Revision 16 of document of the EMA guideline for nitrosamines (EMA/409815/202 Rev.16)
In June 2018, authorities worldwide became aware of the presence of nitrosamines in several sartan drugs. Since then, significant concern has arisen due to the well-known carcinogenic potency of these impurities. Consequently, authorities have been continuously revising their guidelines based on the most up-to-date information.
On July 7th, the EMA published the latest revision of the document “Questions and answers for marketing authorization 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”. This revision includes new guidelines for establishing an acceptable intake (AI) for nitrosamines without robust carcinogenicity data, which incorporates the Carcinogenic Potency Categorization Approach (CPCA). The CPCA enables the determination of an AI based on the structure of the nitrosamine, eliminating the need for comparison with structural analogues. The approach assumes that the α-hydroxylation mechanism of metabolic activation is responsible for the observed mutagenic and carcinogenic response in many N-nitrosamines. CPCA proves particularly useful for nitrosamines lacking hydrogen in the alpha position, which prevents them from following this activation mechanism.
The revision also establishes that nitrosamines with a negative result in the GLP-compliant enhanced Ames test (EAT) may have a limit of 1.5 μg/day.
These modifications significantly impact the calculation of permitted limits for new nitrosamines. Previous versions of the guidelines only allowed deriving the AI through an approach based on structure-activity relationship (SAR) considerations, without taking negative results in the Ames test into account when setting the limit.
Additionally, the list of nitrosamines for which AIs have been established by the Non-clinical Working Party (NcWP) has expanded, including new AIs for N-nitrosamines determined using the CPCA.