Hi @Naiffer_Host
Itās amazing that this is released - and so quickly after Europe - shows that there is real collaboration going on in the background between regulatory authorities.
The multiple NDSRIs is not missing, but it is weak. It doesnāt look like the alternative approach from the EMA etc has been taken into consideration, where it is possible to justify immediately higher levels if you have category 5 and category 1 NSDRIs present in a formulation. Which in itself seems a little odd as for certain drug substances where there are multiple potential nitrosamines the FDA themselves have set different limits for some of the different nitrosamines, so if both we present you could be complying with one allowed limit, but failing overall.
FDA guidance quotes "'Additionally, the predicted
carcinogenic potency categorization approach does not apply to NDSRIs where the N-nitroso group is within an aromatic ring (e.g., nitrosated indoles).
Does this imply that NDSRIs are not required to be monitored or a divergent approach other than CPCA is recommended for these class of molecules? .
Any thought process on this.
However, the available toxicity data for compounds of this nature does not exhibit the same consistent negative trend as that observed with tert-butyl groups. A matter of particular concern upon initial analysis is the discovery that N-nitrosodiphenylamine (NDPhA) demonstrates carcinogenicity in rodents and genotoxicity in the Salmonella Ames assay, even though it lacks an Ī±-carbon oxidation site.
These findings imply that an alternate mechanism, such as trans-nitrosation of DNA base(s) as observed with NDPhA, is likely responsible for DNA reactivity in this case.
3-substituted-N-nitrosoindoles are mutagenic in the Salmonella Ames test in the absence of CYP activation
NDPhA, while an important argument for the potential non-CoC positive results of the Ar-NN=O substructure due to transnitrosation (or indeed denitrosative formation of a hydroxylamine, following the aromatic amine pathway subsequently, as we describe here Tennant et al, Ponting and Foster - we only found this after writing the referenced Ponting et al), isnāt quite the right argument for the nitrosoindoles.
Should note that it is for the nitrosoindolines, where the N-containing ring is not aromatic, and these can be classified as CPCA and will be class 4 or 5 depending on whether the 3-position is substituted (class 4 because (0,2) and in a 5-ring is 5 points, youād need to add both activating features to get to less than 4)
Returning to nitrosoindoles: As you note, they are positive without S9; this is because the pyrrole-type nitrogen behaves a lot like an aromatic carbon (with a bit more electronegative character). The relevant analogues for nitrosated pyrroles and indoles are therefore C-nitroso aromatic rings (such, ironically, as that formed by the transnitrosation of NDPhA, though not of course NDPhA itself where the amine is not in an aromatic ring), which reduce to the hydroxylamine via innate bacterial metabolism and follow the aromatic amine pathway from there. They should as far as I am concerned be treated as normal, non-CoC, potentially mutagenic impurities, though do flag them as an N-nitroso compound you have thought about rather than hiding anythingā¦
Ultimately I think the HAs havenāt been particularly clear with their nomenclature here; I would say pyrroles and indoles are not amines and thus donāt form nitrosamines per se, rather āN-nitroso aromatic systemsā
In this case I would second the idea that this nitroso-compounds should be evaluated in a different assessment that the one from nitrosamines. Nevertheless, evaluated as this compounds goes inside the ICH M7 that is an harmonized guideline and go inside the characterization of impurities evaluation in you API or FP dossier.
I have doubt, whether presence of a secondary amine in an API is enough in your Nitrosamine risk assessment to perform confirmatory testing with the calculated AI limit ?
There are cases, for an API manufacturer, that the API or its impurities are having secondary amine group but there is no source of nitrite used anywhere in the manufacturing process. In such cases, are we still supposed to do confirmatory testing by developing & validating an appropriate analytical method ? Or mere paper risk assessment can suffice.
Also, can water be considered as a source of nitrite even if it is meeting the WHO standards of water with limit 0.9mg/L of Nitrite nitrogen ? If yes, then request you to throw some light on the calculation part.
(One cae: If water is used before API formation.
another case: If water is used during and after API molecule formation)
When it comes to API risk assessment, one needs to consider not just the main reaction steps but also the chemistry involved in the reagents, solvents, and impurities for both Amines and Nitrosating agents sources. Before jumping to conduct confirmatory testing purge calculations can be performed to measure the true risk of nitrosamines forming.
In the post below, Schlingemann et al (@schlinjo1975) clearly utilize these tools and validate their results for the API risk assessment evaluation
Good discussions to help you navigate and answer your question related to water.
Could anyone share some literatures regarding to
" ā¦such as fluid bed drying at an elevated temperature and jet milling because these can create favorable conditions in which nitrogen oxides can react with at-risk APIs."
Many thanks!
You can find a description in the following paper, Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies.
Identifying the source (and exact speciation) of nitrosating agent in excipients is of critical importance as it would enable the rational implementation of corrective measures. For example, if nitrogen oxides formed during hot-air drying unit operations are indeed involved, their concentration could theoretically be reduced by the use of lower temperatures and/or nitrogen-enriched gas stream instead of air.
And Dr. Grahekās presentation provides useful insights into the phenomenon.
The risk posed by NOx gas in the air should be reviewed carefully, especially for API containing secondary/ tertiary amines.
The authors explore the idea that there could be a possible manner in which nitrosamines could come into existence - by means of different phases within the manufacturing procedure.
One of these stages involves wet granulation, which could enhance the interaction between the API and substances capable of generating nitrosamines.
Moreover, certain manufacturing techniques like fluid-bed drying, which rely on the utilization of significant volumes of air, might also contribute.
The reason behind this is that these processes have the potential to expose the combination of the drug product to compounds of nitrogen oxide (NOx), which could potentially undergo a conversion into nitrous acid.
probably - thatās the āproblem referenceā that raised the concern over the Ames test (though I cannot state strongly enough the tests they did werenāt at modern standards), so if I refer to Rao et al without further details thatās the one
I appreciate your detailed analysis of the differences in FDAās guidance document compared to those of HC and EMA. Your insights highlight significant points of clarity and divergence.
I acknowledge the outlined timeline for incorporating NDSRIs into risk assessments and confirmatory testing. Itās crucial that manufacturers reevaluate within 3 months and complete by November 1, 2023. Submission of changes should be done by August 1, 2025, meeting AI limits.
The Complete Response Letter(CRL) requested additional information on nitrosamine impurities to be tested for based on new draft guidance issued after the neffy(epinephrine nasal spray) NDA submission, according to the article.
