Compatibility of Pharmaceutical Solutions and Contact Materials : Safety Assessments of Extractables and Leachables for Pharmaceutical Products

Compatibility of Pharmaceutical Products and Contact Materials Dennis Jenke Important safety aspects of compatibility for therapeutic products and their manufacturing systems, delivery devices, and containers Compatibility of Pharmaceutical Products and Contact Materials helps pharmaceutical, toxicology, analytical, and regulatory affairs professionals assess the safety of leachable and extractable chemicals associated with drug product packaging, manufacturing systems, and devices. The most comprehensive resource available, its coverage includes the strategies, tactics, and regulatory requirements for performing safety assessments, along with the means for interpreting results. Structured around a logical framework for an extractables and leachables safety assessment and closely linked to the pharmaceutical product development process, Compatibility of Pharmaceutical Products and Contact Materials directly addresses the fundamental questions of "what activities need to be performed to completely, efficiently, and effectively address the issue of product safety from an extractables and leachables perspective?" and "when do the various required activities need to be performed?" Specifically, the chapters describe: Pertinent regulations and practical ways to meet guidelines Coordinating manufacturing, storage, and delivery systems development and qualification with therapeutic product development Materials characterization and the materials screening process Component and/or system qualification (illustrated by several case studies) Performing validation/migration studies and interpreting and reporting the results Creating a product registration dossier and putting it through regulatory review Product maintenance (Change Control) from an extractables and leachables perspective Likely future developments in extractables and leachables assessment Additionally, the book's appendix provides a database, including CAS registry numbers, chemical formulas and molecular weights of extractable/leachable substances that have been reported in the chemical literature. Detailing the interconnected roles played by analytical chemistry, biological science, toxicology, and regulatory science, Compatibility of Pharmaceutical Products and Contact Materials supplies a much-needed, comprehensive resource to all those in pharmaceutical product or medical device development. COMPATIBILITY OF PHARMACEUTICAL PRODUCTS AND CONTACT MATERIALS......Page 5 CONTENTS......Page 9 PREFACE AND ACKNOWLEDGMENTS......Page 17 PART A GENERAL CONCEPTS......Page 23 General Discussion......Page 25 The Interacting Parties......Page 28 Extractables versus Leachables......Page 29 Regulatory Perspectives for Performing Compatibility and/or Safety Assessments......Page 35 The U.S. Food and Drug Administration Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics......Page 36 European Medicines Agency (EMEA) Guideline on Plastic Immediate Packaging Materials......Page 37 FDA Guidance for Industry, Inhalation Products......Page 40 Medical Devices......Page 42 An Overview of Strategies for Performing Safety Assessments......Page 43 The Generalized Strategy for Safety Assessments......Page 44 Moving Forward......Page 46 References......Page 47 Nomenclature......Page 49 Primary Definitions......Page 50 Constituents of a Material or Construct......Page 51 Classification of Extracting Media......Page 53 Classification of Extraction Strategies......Page 54 Example Extraction Conditions Applied to a Model System......Page 61 Correlation......Page 65 A Hierarchy for Linkages between Extractables and Leachables......Page 66 Decisions Concerning the Required Rigor for Linkages......Page 69 Circumstances Requiring the Linking of Extractables and Leachables......Page 70 Identification and Quantitation......Page 72 Risks and Risk Management......Page 77 Risk Categories Related to Assessment of Primary Packaging and/or Container–Closure Systems......Page 80 The General Dimensions of Risk......Page 86 Utilization of Risk Classification Profiles......Page 90 Risk Classification in Indirect Contact Situations......Page 93 The Construct Itself as a Contributor to Risk......Page 95 References......Page 96 General......Page 99 Discussion of the Components of the Master Flow Diagram......Page 100 Observations......Page 105 Application of the Process Map......Page 109 PART B MATERIAL CHARACTERIZATION......Page 111 Overview......Page 113 General Principles......Page 116 Compendial Compliance......Page 119 United States Pharmacopeia......Page 120 Japanese Pharmaceopeia......Page 123 European Pharmacopeia......Page 124 Compositional Characterization, General Concepts......Page 125 General......Page 126 Collecting Extractables Information from the Material Supplier......Page 128 Extractables Survey: Extraction......Page 134 Case Studies: The Influence of Extraction Medium on the Extractables Survey......Page 143 Extractables Survey: Extract Analysis......Page 146 Case Study: Extractables Survey for Plastic Tubing Materials......Page 153 Case Study: Extractables Survey for an Elastomer Used in OINDP......Page 158 Case Study: Extractables Survey for a Rubber Closure Used with Semisolid Drug Products......Page 159 Case Study: Extractables Survey for Filter Cartridges Used in Downstream Processing of Pharmaceuticals......Page 160 Bibliography of Analytical Methods......Page 161 Reconciliation as a Survey Tool......Page 162 Case Study: TOC Reconciliation; Characterization of a Polyolefin Material......Page 163 Use of Extractables Information in Safety Assessment: Extractables Profile, Total Pool, and Total Available Pool......Page 164 Extractions to Establish the Total Pool and Total Available Pool......Page 165 Case Study: Total Pool Determination by Successive Extraction......Page 167 Recap: Components of a Complete Extractables Assessment......Page 168 Caveats in Using Extractables Information for Safety Assessment......Page 171 Chemical Characterization: Device Perspective per ISO 10993-18......Page 174 References......Page 176 PART C CONSTRUCT QUALIFICATION......Page 179 General Comments......Page 181 The Simulation Study......Page 183 Generating the Simulating Extract......Page 184 Simulating the Contact Parameters......Page 186 Simulating the Therapeutic Product......Page 188 Simulating the Exposure Parameters......Page 191 Analyzing the Simulating Extract......Page 193 Case Study: Modeling of the Impact of Solubilizing Agents on Leachables Accumulation......Page 194 Case Study: Accumulation of Organic Leachables from Plastic Biopharmaceutical Process Containers......Page 196 Case Study: Accumulation of Label-Related Leachables in a Solid Dosage Form......Page 201 Case Study: Accumulation of Caprolactam Oligomers Leached from Nylon-6 Material......Page 202 Application of the Analytical Threshold......Page 203 The Preliminary Toxicological Assessment......Page 206 Exiting the Prototype Stage......Page 210 References......Page 211 General Comments......Page 213 Target Leachables......Page 214 Method Development, Evaluation, and Validation......Page 216 Prerequisites to Method Optimization......Page 217 Overview of the Method Optimization Process......Page 219 Conduct of a Method Optimization Study......Page 222 Primary Performance Assessment......Page 223 Troubleshooting Guide......Page 224 Secondary Performance Assessment......Page 226 Robustness......Page 227 General......Page 228 Overview of the Method Evaluation Process......Page 229 Template for the Conduct of a Method Evaluation Study......Page 231 Validation......Page 236 General......Page 237 Experimental......Page 238 Validation Study......Page 240 Validation......Page 247 References......Page 250 PART D CONSTRUCT VALIDATION......Page 251 General: The Migration Study......Page 253 FDA Guidance......Page 255 Optimal Design of a Migration Study......Page 256 Disaster Management......Page 260 Class A Disaster: Unusual or Unexpected Change in the Concentration of a Target Leachable......Page 261 Class B Disaster: A Previously Unobserved Response Is Obtained During Testing......Page 263 Specificity Check in Drug Product Analysis Methods......Page 264 Product Stability Issues Associated with Leachables......Page 266 References......Page 267 General Discussion......Page 271 Dossier Format: The Common Technical Document......Page 272 Section 3.2.P.7, Description......Page 274 Section 3.2.P.2.4, Suitability......Page 276 Closing Observations......Page 284 References......Page 285 9. Launch......Page 287 PART E PRODUCT MAINTENANCE......Page 293 General Discussion......Page 295 Incoming Raw Materials......Page 297 Manufactured In-Process Goods......Page 300 Finished Goods (Final Product)......Page 301 Process of Developing–Implementing QC Extractables Specifications......Page 303 General......Page 304 Change Control Impact Assessment......Page 307 Evaluation Recommendation......Page 317 Factors to Consider When Contemplating Changes to Registered Products......Page 318 General Test Strategy......Page 319 Experimental......Page 320 Results and Discussion......Page 321 Principles for Judging Toxicological Equivalency......Page 326 Atypical Manufacturing During Product Maintenance......Page 327 Product Use Field Issues Encountered During Product Maintenance......Page 331 Changes in Product Registration Requirements During Product Maintenance......Page 334 References......Page 335 11. Retirement......Page 337 Overview......Page 341 General......Page 342 Regulatory Requirements......Page 343 Industry Recommendations......Page 344 Case Study: Leachables Evaluation for Bulk Drug Substance......Page 348 Process for Performing Extractables and Leachables Assessments for Disposable Materials Used in Bioprocessing......Page 349 A Matter of Semantics......Page 350 Best Demonstrated Practices in Extractables Assessments......Page 353 The Broader Context of Suitability for Use......Page 359 An Important Practical Consideration......Page 362 Future Considerations......Page 364 References......Page 366 Appendix: Materials Used in Pharmaceutical Constructs and Their Associated Extractables......Page 369 References......Page 392 INDEX......Page 393 "Compatibility of Pharmaceutical Products and Contact Materials helps pharmaceutical, toxicology, analytical, and regulatory affairs professionals assess the safety of leachable and extractable chemicals associated with drug product packaging, manufacturing systems, and devices. The most comprehensive resource available, its coverage includes the strategies, tactics, and regulatory requirements fur performing safety assessments, along with the means for interpreting results." "Structured around a logical framework for an extractables and leachables safety assessment and closely linked to the pharmaceutical product development process, Compatibility of Pharmaceutical Products and Contact Materials directly addresses the fundamental questions of "what activities need to be performed to completely, efficiently, and effectively address the issue of product safety from an extractables and leachables perspective?" and "when do the various required activities need to be performed?"" --Book Jacket