We have had several ongoing discussions within the community regarding N-nitroso-Quinapril, and the Prils (ACE Inhibitors) class.
I recently participated in USP’s Nitrosamine Workshop (India) and received several inquiries about Ramipril, Benzapril, and Quinapril… Is anybody receiving questions from regulatory agencies about these products? Any agreement on the limits?
Class features:
benazepril (Lotensin, Lotensin Hct), - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
captopril (Capoten) – No secondary amine, hence not possible.
enalapril (Vasotec), - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
fosinopril (Monopril) – No Secondary amine, hence no possibility.
lisinopril (Prinivil, Zestril) - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
moexipril (Univasc) - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
perindopril (Aceon) - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative
quinapril (Accupril), - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
ramipril (Altace), - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
trandolapril (Mavik) - Secondary amine is present. Hence there is a possibility of formation of Nitrosamine derivative.
The question is about that ADI level. Quinapril is a bulky molecule. Really not expected to be very carcinogenic. Also it has good possible surrogates. So, the question is how much was the ADI determined to be.
@conudel proposed an interim Acceptable Intake of 1.5 μg/day for the nitroso-ACE Inhibitors in the EFPIA position paper. @conudel, could you kindly help us? Have more in vivo mutagenicity studies become available now?
As far as I know, FDA has not commented on the acceptability of the 1.5 mcg/day for “prils” or “lols”/“olols” though it possibly is a practical approach. In my experience, we have got pushbacks. We may have to wait for the two upcoming meetings to see what we hear about these.
Today i see the new acceptables intakes for N-nitrosamines established by EMA:
Considering the similarity among Enalapril, Ramipril, Benazepril and Quinapril, it is quite strange that only N-nitroso Quinapril was classified as “Not mutagenic impurity”. In my opinion, all the -pril nitroso derivative should be not mutagenic, but I suppose that at the moment EMA received an in vivo mutagenicity study only for N-nitroso Quinapril.
Therefore EMA cautiously keep at 1500 ng/day all the others (at least until new mutagenicity data in vivo will be available).
Exactly that, unless an sponsor submitted a in-vivo assay (TGR as of now) with negative outcome, 1500 ng/day is the limit for the “pril”. That I think > above the 10% of that limit is still a reality. Nonetheless, a huge step forward.
Cant say for sure if this will mean an in-vivo assay per compound will be needed, but I understand that is the approach to use ICH Q3A/Q3B limits if the assay is negative. Same approach is indicated in the guideline for azithromycin related nitrosamines.