GUIDANCE DOCUMENT Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk ICH Topic M7 Published by the authority of the Minister of Health Date Adopted 2016/01/21 Effective Date 2016/01/21 Health Products and Food Branch Our mission is to help the people of Canada The Health Products and Food Branch's mandate is to take maintain and improve their health. an integrated approach to the management of the risks and Health Canada benefits to health related products and food by: Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food branch; and Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health. Health Products and Food Branch © Ministre, Travaux publics et services gouvernementaux Canada 2016 Également disponible en français sous le titre : Ligne directrice l’ICH : M7: Évaluation et contrôle des impuretés réactives de l’ADN (mutagènes) dans les produits pharmaceutiques pour limiter les risques de cancérogénicité Health Canada Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance Document ICH Topic M7 FOREWORD This guidance has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. The ICH Steering Committee has endorsed the final draft and recommended its adoption by the regulatory bodies of the European Union, Japan and the United States of America. In adopting this ICH guidance, Health Canada endorses the principles and practices described therein. This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances. Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with the policies and governing statutes and regulations. They also serve to provide review and compliance guidance to staff, thereby ensuring that mandates are implemented in a fair, consistent and effective manner. Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met. As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this guidance, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented. Date Adopted: 2016/01/21; Effective Date: 2016/01/21 i Assessment and Control of DNA Reactive (Mutagenic) Impurities in Health Canada Pharmaceuticals to Limit Potential Carcinogenic Risk ICH Topic M7 Guidance Document Document History Code History Date M7 Approval by the Steering Committee under Step 2 and release 6 February for public consultation. 2013 M7 Approval by the Steering Committee under Step 4 and 5 June 2014 recommendation for adoption to the three ICH regulatory bodies. Current Step 4 version M7 Corrigendum to fix typographical errors and replace word 23 June “degradants” with “degradation products” throughout the 2014 document. ii Date Adopted: 2016/01/21; Effective Date: 2016/01/21 Health Canada Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance Document ICH Topic M7 Table of contents 1. INTRODUCTION ..................................................................................................................1 2. SCOPE OF GUIDELINE .......................................................................................................1 3. GENERAL PRINCIPLES ......................................................................................................2 4. CONSIDERATIONS FOR MARKETED PRODUCTS .......................................................3 4.1 Post-Approval Changes to the Drug Substance Chemistry, Manufacturing, and Controls .................................................................................................................................4 4.2 Post-Approval Changes to the Drug Product Chemistry, Manufacturing, and Controls ........................................................................................................................................4 4.3 Changes to the Clinical Use of Marketed Products ..............................................................4 4.4 Other Considerations for Marketed Products ........................................................................5 5. DRUG SUBSTANCE AND DRUG PRODUCT IMPURITY ASSESSMENT ....................5 5.1 Synthetic Impurities ..............................................................................................................5 5.2 Degradation Products ............................................................................................................6 5.3 Considerations for Clinical Development .............................................................................7 6. HAZARD ASSESSMENT ELEMENTS ...............................................................................7 7. RISK CHARACTERIZATION .............................................................................................9 7.1 TTC-based Acceptable Intakes .............................................................................................9 7.2 Acceptable Intakes Based on Compound-Specific Risk Assessments .................................9 7.2.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1 in Table 1) .......9 7.2.2 Mutagenic Impurities with Evidence for a Practical Threshold ..............................10 7.3 Acceptable Intakes in Relation to LTL Exposure ...............................................................10 7.3.1 Clinical Development ....................................................................................................11 7.3.2 Marketed Products .........................................................................................................11 7.4 Acceptable Intakes for Multiple Mutagenic Impurities ......................................................11 7.5 Exceptions and Flexibility in Approaches ..........................................................................12 8. CONTROL ...........................................................................................................................13 8.1 Control of Process Related Impurities ................................................................................13 8.2 Considerations for Control Approaches ..............................................................................15 8.3 Considerations for Periodic Testing ....................................................................................15 8.4 Control of Degradation Products ........................................................................................16 Date Adopted: 2016/01/21; Effective Date: 2016/01/21 iii Assessment and Control of DNA Reactive (Mutagenic) Impurities in Health Canada Pharmaceuticals to Limit Potential Carcinogenic Risk ICH Topic M7 Guidance Document 8.5 Lifecycle Management ........................................................................................................17 8.6 Considerations for Clinical Development ...........................................................................18 9. DOCUMENTATION ...........................................................................................................18 9.1 Clinical Trial Applications ..................................................................................................18 9.2 Common Technical Document (Marketing Application) ...................................................18 NOTES ...........................................................................................................................................19 GLOSSARY ..................................................................................................................................25 REFERENCES ..............................................................................................................................27 APPENDICES ...............................................................................................................................29 Appendix 1: Scope Scenarios for Application of the ICH M7 Guideline ..................................29 Appendix 2: Case Examples to Illustrate Potential Control Approaches ...................................31 IMPLEMENTATION OF GUIDELINE .......................................................................................33 iv Date Adopted: 2016/01/21; Effective Date: 2016/01/21 Health Canada Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk Guidance Document ICH Topic M7 1. INTRODUCTION The synthesis of drug substances involves the