Оглавление
Группа авторов. Mutagenic Impurities
Table of Contents
List of Tables
List of Illustrations
Guide
Pages
Mutagenic Impurities. Strategies for Identification and Control
Preface
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
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
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
4. Use of Structure–Activity Relationship (SAR) Evaluation as a Critical Tool in the Evaluation of the Genotoxic Potential of Impurities. 4.1 Introduction
4.2 (Q)SAR Assessment. 4.2.1 Looking‐up Experimental Data
4.2.2 (Q)SAR Methodologies. 4.2.2.1 Overview
4.2.2.2 OECD Validation Principles
4.2.3 Expert Rule‐Based Methodology
4.2.4 Statistical‐Based Methodology
4.2.5 Applying (Q)SAR Models
4.2.6 Expert Review. 4.2.6.1 Overview
4.2.6.1.1 Looking at Chemical Analog(s)
4.2.6.2 Refuting a Statistical‐Based Prediction
4.2.6.3 Mechanistic Assessment
4.2.6.4 Assessing Lack of Chemical Reactivity
4.2.6.4.1 Applying a Third Model
4.2.6.4.2 Assessing the Strength of a Single Prediction
4.2.7 Class Assignment. 4.2.7.1 Overview
4.2.7.1.1 Clear Negative Assessment
4.2.7.1.2 Clear Positive Assessment
4.2.7.1.3 Conflicting Predictions
4.2.7.1.4 Handling Indeterminate predictions
4.2.7.1.5 Handling Out‐of‐Domain Results
4.2.8 Documentation
4.3 Discussion
4.4 Conclusions
Acknowledgments
References
5. Evolution of Quantitative Structure–Activity Relationships ((Q)SAR) for Mutagenicity. 5.1 Introduction
5.2 Pre ICH M7 Guideline
5.3 Post ICH M7. 5.3.1 Evolution of (Q)SAR Platforms
5.3.2 Robust Negative In Silico (Q)SAR Predictions
5.3.3 Development of Composite (Q)SAR Models
5.3.4 Expansion of Training Data Sets to Enhance the Predictive Power of (Q)SAR Tools
5.3.5 Focused Data Sharing Initiatives on Specific Chemical Classes
5.3.5.1 Understanding In Vitro Mechanisms Leading to Mutagenicity
5.3.5.2 Shared Data, Shared Progress. 5.3.5.2.1 Boronic Acids
5.3.5.2.2 Primary Aromatic Amines (PAAs)
5.3.6 Novel Data Mining Approaches. 5.3.6.1 Case Study: Primary Aromatic Amines (PAAs)
5.3.6.2 Case Study: Aromatic N‐oxides
5.4 Expert Knowledge
5.5 Future Direction
References
Note
6 Toxicity Testing to Understand the Mutagenicity of Pharmaceutical Impurities. 6.1 Introduction
6.2 In Vitro Genotoxicity Tests. 6.2.1 Background
6.2.2 Bacterial Reverse Mutation or “Ames” Test
6.2.3 Modifications to the Standard Ames Test
6.2.3.1 Six‐well Ames Assay
6.2.4 Test Strategy
6.3 In Vivo Mutation Assays
6.3.1 In Vivo Pig‐a Gene Mutation Assay
6.3.2 Rodent Micronucleus Test
6.3.3 Rodent “Comet” Assay
6.3.4 Transgenic Rodent (TGR) Mutation Assay
6.4 Conclusions
Glossary
References
7 Compound‐ and Class‐Specific Limits for Common Impurities in Pharmaceuticals. 7.1 Introduction
7.2 Monograph Development
7.2.1 Exposure to the General Population
7.2.2 Mutagenicity/Genotoxicity
7.2.3 Noncarcinogenic Effects
7.2.4 Carcinogenic Effects
7.2.5 Mode of Action (MOA) and Assessment of Human Relevance
7.2.6 Toxicokinetics
7.2.7 Regulatory/Published Limits
7.3 Derivation of the Compound‐specific Limit
7.3.1 PoD Selection
7.3.2 Limited Data Sets
7.3.3 PDE Development
7.3.4 AI Development
7.3.5 Class‐specific Limit
7.3.6 Less than Lifetime (LTL) AIs
7.4 Examples of Published Compound‐specific Limits
7.4.1 Mutagenic Carcinogens
7.4.2 Nonmutagenic Carcinogens
7.4.3 Mutagenic Noncarcinogens
7.4.4 Nonmutagenic Compounds
7.4.5 Mutagenic In vitro but not In vivo
7.4.6 Route of Administration‐specific Limits
7.5 Class‐specific Limits. 7.5.1 Alkyl Chlorides
7.5.2 Alkyl Bromides
7.5.3 N‐Nitrosamines
7.5.3.1 Regulatory Limits for N‐Nitrosamines
7.5.3.2 Additional Proposed Limits for N‐Nitrosamines
7.5.3.3 N‐Nitrosamine Exposure in the General Population
7.5.3.4 Developing a Class‐specific Limit for N‐Nitrosamines
7.5.4 Arylboronic Acids and Esters
7.6 EMS Case Study and Updated Toxicity Analysis
7.6.1 Potential for Human Exposure
7.6.2 Mutagenicity/Genotoxicity
7.6.3 Noncarcinogenic Effects
7.6.4 Carcinogenicity
7.6.5 Regulatory and/or Published Limits
7.6.6 Permitted Daily Exposure
7.7 Extractables and Leachables
7.8 Lhasa AI/PDE Database for Impurities
7.9 Conclusions and Future Directions
7.10 Acknowledgments
References
8 Genotoxic Threshold Mechanisms and Points of Departure. 8.1 Introduction to Genotoxic Dose Responses
8.1.1 The Linear Default Position for Genotoxic Carcinogens
8.1.2 Theoretical Evidence for Rejecting the Linear Approach
8.1.3 In Vitro Experimental Evidence for Threshold Mechanism
8.1.4 In Vivo Evidence for Genotoxic Thresholds
8.2 Threshold Mechanisms
8.2.1 Statistical Assessment of Dose Response Data Sets
8.2.2 Extrapolation from One Chemical to Another
8.2.3 Extrapolation of Threshold Mechanisms and PoDs to Populations
8.3 Conclusions
References
9 Mutagenic Impurities – Assessment of Fate and Control Options. 9.1 Introduction/Background
9.2 Reactivity
9.2.1 Reactivity Classification
9.3 Solubility – Isolated Stages
9.4 Recrystallization
9.4.1 Solubility – Liquid/Liquid Partitioning
9.5 Volatility
9.6 Chromatography
9.7 Other Techniques
9.7.1 Activated Charcoal
9.7.2 Scavenger Resins
9.8 Overall Quantification of Risk
9.9 Alignment to ICH M7 – Control Options
9.10 Control Option Selection
9.10.1 Predicted Purge Factor
9.10.2 Required Purge Factor
9.10.3 Purge Ratio
9.10.4 High Predicted Purge
9.10.5 Moderate Predicted Purge
9.10.6 Low Predicted Purge
9.10.7 ICH M7 Control Option 1, 2, or 3
9.10.8 Representative Data to be Supplied in Regulatory Submission Under an ICH M7 Control Strategy
9.10.9 Summary of PMI Purging Across the Synthetic Route
9.10.10 Details of Individual Impurity Purging Through the Subsequent Downstream Chemistry
9.10.11 Development of a Knowledge Base Expert In Silico System
9.10.12 Experimental Work to Assess Reactivity
9.11 Utilizing Mirabilis for a Purge Calculation
9.11.1 Utility of In Silico Predictions
9.11.1.1 Case Study – Camicinal [38]
References
Notes
10 N ‐Nitrosamines. 10.1 Background
10.2 Generation of N‐Nitrosamines
10.3 Article 31
10.4 Further Issues – Cross Contamination and Ranitidine
10.4.1 Article 5(3) and Associated Q&A Document
10.5 How to Assess the Risk Posed in Pharmaceuticals
10.5.1 Drug Substance
10.5.1.1 Where do Nitrites Come Within Drug Substance Come From?
10.5.1.2 What Other Sources Are There? 10.5.1.2.1 Nitrite in Water, NOx in Nitrogen
10.5.1.3 Other Factors Associated with Drug Substance Synthesis. 10.5.1.3.1 Extrinsic Contamination
10.5.2 Process to Assess Drug Substance‐Related Risk
10.5.3 Drug Product‐Related Risk. 10.5.3.1 Related Risks of Contamination and Formation in Drug Products
Equation 10.1
10.5.4 Container Closure Systems
10.5.5 Elastomeric Components
10.5.6 Nitrosamine Impurities in Biologics
10.5.6.1. Active Substance
10.5.6.2. The Water Used in Formulation Is Depleted in Nitrosating Agents
10.5.6.3. Bioconjugated or Chemically Modified Products
10.5.6.4. Excipients
10.6 Regulatory Guidance Pursuant to N‐Nitrosamines and its Implications
10.6.1 Article 31 Process and Outcomes. 10.6.1.1 Article 31 Request
10.6.2 Sartans Lessons Learnt Report
10.6.2.1 Reflection on the Initial Section of the EMA Report
10.6.3 Article 5(3) Report
10.6.3.1 Quality. 10.6.3.1.1 Root Causes for the Presence of N‐Nitrosamines and Proposed Measures to Mitigate Them
10.6.3.2 Consideration for Analytical Method Development to Identify and Quantify N‐Nitrosamines in Drug Substances and Medicinal Products. Key Points:
10.6.3.3 Safety. 10.6.3.3.1 Considerations for Calculating Risk for Exposed Patients in Case of Detection of N ‐Nitrosamines in Medicinal Product(s)
10.6.3.3.2 N‐Nitrosamine Carcinogenicity in Animals
10.6.3.3.3 Use of in vitro Mutagenicity Data for Carcinogenicity Potency Ranking of N ‐Nitrosamines
Chronology
10.6.3.4 Conclusions
10.6.4 EMA Question and Answer Document [6]
10.6.4.1 Further Revision of the EMA Question and Answer Document
10.6.5 FDA Guideline
10.6.5.1 Introduction and Background
10.6.5.2 Recommendations
10.6.5.3 Acceptable Intakes (section III.A)
10.6.5.4 Quality/Chemistry and Controls. 10.6.5.4.1 Section III (B) Recommendations to API Manufacturers
10.6.5.4.2 Recommendation for Drug Product Manufacturers
10.7 Way Forward
Acknowledgments
References
11. Conditions Potentially Leading to the Formation of Mutagenic Impurities
11.1 Problematic Reagent Combinations per Structural Alert
11.1.1 N‐Nitroso Compounds (COC) 11.1.1.1 Amines and Nitrosating Agents [10]
11.1.1.2 Amine Derivatives and Nitrosating Agents
11.1.1.3 Other
11.1.2 Alkyl‐azoxy Compounds (COC) 11.1.2.1 Reduction [52–54]
11.1.2.2 Oxidation
11.1.2.3 Others
11.1.3 Other N‐O Compounds. 11.1.3.1 Reduction of Nitro Groups
11.1.3.2 Oxidation of Amines and Hydroxylamines
11.1.4 Nitration
11.1.5 Other N‐N Compounds [59, 60]
11.1.6 Aflatoxin‐like Compounds [62] (COC)
11.1.7 Dioxin‐like Compounds (Including Polychlorinated Biphenyls = PCBs) [63]
11.1.8 Alkyl and Acyl Halides. 11.1.8.1 ROH + HCl → RCl + H2O
11.1.8.2 Ether Opening with Halides
11.1.9 Methyl Sulfoxides and Pummerer Rearrangement
11.1.10 Acyl Chlorides Formation [82]
11.1.11 Halogenation of Unsaturated Compounds
11.1.12 Ammonium Salts (Hofmann Elimination)
11.1.12.1 Alkyl Sulfonates [90]
11.1.13 Epoxides and Aziridines [95–97]
11.2 Miscellaneous. 11.2.1 B and P Based Compounds
11.2.2 Formation of N‐Methylol
11.2.3 Acetamide
11.2.4 Quinones and Quinone Derivatives
11.2.5 Anilines [100]
11.2.6 Michael Acceptors
11.2.7 Others
11.3 Mechanism and Processing Factors Affecting the Formation of N‐nitrosamines. 11.3.1 Introduction
11.3.2 Mechanisms of Amine Nitrosation. 11.3.2.1 Nitrosation of Secondary Amines
11.3.2.2 Aqueous Nitrosation
11.3.2.3 Nitrosation in Organic Solvents
11.3.3 Nitrosation of Tertiary Amines
11.3.3.1 Nitrosation of Quaternary Amines
11.3.3.2 Nitrosation of Amine Oxides
11.3.4 Sources of Nitrosating Agents
11.3.4.1 Process Water
11.3.4.2 Nitric Acid
11.3.4.3 Atmospheric Sources
11.3.4.4 Excipients Used in Drug Product Manufacture
11.3.4.5 Nitrocellulose
11.3.4.6 Nitrosating Agent Scavengers
11.3.4.7 Removal of Nitrosamines
11.4 Formation, Fate, and Purge of Impurities Arising from the Hydrogenation of Nitroarenes to Anilines
11.4.1 Primary Reaction Mechanism
11.4.2 Mass and Heat Transfer Effects
11.4.3 Condensation Chemistry
11.4.4 Factors Affecting Aryl Hydroxylamine Accumulation
11.4.5 Aryl Hydroxylamine Control. 11.4.5.1 Use of Cocatalysts
11.4.5.2 Physical Adsorption
11.4.5.3 Kinetic Understanding Around Formation and Consumption
11.4.5.4 Holistic Control of Impurity Profile
11.4.6 Controlling Residual Nitroarene
11.4.7 Specific Considerations of Alkyl Nitro Reductions
11.4.8 Closing Comments on Hydrogenation of Nitroarenes to Anilines
11.5 Mechanism and Processing Parameters Affecting the Formation of Sulfonate Esters – Summary of the PQRI Studies. 11.5.1 Introduction
11.5.2 Reaction Mechanism
11.5.3 Experimental Results. 11.5.3.1 Experimental Results from Study of the Ethyl Methanesulfonate (EMS) System. 11.5.3.1.1 EMS Formation – Effect of Temperature
11.5.3.1.2 EMS Formation – Effect of Water
11.5.3.1.3 EMS Formation – The Impact of the Presence of Base
11.5.3.2 Other Methanesulfonic Acid Systems. 11.5.3.2.1 Experimental Results from Study of the MMS System
11.5.3.3 Experimental Results from Study of the Isopropyl Methanesulfonate (IMS) System
11.5.4 Experimental Results from Study of Toluenesulfonic (Tosic) Acid Systems
11.5.4.1 Experimental Results from Study of the Ethyl Tosylate (ETS) System
11.5.4.2 Kinetic Modeling
11.5.4.3 Key Learnings and Their Implications for Process Design
11.5.4.4 Processing Rules
11.5.5 What About Viracept™?
11.5.6 What About Other Sources of Sulfonate Esters?
11.5.7 Potential for Ester Formation in the Solid Phase
11.5.8 Conclusions
References
Notes
12. Strategic Approaches to the Chromatographic Analysis of Mutagenic Impurities. 12.1 Introduction
12.2 Method Development and Validation
12.3 Analytical Equipment for Mutagenic Impurity Analysis
12.4 Alkyl Halides and Aryl Halides. 12.4.1 Method Selection
12.4.2 Typical Conditions Used for Alkyl‐ and Aryl Halide Analysis by SHS‐GC‐MS and SPME‐GC‐MS
12.4.2.1 Sample Preparation
12.4.2.2 GC‐MS Parameters
12.4.3 Typical Results Obtained for Alkyl‐ and Aryl Halide Analysis by SHS‐GC‐MS and SPME‐GC‐MS
12.5 Sulfonates. 12.5.1 Method Selection
12.5.2 Typical Conditions Used for Sulfonate Analysis by Derivatization SHS‐GC‐MS
12.5.2.1 Sample Preparation
12.5.2.2 Synthesis of Deuterated Internal Standards
12.5.2.3 GC‐MS Parameters
12.5.3 Typical Results Obtained Using Derivatization – SHS – GC‐MS
12.5.4 Confirmation Analysis by PTV‐GC‐MS
12.6 S‐ and N‐mustards. 12.6.1 Method Selection
12.6.2 Typical Analytical Conditions for the Analysis of N‐mustards by Derivatization – SPME‐GC‐MS
12.6.2.1 Sample Preparation
12.6.2.1.1 GC‐MS Conditions
12.6.3 Typical Results for N‐mustards by Derivatization – SPME‐GC‐MS
12.7 Michael Reaction Acceptors. 12.7.1 Method Selection
12.7.2 Typical Analytical Conditions for Michael Reaction Acceptors
12.7.2.1 Sample Preparation
12.7.2.2 Parameters for SHS‐GC‐MS
12.7.2.3 Parameters for Liquid Injection and GC‐MS with Back‐flush
12.7.3 Typical Results Obtained for Trace Analysis of Michael Reaction Acceptors. 12.7.3.1 SHS with PTV
12.7.3.2 Liquid Injection GC‐MS
12.8 Epoxides. 12.8.1 Method Selection
12.8.2 Typical Analytical Conditions for the Analysis of Volatile Epoxides by SHS‐GC‐MS
12.8.2.1 Sample Preparation
12.8.2.2 SHS‐GC‐MS Parameters
12.8.3 Typical Results Obtained for Volatile Epoxides Using SHS‐GC‐MS
12.9 Haloalcohols. 12.9.1 Method Selection
12.9.2 Analytical Conditions for Trace Analysis of Halo‐alcohols by Derivatization and Liquid Injection ‐ 2DGC‐MS. 12.9.2.1 Sample Preparation
12.9.2.2 2D‐GC‐MS Parameters
12.9.3 Typical Results for Analysis of Halo‐alcohols by Derivatization and Liquid Injection ‐ 2DGC‐MS
12.10 Aziridines. 12.10.1 Method Selection
12.10.2 Typical Analytical Conditions for RPLC‐MS and HILIC‐MS Analysis of Aziridines
12.10.2.1 Sample Preparation
12.10.2.2 RPLC‐MS Method Parameters
12.10.2.3 HILIC‐MS Method Parameters
12.10.3 Typical Results Obtained for Aziridine Analysis Using RPLC and HILIC
12.11 Arylamines and Amino Pyridines. 12.11.1 Method Selection
12.11.2 Typical Analytical Conditions for Arylamines and Aminopyridines by RPLC‐MSD
12.11.2.1 Sample Preparation
12.11.2.2 HPLC‐MS Parameters
12.11.3 Typical Results for Arylamines and Aminopyridines by RPLC‐MSD
12.12 Hydrazines and Hydroxylamine. 12.12.1 Method Selection
12.12.2 Analytical Conditions for the Analysis of Hydrazines Using Derivatization and HPLC‐MS
12.12.2.1 Sample Preparation
12.12.2.2 HPLC‐MS Parameters
12.12.3 Typical Results Obtained for Hydrazines Using Derivatization LC‐MS
12.13 Aldehydes and Ketones. 12.13.1 Method Selection
12.13.2 Typical Analytical Conditions for Analysis of Aldehydes and Ketones by DNPH Derivatization, Followed by LC‐MS Analysis
12.13.2.1 Sample Preparation
12.13.2.2 Derivatization Reagent Solution
12.13.2.3 HPLC‐MS Parameters
12.13.3 Typical Results Obtained for Aldehyde Analysis by DNPH Derivatization – LC‐MS
12.14 Nitrosamines. 12.14.1 Method Selection
12.14.2 Sample preparation for SHS‐GC‐MS Analysis (according to ref [85]) 12.14.2.1 SHS‐GC‐MS Analysis [85] Sample Preparation
12.14.2.2 GC‐MS (HRAM‐MS) Conditions
12.14.2.3 UHPLC‐MS Analysis
12.14.2.4 Sample Preparation for Hydrophilic Samples (e.g. Metformin)
12.14.2.5 Sample Preparation for Hydrophobic Matrices
12.14.2.6 UHPLC Conditions
12.14.2.7 HRAM‐MS and MS/MS Conditions
12.14.3 Typical Results Obtained for Volatile N‐nitrosamines Using SHS‐GC‐MS
12.14.4 Typical Results Obtained for N‐nitrosamines Using LC‐MS
12.15 Nontarget Analysis of PMI/MIs
12.16 Conclusions
Acknowledgements
References
13. Analysis of Mutagenic Impurities by Nuclear Magnetic Resonance (NMR) Spectroscopy. 13.1 Introduction to NMR
13.2 Why Is NMR an Insensitive Technique? 13.2.1 Nuclear Spin
13.2.2 Boltzmann Distribution
13.3 How Could NMR Be Used for Trace Analysis?
13.3.1 Generating an NMR Spectrum
13.3.2 Chemical Shift
13.3.3 Scalar Coupling
13.3.4 The Quantitative Nature of NMR
13.3.5 Relaxation
13.3.6 Summary
13.4 What Can Be Done to Maximize Sensitivity?
13.4.1 System Performance
13.4.1.1 Field Strength
13.4.2 Probe Performance
13.4.2.1 Probe Design
13.4.2.2 Probe Diameter
13.4.2.3 Cryogenically Cooled Probes
13.4.3 Substrate Concentration
13.4.4 Molecular Weight Ratio
13.4.5 Acquisition Time and Signal Averaging
13.4.6 Number of Protons and Linewidth
13.4.7 Resolution
13.4.8 Dynamic Range
13.4.8.1 Selective Excitation
13.4.8.2 Shaped Pulses
13.4.8.3 Quantification Using Selective Pulses
13.4.8.4 Excitation Sculpting
13.4.9 Limit Tests
13.4.9.1 Method Development
13.4.9.2 Validation
13.4.9.3 Unresolved Signals
13.4.9.4 Rapid Analysis
13.4.10 Expanded Use of MI NMR Methodology
13.4.11 Summary
13.5 Case Studies
13.5.1 Case Study 1 – An Aldehyde Functionalized MI
13.5.2 Case Study 2 – Use of 19F NMR
13.5.3 Case Study 3 – Epoxide and Chlorohydrin MIs
13.5.4 Case Study 4 – Sulfonate Esters
13.5.5 Case Study 5 – Limit Test for Poorly Resolved Signals
13.5.6 Case Study 6 – Using NMR MI Methodology for Cleaning Validation
13.6 Conclusion
References
14. Addressing the Complex Problem of Degradation‐Derived Mutagenic Impurities in Drug Substances and Products. 14.1 Introduction. 14.1.1 Background
14.2 Working Definitions
14.3 Challenges Associated with the Assessment of Risk Posed by (Potentially) Mutagenic Degradation Products
14.4 Risk Assessment Process for Mutagenic Degradants. 14.4.1 Stability‐Related MRA Process Overview
14.4.2 Stress Studies
14.4.3 Accelerated Stability Studies
14.4.4 Long‐term ICH Stability Studies
14.4.5 Deciding Which Products to Include in the MRA
14.4.6 In Silico Tools for the Prediction of Potential Degradation Products
14.5 Using Stress Testing to Select Degradation Products for Identification
14.5.1 Approach 1: Criteria for Structure Identification After Observation in Accelerated and Long‐term Stability Studies
14.5.2 Approach 2: Criteria for Structure Identification Through Use of an Algorithm in Stress Testing Studies
14.5.3 Approach 3: Structure Identification Through Use of Kinetic Equivalence and Scaled ICH Q3B Thresholds
14.5.3.1 Kinetic Equivalence
14.5.3.2 Scaled ICH Q3B Thresholds
14.6 Development Timeline Considerations. 14.6.1 Drug Discovery Stage
14.6.2 Preclinical to Phases 1/2
14.6.3 Phase 3 to New Drug Application (NDA) Regulatory Submission
14.6.4 Post‐marketing/Line Extensions
14.7 Developing Control Strategies for (Potential) Mutagenic Degradation Products. 14.7.1 Determining Relevancy of Potential Degradation Products and Developing Control Strategies for Actual Degradation Products
14.7.2 Accelerated Stability (40 °C/75% RH Six months) or Kinetic Equivalent
14.7.3 Photostability Studies
14.7.4 Degradation Chemistry Knowledge
14.8 Risk Assessment Process Illustrated
14.8.1 Case Study #1: Molecule A
14.8.2 Case Study #2: Galunisertib
14.8.3 Case Study #3: Naloxegol
14.8.4 Case Study #4: Selumetinib Side Chain
14.9 Significance of the Risk of Forming Mutagenic Degradation Products
14.9.1 Frequency of Alerting Structures in Degradation Products
14.10 Degradation Reactions Leading to Alerting Structures in Degradation Products
14.10.1 Frequency of Alerting Structures Giving Rise to Ames Positive Tests
14.10.2 Mutagenic Degradation Products: Overall Predicted Frequency
14.11 N‐Nitrosamines: Special Considerations
14.11.1 Evaluation of Potential Formation of N‐Nitrosamines in Drug Product
14.12 Conclusions
References
Index
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