A number of organisations have flagged receipt of a specific request relating to Azithromycin. The request is immediate testing of all batches for the presence of both NDMA and NDBA. What is concerning is the lack of detail as to why this has been requested as opposed to a request for re-examination of the individual company / process specific risk assessment for N-NOs Azithromycin containing products. It is certainly not clear as to whether both NDMA and NDBA present a risk across all such products
Hi, I have been contacted by one of our clients regarding this topic and as Andy was mentioning, no details were provided and it is not clear at all why those specific nitrosamines should be tested
Hi Naiffer @Naiffer_Host
Am unable to comprehend the stress on testing of batches, perhaps the request is subsequent to considering issues due to Risks associated with the process of the batches under consideration.
Is at the least, very interesting the request for Azithromycin. The route cause should be disclosed for such a request under my perspective.
It is also interesting why Erythromycin and Clarithromicyn has not been also put into discussion. That would seem to be that if the issue is into the API it is related to the section of the antibiotic in yellow.
However, it seems more plausible for NDMA to be formed from the other tertiary amine present in the structure as it has been already studied for wastewaters and other old studies in tetracyclines.
I have seen that hydroxylamine HCl is used to form the section yellow along with other reagents/reactants. However, even if this material itself is a nitrosamine precursor, other conditions should be present also. As an hydrazine like compound could be formed with hydroxylamine and a secondary amine but further oxidation would be needed to form a nitrosamine.
Also I understand NDBA is also requested. However, it makes no sense after looking into the API. That should be more related to any catalyst used for the hydrogenation with Tetrabutylammonium salt. however, why use it instead of a common Pt/C catalyst.
Finally, if this is a topic, should it be of concern to expect the Nitrosamines coming from the API, the desmethyl ones, etc? In any case such big molecule would be difficult to metabolize with the common pathway and thus less potent.
@Diego_HM Thanks for sharing your perspective… Perhaps to complement the discussion I found this publication from Environmental Science: Water Research & Technology ‘Defining the molecular properties of N -nitrosodimethylamine (NDMA) precursors using computational chemistry’ where Bond et all. used computational chemistry methods to calculate molecular descriptors for 64 NDMA precursors containing a dimethylamine (DMA) moiety.
Interested enough the free access supplementary information contains a list of potential NDMA precursors from Merck index search (n = 233)… Azithromycin is in the list. I do recognize this researcher is looking through the environmental process perspective.
Just a quick follow up. I understand the CMDh expressed its agreement on testing of a representative number of batches and to extend the testing exercise only when nitrosamine presence is confirmed. Further testing has to be conducted when nitrosamines are found >30% AI in selective testing.
No root cause or additional information provided, but it was highlighted this is an exceptional case.
