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

by Jenke, Dennis

• ISBN13: 9780470281765
• ISBN10: 0470281766
• Edition: 1st
• Format: Hardcover
• Copyright: 2009-06-02
• Publisher: Wiley-Interscience

Summary

This book specifically addresses the safety aspects of compatibility for drugs and their delivery devices and containers. The author deals with issues such as how the leachables impact safety of a therapeutic product and, more importantly, how one ascertains the magnitude of the impact. The book examines the strategies and tactics for performing safety assessments for leachables and extractables and establishes the means for interpreting the results obtained from such assessments. It helps the pharmaceutical industry unify methodology for assessing leachables and extractables safety of drug packaging.

Author Biography

Dennis Jenke is Principal Scientist in the Technology Resources Division of the Baxter Healthcare Corporation. He works with a team of analytical chemistry professionals in areas including the assessment of material/product compatibility, specifically with respect to leachables/extractables and product ingredient binding. He has published extensively in the areas of analytical chemistry, environmental science, and material/solution compatibility; serves as an expert reviewer for numerous pharmaceutical and analytical journals; is a frequently invited speaker in the general areas of analytical chemistry and material/solution compatibility; and is currently an active participant in ongoing collaborative activities designed to establish harmonized best demonstrated practices for extractables/leachables assessment.

Table of Contents

Preface and Acknowledgments	p. xv
General Concepts	p. 1
Introduction	p. 3
General Discussion	p. 3
Key Definitions	p. 6
The Interacting Parties	p. 6
Extractables versus Leachables	p. 7
Regulatory Perspectives for Performing Compatibility and/or Safety Assessments	p. 13
The U.S. Food and Drug Administration Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics	p. 14
European Medicines Agency (EMEA) Guideline on Plastic Immediate Packaging Materials	p. 15
FDA Guidance for Industry, Inhalation Products	p. 18
Medical Devices	p. 20
An Overview of Strategies for Performing Safety Assessments	p. 21
The Generalized Strategy for Safety Assessments	p. 22
Moving Forward	p. 24
References	p. 25
Nomenclature and General Concepts	p. 27
General	p. 27
Nomenclature	p. 27
Primary Definitions	p. 28
Constituents of a Material or Construct	p. 29
Classification of Extracting Media	p. 31
Classification of Extraction Strategies	p. 32
Example Extraction Conditions Applied to a Model System	p. 39
Correlation	p. 43
Factors That Influence the Linking of Extractables and Leachables	p. 44
A Hierarchy for Linkages between Extractables and Leachables	p. 44
Decisions Concerning the Required Rigor for Linkages	p. 47
Circumstances Requiring the Linking of Extractables and Leachables	p. 48
Identification and Quantitation	p. 50
Risks and Risk Management	p. 55
Risk Categories Related to Biological Assessment of Medical Devices	p. 58
Risk Categories Related to Assessment of Primary Packaging and/or Container-Closure Systems	p. 58
The General Dimensions of Risk	p. 64
Utilization of Risk Classification Profiles	p. 68
Risk Classification in Indirect Contact Situations	p. 71
The Construct Itself as a Contributor to Risk	p. 73
References	p. 74
Extractables, Leachables, and the Product Life Cycle	p. 77
General	p. 77
Discussion of the Components of the Master Flow Diagram	p. 78
Observations	p. 83
Application of the Process Map	p. 87
Material Characterization	p. 89
Material Screening and Characterization	p. 91
Overview	p. 91
General Principles	p. 94
Compendial Compliance	p. 97
United States Pharmacopeia	p. 98
Japanese Pharmaceopeia	p. 101
European Pharmacopeia	p. 102
Compositional Characterization, General Concepts	p. 103
Compositional Characterization by Collecting Available Material Information	p. 104
General	p. 104
Collecting Extractables Information from the Material Supplier	p. 106
Compositional Characterization by Material Testing, Extractables Survey	p. 112
Extractables Survey: Extraction	p. 112
Case Studies: The Influence of Extraction Medium on the Extractables Survey	p. 121
Extractables Survey: Extract Analysis	p. 124
Case Study: Extractables Survey for Plastic Tubing Materials	p. 131
Case Study: Extractables Survey for an Elastomer Used in OINDP	p. 136
Case Study: Extractables Survey for a Rubber Closure Used with Semisolid Drug Products	p. 137
Case Study: Extractables Survey for Filter Cartridges Used in Downstream Processing of Pharmaceuticals	p. 138
Bibliography of Analytical Methods	p. 139
Reconciliation as a Survey Tool	p. 140
Case Study: TOC Reconciliation; Characterization of a Polyolefin Material	p. 141
Use of Extractables Information in Safety Assessment: Extractables Profile, Total Pool, and Total Available Pool	p. 142
Extractions to Establish the Total Pool and Total Available Pool	p. 143
Case Study: Total Pool Determination by Successive Extraction	p. 145
Recap: Components of a Complete Extractables Assessment	p. 146
Caveats in Using Extractables Information for Safety Assessment	p. 149
Chemical Characterization: Device Perspective per ISO 10993-18	p. 152
References	p. 154
Construct Qualification	p. 157
The Prototype Stage	p. 159
General Comments	p. 159
The Simulation Study	p. 161
Generating the Simulating Extract	p. 162
Simulating the Contact Parameters	p. 164
Simulating the Therapeutic Product	p. 166
Simulating the Exposure Parameters	p. 169
Analyzing the Simulating Extract	p. 171
Case Study: Modeling of the Impact of Solubilizing Agents on Leachables Accumulation	p. 172
Case Study: Accumulation of Organic Leachables from Plastic Biopharmaceutical Process Containers	p. 174
Case Study: Accumulation of Label-Related Leachables in a Solid Dosage Form	p. 179
Case Study: Accumulation of Caprolactam Oligomers Leached from Nylon-6 Material	p. 180
Application of the Analytical Threshold	p. 181
The Preliminary Toxicological Assessment	p. 184
Case Study: Assessment of Cyclohexanone Limits for Containers	p. 188
Exiting the Prototype Stage	p. 188
References	p. 189
The Early Development Stage	p. 191
General Comments	p. 191
Target Leachables	p. 192
Method Development, Evaluation, and Validation	p. 194
Method Development (Optimization)	p. 195
Prerequisites to Method Optimization	p. 195
Overview of the Method Optimization Process	p. 197
Conduct of a Method Optimization Study	p. 200
Primary Performance Assessment	p. 201
Troubleshooting Guide	p. 202
Secondary Performance Assessment	p. 204
System Suitability	p. 205
Robustness	p. 205
Exiting Method Development-Optimization	p. 206
The Method Evaluation Process	p. 206
General	p. 206
Aspects of the Evaluation and Validation Processes	p. 207
Overview of the Method Evaluation Process	p. 207
Template for the Conduct of a Method Evaluation Study	p. 209
Validation	p. 214
Case Study: Validation of an LC/MS Method for the Quantitation of Leachables from a Packaging System	p. 215
General	p. 215
Experimental	p. 216
Validation Study	p. 218
Case Study: Validation of an HPLC Method for Quantitating Stopper Leachables in a Complex Surfactant Vehicle	p. 225
General	p. 225
Validation	p. 225
Exiting the Early Development Stage	p. 228
References	p. 228
Construct Validation	p. 229
Late Stage Product Development	p. 231
General: The Migration Study	p. 231
Design of the Migration Study	p. 233
EMEA Guideline on Plastic Immediate Packaging Materials	p. 233
FDA Guidance	p. 233
Optimal Design of a Migration Study	p. 234
Interpretation of the Migration Study: Toxicological Assessment	p. 238
Disaster Management	p. 238
Class A Disaster: Unusual or Unexpected Change in the Concentration of a Target Leachable	p. 239
Class B Disaster: A Previously Unobserved Response Is Obtained During Testing	p. 241
Documenting a Disaster Investigation	p. 242
Specificity Check in Drug Product Analysis Methods	p. 242
Product Stability Issues Associated with Leachables	p. 244
References	p. 245
Submission	p. 249
General Discussion	p. 249
Dossier Format: The Common Technical Document	p. 250
Contents of the CTD Sections Relevant to Container Closure Systems and Their Safety Assessment	p. 252
Section 3.2.P.7, Description	p. 252
Section 3.2.P.2.4, Suitability	p. 254
Closing Observations	p. 262
References	p. 263
Launch	p. 265
Product Maintenance	p. 271
Product Maintenance	p. 273
General Discussion	p. 273
Ongoing Quality Control	p. 275
General	p. 275
Incoming Raw Materials	p. 275
Manufactured In-Process Goods	p. 278
Finished Goods (Final Product)	p. 279
Process of Developing-Implementing QC Extractables Specifications	p. 281
Change Control	p. 282
General	p. 282
Change Control Impact Assessment	p. 285
Evaluation Recommendation	p. 295
Factors to Consider When Contemplating Changes to Registered Products	p. 296
Case Study: Differential Approach	p. 297
Overview	p. 297
General Test Strategy	p. 297
Experimental	p. 298
Results and Discussion	p. 299
Principles for Judging Toxicological Equivalency	p. 304
Disaster Management During Product Maintenance	p. 305
A typical Manufacturing During Product Maintenance	p. 305
Product Use Field Issues Encountered During Product Maintenance	p. 309
Changes in Product Registration Requirements During Product Maintenance	p. 312
Exiting the Product Maintenance Stage	p. 313
References	p. 313
Retirement	p. 315
Focus on Emerging Concepts	p. 319
Overview	p. 319
Plastic Materials used in Manufacturing Applications	p. 320
General	p. 320
Regulatory Requirements	p. 321
Industry Recommendations	p. 322
Case Study: Leachables Evaluation for Bulk Drug Substance	p. 326
Process for Performing Extractables and Leachables Assessments for Disposable Materials Used in Bioprocessing	p. 327
A Matter of Semantics	p. 328
Best Demonstrated Practices in Extractables Assessments	p. 331
The Broader Context of Suitability for Use	p. 337
An Important Practical Consideration	p. 340
Future Considerations	p. 342
References	p. 344
Appendix: Materials Used in Pharmaceutical Constructs and Their Associated Extractables	p. 347
References	p. 370
Index	p. 371
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