Estimation of TD50 (50% Tumor Dose) and Acceptable Intake (AI) values of nitrosamines as impurities in medicinal products based on read-across methodology.
According to the ICH M7(R1) guideline, a preliminary analysis of actual and potential impurities should be done by searching the database and literature on carcinogenicity and mutagenicity on bacteria.
The QSAR Lab offer includes read-across and determination of TD50 and AI values for the substance defined by a client (compound name/compound CAS number).
The analyses are based on the expert knowledge and the results of in silico research according to:
- ICH guideline Q3A (R2) Impurities in New Drug Substances CPMP/ICH 2737/99 was last updated by EMA in October 2006,
- M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, which was first issued in 2014 with the most recent revision adopted by CHMP in February 2018,
- 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,
- Read-across Assessment Framework.
Read-across approach includes the SAR (Structure-Activity Relationship) analysis of the impurity/ies defined by the client (target compound/s) and the analogs (source compounds) selected as sufficiently structurally similar compounds (showing the same structure alerts that define the carcinogenicity of the target compound).
The results of the analyses are compiled in the report.
The report includes:
- detailed documentation on the methodology of searching for analogues for a defined compound,
- SAR similarity analysis for selected analogues and a defined compound,
- the estimated TD50 value for the defined compound based on the selected analog(s).
- assessment of source publications on carcinogenicity of analogues used to determine the TD50 value in terms of the quality of each of the study performed and its results (e.g. compliance with OECD guidelines, GLP system, etc.)