ICH adopts M7(R2) guideline on mutagenic impurities to limit carcinogenic risk
The International Council for Harmonisation (ICH) earlier this week announced the adoption of its M7(R2) guideline that aims to harmonize the framework for assessing and controlling DNA mutagenic impurities in pharmaceuticals as well as an addendum listing the 21 impurities that should be tested along with their daily permissible limits (PDEs). Both were adopted on 3 April.“The focus of this guideline is on DNA reactive substances that have a potential to directly cause DNA damage when present at low levels leading to mutations and therefore, potentially causing cancer,” ICH wrote. “This type of mutagenic carcinogen is usually detected in a bacterial reverse mutation (mutagenicity) assay.”
The adopted guideline is little changed from the draft, with the addendum incorporating the seven additional DNA reactive compounds that were earlier proposed for inclusion, bringing the total to 21 mutagenic impurities (RELATED: ICH guideline proposes daily limits for seven mutagenic impurities, Regulatory Focus, 8 October 2021).
The guideline recommends methods to assess and control mutagenic impurities that are “reasonably expected to reside in final drug substance or product, taking into consideration the intended conditions for human use.”
ICH said there is “limited guidance” addressing impurities that are DNA reactive; the guideline aims to “provide a practical framework that is applicable to the identification, categorization, qualification, and control of these mutagenic impurities to limit potential carcinogenic risk.”
The guideline is meant to complement ICH Q3A(R2) on impurities in new drug substances, Q3B(R2) covering impurities in new drug products, and ICH M3(R2) on nonclinical safety studies.
The guideline is not intended to be applied retrospectively; however, ICH noted that “some types of post-approval changes warrant a reassessment of safety relative to mutagenic impurities.
The addendum lists PDEs which have derived for a set of chemicals “considered to be mutagens and carcinogens and are common in pharmaceutical manufacturing.”
While ICH encourages the implementation of the guideline after publication, it notes that because of the guideline’s “complexity” it does not expect its implementation prior to 18 months. ICD did not, however, that Ames tests should be conducted upon ICH publication, yet tests conducted prior to publication of M7 need not be repeated.
The justification for updating the guideline was outlined in a concept paper published in August 2018. It states that after ICH M7 was finalized in 2014, “interest was expressed by industry representatives in developing AIs or PDEs for new DNA reactive (mutagenic) impurities commonly found or used in drug synthesis.”
ICH M7(R2) guideline
ICH M7(R2) addendum
×
Welcome to the new RAPS Digital Experience
We have completed our migration to a new platform and are pleased to introduce the updated site.
What to expect: If you have an existing login, please RESET YOUR PASSWORD before signing in. After you log in for the first time, you will be prompted to confirm your profile preferences, which will be used to personalize content.
We encourage you to explore the new website and visit your updated My RAPS page. If you need assistance, please review our FAQ page.
We welcome your feedback. Please let us know how we can continue to improve your experience.