Preface and Acknowledgments xv Part A General Concepts 1 1. Introduction 3 General Discussion 3 Key Definitions 6 The Interacting Parties 6 Extractables versus Leachables 7 Regulatory Perspectives for Performing Compatibility and/or Safety Assessments 13 The U.S. Food and Drug Administration Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics 14 European Medicines Agency (EMEA) Guideline on Plastic Immediate Packaging Materials 15 FDA Guidance for Industry Inhalation Products 18 Medical Devices 20 An Overview of Strategies for Performing Safety Assessments 21 The Generalized Strategy for Safety Assessments 22 Moving Forward 24 References 25 2. Nomenclature and General Concepts 27 General 27 Nomenclature 27 Primary Definitions 28 Constituents of a Material or Construct 29 Classification of Extracting Media 31 Classification of Extraction Strategies 32 Example Extraction Conditions Applied to a Model System 39 Correlation 43 Factors That Influence the Linking of Extractables and Leachables 44 A Hierarchy for Linkages between Extractables and Leachables 44 Decisions Concerning the Required Rigor for Linkages 47 Circumstances Requiring the Linking of Extractables and Leachables 48 Identification and Quantitation 50 Risks and Risk Management 55 Risk Categories Related to Biological Assessment of Medical Devices 58 Risk Categories Related to Assessment of Primary Packaging and/or Container-Closure Systems 58 The General Dimensions of Risk 64 Utilization of Risk Classification Profiles 68 Risk Classification in Indirect Contact Situations 71 The Construct Itself as a Contributor to Risk 73 References 74 3. Extractables, Leachables, and the Product Life Cycle 77 General 77 Discussion of the Components of the Master Flow Diagram 78 Observations 83 Application of the Process Map 87 Part B Material Characterization 89 4. Material Screening and Characterization 91 Overview 91 General Principles 94 Compendial Compliance 97 United States Pharmacopeia 98 Japanese Pharmaceopeia 101 European Pharmacopeia 102 Compositional Characterization, General Concepts 103 Compositional Characterization by Collecting Available Material Information 104 General 104 Collecting Extractables Information from the Material Supplier 106 Compositional Characterization by Material Testing, Extractables Survey 112 Extractables Survey: Extraction 112 Case Studies: The Influence of Extraction Medium on the Extractables Survey 121 Extractables Survey: Extract Analysis 124 Case Study: Extractables Survey for Plastic Tubing Materials 131 Case Study: Extractables Survey for an Elastomer Used in OINDP 136 Case Study: Extractables Survey for a Rubber Closure Used with Semisolid Drug Products 137 Case Study: Extractables Survey for Filter Cartridges Used in Downstream Processing of Pharmaceuticals 138 Bibliography of Analytical Methods 139 Reconciliation as a Survey Tool 140 Case Study: TOC Reconciliation; Characterization of a Polyolefin Material 141 Use of Extractables Information in Safety Assessment: Extractables Profile, Total Pool, and Total Available Pool 142 Extractions to Establish the Total Pool and Total Available Pool 143 Case Study: Total Pool Determination by Successive Extraction 145 Recap: Components of a Complete Extractables Assessment 146 Caveats in Using Extractables Information for Safety Assessment 149 Chemical Characterization: Device Perspective per ISO 10993-18 152 References 154 Part C Construct Qualification 157 5. The Prototype Stage 159 General Comments 159 The Simulation Study 161 Generating the Simulating Extract 162 Simulating the Contact Parameters 164 Simulating the Therapeutic Product 166 Simulating the Exposure Parameters 169 Analyzing the Simulating Extract 171 Case Study: Modeling of the Impact of Solubilizing Agents on Leachables Accumulation 172 Case Study: Accumulation of Organic Leachables from Plastic Biopharmaceutical Process Containers 174 Case Study: Accumulation of Label-Related Leachables in a Solid Dosage Form 179 Case Study: Accumulation of Caprolactam Oligomers Leached from Nylon-6 Material 180 Application of the Analytical Threshold 181 The Preliminary Toxicological Assessment 184 Case Study: Assessment of Cyclohexanone Limits for Containers 188 Exiting the Prototype Stage 188 References 189 6.

The Early Development Stage 191 General Comments 191 Target Leachables 192 Method Development, Evaluation, and Validation 194 Method Development (Optimization) 195 Prerequisites to Method Optimization 195 Overview of the Method Optimization Process 197 Conduct of a Method Optimization Study 200 Primary Performance Assessment 201 Troubleshooting Guide 202 Secondary Performance Assessment 204 System Suitability 205 Robustness 205 Exiting Method Development-Optimization 206 The Method Evaluation Process 206 General 206 Aspects of the Evaluation and Validation Processes 207 Overview of the Method Evaluation Process 207 Template for the Conduct of a Method Evaluation Study 209 Validation 214 Case Study: Validation of an LC/MS Method for the Quantitation of Leachables from a Packaging System 215 General 215 Experimental 216 Validation Study 218 Case Study: Validation of an HPLC Method for Quantitating Stopper Leachables in a Complex Surfactant Vehicle 225 General 225 Validation 225 Exiting the Early Development Stage 228 References 228 Part D Construct Validation 229 7. Late Stage Product Development 231 General: The Migration Study 231 Design of the Migration Study 233 EMEA Guideline on Plastic Immediate Packaging Materials 233 FDA Guidance 233 Optimal Design of a Migration Study 234 Interpretation of the Migration Study: Toxicological Assessment 238 Disaster Management 238 Class A Disaster: Unusual or Unexpected Change in the Concentration of a Target Leachable 239 Class B Disaster: A Previously Unobserved Response is Obtained During Testing 241 Documenting a Disaster Investigation 242 Specificity Check in Drug Product Analysis Methods 242 Product Stability Issues Associated with Leachables 244 References 245 8. Submission 249 General Discussion 249 Dossier Format: The Common Technical Document 250 Contents of the CTD Sections Relevant to Container Closure Systems and Their Safety Assessment 252 Section 3.2.P.7, Description 252 Section 3.2.P.

2.4, Suitability 254 Closing Observations 262 References 263 9. Launch 265 Part E Product Maintenance 271 10. Product Maintenance 273 General Discussion 273 Ongoing Quality Control 275 General 275 Incoming Raw Materials 275 Manufactured In-Process Goods 278 Finished Goods (Final Product) 279 Process of Developing-Implementing QC Extractables Specifications 281 Change Control 282 General 282 Change Control Impact Assessment 285 Evaluation Recommendation 295 Factors to Consider When Contemplating Changes to Registered Products 296 Case Study: Differential Approach 297 Overview 297 General Test Strategy 297 Experimental 298 Results and Discussion 299 Principles for Judging Toxicological Equivalency 304 Disaster Management During Product Maintenance 305 Atypical Manufacturing During Product Maintenance 305 Product Use Field Issues Encountered During Product Maintenance 309 Changes in Product Registration Requirements During Product Maintenance 312 Exiting the Product Maintenance Stage 313 References 313 11. Retirement 315 12. Focus on Emerging Concepts 319 Overview 319 Plastic Materials used in Manufacturing Applications 320 General 320 Regulatory Requirements 321 Industry Recommendations 322 Case Study: Leachables Evaluation for Bulk Drug Substance 326 Process for Performing Extractables and Leachables Assessments for Disposable Materials Used in Bioprocessing 327 A Matter of Semantics 328 Best Demonstrated Practices in Extractables Assessments 331 The Broader Context of Suitability for Use 337 An Important Practical Consideration 340 Future Considerations 342 References 344 Appendix: Materials Used in Pharmaceutical Constructs and Their Associated Extractables 347 References 370 Index 371.