Mutagenic impurities assessment following ICH M7 guideline comprises impurities identification and classification, followed by a control strategy when DNA reactivity is confirmed for the impurity.
According to this guideline, the first step in impurities assessment consist on the identification of both actual and potential impurities which could arise in the drug substance or product synthesis and storage.
A second step requires a bibliographic search for carcinogenicity and mutagenicity data of the impurities under assay. Preclinical mutagenicity and carcinogenicity studies shall be performed when no scientific information is available. In the absence of accurate data, a QSAR analysis may be performed, using two complementary methodologies, named the “expert rule-based” QSAR and the “statistical based” QSAR, which should comply with the OECD principles. Results obtained from this second step enable to classify the impurity in classes 1 to 5, being the mutagenic and carcinogen compounds included in class 1 and the non-mutagenic structures in class 5, as it can be seen in the figure.
Class 1 and 2 include mutagenic and carcinogenic or just mutagenic compounds respectively. Compounds which do not exhibit mutagenicity or carcinogenicity potential are categorized in class 5. When there is no mutagenicity data available and QSAR alerts appear, the submitted compound is classified in group 4 when alerts are shared with the drug substance or in Class 3, when alerts are not shared.
Following the hazard assessment and classification, a risk analysis must be performed in order to define security boundaries for compounds in classes 1 and 2. Thresholds for compounds in groups 4 and 5 are included in ICH Q3A/B guidelines. For class 1 and 2, limits shall be established with a case by case analysis with acceptable intakes (AIs) or permissible daily exposures (PDEs) derived from preclinical studies. A general TTC value of 1.5µg/person/day can be also considered for most pharmaceuticals as a default value to derive an acceptable intake. Acceptable intakes derived from compound-specific risk assessments can be adjusted for short-term exposures by means of a “less than lifetime” approach (LTL). In this regard, it is noteworthy that the ICH M7 has been recently updated to include an addendum where AIs and PDEs have been derived for a set of carcinogens which commonly appears in pharmaceuticals.
Finally, for impurities characterized as Classes 1 or 2, it is important to develop a control strategy which ensures that the level of this impurity in the drug substance and drug product is below the acceptable limit. ICH M7 guideline proposes up to four control strategies which varies from an impurity specification with an acceptance criterion below the acceptable limit (Option 1) to a non-testing strategy, based on the impurity removal throughout the process and supported by purge factors estimations.
At Azierta we have a team of expert toxicologist certified by EUROTOX with a broad experience in accomplishing robust and accurate mutagenic impurities assessments, always in compliance with Health Authorities requirements.
If you want to learn more details, visit https://azierta.eu/toxicological-experts/mutagenical-impurities/?lang=en and contact us.