Apotex Inc. is recalling four additional lots of Apo-Acyclovir (acyclovir) tablets, in 200 mg and 800 mg strengths, due to the presence of a nitrosamine impurity ( N -nitrosodimethylamine [NDMA]) above or close to the acceptable level.
The original process for Acyclovir production used Dimethylformaide as solvent in the first step of the process. This was described apparently in the original article in JACS (https://doi.org/10.1021/jm00286a024, notice this is from Wikipedia page for Acyclovir). If the process is still the same, and DMF was sourced as a recycled DMF, there is a possibility the root cause for the contamination is not related to the product itself, but from a contamination from external sources (solvents). Or from a NDMA carry over from the equipment (just an hypothesis, obviously).
Hi, which amine are more prone to form the nitrosamine, either tertiary or secondary amine?
Could you please clarify one thing, before launching new product into market, industry will always do the Nitrosamine risk assessment by QSAR modelling (to confirm is there any predictable mutagenic impurities or positive mutagenicity) and by manufacturing process (to confirm is there any step or process to form the mutagenic impurities) and by other possible ways (contamination, excipient qualification)
Finally, Industry will ensure that there will not be any nitrosamine impurities or below AI limit.
Then, why product is getting recalled due to structure and by manufacturing process, exceptional case will be if it is forming during stability.
It is well known that secondary amines are several times fold more prone to nitrosation that tertiary amines.
Regarding the aciclovir topic, this kind of products I think are OTC in Canada. Thus it should be a very old marketing authorization as aciclovir is an old molecule. What you are mentioning is to launch of new products. This specific one seems to be from late 90s and revised in 2014. By that time of release there was no clear information or any regulatory enforcement about N-N=0s.
In particular I have seen in the synthesis of the API that triethylamine is used as a solvent that can contain traces of diethylamine (up to 500 ppm as per manuf. spec.). Also, I have seen nitrous acid used in the process in some route of synthesis. So this could be one of the root causes for NDEA formation instead of NDMA. I am not sure if triethylamine can contain traces of dimethylamine. So the DMF theory makes sense unless more details are known.
Hi, @villain17. Thank you for sharing your thoughts. I’m concerned the company couldn’t avoid the second recall three months after the first recall. As they moved to confirmatory testing from the risk assessment, the contamination from external sources could be identified.
Of course, it’s just a hypothesis. As @Diego_HM pointed out, nitrous acid may be concerned with NDMA formation. And we should carefully collect further information.