appeared in the SPC which is not correlated with advance cancer, then testing under ICHQ3B is not valid.
Please see also the Kisqali discussion, where our member ‘‘paliog’’ explain very nice why N-nitroso-Ribociclib should be tested as typical nitrosamine and not as common impurty.

regards
Christos

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