Analytical Testing for the Pharmaceutical GMP Laboratory

Cover
Title Page
Copyright Page
Contents
Einstein Quotation
Preface
About the Editor
Biographies of Contributing Authors
Editorial Notes
Acknowledgments
Chapter 1 Drug Regulations and the Pharmaceutical Laboratories
1.1 Introduction
1.2 Food and Drug Administration: Roles and Its Regulations
1.2.1 Code of Federation Regulations
1.2.2 FDA Guidance Documents
1.2.3 FDA Manual of Policies and Procedures
1.3 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and Its Role
1.3.1 ICH Background
1.3.2 ICH Structure
1.3.3 ICH Organization
1.3.4 ICH Topics
1.4 Pharmaceutical Analysis
1.4.1 Analytical Testing
1.4.2 Interaction of the Analytical Development Department and Other Functional Areas
1.4.3 Drug Development Process
1.5 Summary
List of Abbreviations
References
Chapter 2 Good Manufacturing Practices (GMPs) and the Quality Systems
2.1 Introduction to Good Manufacturing Practices
2.2 Objectives of GMPs
2.2.1 Definitions
2.2.2 Organization of 21 CFR Regulations
2.3 Personnel Qualification and Responsibilities – Subpart B
2.3.1 Responsibilities of the Quality Control Unit
2.3.2 Personnel Qualifications and Responsibilities
2.4 Equipment – Subpart D
2.4.1 Metrology Functions
2.4.2 Qualification Phases
2.5 Laboratory Controls
2.5.1 General Requirements
2.5.2 Testing and Release for Distribution
2.5.3 Stability Program
2.5.4 Retention Program
2.6 Records and Reports
2.7 Pharmaceutical Quality
2.7.1 Quality Manual
2.7.2 Quality Risk Management
2.7.3 Product Quality Review
2.7.4 Pharmaceutical Quality Systems
List of Abbreviations
References
Chapter 3 Analytical Techniques Used in the GMP Laboratory
3.1 Introduction
3.2 Definitions
3.2.1 Raw Data and Analytical Data
3.2.2 Analyses
3.2.3 Analytical Documents
3.3 Basic Laboratory Procedures
3.3.1 Balances
3.3.2 Volumetric Glassware
3.3.3 Potentiometry (Ion-Selective Electrode) and pH Test
3.3.4 The Density Test
3.3.5 The Friability Test
3.3.6 The Hardness Test
3.3.7 The Titration Test
3.3.8 The Karl Fischer Titration–Water Determination
3.3.9 Loss on Drying
3.3.10 Residue on Ignition/Sulfated Ash
3.3.11 Thermo Gravimetric Analysis
3.3.12 Differential Scanning Calorimetry
3.3.13 The Disintegration Test
3.3.14 Particulate Matter
3.3.15 Osmolality
3.4 Chromatography
3.4.1 High-Performance Liquid Chromatography
3.4.2 Ultra-High-Pressure Liquid Chromatography
3.4.3 Detectors of Liquid Chromatography
3.4.4 System Suitability Tests for Chromatographic Methods
3.4.5 Maintenance of HPLC and UHPLC
3.4.6 Gas Chromatography
3.4.7 Thin-Layer Chromatography
3.4.8 Bio-Pharmaceutical Separations
3.5 Spectroscopic Sciences
3.5.1 Ultraviolet–Visible
3.5.2 Infrared-Absorption
3.5.3 Mass Spectroscopy
3.5.4 Atomic Absorption, Inductively Coupled Plasma, Inductively Coupled Plasma/Mass Spectrometry, and Inductively Coupled Plasma/Optical Emission Spectrometry
3.5.5 Nuclear Magnetic Resonance Spectroscopy
3.5.6 X-ray Absorption and X-ray Emission Spectrometry
3.6 Uniformity of Dosage Units
3.6.1 Weight Variation
3.6.2 Acceptance Criteria per USP <905>
3.7 Elemental Analysis
3.8 Appearance
3.9 Visual Inspection
3.10 Microbiological Testing
3.10.1 Microbial Limits
3.10.2 Sterility
3.10.3 Bacterial Endotoxins
3.10.4 Antimicrobial Effectiveness Testing
3.11 Summary
References
Chapter 4 Control Strategies for Pharmaceutical Development
4.1 Introduction
4.2 Quality-by-Design Concept
4.3 Risk Management
4.3.1 Risk Assessment
4.3.2 Risk Control
4.4 Establishing Specifications
4.4.1 What Is the Specification?
4.4.2 Typical Tests Included in the Specification of a Small Molecule Drug
4.4.3 Typical Tests Included in the Specification of Biological Drugs
4.4.4 Considerations of Setting Acceptance Criteria
4.5 Design of Experiments
4.5.1 Common Terms
4.5.2 Conducting the Study
4.5.3 Results Interpretation
4.5.4 Summary
4.6 Common Statistical Analysis
4.6.1 Mean, Standard Deviation (SD), and Relative Standard Deviation (RSD)
4.6.2 Confidence Interval
4.6.3 Statistical Significance (t-Test)
4.6.4 Outlier Detection
4.7 Summary
List of Abbreviations
References
Chapter 5 Development and Validation of Analytical Procedures
5.1 Introduction
5.2 Method Development
5.2.1 Development of Physical, Chemical, and Microbiological Procedures
5.3 Qualification, Validation, and Verification
5.3.1 Qualification
5.3.2 Validation
5.3.3 Verification
5.3.4 Frequency of Study
5.4 Validation Parameters
5.4.1 Accuracy
5.4.2 Precision
5.4.3 Specificity
5.4.4 Quantitation and Detection Limits (QL and DL)
5.4.5 Linearity
5.4.6 Range
5.4.7 Robustness
5.4.8 System Suitability Tests (SST)
5.4.9 Stability of Samples During Analysis
5.4.10 Tie the Pieces Together
5.5 Validation for Physical, Chemical, Biotechnological, and Microbiological Procedures
5.6 Validation of In-process, Environmental, Release, and Stability Procedures
5.6.1 In-process Procedures
5.6.2 Environmental Procedures
5.6.3 Release and Stability Procedures
5.7 Other Procedures
5.7.1 Process Analytical Technology (PAT)
5.7.2 Parametric Release and Real-time Release
5.8 Validation of Procedures in Continuous and Batch Manufacturing
5.9 Summary
List of Abbreviations
References
Chapter 6 Transfer of Analytical Procedures
6.1 Introduction
6.2 Purpose of Method Transfer
6.3 Transfer Options
6.3.1 Method Transfer Plan
6.3.2 Comparative Testing
6.3.3 Co-validation
6.3.4 Extended Validation or Partial Validation
6.3.5 Transfer Waiver
6.4 Method Transfer Process
6.4.1 Preparation Phase
6.4.2 Gap Analysis
6.4.3 Method Training Phase
6.4.4 Method Qualification Phase
6.5 Transfer Protocol
6.5.1 Content of a Transfer Protocol
6.5.2 Objectives/Scope
6.5.3 Roles and Responsibilities
6.5.4 Assessment of Receiving Lab
6.5.5 Materials, Facilities, and Instrumentation
6.5.6 Analyst Training
6.5.7 Qualification Procedure
6.5.8 Acceptance Criteria
6.5.9 Protocol Amendment and Deviation
6.6 Method Transfer Report
6.6.1 Objectives
6.6.2 Data Evaluation
6.6.3 Conclusion of Transfer Report
6.6.4 Analytical Transfer File
6.7 Related Documents
6.8 Handling Transfer Failures
6.9 Transfer to a Contract Lab
6.10 Transfer to an International Site
6.11 Summary
References
Chapter 7 Dissolution Testing in the Pharmaceutical Laboratory
7.1 Introduction
7.2 Regulatory and Compendial Role in Dissolution Testing
7.3 Theory
7.4 Equipment Operation and Sources of Error
7.4.1 Equipment Variables
7.4.2 Media Deaeration
7.4.3 Vibration
7.4.4 Water Bath of Dissolution Equipment
7.4.5 Glass Vessels
7.5 Common Errors of Dissolution Apparatus
7.5.1 USP Apparatus 1 and 2
7.5.2 USP Apparatus 3
7.5.3 USP Apparatus 4
7.5.4 USP Apparatus 5
7.5.5 USP Apparatus 6
7.5.6 USP Apparatus 7
7.6 Dissolution Method Considerations
7.6.1 Sample Introduction
7.6.2 Media Attributes
7.6.3 Observations
7.6.4 Sinkers
7.6.5 Filters
7.6.6 Manual Sampling
7.6.7 Automation of Dissolution Sampling
7.6.8 Cleaning of Dissolution Equipment
7.7 Method Development
7.7.1 Drug Properties
7.7.2 Dosage Form Properties
7.7.3 Dissolution Profile
7.7.4 Dissolution Media
7.7.5 Medium Volume
7.7.6 Deaeration
7.7.7 Speed
7.7.8 Sinkers
7.7.9 Filtration
7.7.10 Time Points – Immediate Release
7.7.11 Fast Stir or Infinity Point
7.7.12 Time Points for Extended-Release Products
7.8 Poorly Soluble Drugs
7.8.1 Sink Conditions
7.8.2 Apparatus Selection
7.8.3 The Discriminatory Power of the Method
7.9 Setting Specifications
7.10 Harmonization
7.11 Method Validation
7.12 Validation of Product Performance Parameters
7.12.1 Accuracy/Recovery
7.12.2 Selectivity
7.12.3 Solution Stability
7.12.4 Filter
7.12.5 Robustness
7.12.6 Intermediate Precision
7.12.7 Automated Methodology
7.13 Validation of the Analytical Finish
7.14 Method Transfer Considerations
7.14.1 Robustness
7.14.2 Details of the Analytical Method
7.14.3 Other Considerations
7.15 Good Manufacturing Practices (GMP) in the Dissolution Testing Laboratory
7.15.1 Metrology
7.15.2 Notebook Documentation
7.15.3 Equipment Qualification, Validation, and Method Critical Factors
7.15.4 Good Manufacturing Practice Audits
7.15.5 Training
7.16 Summary
Acknowledgment
List of Abbreviations
Chapter 8 Analytical Data and the Documentation System
8.1 Introduction
8.1.1 Types of Documents
8.2 GMP for Records and Reports–Subpart J
8.2.1 General Requirements
8.2.2 Equipment Cleaning and Use Log
8.2.3 Component, Drug Product Container, Closure, and Labeling Records
8.2.4 Master Production and Control Records
8.2.5 Batch Production and Control Records
8.2.6 Production Record Review
8.2.7 Laboratory Records
8.3 Keeping Good Records
8.3.1 Writing Good Procedures
8.3.2 Following Procedures
8.4 Raw Data Documentation
8.4.1 Data Recording Practices
8.4.2 Witness Responsibilities
8.4.3 Changes in Notebook
8.4.4 Recording Date and Time
8.4.5 Voiding and Restoring GMP Records
8.4.6 Computer-Collected Data
8.4.7 Reporting Analytical Results
8.5 Samples, Reagents, Standards, Reference Standards
8.5.1 Samples
8.5.2 Reagents
8.5.3 Analytical Standards
8.5.4 Reference Standards
8.6 Drug Substance Analysis
8.7 Drug Product Analysis
8.8 Batch Release
8.8.1 Batch Packaging Record
8.8.2 Batch Processing Record
8.8.3 Distribution Record
8.9 Establishment of Specifications
8.9.1 Content of Specifications
8.9.2 Setting Specifications
8.9.3 Periodic Revisions
8.9.4 Test Procedures
8.10 Out-of-Specification (OOS) Results
8.10.1 Lab-Phase Investigation
8.10.2 Full Scale Investigation
8.11 Compendial Testing
8.11.1 Validation and Verification of Compendial Procedures
8.11.2 USP Reference Standards
8.12 Standard Operating Procedures
8.12.1 Control of SOPs
8.12.2 Format of SOPs
8.12.3 Flow of Documents
8.13 Analytical Documents
8.13.1 Hierarchy of Documentation Systems
8.13.2 Analytical Protocols
8.13.3 Analytical Reports
8.13.4 Annual Product Review
8.13.5 Changes to Documentation
8.14 Quality Assurance
8.14.1 Six Quality Systems and Their Supporting Programs
8.14.2 Quality System Performance
8.14.3 Lifecycle Management Approach for Analytical Procedures
8.14.4 Audit and Inspection program of the Laboratory
8.15 Summary
References
Chapter 9 Stability Program Supporting Pharmaceutical Products
9.1 Introduction
9.2 Regulatory Requirements for Stability Testing
9.3 Types of Stability Studies
9.3.1 Stability Studies of Materials Used in Clinical Development
9.3.2 Stability Studies of an Active Pharmaceutical Ingredient (API) or Drug Substance (DS)
9.3.3 Stability Studies to Support Formulation Development
9.3.4 Stability Studies to Support Drug Product (DP) Registration
9.3.5 Stability Studies to Support Marketed Products
9.3.6 Bulk Stability
9.3.7 In-Process Testing
9.3.8 In-Use Testing
9.3.9 Stability Studies to Support Excursions
9.4 Stability Program
9.4.1 Fundamental Principle of Stability
9.4.2 Specifications
9.5 Stability Chambers
9.6 Stability Sample Management
9.6.1 Study Start Date
9.6.2 Sample Pull Dates
9.6.3 Study End Date
9.6.4 Sample Inventory
9.7 Stability Protocol
9.7.1 Deviation of Stability Protocol
9.7.2 Study Cancelation
9.7.3 Reduce Testing with Bracketing and Matrixing
9.8 Stability Report
9.9 Annual Product Review (APR)
9.10 Summary
List of Abbreviations
References
Chapter 10 Laboratory Information Management System (LIMS) and Electronic Data
10.1 Introduction
10.2 Analytical and Quality Data Management
10.3 Quality System
10.4 Process Control in Quality Management
10.5 Material Management
10.6 Product Release
10.7 Stability Studies
10.8 Cleaning Validation – Contamination Control
10.9 Equipment Management (Metrology)
10.10 Laboratory Operations
10.11 Automation of Risk Management
10.12 Automated Training Management
10.13 SOPs and Document Management
10.14 Audit Management and Compliance
10.15 Corrective and Preventive Actions (CAPAs)
10.16 Change Management
10.17 Computer Systems Validation
10.18 Evolution in the Data Integrity Regulation
10.19 Data Integrity
10.20 Quality Data
10.21 Benefits of Computerized Systems
10.22 Big Data
List of Abbreviations
References
Index
EULA