Provides practical guidance on pharmaceutical analysis, written by leading experts with extensive industry experience
Analytical Testing for the Pharmaceutical GMP Laboratory presents a thorough overview of the pharmaceutical regulations, working processes, and drug development best practices used to maintain the quality and integrity of medicines. With a focus on smaller molecular weight drug substances and products, the book provides the knowledge necessary for establishing the pharmaceutical laboratory to support Quality Systems while maintaining compliance with Good Manufacturing Practices (GMP) regulations.
Concise yet comprehensive chapters contain up-to-date coverage of drug regulations, pharmaceutical analysis methodologies, control strategies, testing development and validation, method transfer, electronic data documentation, and more. Each chapter includes a table of contents, definitions of acronyms, a reference list, and ample tables and figures. Addressing the principal activities and regulatory challenges of analytical testing in the development and manufacturing of pharmaceutical drug products, this authoritative resource:
- Describes the structure, roles, core guidelines, and GMP regulations of the FDA and ICH.
- Covers the common analytical technologies used in pharmaceutical laboratories, including examples of analytical techniques used for the release and stability testing of drugs.
- Examines control strategies established from quality systems supported by real-world case studies.
- Explains the use of dissolution testing for products such as extended-release capsules, aerosols, and inhalers.
- Discusses good documentation and data reporting practices, stability programs, and the Laboratory Information Management System (LIMS) to maintain compliance.
- Includes calculations, application examples, and illustrations to assist readers in day-to-day laboratory operations.
- Contains practical information and templates to structure internal processes or common Standard Operating Procedures (SOPs).
Analytical Testing for the Pharmaceutical GMP Laboratory is a must-have reference for both early-career and experienced pharmaceutical scientists, analytical chemists, pharmacists, and quality control professionals. It is also both a resource for GMP laboratory training programs and an excellent textbook for undergraduate and graduate courses of analytical chemistry in pharmaceutical sciences or regulatory compliance programs.
Table of Contents:
Dedication
((Einstein quotation))
Preface
About the Editor
Biographies of Contributing Authors
Editorial Notes
Dedication
Acknowledgments
Chapter 1 – Drug Regulations and the Pharmaceutical Laboratories
1.1 Introduction
1.2 Food and Drug Administration: Role and its Regulations
1.2.1 Code of Federal 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
1.3.3.1 Steering Committee
1.3.3.2 Global Cooperation Group
1.3.3.3 MedDRA Management Board
1.3.3.4 Working Groups
1.3.3.5 Secretariat
1.3.3.6 Coordinators
1.3.4 ICH Topics
1.4 Pharmaceutical Analysis
1.4.1 Analytical Testing
1.4.2 Interaction Between the Analytical Development Department and Other Functional Areas
1.4.3 Drug Development Process
1.4.3.1 Toxicological Phase
1.4.3.2 Investigational New Drug
1.4.3.3 Clinical Phase
1.4.3.4 Registration Phase
1.4.3.5 New Drug Application
1.4.3.6 Post-Approval Phase
References
List of Abbreviations
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 Qualifications and Responsibilities – Subpart B
2.3.1 Responsibilities of 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 – Subpart I
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
References
List of Abbreviations
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 Thermal 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
3.4.1.1 Normal Phase Separation Mode
3.4.1.2 Reversed-Phase Separation Mode
3.4.1.3 Other HPLC Separation Modes
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
3.4.6.1 Residual Solvents
3.4.6.2 Hyphenated Technologies
3.4.7 Thin Layer Chromatography
3.4.8 Bio-Pharmaceutical Separations
3.4.8.1 Capillary Zone Electrophoresis
3.4.8.2 Isoelectric focusing
3.4.8.3 Sodium dodecyl sulfate-Polyacrylamide Gel electrophoresis (SDS-Page)
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 Endotoxin
3.10.4 Antimicrobial Effectiveness Testing
3.11 Summary
References
List of Abbreviations
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
4.3.1.1. Risk identification
4.3.1.2. Risk assessment
4.3.2. Risk Control
4.4 Establishing Specifications
4.4.1. What is specification?
4.4.2. Typical tests included in the specification of a small molecule drug
4.4.1. Drug substance
4.4.2. Drug product
4.4.3. Typical tests included in the specification of biological drugs
4.4.3.1. Drug substance
4.4.3.2. Drug product
4.4.4. Considerations of setting acceptance criteria
4.4.4.1. Process capability
4.4.4.2. Impact of drug substance to drug product specification
4.4.4.3. Release vs. shelf life
4.5 Design of Experiments (DoE)
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
References
Chapter 5 – Development and Validation of Analytical Procedures
5.1 Introduction
5.2 Method Development
5.2.1 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
5.4.5 Linearity
5.4.6 Range
5.4.7 Robustness
5.4.8 Suitability System Testing
5.4.9 Sample Stability during Analysis
5.4.10 Tie the Pieces Together
5.5 Validation for Physical, Chemical, Biotechnological and Microbiological Procedures
5.6 Validation for 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
References
List of Abbreviations
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
6.4.1.1 Select a Method Transfer Team
6.4.1.2 Method Transfer Package
6.4.2 Gap Analysis
6.4.2.1 Equipment Capabilities
6.4.2.2 Facilities Readiness
6.4.2.3 Analyst Qualifications
6.4.2.4 Materials used in the Transfer
6.4.3 Method Training Phase
6.4.3.1 Method Familiarization
6.4.3.2 Method Demonstration
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
6.5.3.1 Transferring Laboratory
6.5.3.2 Receiving Laboratory
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
List of Abbreviations
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
7.5 Common Errors of Dissolution Apparatus
7.6 Dissolution Method Considerations
7.7 Method Development
7.8 Poorly Soluble Drugs
7.9 Setting Specifications
7.10 Harmonization
7.11 Method Validation
7.12 Validation of Product Performance Parameters
7.13 Validation of the Analytical finish
7.14 Method Transfer Considerations
7.15 Good Manufacturing Practices in the Dissolution Testing Laboratory
7.16 Summary
7.17 Resources
References
List of Abbreviations
Chapter 8 – Analytical Records 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
8.4.7.1 Decimal Places and Significant Figures
8.4.7.2 Mathematical Operations
8.4.7.3 Rounding Rules
8.4.7.4 Reporting Impurity Results
8.5 Sampling, 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 Results
8.10.1 Lab Phase Investigation
8.10.1.1 Identifying an OOS Result
8.10.1.2 Laboratory Error
8.10.1.3 Determining Root Cause
8.10.1.4 Retesting
8.10.1.5 Outlier Test
8.10.1.6 Averaging Results
8.10.1.7 Field Alert Report
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 System
8.13.2 Analytical Protocols
8.13.3 Analytical Reports
8.13.4 Annual Product Review
8.13.5 Change of documentation
8.14 Quality Assurance
8.14.1 Six Quality Systems and Supporting Programs
8.14.2 Quality System Performance
8.14.3 Lifecycle Management Approach for Analytical Procedures
8.14.4 Audit and Inspection Program
8.15 Summary
References
List of Abbreviations
Chapter 9 – The Stability Program
9.1. Introduction
9.2. Regulatory Requirement 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 Cancellation
9.7.3. Reduce Testing with Bracketing and Matrixing
9.8. Stability Report
9.9. Annual Product Review (APR)
9.10. Summary
References
List of Abbreviations
Chapter 10 – Laboratory Information Management System (LIMS) and Electronic Data
10 Introduction
10.1 Analytica Data to Support Quality decisions
10.2 Quality System
10.3 Metrics in Quality Management
10.4 Material Management
10.5 Product Release
10.6 Stability Studies
10.7 Cleaning Validation – Contamination Control
10.8 Equipment Management (Metrology)
10.9 Laboratory Operations
10.10 Automation of Risk Management
10.11 Automated Training Management
10.12 SOPs and Document Management
10.13 Audit Management and Compliance
10.14 Corrective and Preventive Actions (CAPA)
10.15 Change Management
10.16 Computer Systems Validation
10.17 Data Integrity – Regulatory Evolution
10.18 Data Integrity
10.19 Quality Data
10.20 Benefits of Computerized Systems
10.21 Big Data
References
List of Abbreviations
Index
About the Author :
Kim Huynh-Ba, M.Sc., PMP, FAAPS, is the Chief Executive Officer and Managing Director of Pharmalytik LLC, where she provides consulting and training services to leading pharmaceutical companies and global organizations. She has decades of experience in strategic analytical development, risk management, strategic drug development, and stability sciences. She is an Adjunct Professor at Temple University School of Pharmacy and Illinois Institute of Technology (IIT) teaching GMPs and various regulatory compliance subjects.
