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Mutagenic Impurities
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Вернуться на страницу книги Mutagenic Impurities
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Страница 1
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
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1
Historical Perspective on the Development of the EMEA Guideline and Subsequent ICH M7 Guideline 1.1 Introduction
1.1.1 CPMP – Position Paper on the Limits of Genotoxic Impurities –2002 1.1.1.1 Scope/Introduction
1.1.1.2 Toxicological Background
1.1.1.3 Pharmaceutical (Quality) Assessment
1.1.1.4 Toxicological Assessment
1.1.2 Guideline on the Limits of Genotoxic Impurities – Draft June 2004
1.1.3 PhRMA (Mueller) White Paper
1.1.4 Finalized EMA Guideline on the Limits of Genotoxic Impurities – June 2006
1.1.4.1 Issues Associated with Implementation
1.1.4.1.1 The Relevance of the TTC Concept for Short Durational Exposure
1.1.4.1.2 Application to Existing Products
1.1.4.1.3 Standards Required of Investigational Products
1.1.4.1.4 Circumstances that Support Modification of the TTC Limit
1.1.4.1.5 Control Requirements When Multiple GIs May Be Present
1.1.4.1.6 Application to New Marketing Authorisation Approval (MAA) Applications Relating to Existing Products
1.1.4.2 Control Expectations for Excipients
1.1.4.3 Control Expectations for Natural/Herbal Products
1.1.4.4 Identification of Potential Impurities
1.1.4.5 The Principle of Avoidance
1.1.4.6 The ALARP Principle
1.1.4.7 Overall
1.1.5 SWP Q&A Document
1.1.5.1 The Application of the Guideline in the Investigational Phase and Acceptable Limits for GIs Where Applied to Studies of Limited Duration
1.1.5.2 Application of the Guideline to Existing Products
1.1.5.3 Avoidance and ALARP
1.1.5.4 ICH Identification Threshold and its Relation to MI Assessment
1.1.6 FDA Draft Guideline
1.1.7 Other Relevant Guidance
1.1.7.1 Excipients
1.1.8 Herbals
1.1.9 ICH S9
1.1.10 Conclusions
References
Notes
Страница 46
2
ICH M7 – Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk 2.1 Introduction
2.2 ICH M7
2.2.1 Introduction
2.2.2 Scope
2.2.2.1 Established Products
2.2.2.2 Anticancer Treatments
2.2.2.3 Nature of Therapeutic Agent/Excipients
2.2.3 General Principles
2.2.4 Considerations for Marketed Products
2.2.4.1 Post‐approval Changes to Drug Substance, Chemistry, and Manufacturing Controls
2.2.4.2 Post‐approval Changes to Drug Product Chemistry, Manufacturing, and Controls
2.2.4.3 Changes to the Clinical Use of Drug Products
2.2.5 Other Considerations for Marketed Products
2.2.6 Drug Substance and Drug Product Impurity Assessment
2.2.6.1 Synthetic Impurities
2.2.6.2 Degradation Products
2.2.7 Hazard Assessment
2.2.8 Risk Characterization
2.2.8.1 Acceptable Intakes Based on Compound‐specific Risk Assessments
2.2.8.1.1 Mutagenic Impurities with Positive Carcinogenicity Data (Class 1)
2.2.8.2 Acceptable Intakes for Class 2 and Class 3 Compounds
2.2.8.3 Multiple Impurities
2.2.8.4 Exceptions and Flexibility in Approaches
2.2.9 Control Strategy
2.2.9.1 Considerations for Control Approaches
2.2.9.2 Considerations for Periodic Testing
2.2.9.3 Control of Degradation Products
2.2.10 Lifecycle Management
2.2.11 Documentation
2.2.11.1 Clinical Trail Applications
2.2.11.2 Common Technical Document (Marketing Application)
2.2.12 Other Aspects 2.2.12.1 Relationship Between ICH M7 and ICH Q3A
2.3 Conclusions
2.4 Commentary on ICH M7 Questions and Answers
2.4.1
Section 1
– Introduction
2.4.1.1 Question 1.1
2.4.1.2 Question 1.2
2.4.1.3 Question 1.3
2.4.1.4 Question 1.4
2.4.2
Section 2
– Scope
2.4.2.1 Question 2.1
2.4.3
Section 3
– General Principles
2.4.3.1 Question 3.1
2.4.3.2 Question 3.2
2.4.4
Section 4
– Considerations for Marketed Products
2.4.4.1 Question 4.1
2.4.5 Section 5 – Drug Substance and Drug Product Impurity Assessment
2.4.6 Section 6 – Hazard Assessment Elements
2.4.6.1 Question 6.1
2.4.6.2 Question 6.2
2.4.6.3 Question 6.3
2.4.6.4 Question 6.4
2.4.7 Section 7 – Risk Characterization
2.4.7.1 Question 7.1
2.4.7.2 Question 7.2
2.4.7.3 Question 7.3
2.4.7.4 Question 7.4
2.4.7.5 Question 7.5
2.4.7.5.1 Section 8 – Control
2.4.8 Section 9 – Documentation
References
Страница 107
3
Control Strategies for Mutagenic Impurities 3.1 Introduction
3.2 Assessment Process 3.2.1 General
3.2.2 Step 1 – Evaluation of Drug Substance and Drug Product Processes for Sources of Potentially Mutagenic Impurities
3.2.3 Step 2 – Structural Assessment
3.2.4 Step 3 – Classification
3.2.5 Step 4 – Assessment of Risk of Potential Carryover of Impurities
3.2.6 Overall Quantification of Risk
3.2.6.1 Predicted Purge Factor
3.2.6.2 Required Purge Factor
3.2.6.3 Purge Ratio
3.2.6.4 High Predicted Purge
3.2.6.5 Moderate Predicted Purge
3.2.6.6 Low Predicted Purge
3.2.6.7 ICH M7 Control Option 1, 2, or 3
3.2.6.8 Step 5 – Further Evaluation
3.2.6.9 Safety Testing
3.2.7 Quantification of Level Present
3.3 Step 6 – Overall Risk Assessment
3.4 Further Evaluation of Risk – Purge (Spiking) Studies
3.5 Conclusion
3.6 Case Studies 3.6.1 Case Study 1 – GW641597X
3.6.1.1 Ethyl Bromoisobutyrate 2
3.6.1.2 Hydroxylamine
3.6.1.3 Alkyl Chloride 8
3.6.1.4 Additional Evidence for the Purging of Ethyl Bromoisobutyrate and Alkyl Chloride 8
cssStyle="font-weight:bold;font-style:italic;" 3.6.1.4.1 Including “Measured” Purge into the Purge Rationale for Ethyl Bromoisobutyrate 2
cssStyle="font-weight:bold;font-style:italic;" 3.6.1.4.2 Inclusion of “Measured” Purge into the Purge Rationale for Alkyl Chloride 8
3.6.2 Proposed ICH M7‐aligned Potential Mutagenic Control Regulatory Discussion
3.6.3 Case Study 2 – Candesartan
References
Notes
Страница 139
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