We Japanese pharmaceutical companies had a discussion to share knowledge related to the risk assessment of nitrosamines at the beginning of March, and we found generic pharmaceutical companies suffered from the lack of NDSRIs standards. The synthesis of NDSRIs brings lots of helpful information for risk assessment, but most generic providers in Japan are not likely to own a chemical synthesis department. Some companies could get the NDSRI samples from vendors, but others not, even though they tried hard to look for vendors accepting the synthesis of NDSRIs. What should we do to get the NDSRI samples unless in-house chemical synthesis groups are available? Are there any contract labs to synthesize NDSRIs? I think this is not a rare case. I would appreciate it if you could give me your opinions or share your experiences, @Naiffer_Host, @ASrinivasan, @DAB, @conudel, @Diego_HM, @AndyTeasdale, and others.
@Yosukemino depending on the type of NDSRIs in need, I can connect our USP Nitrosamines in charge of development of Analytical Impurities.
Do we have a list of candidates? @Mrunal@Zeenat@levelchange
What I could tell is that NDSRI are commercially available or by demand, but needs to be sourced from abroad in my case.
What is important is that the standard has all the neccesary documentation to give reliable results (characterized with several techniques, etc.).
Additionally, I didnt know about the possiblity to look into USP support for getting nitrosamines standards, so would be interesting to get in touch with Naiffer and his/her colleagues.
Thank you for sharing helpful information, @Naiffer_Host and @Diego_HM. I am interested in the USP project related to NDSRI standards. I am going to suggest generic pharmaceutical companies look for NDSRI providers abroad. And I will keep in mind to carefully review necessary documents such as the elucidation of the structure, certificates, and handling manuals. A testing method is also available in some cases. It’s helpful.
If you are thinking about contract synthesis of NDSRIs, I would look for laboratories specializing in working with highly toxic substances, adapted to work with the OEB-6 class of carcinogens. Of course, it will be expensive, but outsourcing such syntheses to small companies unaware of the threat is heartless.
Hi, thanks for your interest in USP pharmaceutical analytical impurities. You and your colleagues can stay informed at Pharmaceutical Analytical Impurities.
Resurrecting this thread. It is still very difficult to find standards. Industry needs standards for all FDA listed nitrosamines.
We have found that not only are few available, but the purity can also be quite poor. While we had good luck with the first product we had to test, as we have moved forward, that has changed significantly. Sometimes, standards are not available anywhere. New standards may not have been properly characterized and are actually of a different molecule. Others have degraded.
Personally, I do not think that the 2025 deadline for compliance with FDA limits is attainable due to this problem, irrespective of others.
What I could also say, is that for toxicological tests, the NDSRI standards needs to be of very high purity, very well characterized and where no Class 1 solvents where used for synthetize them as well the CRO to have at least an ISO certification (17025 or similar). Because without that you could go to any Tox. CRO and they will not feel confortable to indicate that the study is under GLP/GMP if the main material to be evaluated do not have this considerations. If the study is not GLP then for regulatory purposes it may be pushed back.
That heavilly, reduces the quantity of available suppliers fulfilling this conditions.
The FDA listed nitrosamine list is theoretically built (not based on testing reporting like in EU) and can be expected to contain nitrosamines that are not synthesisible.
These considerations are also taken into account when APIs under development are synthesised and undergo in vitro toxicological testing (same for their impurities), so there is a market with companies specialising in these things.
When I asked a GE manufacturer, he explained most of the NDSRI standards were expensive, more than 1,000 dollars per 100mg. He said it took more than two months to receive the standards because they were made to order. It sounded unrealistic for GE manufacturers to buy all necessary NDSRIs.
I agree , if the nitrosamine standard is available the cost is less but if it is needed to synthetize from zero the cost is much higher. When you have dozens or more of melecules the cost is significant.
And that is for analytical testing. For in-vitro you will need a few grams and in-vivo… hundreds of grams.
Right. Without getting into specifics, we just reordered a standard from a very well known standard supplier. We have purchased this same product multiple times for over 2 years. We found that they are still on their first lot & it has degraded.
Lack of stability study initiation for the ones in the standard online catalogs is indeed a problem, next to the fact that most only report relative purity data on CoAs and no assay data based on qNMR.
Many NDSRIs are found to be stable (e.g. 3 year real stability data on very pure NDSRIs).
