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.