ICH M7 Mutagenic Impurities Guidelines

ICH M7 Human Medicinal Products

ICH Q3A (R2): Impurities in New Drug Substances – Step 5 CPMP/ICH/2737/99

ICH Q3B (R2): Impurities in New Drug Products – Step 5 CPMP/ICH/2738/99

These regulations provide guidance for the qualification and control of most impurities, limited guidance is provided for those impurities that are DNA reactive.

The purpose of ICH M7 guidelines is to provide a practical framework that can be applied for the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk.

This guideline is intended to complement:

• ICH Q3A (R2)
• ICH Q3B (R2)
• ICH M3 (R2): Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals – Step 5 EMA/CPMP/ICH/286/1995

Current Effective Version:

ICH M7 (R2): Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risks – Step 5 EMA/CHMP/ICH/83812/2013 (Last updated: 18/07/2023)

ICH M7 (R2):  Addendum on Application of the Principles of the ICH M7 Guideline to Calculation of Compound-Specific Acceptable Intakes – Step 5 EMA/CHMP/ICH/502766/2021

The ICH M7 document is physically separated in tow documents:

• The main guideline
• An addendum including methods to calculate acceptable intakes and a series of monographs on chemicals that are considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing or are useful to illustrate the principles for deriving compound-specific intakes described in ICH M7.

This guideline emphasizes considerations of both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk.

It outlines recommendations for assessment and control of mutagenic impurities that reside or are reasonably expected to reside in the final drug substance or product, taking into consideration the intended conditions of human use.

Scope of the Guideline:

Provide guidance for new drug substances and new drug products during their clinical development and subsequent applications for marketing.

Applies to post-approval submissions of marketed products, and to new marketing applications for products with a drug substance that is present in a previously approved product, in both cases only where:

§ Changes to the drug substance synthesis result in new impurities or increased acceptance criteria for existing impurities

§ Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for existing degradation products.

§ Changes in indication or dosing regimen are made which significantly affect the acceptable cancer risk level.

The safety risk assessment principles of this guideline can be used if warranted for impurities in excipients that are used for the first time in a drug product and are chemically synthesized.

Veterinary Medicinal Products

• VICH GL10: Impurities in New Veterinary Drug Substances (Revision) EMEA/CVMP/VICH/837/99-Rev.1
• VICH GL11: Impurities in New Veterinary Medicinal Products (Revision) EMEA/CVMP/VICH/838/99-Rev.1

These regulations provide guidance for the qualification and control of most impurities, limited guidance is provided for those impurities that are DNA reactive.

The purpose of the guidelines is to provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk associated with the exposure to potentially mutagenic impurities.

This guideline is intended to complement:

• VICH GL10
• VICH GL11
• VICH GL23 (R): Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: Genotoxicity Testing EMA/CVMP/VICH/526/2000

Current Effective Version:

Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Veterinary Medicinal Products EMA/CVMP/SWP/377245/2016

This guideline considers both safety and quality risk management in establishing levels of mutagenic impurities that are expected to pose negligible carcinogenic risk.

It outlines recommendations for assessment and control of mutagenic impurities that remain or are reasonably expected to remain in the final drug substance or VMP.

The approach of this guideline is based on that of ICH M7 Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk which was used as a template, with amendments introduced in order to cover the issues specific to VMPs.

Scope of the Guideline:

Provide guidance for new veterinary drug substances and new VMPs, including cases where drug substances can be used in both human and veterinary drug products.

Applies to post-approval submissions of authorized products, or applications for new marketing authorizations for VMPs that include drug substances that have previously been present in authorized VMPs, only in cases where:

§ Changes to the synthesis of the drug substance result in new impurities or increased acceptance criteria for specific impurities.

§ Changes in the formulation, composition or manufacturing process result in new degradation products or increased acceptance criteria for specific degradation products.

§ Changes in indication, dosing regimen or target species are made which significantly affect the acceptable exposure level.