Compatibility of Pharmaceutical Products and Contact Materials: Safety Considerations Associated with Extractables and Leachables

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