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

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