Preface Acknowledgments 1. INTRODUCTION AND ESSENTIAL CONCEPTS 1.1 General Discussion 1.2 Regulations, Guidelines, Standards and Recommendations for Chemical Compatibility Assessments 1.3 Why Chemical Assessment? 1.4 An Overview of the Chemical Compatibility Assessments Process 1.5 Looking Ahead 1.6 References 2.
GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; EXTRACTION AND LEACHING 2.1 Key Definitions and Concepts, Extractables and Leachables 2.2 Extraction Studies 2.2.1 Key Definitions and Concepts 2.2.2 Types of Extractions 2.2.
3 Examples of Extraction Sequences 2.2.4 Required/Recommended Extractions 2.2.5 Principles of Extraction 2.2.5.1 Thermodynamics and Kinetics of Extraction and Leaching 2.
2.5.2 Extraction Solvents, Polarity 2.2.5.3 Extraction Solvents, pH 2.2.5.
4 Temperature/Duration 2.2.5.5 Stoichiometry 2.2.5.6 Additional Factors to Consider 2.2.
6 Compromised Extracts 2.3. Leaching Studies 2.4 Variation in Extraction and Leaching Studies 2.5 References 3. GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; ANALYTICAL TESTING FOR EXTRACTABLES AND LEACHABLES; ORGANIC COMPOUNDS 3.1 Key Definitions and Concepts 3.2 Organic Substance Analysis, Screening 3.
2.1 Relevant Analytical Methods 3.2.2 Survey of Chromatographic Screening Methods 3.2.3 Derivation and Use of the Analytical Evaluation Threshold (AET) 3.2.3.
1 Definitions and Concepts 3.2.3.2 Sample AET Calculations 3.2.3.3 Uncertainty Adjustments to the AET 3.2.
3.4 Selecting the Basis for the AET 3.2.3.5 The Relationship Between the AET and other Measures of Analytical Sensitivity 3.2.4 Discovery 3.2.
5 Identification and Identification Categories 3.2.6 The Identification Process 3.2.7 "Quantitation" 3.2.8 Uncertainty Adjustments to Quantitative Data 3.2.
9 Reducing Variation via Process Optimization 3.2.10 Screening Errors and their Mitigation - Extractables/Leachables Database 3.2.11 Method Qualification 3.3 Organic Substance Analysis, Targeting 3.3.1 Intent and Purpose 3.
3.2 Selection and Justification of Targets 3.3.3 Establishing Reporting Practices 3.3.4 Method Validation 3.4 Organic Substance Analysis, Targeted Screening 3.5.
Extractables/Leachables Correlations 3.5.1 Linking Extractables and Leachables 3.5.2 A Hierarchy for Linkages between Extractables and Leachables 3.5.3 Decisions Concerning the Required Rigor for Linkages 3.5.
4 Circumstances Requiring the Linking of Extractables and Leachables 3.5.5 Examples of Linkages between Extractables and Leachables 3.5.6 Practical Realities Associated with Linking Extractables and Leachables 3.6 Intra-laboratory Variation in Extractables/Leachables Profiles 3.6.1 PQRI Controlled Extraction Study 3.
6.2 Investigation of Lab-to-Lab Variation Between Four Testing Laboratories 3.6.3 Investigation of Extraction Conditions for Medical Devices 3.6.4 If You Play this Game Long Enough, You are Bound to Repeat Yourself 3.6.5 Addressing Variation in Environmental Testing 3.
6.6 Concluding Thoughts 3.7 References 4. GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; ANALYTICAL TESTING FOR EXTRACTABLES AND LEACHABLES; ELEMENTS, ANIONS AND GENERAL TESTING 4.1 Elemental Analysis 4.1.1 The Mandate for Extractable Element Testing 4.1.
2 Identifying Proper Articles for Extractable Elements Testing 4.1.3 Establishing Proper Test Parameters 4.1.3.1 Generating the Extract 4.1.3.
2 Testing the Extract 4.1.4 Selecting Target Elements 4.1.5 Reporting and Interpreting Extracted Elements Test Results 4.1.6 Other Considerations 4.1.
6.1 Extracted Elements and the Product Lifecycle 4.1.6.2 Global Standards for Extracted Elements Testing 4.1.6.3 Use and Value of Vendor-supplied Information 4.
1.7 Existing Knowledge Concerning Extracted Elements in Materials and Systems 4.2 Ionic Extractables 4.3 Scouting via General Chemical Analysis 4.3.1 General Discussion 4.3.2 pH 4.
3.3 UV Absorbance 4.3.4 TOC 4.3.4.1 Use of TOC in Screening 4.3.
4.2 Performing a TOC Reconciliation 4.3.4.3 Using TOC Reconciliation to Judge the Completeness of Extractables Profiling 4.3.4.4 Using Unreconciled TOC to estimate the Level of Unknown Extractables 4.
4 References 5. EXTRACTABLES, LEACHABLES AND THE PRODUCT LIFECYCLE THROUCH PRODUCT APPROVAL AND LAUNCH 5.1 Introduction 5.2 Situation 5.3 Definitions 5.4 The Chemical Compatibility Assessment Process 5.4.1 Material Selection 5.
4.2 System Qualification 5.4.3 Product Qualification 5.4.4 Product Maintenance, Change Control 5.4.5 Component Testing 5.
5 Elements of the Chemical Compatibility Assessment Process 4.5.1 Stage 1: Material Selection 5.5.1.1 General Discussion 5.5.1.
2 Vendor Information 5.5.1.3 Material Assessment 5.5.1.4 The Material Characterization and Selection Report 5.5.
2 Supporting Product Development Between Stages 1 and 2 5.5.2.1 Revision Control during Product Development 5.5.2.2 Supplemental Testing during Product Development 5.5.
3 Stage 2: System Qualification 5.5.3.1 Discussion 5.5.3.2 The System Qualification process 5.5.
3.3 Extractables Profiling 5.5.3.4 Impact Assessment of the Extractables Profile 5.5.3.5 The Analytical Evaluation Threshold (AET) 5.
5.4 Stage 3: Product Qualification 5.5.4.1 Discussion 5.5.4.2 The Concept of Target Leachables 5.
5.4.3 Product Qualification via a Targeted Migration Study Performed on Stability 5.5.4.4 Impact Assessment of Target Leachables 5.5.4.
5 Leachables Screening 5.6 Advanced Topics in Chemical Compatibility Assessment 5.6.1 Application of Design Space Concepts to Chemical Compatibility Assessment 5.6.2 Migration Modelling to Reduce Study Duration 5.6.3 Extractables and Leachables Database to Facilitate the Transition from Scouting to Profiling 5.
6.4 Regulatory Status 5.7 References 6. EXTRACTABLES, LEACHABLES AND THE PRODUCT LIFECYCLE, CHANGE CONTROL 6.1 Stage 4: Life Cycle Management; Change Control via a Comparability Protocol 6.1.1 A Tiered Approach to Change Control 6.1.
2 Two levels of Change, T0 Assessment 5.1.2.1 Material Level Changes (Tier 0) 5.1.2.2 System Level Changes (Tier 0) 6.1.
3 Tier 1 Assessment 6.1.4 Tier 2 Assessment 6.1.5 Additional Lifecycle Management Considerations 6.1.5.1 Refreshing a System''s Extractables Profile 6.
1.5.2 Control of Incoming Materials 6.2. Stage 4: Life Cycle Management; Change Control via a Risk-based Approach 6.2.1 Discussion 6.2.
2 Definitions 6.2.3 Essential Principles of Change Categorization 6.2.4 Understanding the Absolute Risk 6.2.5 Stage 1 Categorization; Use of Prior Knowledge to Drive Categorization 6.2.
6 Stage 2 Categorization; General Process 6.2.6.1 Change Dimensions 6.2.6.2 Dimension #1, Where in the packaging system is the change being made? 6.2.
6.3 Dimension #2, What type of change is being considered? 6.2.6.4 Dimension #3, How is the packaging system being changed? 6.2.6.5 Dimension #4, What is the magnitude of the change? 6.
2.7 Completing Stage 2 Categorization 6.3 References 7. APPLICATIONS - PHARMACUETICAL DRUG PRODUCTS - PACKAGING 7.1 Classification of Packaging Systems and Components 7.2 Pharmacopeial Monographs 7.2.1 The Role of the Pharmacopeia in Setting Standards for Chemical Characterization of Packaging 7.
2.2 Pharmacopeial Guidance; Compendial Monographs 7.2.3 The United States Pharmacopeia (USP) Monographs on Packaging Materials and Systems 7.2.3.1 General Discussion 7.2.
3.2 Plastic Packaging Systems and Their Materials of Constructions; , , , 7.2.3.3 Plastic Packaging; Extractables and Leachables, and 7.2.3.4 Containers - Glass; and 7.
2.3.5 Elastomeric Components; , 7.2.4 The European Pharmacopeia (Pharm Eur) Monographs on Packaging Materials and Systems 7.2.5 Other Pharamcopeia 7.3 Regulatory Guidance 7.
3.1 The FDA 1999 Container Closure Guidance 7.3.2 The FDA Guidance for OIDNP 7.3.3 The EMEA Guideline on Plastic Immediate Packaging (2006) 7.4 Best Practice Recommendations 7.4.
1 PQRI OINDP 7.4.2 PQRI PDP 7.4.3 PQRI POP 7.5 Risk Classification of Packaging Systems 7.6 Extractables Profiling of Packaging Systems based on Risk Classification 7.7 Case Studies 7.
7.1 Injectable Drug Products 7.7.2 Other Dosage Forms 7.8 References 8. APPLICATIONS - PHARMACEUTICAL DRUG PRODUCTS - MANUFACTURING COMPONENTS AND SYSTEMS 8.1 Introduction 8.2 Industry Perspectives 8.
2.1 Vendor Perspective, Bio-Process Systems Alliance (BPSA) 8.2.2 User Perspective, BioPhorum (BPOG) 8.2.2.1 General Discussion 8.2.
2.2 Performing Extractions 8.2.2.3 Analysis of Extracts 8.2.2.4 Reporting Extractables Test Results 8.
2.2.5 Leachables 8.3 Compendial Guidance, USP and 8.3.1 Perspectives on the Development of a USP Monograph for the Chemical Characterization.