For the nitrosamines N-nitroso-amlodipine and N-nitroso-felodipine, official limits are published by the FDA. FDA Guidance
In the past, we contacted several suppliers who offered the N-nitroso-amlodipine on their web pages: However, N-nitroso-amlodipine could not be synthesized in the end.
This outcome is confirming the EFPIA position paper. Position Paper (efpia)
Does anyone from the community know if the FDA or EMA have been contacted to remove these compounds from the official list?
What I would suggest here and is indicated in EMA guideline in some way. If the risk assessment says risk currently a risk is present, generate a new version highlighting there is no risk and attaching evidence of the imposibility to synthetize the molecule. I would say the EFPIA paper plus any experimental evidence from any CRO and then go to EMA if the product is a Centrally Authorized One or locally.
For FDA in their list there is a part where they mention the list do not means someone detected something but theoretically it seems posssible. When experimental data is there indicating theory was not confirmed the sponsor could mention that to the HA.
In most cases is the sponsor that should go to the HA when an hypothetical case or hypothesis is either confirmed or denied.
In the case of NDSRIs, evidence can also be generated experimentally… by a simple NAP test or in a more standardized approach, as Ashworth et all. proposed in their recent publication “Approaches and Considerations for the Investigation and Synthesis of N-Nitrosamine Drug Substance-Related Impurities (NDSRIs)”
What is outlined here is an important missing piece in the risk assessment process. After you say there is a risk, you want to show that the nitrosamine can be formed and is stable. If you can show that it cannot stably form, the risk is nullified.
No-one will be able to, that’s the point of this discussion! It does not form, aromatising instead - and if a manufacturer claims to supply it I wouldn’t believe them.
We experience something similar with some agencies and clients demanding information and testing of nitrosamines from API of the -dipine family.
We demonstrated that N-Nitrosamines for APIs belonging to Hantzsch ester family of compounds could not be obtained. Even if formed these N-nitrosamines will deliver rapid aromatization and will end up generating the corresponding piridine products.
There is literature evidence for such observations ( Mechanisms of the Oxidations of NAD(P)H Model Hantzsch 1,4-Dihydropyridines by Nitric Oxide and Its Donor N-Methyl-N-nitrosotoluene-p-sulfonamide, X.-Q. Zhu, B.-J. Zhao, J.-P. Cheng, J. Org. Chem. 2000, 65, 8158-8163. doi: 10.1021/jo000484h.)
Additionally, we bought some of these N-nitrosamine standards to third-party companies, but we end up demonstrating by HPLC-MS and NMR that these standards were actually the piridine products.
