A pleasure to have been a part of the process - congratulations to @AndyTeasdale on bringing together so many disparate groups of authors to create a brilliant special issue!
Thanks a lot, Naiffer, great to have all of these in one place.
A little light bed-time reading!!
But fantastic work by all involved.
What implications does the following have for other nitrosamines?? Are they stable within the body?
I really appreciate all the information, is very valuable! Now I’m going to do a time block to read all this amazing data.
Thanks @Naiffer_Host for providing the topic published in OPR&D’s special issue on Nitrosamines.
Reverence to entire team for a great work, who is behind all the work…
Nitrosamines has set up an example, when everybody decides and work as a team, any problem can be handled in a well and smooth way with deep science!
it was a pleasure to work with so many great contributors on this. key with N-Nitrosamines remains our scientific understanding and its advancement
Nitrosamine Risk Assessments in Oligonucleotides
The European Medicines Agency, the U.S. Food and Drug Administration, and other regulatory agencies expect that all pharmaceutical products be assessed for the potential presence of N -nitrosoamine (nitrosamine) impurities. This white paper addresses general considerations for nitrosamine risk assessments of oligonucleotide products. The authors propose a general risk assessment platform which should facilitate safe, consistent development of new treatments and alignment with regulatory expectations.
Drawing a Line: Where Might the Cohort of Concern End?
The definitions of the chemical classes in the Cohort of Concern (CoC) by Kroes and co-workers are based on broad structural alerts, in particular for N -nitroso compounds─for which the alert consists essentially of the N–N═O substructure without further refinement. Recent pharmaceutical recalls have focused on the presence of dialkyl N -nitrosamine impurities, some of which are exceptionally potent carcinogens─2 orders of magnitude more potent than the pharmaceutical Threshold of Toxicological Concern (TTC), 1.5 μg/day. However, the class of “N -nitroso compounds” is potentially significantly broader. This Perspective looks at the N -nitroso compounds that are at the edges of the cohort, where changes in mechanism, metabolic activation potential, stability, or indeed toxicity data lead to questions about whether these compounds should be classed as CoC. The critical mechanism of action, metabolic α-hydroxylation leading to a diazonium ion, is presented, along with the pathways by which N -nitroso compounds that are not dialkyl N -nitrosamines can lead to comparable DNA adducts.
A Consideration of the Extent That Tertiary Amines Can Form N-Nitroso Dialkylamines in Pharmaceutical Products
Most secondary amines have the potential to undergo nitrosation in the presence of nitrite under certain conditions, particularly at low pH, to generate N-nitrosamines. Tertiary amines are generally considered to be less prone to nitrosamine formation as they require an additional dealkylation step. A review of the published literature combined with recently generated experimental data from nitrosation experiments carried out on several trialkyl amines further informs on the extent that tertiary amines can form N-nitrosamines by reaction with trace levels of nitrite, which may be present during drug substance or drug product manufacture. Simple trialkylamines, amines containing no additional heteroatoms, have been demonstrated to react via a nitrosative dealkylation mechanism that slowly generates a dialkylamine, which in turn nitrosates. This sequence of reactions to generate a N-nitrosamine is approximately 1000-fold slower than the simple nitrosation of a secondary amine of comparable pK a. Therefore, the formation of N-nitrosamines from simple trialkylamines in pharmaceutical products is typically not considered to be a risk. Dialkylanilines are able to access alternative reaction mechanisms and may undergo dealkylative nitrosation with greater ease than simple trialkylamines and therefore require a more focused risk assessment. Finally, certain structurally complex tertiary amines may contain functional groups that can facilitate the formation of N-nitrosamines through resonance and/or inductive electronic effects. Therefore, structures containing highly functionalized tertiary amines require a thorough, compound-specific assessment to determine the level of risk of nitrosamine generation. Note that in situations where higher amounts of nitrosating agents are present, such as when nitrosation chemistry is used during the drug substance manufacturing process, simple trialkylamines should be considered for N-nitrosamine generation during the risk assessment.
the paper highlights that as NO-HCTZ degrades at physiological pH it does not form the diazonium ion of concern.