Now CPCA Approach is available in Japan. I add the translation by DeepL translation.
Q15.
Attachment 2 (2) of the Voluntary Inspection Notice states, "If carcinogenicity test data are not available, limit values should be set using a scientifically valid method, such as setting limits based on structure-activity relationships or genotoxicity tests. However, the EMA guidance has recently been updated and The Carcinogenic Potency Categorization Approach (CPCA) for N-nitrosamines (Annex 2) has been presented. Is it acceptable to use the CPCA for setting limits in Japan?
A15.
For nitrosamines for which there is no sufficient carcinogenicity test data, it is acceptable to set limit values using the CPCA presented by the EMA. In the case of setting the limit values using the CPCA in the case of Attachment 2 (2) (ii) of the Voluntary Inspection Notice, consultation with the MHLW regarding the validity of the limit values is not required. In cases where the limit value can be regarded as scientifically valid, setting the limit value based on the conventional structure-activity relationship is not denied.
Can we extrapolate invivo data of Nitroso Quinapril to other ACE inhibitors like Lisinopril, Ramipril, Enalapril etc. if we have negative results of enhanced Ames test using test conditions described in guidance for their respective nitroso impurity (Nitroso Lisinopril, Nitroso Ramipril etc) to prove that these are not a CoC and can be controlled as per ICHQ3B?, as these all impurity have almost similar chemical environment.
Reference to EMA Rev No. 16 for Eu and US Federal register on going harmonization,
how do one approach for method validation to comply current limit as per US (e.g. based on 96 ng/day) and Eu (CPCA approach e.g. 400 ng/day) to take care of linearity considering risk assessment with target concentration based on 96 ng and linearity to comply Eu requirement (based on 400 ng)?
What α-Hydrogen Score shall be assigned for 0,1 count of Hydrogen Atoms on Each
α-Carbon?. EMA/HC guidance does not defined same. For example, what shall be the CPCA score for below impurity?
Hi Naiffer,
This is regarding “Nitroso Desmethyl Edoxaban” considering CAPA what will be the category?
find the structure below.
As per my point of view…
Alpha-carbon is (2,2) which gives the score of 1
Considering 6 membered piperidine ring, can we apply +2? because the ambiguity is related to the double bond in the subsequent 5 membered ring.
So what score shall we consider either 1+2 = 3 or only 1?
Actually the question is when 6 membered piperidine ring is directly fused with thiazole ring, can we consider piperidine ring as non-aromatic or aromatic?
considering the example- 8 of N-Nitroso Locaserin, mentioned in EMA Rev 17 and Health canada guidance. see screenshot below for reference.
Note that in this example a 7 membered ring is considered as non-aromatic and it is directly fused with benzene ring.
Great work, indeed. The CPCA approach will be useful in many situations, but it has also set limits for certain nitrosamines at rather low levels.
What are your thoughts on possibility of setting different limit than those listed in the Appendix 1? Is there any way to ‘overrule’ the limits set in the Appendix 1? Do we have any options for setting different limits for registration purposes? I do understand that there is an option for the SAR or read across, enhanced Ames test and in vivo mutagenicity study. Are they even applicable for nitrosamines listed in the Appendix 1? Does anyone have experience of justifying limits different than already set limits with read across approach or any other approach for registration purposes, (preferably as easier and quicker as possible)?
There are options for justifying the exceeding AI values for authorized drug products (during CAPA implementation) and even the dosing regimen can be taken into account.
The six-membered ring is not strictly a piperidine, because of the aromatic thiazole fused to it (and the six-membered ring is definitely not aromatic itself, fails Huckel’s rule) - piperidine implies all ring bonds are single. However, the CPCA rule gives two points both to piperidines and to all 6-membered rings other than sulphur-containing and morpolines, so still two points
That fused thiazole, though, means that the a-carbon is activated by being in a benzylic-like position (the first-listed activating feature), for -1 point
The nature of the fusions to the ring don’t (as a general rule) affect the aromaticity of the ring itself - the 7-membered ring here cannot be aromatic since it does not obey Huckel’s rule.
Currently, I do not know the basis of the scoring system. However, I have been informed that a detailed explanation of the scoring system may be coming soon from the regulators as a separate notification or in the next revision.
Hi David,
I confirm that the limit of 5 ppm for (2RS)-2-methyl-1-nitroso-2,3-dihydro-1H-indole (impurity A) has been already present in Indapamide monograph since Jan.2008 (or even before).
Therefore, this limit was stated well before the “nitrosamine saga” and probably it was stated taking in account the sensitivity of the Ph.Eur. method (UV-HPLC).
Other cases of “legacy limits” of nitrosamine impurities are:
2-nitroso-octahydrocyclopenta [c] pyrrole (impurity B of Glicazide) NMT 2 ppm
N-nitrosodiethanolamine [impurity C of Trolamine (Triethanolamine)] NMT 24 ppb
The NDELA 24 ppb specification in the EP monograph seems to have at first glance a link with the SED of 24 ng/kg bw/d from the SCCS calculations and opinion on NDELA I think (review of 6 animal studies on NDELA and determination of HT25 factor (for rat to human extrapolation), lifetime cancer risk factor 10^-5). I think the EPC considered body weight 65 kg and correction for 65% absorption of NDELA according to Franz 1993 (not assuming they used 100 kg BW and 100%) and an arbitrary use of max. 100 g per day. For cosmetics 50 ppb is the regulatory specification though.
The EPC recommended recently that the NDELA test remains part of the EP monograph for triethanolamine. In below link a summary of the EP specifications for nitrosamines and future strategy.
For NDELA the limit is updated to 1900 ng/day.
I don’t know if there is any particular medication that prevails in some monograph.
At the time it was curious to see raw material suppliers that were specific for cosmetics (no more 50 ppb or 25 ppb), but they did not specify it in pharmaceutical quality raw materials … Here the regulatory authorities were playing a double game and… anyway …
And it was not an easy assessment to come to the 1900 ng/day apparently, considering that CHMP had to give the request twice to NcWP to set the limit (once in 2021 and once in 2022). As far as I can understand the derivatisation of 1900 ng/day I assume it is also an example where the lower CI approach was used. I never understood if that was the element delaying the assessment or if it was the tension between 24 ppb and 50 ppb.
… Here the regulatory authorities were playing a double game and… anyway … 
