You do not want to miss OPR&D’s special issue on Nitrosamines. Most of the articles are open-access. Incredible amount of knowledge for you and your team !!
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!
Abstract:
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?
Abstract:
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
Abstract:
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.
