Extractables and Leachables: Characterization of Drug Products, Packaging, Manufacturing and Delivery Systems, and Medical Devices

ISBN-13: 9781119605072 / Angielski / Twarda / 2022 / 448 str.

Dennis Jenke

Spis treści

PrefaceAcknowledgments1. INTRODUCTION AND ESSENTIAL CONCEPTS1.1 General Discussion1.2 Regulations, Guidelines, Standards and Recommendations for Chemical Compatibility Assessments1.3 Why Chemical Assessment?1.4 An Overview of the Chemical Compatibility Assessments Process1.5 Looking Ahead1.6 References2. GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; EXTRACTION AND LEACHING2.1 Key Definitions and Concepts, Extractables and Leachables2.2 Extraction Studies2.2.1 Key Definitions and Concepts2.2.2 Types of Extractions2.2.3 Examples of Extraction Sequences2.2.4 Required/Recommended Extractions2.2.5 Principles of Extraction2.2.5.1 Thermodynamics and Kinetics of Extraction and Leaching2.2.5.2 Extraction Solvents, Polarity2.2.5.3 Extraction Solvents, pH2.2.5.4 Temperature/Duration2.2.5.5 Stoichiometry2.2.5.6 Additional Factors to Consider2.2.6 Compromised Extracts2.3. Leaching Studies2.4 Variation in Extraction and Leaching Studies2.5 References3. GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; ANALYTICAL TESTING FOR EXTRACTABLES AND LEACHABLES; ORGANIC COMPOUNDS3.1 Key Definitions and Concepts3.2 Organic Substance Analysis, Screening3.2.1 Relevant Analytical Methods3.2.2 Survey of Chromatographic Screening Methods3.2.3 Derivation and Use of the Analytical Evaluation Threshold (AET)3.2.3.1 Definitions and Concepts3.2.3.2 Sample AET Calculations3.2.3.3 Uncertainty Adjustments to the AET3.2.3.4 Selecting the Basis for the AET3.2.3.5 The Relationship Between the AET and other Measures of Analytical Sensitivity3.2.4 Discovery3.2.5 Identification and Identification Categories3.2.6 The Identification Process3.2.7 "Quantitation"3.2.8 Uncertainty Adjustments to Quantitative Data3.2.9 Reducing Variation via Process Optimization3.2.10 Screening Errors and their Mitigation - Extractables/Leachables Database3.2.11 Method Qualification3.3 Organic Substance Analysis, Targeting3.3.1 Intent and Purpose3.3.2 Selection and Justification of Targets3.3.3 Establishing Reporting Practices3.3.4 Method Validation3.4 Organic Substance Analysis, Targeted Screening3.5. Extractables/Leachables Correlations3.5.1 Linking Extractables and Leachables3.5.2 A Hierarchy for Linkages between Extractables and Leachables3.5.3 Decisions Concerning the Required Rigor for Linkages3.5.4 Circumstances Requiring the Linking of Extractables and Leachables3.5.5 Examples of Linkages between Extractables and Leachables3.5.6 Practical Realities Associated with Linking Extractables and Leachables3.6 Intra-laboratory Variation in Extractables/Leachables Profiles3.6.1 PQRI Controlled Extraction Study3.6.2 Investigation of Lab-to-Lab Variation Between Four Testing Laboratories3.6.3 Investigation of Extraction Conditions for Medical Devices3.6.4 If You Play this Game Long Enough, You are Bound to Repeat Yourself3.6.5 Addressing Variation in Environmental Testing3.6.6 Concluding Thoughts3.7 References4. GENERAL PRINCIPLES OF CHEMICAL ASSESSMENT; ANALYTICAL TESTING FOR EXTRACTABLES AND LEACHABLES; ELEMENTS, ANIONS AND GENERAL TESTING4.1 Elemental Analysis4.1.1 The Mandate for Extractable Element Testing4.1.2 Identifying Proper Articles for Extractable Elements Testing4.1.3 Establishing Proper Test Parameters4.1.3.1 Generating the Extract4.1.3.2 Testing the Extract4.1.4 Selecting Target Elements4.1.5 Reporting and Interpreting Extracted Elements Test Results4.1.6 Other Considerations4.1.6.1 Extracted Elements and the Product Lifecycle4.1.6.2 Global Standards for Extracted Elements Testing4.1.6.3 Use and Value of Vendor-supplied Information4.1.7 Existing Knowledge Concerning Extracted Elements in Materials and Systems4.2 Ionic Extractables4.3 Scouting via General Chemical Analysis4.3.1 General Discussion4.3.2 pH4.3.3 UV Absorbance4.3.4 TOC4.3.4.1 Use of TOC in Screening4.3.4.2 Performing a TOC Reconciliation4.3.4.3 Using TOC Reconciliation to Judge the Completeness of Extractables Profiling4.3.4.4 Using Unreconciled TOC to estimate the Level of Unknown Extractables4.4 References5. EXTRACTABLES, LEACHABLES AND THE PRODUCT LIFECYCLE THROUCH PRODUCT APPROVAL AND LAUNCH5.1 Introduction5.2 Situation5.3 Definitions5.4 The Chemical Compatibility Assessment Process5.4.1 Material Selection5.4.2 System Qualification5.4.3 Product Qualification5.4.4 Product Maintenance, Change Control5.4.5 Component Testing5.5 Elements of the Chemical Compatibility Assessment Process4.5.1 Stage 1: Material Selection5.5.1.1 General Discussion5.5.1.2 Vendor Information5.5.1.3 Material Assessment5.5.1.4 The Material Characterization and Selection Report5.5.2 Supporting Product Development Between Stages 1 and 25.5.2.1 Revision Control during Product Development5.5.2.2 Supplemental Testing during Product Development5.5.3 Stage 2: System Qualification5.5.3.1 Discussion5.5.3.2 The System Qualification process5.5.3.3 Extractables Profiling5.5.3.4 Impact Assessment of the Extractables Profile5.5.3.5 The Analytical Evaluation Threshold (AET)5.5.4 Stage 3: Product Qualification5.5.4.1 Discussion5.5.4.2 The Concept of Target Leachables5.5.4.3 Product Qualification via a Targeted Migration Study Performed on Stability5.5.4.4 Impact Assessment of Target Leachables5.5.4.5 Leachables Screening5.6 Advanced Topics in Chemical Compatibility Assessment5.6.1 Application of Design Space Concepts to Chemical Compatibility Assessment5.6.2 Migration Modelling to Reduce Study Duration5.6.3 Extractables and Leachables Database to Facilitate the Transition from Scouting to Profiling5.6.4 Regulatory Status5.7 References6. EXTRACTABLES, LEACHABLES AND THE PRODUCT LIFECYCLE, CHANGE CONTROL6.1 Stage 4: Life Cycle Management; Change Control via a Comparability Protocol6.1.1 A Tiered Approach to Change Control6.1.2 Two levels of Change, T0 Assessment5.1.2.1 Material Level Changes (Tier 0)5.1.2.2 System Level Changes (Tier 0)6.1.3 Tier 1 Assessment6.1.4 Tier 2 Assessment6.1.5 Additional Lifecycle Management Considerations6.1.5.1 Refreshing a System's Extractables Profile6.1.5.2 Control of Incoming Materials6.2. Stage 4: Life Cycle Management; Change Control via a Risk-based Approach6.2.1 Discussion6.2.2 Definitions6.2.3 Essential Principles of Change Categorization6.2.4 Understanding the Absolute Risk6.2.5 Stage 1 Categorization; Use of Prior Knowledge to Drive Categorization6.2.6 Stage 2 Categorization; General Process6.2.6.1 Change Dimensions6.2.6.2 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 Categorization6.3 References7. APPLICATIONS - PHARMACUETICAL DRUG PRODUCTS - PACKAGING7.1 Classification of Packaging Systems and Components7.2 Pharmacopeial Monographs7.2.1 The Role of the Pharmacopeia in Setting Standards for Chemical Characterization of Packaging7.2.2 Pharmacopeial Guidance; Compendial Monographs7.2.3 The United States Pharmacopeia (USP) Monographs on Packaging Materials and Systems7.2.3.1 General Discussion7.2.3.2 Plastic Packaging Systems and Their Materials of Constructions; , , ,7.2.3.3 Plastic Packaging; Extractables and Leachables, and7.2.3.4 Containers - Glass; and7.2.3.5 Elastomeric Components; ,7.2.4 The European Pharmacopeia (Pharm Eur) Monographs on Packaging Materials and Systems7.2.5 Other Pharamcopeia7.3 Regulatory Guidance7.3.1 The FDA 1999 Container Closure Guidance7.3.2 The FDA Guidance for OIDNP7.3.3 The EMEA Guideline on Plastic Immediate Packaging (2006)7.4 Best Practice Recommendations7.4.1 PQRI OINDP7.4.2 PQRI PDP7.4.3 PQRI POP7.5 Risk Classification of Packaging Systems7.6 Extractables Profiling of Packaging Systems based on Risk Classification7.7 Case Studies7.7.1 Injectable Drug Products7.7.2 Other Dosage Forms7.8 References8. APPLICATIONS - PHARMACEUTICAL DRUG PRODUCTS - MANUFACTURING COMPONENTS AND SYSTEMS8.1 Introduction8.2 Industry Perspectives8.2.1 Vendor Perspective, Bio-Process Systems Alliance (BPSA)8.2.2 User Perspective, BioPhorum (BPOG)8.2.2.1 General Discussion8.2.2.2 Performing Extractions8.2.2.3 Analysis of Extracts8.2.2.4 Reporting Extractables Test Results8.2.2.5 Leachables8.3 Compendial Guidance, USP and8.3.1 Perspectives on the Development of a USP Monograph for the Chemical Characterization of Pharmaceutical Plastics8.3.2 Objectives and Scope8.3.3 The Concept of a Comparator; Initial Assessment8.3.4 Risk Assessment and Risk Classification8.3.5 Risk-based Testing of Plastic Components and Systems8.3.6 The Standard Extraction Protocol per USP8.4 Flexibility in the Implementation of USP8.5 Risk Classification of Manufacturing Components8.5.1 General Requirements per USP8.5.2 A Scientifically Rigorous Risk Assessment Process8.5.3 The BioPhorum Leachables Risk Assessment Process8.5.4 The USP Extractables Risk Assessment Process8.6 Case Studies8.7 References9. APPLICATIONS - MEDICAL DEVICES9.1 Introduction9.2 Regulatory Landscape - ISO 10993; Extraction9.2.1 ISO 10993:12(2012)9.2.2 ISO 10993:20(2020)9.2.3 Reconciling the Extraction Conditions Contained in Parts 12 and 189.3 Linking Extraction Conditions to Medical Device Categories9.4 Regulatory Landscape - ISO 10993; Testing of Extracts9.4.1 Test Methods9.4.2 Test Method Qualification9.4.3 Reporting of Test Data9.5 The Chemical Characterization Process for Medical Devices per 10993:18(2020)9.5.1 The Chemical Characterization Flow Chart9.5.2 Compositional Assessment9.5.3 Extractables Assessment9.5.4 Leachables Assessment9.6 FDA Recognition of Part 189.7 Medical Device Packaging9.8 Case Studies9.9 References10. GENERAL PRINCIPLES FOR RISK ASSESSMENT OF EXTRACTABLES AND LEACHABLES10.1 Toxicological Safety Risk Assessment of Extractables and Leachables10.1.1 Introduction10.1.2 Key Definitions and Concepts10.1.3 The Toxicological Safety Risk Assessment Process Simplified10.1.4 Toxicological Safety Risk Assessment of Pharmaceutical Packaging10.1.5 Toxicological Safety Risk Assessment of Medical Devices10.1.6 Toxicological Safety Risk Assessment of Manufacturing Components10.1.7 Toxicological Safety Risk Assessment of Incompletely Identified Compounds10.2 The Special Case of Biologics10.3 Biological Safety Risk Assessment10.3.1 Key Definitions and Concepts10.3.2 Biological Tests and Test Methods10.4 The Use of Auxiliary Information in Safety Risk Assessment10.5 Are Organic Extractables and Leachables Inherently Unsafe?10.6 Assessing Risks other than Patient Safety10.7 References11. FOCUS ON EMERGING CONCEPTS11.1 A Dose of Reality11.2 Designing and Implementing Better Extractions11.3 Achieving Better Analytical Outcomes11.3.1 Making the Case for Standardized Methods11.3.2 Reducing, Mitigating and Eliminating Errors and Variation in E&L Testing11.3.3 The Final Word on Setting the Uncertainty Factor, UF, for AET Adjustment11.4 Information Sharing for the Common Good11.5 Reduction of Redundant Testing11.6 Replacing the Lab with a Computer (Mathematical Modeling)11.6 Consider the Impact of a Result Before Attempting to Improve It11.7 The End of E&L?11.8 References12. GLOSSARY AND ABBREVIATIONSAPPENDIX: Principles for Identifying Organic Extractables and LeachablesA.1 Identification Classes, Processes and PracticesA.1.1 IntroductionA.1.2 IdentificationA.1.3 Identifying Information and Its UseA.1.3.1 Mass Spectral matchingA.1.3.2 Manual Mass Spectral Interpretation - Structural ElucidationA.1.3.3 Additional Evidences - Securing the Identity with the Highest ConfidenceA.1.4 Practical Considerations in IdentificationA.2 Identification via Mass Spectral MatchingA.2.1 Introduction to Mass Spectral MatchingA.2.2 Relevance of External Mass Spectral Libraries for IdentificationA.2.3 Detection and Discrimination of Analyte Signals (Spectra) for IdentificationA.2.4 Evaluation of Mass Spectral Matching ResultsA.2.5 Examples of Identification by Mass Spectral MatchingA.2.5.1 Example 1: Correct Identification for Best Hit (MF > 900); GC/MSA.2.5.2 Example 2: Correct identification for Best Hit (800A.2.5.3 Example 3: Incorrect identification for Best Hit (800A.2.5.4 Example 4: False Positive Identification for Best Hit (700A.2.6 Closing CommentsA.3 Identification by Mass Spectral InterpretationA.3.1 Introduction to Mass Spectral InterpretationA.3.2 Identification of the Molecular FormulaA.3.3 Interpretation of Isotopic DataA.3.4 Interpretation of Mass Fragments: De Novo Structural ElucidationA.3.5 Case StudiesA.3.5.1 Case 1: Molecular Ion Not IdentifiedA.3.5.2 Case 2: Molecular Ion is Identified (unit mass)A.3.5.3 Case 3: Molecular Formula is Identified (accurate mass)A.3.6 ConclusionA.4 Additional Evidences - Securing the Identity with the Highest ConfidenceA.4.1 Retention Time/Index MatchingA.4.2 Tandem Mass SpectrometryA.4.3 Additional Evidences from Orthogonal TechniquesA.4.4 DerivatizationA.4.5 Indirect InferencesA.4.6 The Use of a Database to Capture the Identification EffortsA.4.7 ConclusionA.5 Overall ConclusionA.6 References

O autorze

Dennis Jenke, PhD, is the Chief Executive Scientist at Triad Scientific Solutions and has over 40 years of direct technical experience in the pharmaceutical, environmental, mining, geoscience, and chemical industries.