😞 Aripiprazole is not approvable since 'major objections' have been identified

I recently came across a public withdrawal assessment report for Aripiprazole, and I wanted to share the language related to the Nitrosamine assessment and objections identified by the regulatory body. I intend to bring awareness of the criticality of Nitrosamine for any new submission.

The characterisation of the active substance and its impurities are generally in accordance with the EU guideline on chemistry of new active substances. Potential and actual impurities were well discussed with regards to their origin and characterised. However, nitrosamines risk assessment is still not fully acceptable and requires further clarification from the ASMF holder

A risk evaluation concerning the presence of nitrosamine impurities in the finished product has been performed, however as it has been presented only in form of simple description, further data, along with proper declaration of risk / no risk identified has been requested. in line with the “Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products” (EMA/409815/2020) and the “European Medicines Regulatory Network approach for the implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) Nº 726/2004 for nitrosamine impurities in human medicines (EMA/425645/2020). As currently nitrosamine data is not considered adequate, Major Objection has been raised. While the applicant has provided response to MO, it is not considered sufficient and further data is expected – according to the conclusion presented by the applicant a risk of presence of nitrosamines is very low, what is not equal to “no risk”. Therefore it should be either declared as “no risk has been identified” or that the risk has been identified and proceed with step 2 confirmatory testing of the drug product.


I added the structure of Aripiprazole. It has two tertiary amines. Appropriate risk assessment is required.


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I think is a bit awkward to be absolute in an statement (just my opinion). I have seen quite a bit the “very low risk” term. I think you can use it if you back up it with evidence that I think is more the point from the regulator.


Numerous nitrosamines can be formed based on intermediates and while nobody wants to accept the tertiary amine nitrosation, it happens. So, I am wondering if the sponsor did a good risk evaluation.



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The fact that the regulators have a problem with the correct use of the English is indeed a problem. No risk is an absolute term which is actually impossible-as Benjamin Franklin wrote “in this world nothing can be said to be certain, except death and taxes”

So there is always risk - we now know that NOx in the air can create nitrosamines so stop breathing. If you don’t like low risk then go for acceptable or tolerable risk whatever you like but forcing a scientist to state no risk is simply an abuse of power.


So now we are playing semantics----I would follow the suggestion write no risk has been identified - but of course that implies that you have looked properly-after all up to 2018 there was no identified risk of nitrosamines in pharmaceuticals in spite of the fact that the food, drink, cosmetics and tobacco industry had “identified” risk some 20 to 30 years ago.

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