Description
The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk” (M7(R2) Guidance) and two supplemental documents entitled “M7(R2) Addendum: Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes” (M7(R2) Addendum) and “M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Questions and Answers” (M7(R2) Questions and Answers). The M7(R2) Guidance, M7(R2) Addendum, and M7(R2) Questions and Answers were prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The guidance and supplemental documents are intended to harmonize the considerations for assessment and control of DNA reactive (mutagenic) impurities.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
3Scope of the mutagenic impurities assessment; AI calculated for potential pharmaceutical impurities; General context of ICH guidelines for industry; benzyl chloride as an impurity in drugs; Hydrazine is used in the synthesis of these products; Derivation of an AI for inhaled pharmaceuticals; Application of limits in pharmaceutical products; Application of ICH M7 principles to pharmaceutical impurities.
Pharmaceuticals intended to treat cancer in patients with serious and life-threatening malignancies
Guidance applies to synthetic steps in semisynthetic drug substances
Stakeholders
2Entity responsible for submitting applications under section 524B
new facilities added by the DMF holder
Regulatory Context
Regulatory Activities
2Regulatory submission requiring assessment of impurities
Submission for product approval
Document Types
5Applicable to regulatory submissions.
OECD (Q)SAR Model Reporting Format (QMRF)
QMRF template for reporting model validation
A submission to FDA that may be used to provide confidential information about facilities or processes.; cross-referencing a DMF in a BLA
Format for submitting development information; Module 3 of the CTD for detailed descriptions of analytical procedures; ICH guideline M4Q(R1) for the registration of pharmaceuticals.
Attributes
2Threshold for expectations of mutagenic potential evaluation
Scenario of >10 years to lifetime
Technical Details
Substances
4Formed in the drug product
Assessment and control of these substances to limit carcinogenic risk; Impurities that reside in drug substances and drug products; Impurities that induce direct DNA damage through chemical reaction; Assessment and control of mutagenic impurities
Substance intended for incorporation into a finished drug product
DNA reactive impurities in pharmaceuticals to limit carcinogenic risk; DNA reactive impurities to be controlled below acceptable limits
Testing Methods
7Ames test used as main criterion for determining mutagenicity; Ames test used to evaluate DMS mutagenicity; Ames test used for mutagenicity testing
Quantitative Structure-Activity Relationship analyses used for mutagenic impurity assessment
quantitative structure-activity relationship assessment
Used to evaluate genotoxic potential/clastogenicity
Scientific principles used to justify Option 4 control
Used to update (Q)SAR models and assess hazard
Also known as skip testing per ICH Q6A; Also known as skip testing in ICH Q6A
Processes
3Phase during which information on impurities should be provided
Changes resulting in new impurities
Purification process involving solvents
Clinical Concepts
1treatment duration category changed due to clinical advances
Identified Hazards
Hazards
4Potential risk limited by controlling mutagenic impurities; Potential risk from DNA reactive impurities; Limit potential carcinogenic risk from impurities
DNA Reactive Impurities in Pharmaceuticals
Ability of a compound to induce point mutations
Refers to mutagenic, clastogenic, or aneugenic potential
Standards & References
External Standards
1General validation principles for (Q)SAR models
Specifications
3TTC used to control impurities; TTC used for impurity risk assessment
Classification for impurities with negative mutagenicity results
AI limits for mutagenic impurities
ICH References (10)
Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes; ICH guidance for industry M7(R2) Assessment and Control of DNA Reactive (Mutagenic) Impurities; Document title and version; Document title and addendum reference; Guidance for assessment and control of DNA reactive impurities.; Assessment and Control of DNA Reactive Impu
Nonclinical Evaluation for Anticancer Pharmaceuticals; Guideline regarding pharmaceuticals for advanced cancer.
Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk
The CTD — Safety
The CTD — Quality
Organization of the Common Technical Document; Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use
Application of the Principles of the ICH M7 Guidance to Calculation of Compound-Specific Acceptable Intakes; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes; principles applied to calculation of compound-specific AIs; application of principles to calculation of compound-specific acceptable intakes; Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes.
impurities in new drug substances; Referenced regarding impurities and polymorphism.
Impurities in New Drug Products
Development and Manufacture of Drug Substances; General principles for selection of starting materials
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- E11A Pediatric Extrapolation
- M15 General Principles for Model-Informed Drug Development
- Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product
- Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
- Rare Diseases: Considerations for the Development of Drugs and Biological Products
- Q3C Impurities: Residual Solvents_2011
- Providing Regulatory Submissions in Electronic Format --Content of the Risk Evaluation and Mitigation Strategies Document Using Structured Product Labeling: Guidance for Industry
- Q4B Annex 5: Disintegration Test General Chapter