Is AZBT (azidomethyl-biphenyl-tetrazole) the new Nitrosamine?

[Naiffer_Host]

We are starting to see some noise on this Azido impurity. This is the information I have been able to collect so far:

• CMDh - notified authorization holders that Azido impurity in irbesartan confirmed positive in bacterial mutagenicity test – https://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Advice_from_CMDh/CMDh_430_2021_Rev.0_2021_04_Request_for_investigation_Sartans-Azido_impurity_in_irbesartan_confirmed_positive_in_bacterial_mutagenicity_tests.pdf

• SwissMedic - Notified about findings of AZBT in batched of the active substance irbesartan. AZBT most likely a by-product in certain synthesis steps. Monitoring of sartan medicines stepped up: traces of a new foreign substance detected

• Hong Kong FDA - On 31 May 2021, the Department of Health (DH) endorsed T-boma to recall PMS-Irbesartan Tab 150mg, PMS-Irbesartan Tab 300mg from the market as a precautionary measure due to the presence of an impurity in the products. Medicine recalls - 2021-05-31 (2)

• Health Canada - Multiple lots of irbesartan, losartan and valsartan drugs recalled due to azido impurity Multiple lots of irbesartan, losartan and valsartan drugs recalled due to azido impurity - Recalls and safety alerts

[AndyTeasdale]

My short answer to this question is no. Why do I say this ? Because the risk is specific to the API and the route of synthesis and process. As highlighted some but not all Sartans are imparted. Unlike N-NOs there is no additional product related risk.

Another key point is that such an impurity while it may be mutagenic it is not part of the COC and thus falls entirely under the control of ICH M7.

[Yosukemino]

@Naiffer_Host This topic is very interesting, because the authorisation holders of sartan preparations were required to check their active substance batches specifically for AZBT, according to SwissMedic, despite it is not nitrosamine but mutagenic impurity. This detection of a previously unidentified impurity in well-known active substances is also attributable to the ever growing sensitivity of the analytical methods used in the quality control of medicines, as mentioned in the article of SwissMedic. I agree with it. And new mutagenic impurities contained and found in the similar cases as AZBT may cause further recalls in future, though their structure are now unidentified. This is really tough problem.

Anyway AZBT is considered as class2 and its acceptable intake is TTC. I’m concerned title of this thread may be confusing. To treat AZBT in ICH M7 is a better way, I think. (It may be even out of scope of ICH M7, strictly speaking…)

[jbercu]

This may be an issue for the Sartans, but the nitrosamines are a much broader concern

[Yosukemino]

I add the part of implementation plan which means retrospective application of ICH M7.

Implementation plan is https://www.ema.europa.eu/en/documents/other/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines-implementation-plan_en.pdf.

I’m not sure the current situation, however we should pay attention to it anyway.

[Frabaneda]

Just in case, this is the link to the EDQM method for the quantification of AZBT impurity in Valsartan, Irbesartan, Losartan and Candesartan using LC-MS

general-methodparameters-azbt-lcms.pdf

[dheeraj]

Is there anybody has worked for azidomethyl-biphenyl-tetrazole (AZBT) impurity in Sartans analysis by GC-MS/MS.