A community member brought to my attention that there is a reference material supplier that is currently offering Synthesis Attempts and Failure Reportsā¦ I know organizations have used these types of reports to justify the derisking of particular nitrosamines. I imagine the depth of this report has to be significant for a regulatory body to accept, including all the characterization and analytical evidence.
I have not seen any of these āfor-purchaseā reports, so I cannot speak on their rigurosity. I wonder if anybody has had experience with these types of off-the-shelf reports.
Dear Naiffer,
is just some days ago that we have asked for this type of a failure report from an impurity supplier.
The draft sample which have been send to us was very nice with a lot of information regarding synthetic trials and identification data.
In this sample it was noticeable that they have also implemented the 3-armed nitrosation based on the paper of I. W. Ashworth et al (Approaches and Considerations for the Investigation and Synthesis of
NāNitrosamine Drug Substance-Related Impurities (NDSRIs). Org. Process Res. Dev. 2023, 27, 1784ā1791.
Here is a part of the content from the sample report (only two out of 10 synthetic trials is presented here)
I didnāt want to be seen advertising any particular company on LinkedIn - it shouldnāt have taken a lot for people to have been able to find who was offering this service for themselves.
I donāt know if this is from the company I had seen, but it looks a promising, positive start.
We are also working on a similar topic. For some nitrosamine impurities, we believe they are unlikely to form under practical conditions. Typically, we apply classic nitrosation reaction conditions and monitor the reaction using LC-MS to check whether the target molecular weight appears. Based on these results, we assess the likelihood of nitrosamine formation.
Our goal is to compile a public report listing APIs for which nitrosamines could not be generated, along with our experimental data. We hope this can help reduce redundant research efforts in the community. Weāve shared some of these reports with our clients, and the feedback so far has been quite positive.
However, weāre unsure whether such a report would be considered sufficiently comprehensive. If there is any suggestions on how we could improve it or make it more broadly useful?
No doubt, it would be very useful, especially if you can share your results in a peer reviewed publication. Even if the authorities would not just accept citing your work, it would ease further experimental efforts and additional data can be built on it.
As many have noted, having this information readily available is extremely valuable. Publishing it in a peer-reviewed publication will provide strong evidence for regulatory discussions on the potential of nitrosamine formation.
I will be interested in collaborating on such efforts to make this information available. I am tagging my colleague @Guohao, who might be able to help us out.
Dear liyang,
the idea of this report is very nice and indeed would be very useful.
As an organic chemist i would like to highlight that monitoring the reaction only with an LC-MS and decided that a nitrosamine is formed or not, could be questionable.
In case you do not identify this, it could be due to the LC method which is applied and in case you identify this, in order to prove its possibility to be formed it should be isolated and identified with NMR technics as well. I just remind here the case of fake āāN-nitrosoticagrelorāā for which using a simple LC-MS spectra the result for its validity would be āāpositiveāā but at the end of the day a derivative of this molecule was formed during the nitrosation which was not a nitrosamine at all and has the same mass with N-nitrosoticagrelor!!
Overall, the idea of a database of nitrosamines which could not be formed is in a right way, but is necessary to point out that this does not mean that the all the others which will not be in the list could be formed.
with appreciates,
Christos
There are some vendors in market who provide a detailed Report for failure to synthesize particular Nitrosamine Impurity. Many organizations use them for filling purpose. It does not involve much rigourous attepmts to synthesise. Definitely an organisation can work more rigorously on a particular NDSRI of their drug substance and prepare a more detailed report alongwith its analytical data. Second thing a vendor can share the similar report with many organisations. Inturn if it is used by the organisations for regulatory filling, then the regulatory Agenacy may receive similar reports from different organisations.
I have my doubts that a commercially available off-the-shelf report will carry much weight in a regulatory discussion. For the contrary if the information has been betted in a peer-review publication as a scientific finding and robust report, the evidence will be more impactful.
To be honest itās the equivalent of the copy & paste the risk assessments (I have seen it done by many consultants).
I agree with your point - results published in peer-reviewed journals are indeed more persuasive. May discuss the feasibility of this approach with our management and compliance departments.
Thank you for pointing this out. We do share concerns about confirming the reliability of the data, particularly given that many āFakeā nitrosamines are frequently reported in the market. This requires us to undertake substantial analytical work to determine whether the corresponding nitrosamines are indeed present or absent.
Yes, our company is indeed one of the vendors in the market, and we have encountered many such cases. We have conducted some work in this area, but it has often been limited to specific cases or individual clients. It is likely that a lot of similar work is being repeated independently in different labs, which we see as a form of inefficiency. We hope that negative findings can be shared or made publicly available.
Yes, a peer-reviewed publication would certainly be more helpful in addressing such issues. We have previously investigated potential nitrosamine impurities related to several dihydropyridine-based drugs and finerenone, and confirmed that these nitrosamines are not likely to form under realistic conditions. Some of our findings have been shared intermittently on Chinese social media platforms, but they are often challenged by unverified reports of so-called āFake Nitrosaminesā circulating in the market. As you rightly pointed out, a rigorous academic publication may be a more appropriate and impactful approach. I will need to coordinate internal resources and obtain the necessary approvals from our company, and we hope we will be able to bring such a paper to publication.
VEEPRHO is proactively publishing a list of nitrosamines available through Nitrosamine (NDSRI) Formation and Failure Report Services. Currently, 15 nitrosamines are included in the list. It is also useful to consider why the nitrosamine does not form.
Great addition Yosuke!!
recently we have been provided some justification reports from them, they are very detailed and with a lot of experimental data.
thanks a lot
Christos
This is really cool! Would be great to get this from other suppliers as well and summarize in a public database. I guess these are all compounds they tried to synthesize on their own account. There are probably many more failed syntheses from customer requests, but their publication would require prior approval.
