M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

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M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk

The ICH M7(R2) Guideline reached Step 4 of the ICH process on 3 April 2023.

The M7(R2) Guideline is intended to provide guidance for new drug substances and products during their clinical development and subsequent applications for marketing. It also 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 ICH M7(R2) Addendum describes AIs (Acceptable Intakes) or Permissible Daily Exposures (PDEs) which have been derived for a set of 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(R2).

The ICH Harmonised Guideline was finalised under Step 4 in July 1997. This document covers the preclinical safety testing requirements for biotechnological products. It addresses the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies.

An addendum was proposed to provide clarification on S6 and an update of the following topics discussed in the original ICH S6 Guideline: species selection, study design, immunogenicity, reproductive and developmental toxicity and assessment of carcinogenic potential. The Harmonised addendum provides further complementary guidance to the S6 Guideline and helps to define the current recommendations and reduce the likelihood that substantial differences will exist among regions.

The addendum reached Step 4 of the harmonisation process in June 2011 and was integrated as part II in the core Guideline that was then renamed S6(R1).

Guideline

M7(R2) Guideline

M7(R2) Addendum

Endorsed Documents

M7(R2) Concept Paper

WG Presentation / Trainings

M7(R2) Step 4 Presentation

M7(R1) Training Material

Annexes

Guideline implementation

ANMAT, Argentina

Not yet implemented;

ANVISA, Brazil

In the process of implementation; Date: 1 November 2029;

COFEPRIS, Mexico

Not yet implemented;

EC, Europe

Implemented; Date: 30 September 2023; Reference: EMA/CHMP/ICH/83812/2013

EDA, Egypt

Implemented; Date: 3 April 2023; Reference: Egyptian Guidelines on CTD Quality Module for Human Pharmaceuticals

FDA, United States

Implemented; Date: 25 July 2023; Reference: Vol.87, No. 67, p.20435

HSA, Singapore

Implemented; Date: 24 June 2023;

Health Canada, Canada

Implemented; Date: 29 September 2023; Reference: File #: 23-105639-669

JFDA, Jordan

Not yet implemented;

MFDS, Republic of Korea

Implemented; Date: 27 September 2023; Reference: Guideline on Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals [Guideline-0166-03]

MHLW/PMDA, Japan

Implemented; Date: 14 February 2024; Reference: PSB/PED Notification No. 0214-1; PSB/PED Notification No. 0214-2; PSB/PED Administrative Notice

MHRA, UK

Implemented; Date: 1 December 2023;

NAFDAC, Nigeria

Not yet implemented;

NMPA, China

Implemented; Date: 3 January 2024; Reference: NMPA, China Announcement No. 1 (2024)

SAHPRA, South Africa

In the process of implementation;

SFDA, Saudi Arabia

Implemented; Date: 15 April 2026;

Swissmedic, Switzerland

Implemented; Date: 3 April 2023;

TFDA, Chinese Taipei

Implemented;

TITCK, Türkiye

Implemented; Date: 22 January 2024; Reference: Guidelines on Chemical and Pharmaceutical Quality Requirements for Investigational Medicinal Products for Human Use in Clinical Trials (22.01.2024) and Guideline on Requirements for Quality of Biological Investigational Medicinal Products in Clinical Trials (22.01.2024)

Q+A

Q&As

M7(R2) Q&As

Endorsed Documents

M7(R2) Maintenance Concept Paper

WG Presentation / Trainings

M7(R2) Q&As Step 4 Presentation

Q+A implementation

The ICH M7(R2) Questions and Answers (Q&As) reached Step 4 of the ICH process on 24 May 2022.

The M7(R2) Q&A document is intended to provide additional clarification and to promote convergence and improve harmonisation of the considerations for assessment and control of DNA reactive (mutagenic) impurities and of the information that should be provided during drug development, marketing authorization applications and/or Master Files submissions.

Health Canada, Canada

Implemented; Date: 29 September 2023; Reference: File #: 25-105639-669

MHLW/PMDA, Japan

Implemented; Date: 14 February 2024; Reference: PSB/PED Administrative Notice