An Addendum to ICH M7 provides practical Examples to calculate compound-specific Acceptable Intakes

Recommendation

23-25 April 2024
Barcelona, Spain

Global Registration and Life Cycle Management for APIs

The ICH M7 Guideline has reached Step 4 of the ICH process in June last year. It outlines recommendations for the assessment and control of mutagenic impurities that are present or expected to be present in drug substances or drug products, taking into consideration the intended conditions of human use.

In Section 7.2.1 of the Guideline it is stated that "Compound-specific risk assessments to derive acceptable intakes should be applied instead of the TTC-based (Threshold of Toxicological Concern-based) acceptable intakes where sufficient carcinogenicity data exist." These compound-specific acceptable intakes (AIs) can be calculated for known mutagenic carcinogens by linear extrapolation based on their carcinogenic potency.

In the recently published Addendum to ICH M7 entitled "Application of the principles of the ICH M7 Guideline to calculation of compound-specific acceptable intakes" the statement of the M7 Guideline is picked up. AIs and PDEs (PDE = permitted daily exposure) of 15 compounds are calculated. These compounds were selected because they are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7. Every calculation is supported by a rationale for selection of study for the AI or PDE calculation followed by a comprehensive list of publications about the toxicological studies of the respective compound.

The Addendum to M7 was published on 10 July 2015. It has reached Step 2 of the ICH process and is currently open for comment. An audio and slide presentation from 2 FDA representatives (Aisar Atrakchi and Stephen Miller; ICH topic lead and deputy topic lead for ICH M7) is also available on the ICH website.