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.

• Dedication((Einstein quotation))PrefaceAbout the EditorBiographies of Contributing AuthorsEditorial NotesDedicationAcknowledgments  Chapter 1 – Drug Regulations and the Pharmaceutical Laboratories1.1         Introduction1.2         Food and Drug Administration: Role and its Regulations1.2.1      Code of Federal Regulations1.2.2      FDA Guidance Documents1.2.3      FDA Manual of Policies and Procedures1.3         International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and its Role1.3.1      ICH background1.3.2      ICH Structure1.3.3      ICH Organization1.3.3.1  Steering Committee1.3.3.2  Global Cooperation Group1.3.3.3  MedDRA Management Board1.3.3.4  Working Groups1.3.3.5  Secretariat1.3.3.6  Coordinators1.3.4      ICH Topics1.4         Pharmaceutical Analysis1.4.1      Analytical Testing1.4.2      Interaction Between the Analytical Development Department and Other Functional Areas    1.4.3      Drug Development Process1.4.3.1  Toxicological Phase1.4.3.2  Investigational New Drug1.4.3.3  Clinical Phase1.4.3.4  Registration Phase1.4.3.5  New Drug Application1.4.3.6  Post-Approval PhaseReferencesList of Abbreviations  Chapter 2 – Good Manufacturing Practices (GMPs) and the Quality Systems2.1         Introduction to Good Manufacturing Practices2.2         Objectives of GMPs2.2.1      Definitions2.2.2      Organization of 21 CFR Regulations2.3         Personnel Qualifications and Responsibilities – Subpart B2.3.1      Responsibilities of Quality Control Unit2.3.2      Personnel Qualifications and Responsibilities2.4         Equipment – Subpart D2.4.1      Metrology Functions2.4.2      Qualification Phases2.5         Laboratory Controls – Subpart I2.5.1      General Requirements2.5.2      Testing and Release for Distribution2.5.3      Stability Program2.5.4      Retention Program2.6         Records and Reports2.7         Pharmaceutical Quality2.7.1      Quality Manual2.7.2      Quality Risk Management2.7.3      Product Quality Review2.7.4      Pharmaceutical Quality SystemsReferencesList of Abbreviations  Chapter 3 – Analytical Techniques Used in the GMP Laboratory3.1         Introduction3.2         Definitions3.2.1      Raw Data and Analytical Data3.2.2      Analyses3.2.3      Analytical Documents3.3         Basic Laboratory Procedures3.3.1      Balances3.3.2      Volumetric Glassware3.3.3      Potentiometry (ion-selective electrode) and pH Test3.3.4      The Density Test3.3.5      The Friability Test3.3.6      The Hardness Test3.3.7      The Titration Test3.3.8      The Karl Fischer Titration – Water Determination3.3.9      Loss on Drying3.3.10    Residue on Ignition/Sulfated Ash3.3.11    Thermal Gravimetric Analysis3.3.12    Differential Scanning Calorimetry3.3.13    The Disintegration Test3.3.14    Particulate Matter3.3.15    Osmolality3.4         Chromatography3.4.1      High-Performance Liquid Chromatography3.4.1.1  Normal Phase Separation Mode3.4.1.2  Reversed-Phase Separation Mode3.4.1.3  Other HPLC Separation Modes3.4.2      Ultra-High Pressure Liquid Chromatography3.4.3      Detectors of Liquid Chromatography3.4.4      System Suitability Tests for Chromatographic Methods3.4.5      Maintenance of HPLC and UHPLC3.4.6      Gas Chromatography3.4.6.1  Residual Solvents3.4.6.2  Hyphenated Technologies3.4.7      Thin Layer Chromatography3.4.8      Bio-Pharmaceutical Separations3.4.8.1  Capillary Zone Electrophoresis3.4.8.2  Isoelectric focusing3.4.8.3  Sodium dodecyl sulfate-Polyacrylamide Gel electrophoresis (SDS-Page)3.5         Spectroscopic Sciences3.5.1      Ultraviolet-Visible3.5.2      Infrared Absorption3.5.3      Mass Spectroscopy3.5.4      Atomic Absorption, Inductively-Coupled Plasma, Inductively Coupled Plasma/Mass Spectrometry, and Inductively Coupled Plasma/Optical Emission Spectrometry3.5.5      Nuclear Magnetic Resonance Spectroscopy3.5.6      X-ray Absorption and X-ray Emission Spectrometry3.6         Uniformity of Dosage Units3.6.1      Weight Variation3.6.2      Acceptance Criteria per USP <905>3.7         Elemental Analysis3.8         Appearance3.9         Visual Inspection3.10       Microbiological Testing3.10.1    Microbial Limits3.10.2    Sterility3.10.3    Bacterial Endotoxin3.10.4    Antimicrobial Effectiveness Testing3.11       SummaryReferencesList of Abbreviations  Chapter 4 – Control Strategies for Pharmaceutical Development4.1         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 substance4.4.2.     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 criteria4.4.4.1. 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 Procedures5.1         Introduction5.2         Method Development5.2.1      Physical, Chemical, and Microbiological Procedures5.3         Qualification, Validation, and Verification5.3.1      Qualification5.3.2      Validation5.3.3      Verification5.3.4      Frequency of Study5.4         Validation Parameters5.4.1      Accuracy5.4.2      Precision5.4.3      Specificity           5.4.4      Quantitation and Detection Limits5.4.5      Linearity5.4.6      Range5.4.7      Robustness5.4.8      Suitability System Testing5.4.9      Sample Stability during Analysis5.4.10    Tie the Pieces Together5.5         Validation for Physical, Chemical, Biotechnological and Microbiological Procedures5.6         Validation for In-process, Environmental, Release and Stability Procedures5.6.1      In-Process Procedures5.6.2      Environmental Procedures5.6.3      Release and Stability Procedures              5.7         Other Procedures5.7.1      Process Analytical Technology (PAT)5.7.2      Parametric Release and Real-Time Release5.8         Validation of Procedures in Continuous and Batch Manufacturing5.9         SummaryReferencesList of Abbreviations  Chapter 6 – Transfer of Analytical Procedures6.1         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 Transfer6.4.3      Method Training Phase6.4.3.1  Method Familiarization6.4.3.2  Method Demonstration               6.4.4      Method Qualification Phase       6.5         Transfer Protocol                           6.5.1      Content of a Transfer Protocol6.5.2      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 Lab6.5.5      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 Deviation6.6         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 Failures6.9         Transfer to a Contract Lab           6.10       Transfer to an International Site6.11       Summary                          ReferencesList of Abbreviations  Chapter 7 – Dissolution Testing in the Pharmaceutical Laboratory7.1 Introduction7.2 Regulatory and Compendial Role in Dissolution Testing7.3 Theory7.4 Equipment Operation and Sources of Error7.5 Common Errors of Dissolution Apparatus7.6 Dissolution Method Considerations7.7 Method Development7.8 Poorly Soluble Drugs7.9 Setting Specifications7.10 Harmonization7.11 Method Validation7.12 Validation of Product Performance Parameters7.13 Validation of the Analytical finish7.14 Method Transfer Considerations7.15 Good Manufacturing Practices in the Dissolution Testing Laboratory7.16 Summary7.17 ResourcesReferencesList of Abbreviations  Chapter 8 – Analytical Records and the Documentation System8.1         Introduction8.1.1      Types of Documents8.2         GMP for Records and Reports–Subpart J8.2.1      General Requirements8.2.2      Equipment Cleaning and Use Log8.2.3      Component, Drug Product Container, Closure, and Labeling Records8.2.4      Master Production and Control Records8.2.5      Batch Production and Control Records8.2.6      Production Record Review8.2.7      Laboratory Records8.3         Keeping Good Records8.3.1      Writing Good Procedures8.3.2      Following Procedures8.4         Raw Data Documentation8.4.1      Data Recording Practices8.4.2      Witness Responsibilities8.4.3      Changes in Notebook8.4.4      Recording Date and Time8.4.5      Voiding and Restoring GMP Records8.4.6      Computer Collected Data8.4.7      Reporting Analytical Results8.4.7.1 Decimal Places and Significant Figures8.4.7.2  Mathematical Operations8.4.7.3  Rounding Rules8.4.7.4  Reporting Impurity Results8.5         Sampling, Reagents, Standards, Reference standards8.5.1      Samples8.5.2      Reagents8.5.3      Analytical Standards8.5.4      Reference Standards8.6         Drug Substance Analysis8.7         Drug Product Analysis8.8         Batch Release8.8.1      Batch Packaging Record8.8.2      Batch Processing Record8.8.3      Distribution Record8.9         Establishment of Specifications8.9.1      Content of Specifications8.9.2      Setting Specifications8.9.3      Periodic Revisions8.9.4      Test Procedures8.10       Out-of-Specification Results8.10.1   Lab Phase Investigation8.10.1.1               Identifying an OOS Result8.10.1.2               Laboratory Error8.10.1.3               Determining Root Cause8.10.1.4               Retesting8.10.1.5               Outlier Test8.10.1.6               Averaging Results8.10.1.7               Field Alert Report8.10.2    Full Scale Investigation8.11       Compendial Testing8.11.1   Validation and Verification of Compendial Procedures8.11.2   USP Reference Standards8.12       Standard Operating Procedures8.12.1   Control of SOPs8.12.2   Format of SOPs8.12.3   Flow of documents8.13       Analytical Documents8.13.1   Hierarchy of Documentation System8.13.2   Analytical Protocols8.13.3   Analytical Reports8.13.4   Annual Product Review8.13.5    Change of documentation8.14       Quality Assurance8.14.1   Six Quality Systems and Supporting Programs8.14.2   Quality System Performance8.14.3    Lifecycle Management Approach for Analytical Procedures8.14.4   Audit and Inspection Program8.15       SummaryReferencesList of Abbreviations  Chapter 9 – The Stability Program9.1.        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            ReferencesList of Abbreviations  Chapter 10 – Laboratory Information Management System (LIMS) and Electronic Data10           Introduction      10.1       Analytica Data to Support Quality decisions10.2       Quality System  10.3       Metrics in Quality Management10.4       Material Management   10.5       Product Release              10.6       Stability Studies10.7       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 Data10.20     Benefits of Computerized Systems10.21     Big Data              ReferencesList of Abbreviations  Index

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.

• Dedication((Einstein quotation))PrefaceAbout the EditorBiographies of Contributing AuthorsEditorial NotesDedicationAcknowledgments  Chapter 1 – Drug Regulations and the Pharmaceutical Laboratories1.1         Introduction1.2         Food and Drug Administration: Role and its Regulations1.2.1      Code of Federal Regulations1.2.2      FDA Guidance Documents1.2.3      FDA Manual of Policies and Procedures1.3         International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and its Role1.3.1      ICH background1.3.2      ICH Structure1.3.3      ICH Organization1.3.3.1  Steering Committee1.3.3.2  Global Cooperation Group1.3.3.3  MedDRA Management Board1.3.3.4  Working Groups1.3.3.5  Secretariat1.3.3.6  Coordinators1.3.4      ICH Topics1.4         Pharmaceutical Analysis1.4.1      Analytical Testing1.4.2      Interaction Between the Analytical Development Department and Other Functional Areas    1.4.3      Drug Development Process1.4.3.1  Toxicological Phase1.4.3.2  Investigational New Drug1.4.3.3  Clinical Phase1.4.3.4  Registration Phase1.4.3.5  New Drug Application1.4.3.6  Post-Approval PhaseReferencesList of Abbreviations  Chapter 2 – Good Manufacturing Practices (GMPs) and the Quality Systems2.1         Introduction to Good Manufacturing Practices2.2         Objectives of GMPs2.2.1      Definitions2.2.2      Organization of 21 CFR Regulations2.3         Personnel Qualifications and Responsibilities – Subpart B2.3.1      Responsibilities of Quality Control Unit2.3.2      Personnel Qualifications and Responsibilities2.4         Equipment – Subpart D2.4.1      Metrology Functions2.4.2      Qualification Phases2.5         Laboratory Controls – Subpart I2.5.1      General Requirements2.5.2      Testing and Release for Distribution2.5.3      Stability Program2.5.4      Retention Program2.6         Records and Reports2.7         Pharmaceutical Quality2.7.1      Quality Manual2.7.2      Quality Risk Management2.7.3      Product Quality Review2.7.4      Pharmaceutical Quality SystemsReferencesList of Abbreviations  Chapter 3 – Analytical Techniques Used in the GMP Laboratory3.1         Introduction3.2         Definitions3.2.1      Raw Data and Analytical Data3.2.2      Analyses3.2.3      Analytical Documents3.3         Basic Laboratory Procedures3.3.1      Balances3.3.2      Volumetric Glassware3.3.3      Potentiometry (ion-selective electrode) and pH Test3.3.4      The Density Test3.3.5      The Friability Test3.3.6      The Hardness Test3.3.7      The Titration Test3.3.8      The Karl Fischer Titration – Water Determination3.3.9      Loss on Drying3.3.10    Residue on Ignition/Sulfated Ash3.3.11    Thermal Gravimetric Analysis3.3.12    Differential Scanning Calorimetry3.3.13    The Disintegration Test3.3.14    Particulate Matter3.3.15    Osmolality3.4         Chromatography3.4.1      High-Performance Liquid Chromatography3.4.1.1  Normal Phase Separation Mode3.4.1.2  Reversed-Phase Separation Mode3.4.1.3  Other HPLC Separation Modes3.4.2      Ultra-High Pressure Liquid Chromatography3.4.3      Detectors of Liquid Chromatography3.4.4      System Suitability Tests for Chromatographic Methods3.4.5      Maintenance of HPLC and UHPLC3.4.6      Gas Chromatography3.4.6.1  Residual Solvents3.4.6.2  Hyphenated Technologies3.4.7      Thin Layer Chromatography3.4.8      Bio-Pharmaceutical Separations3.4.8.1  Capillary Zone Electrophoresis3.4.8.2  Isoelectric focusing3.4.8.3  Sodium dodecyl sulfate-Polyacrylamide Gel electrophoresis (SDS-Page)3.5         Spectroscopic Sciences3.5.1      Ultraviolet-Visible3.5.2      Infrared Absorption3.5.3      Mass Spectroscopy3.5.4      Atomic Absorption, Inductively-Coupled Plasma, Inductively Coupled Plasma/Mass Spectrometry, and Inductively Coupled Plasma/Optical Emission Spectrometry3.5.5      Nuclear Magnetic Resonance Spectroscopy3.5.6      X-ray Absorption and X-ray Emission Spectrometry3.6         Uniformity of Dosage Units3.6.1      Weight Variation3.6.2      Acceptance Criteria per USP <905>3.7         Elemental Analysis3.8         Appearance3.9         Visual Inspection3.10       Microbiological Testing3.10.1    Microbial Limits3.10.2    Sterility3.10.3    Bacterial Endotoxin3.10.4    Antimicrobial Effectiveness Testing3.11       SummaryReferencesList of Abbreviations  Chapter 4 – Control Strategies for Pharmaceutical Development4.1         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 substance4.4.2.     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 criteria4.4.4.1. 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 Procedures5.1         Introduction5.2         Method Development5.2.1      Physical, Chemical, and Microbiological Procedures5.3         Qualification, Validation, and Verification5.3.1      Qualification5.3.2      Validation5.3.3      Verification5.3.4      Frequency of Study5.4         Validation Parameters5.4.1      Accuracy5.4.2      Precision5.4.3      Specificity           5.4.4      Quantitation and Detection Limits5.4.5      Linearity5.4.6      Range5.4.7      Robustness5.4.8      Suitability System Testing5.4.9      Sample Stability during Analysis5.4.10    Tie the Pieces Together5.5         Validation for Physical, Chemical, Biotechnological and Microbiological Procedures5.6         Validation for In-process, Environmental, Release and Stability Procedures5.6.1      In-Process Procedures5.6.2      Environmental Procedures5.6.3      Release and Stability Procedures              5.7         Other Procedures5.7.1      Process Analytical Technology (PAT)5.7.2      Parametric Release and Real-Time Release5.8         Validation of Procedures in Continuous and Batch Manufacturing5.9         SummaryReferencesList of Abbreviations  Chapter 6 – Transfer of Analytical Procedures6.1         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 Transfer6.4.3      Method Training Phase6.4.3.1  Method Familiarization6.4.3.2  Method Demonstration               6.4.4      Method Qualification Phase       6.5         Transfer Protocol                           6.5.1      Content of a Transfer Protocol6.5.2      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 Lab6.5.5      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 Deviation6.6         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 Failures6.9         Transfer to a Contract Lab           6.10       Transfer to an International Site6.11       Summary                          ReferencesList of Abbreviations  Chapter 7 – Dissolution Testing in the Pharmaceutical Laboratory7.1 Introduction7.2 Regulatory and Compendial Role in Dissolution Testing7.3 Theory7.4 Equipment Operation and Sources of Error7.5 Common Errors of Dissolution Apparatus7.6 Dissolution Method Considerations7.7 Method Development7.8 Poorly Soluble Drugs7.9 Setting Specifications7.10 Harmonization7.11 Method Validation7.12 Validation of Product Performance Parameters7.13 Validation of the Analytical finish7.14 Method Transfer Considerations7.15 Good Manufacturing Practices in the Dissolution Testing Laboratory7.16 Summary7.17 ResourcesReferencesList of Abbreviations  Chapter 8 – Analytical Records and the Documentation System8.1         Introduction8.1.1      Types of Documents8.2         GMP for Records and Reports–Subpart J8.2.1      General Requirements8.2.2      Equipment Cleaning and Use Log8.2.3      Component, Drug Product Container, Closure, and Labeling Records8.2.4      Master Production and Control Records8.2.5      Batch Production and Control Records8.2.6      Production Record Review8.2.7      Laboratory Records8.3         Keeping Good Records8.3.1      Writing Good Procedures8.3.2      Following Procedures8.4         Raw Data Documentation8.4.1      Data Recording Practices8.4.2      Witness Responsibilities8.4.3      Changes in Notebook8.4.4      Recording Date and Time8.4.5      Voiding and Restoring GMP Records8.4.6      Computer Collected Data8.4.7      Reporting Analytical Results8.4.7.1 Decimal Places and Significant Figures8.4.7.2  Mathematical Operations8.4.7.3  Rounding Rules8.4.7.4  Reporting Impurity Results8.5         Sampling, Reagents, Standards, Reference standards8.5.1      Samples8.5.2      Reagents8.5.3      Analytical Standards8.5.4      Reference Standards8.6         Drug Substance Analysis8.7         Drug Product Analysis8.8         Batch Release8.8.1      Batch Packaging Record8.8.2      Batch Processing Record8.8.3      Distribution Record8.9         Establishment of Specifications8.9.1      Content of Specifications8.9.2      Setting Specifications8.9.3      Periodic Revisions8.9.4      Test Procedures8.10       Out-of-Specification Results8.10.1   Lab Phase Investigation8.10.1.1               Identifying an OOS Result8.10.1.2               Laboratory Error8.10.1.3               Determining Root Cause8.10.1.4               Retesting8.10.1.5               Outlier Test8.10.1.6               Averaging Results8.10.1.7               Field Alert Report8.10.2    Full Scale Investigation8.11       Compendial Testing8.11.1   Validation and Verification of Compendial Procedures8.11.2   USP Reference Standards8.12       Standard Operating Procedures8.12.1   Control of SOPs8.12.2   Format of SOPs8.12.3   Flow of documents8.13       Analytical Documents8.13.1   Hierarchy of Documentation System8.13.2   Analytical Protocols8.13.3   Analytical Reports8.13.4   Annual Product Review8.13.5    Change of documentation8.14       Quality Assurance8.14.1   Six Quality Systems and Supporting Programs8.14.2   Quality System Performance8.14.3    Lifecycle Management Approach for Analytical Procedures8.14.4   Audit and Inspection Program8.15       SummaryReferencesList of Abbreviations  Chapter 9 – The Stability Program9.1.        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            ReferencesList of Abbreviations  Chapter 10 – Laboratory Information Management System (LIMS) and Electronic Data10           Introduction      10.1       Analytica Data to Support Quality decisions10.2       Quality System  10.3       Metrics in Quality Management10.4       Material Management   10.5       Product Release              10.6       Stability Studies10.7       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 Data10.20     Benefits of Computerized Systems10.21     Big Data              ReferencesList of Abbreviations  Index

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.

• Dedication((Einstein quotation))PrefaceAbout the EditorBiographies of Contributing AuthorsEditorial NotesDedicationAcknowledgments  Chapter 1 – Drug Regulations and the Pharmaceutical Laboratories1.1         Introduction1.2         Food and Drug Administration: Role and its Regulations1.2.1      Code of Federal Regulations1.2.2      FDA Guidance Documents1.2.3      FDA Manual of Policies and Procedures1.3         International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and its Role1.3.1      ICH background1.3.2      ICH Structure1.3.3      ICH Organization1.3.3.1  Steering Committee1.3.3.2  Global Cooperation Group1.3.3.3  MedDRA Management Board1.3.3.4  Working Groups1.3.3.5  Secretariat1.3.3.6  Coordinators1.3.4      ICH Topics1.4         Pharmaceutical Analysis1.4.1      Analytical Testing1.4.2      Interaction Between the Analytical Development Department and Other Functional Areas    1.4.3      Drug Development Process1.4.3.1  Toxicological Phase1.4.3.2  Investigational New Drug1.4.3.3  Clinical Phase1.4.3.4  Registration Phase1.4.3.5  New Drug Application1.4.3.6  Post-Approval PhaseReferencesList of Abbreviations  Chapter 2 – Good Manufacturing Practices (GMPs) and the Quality Systems2.1         Introduction to Good Manufacturing Practices2.2         Objectives of GMPs2.2.1      Definitions2.2.2      Organization of 21 CFR Regulations2.3         Personnel Qualifications and Responsibilities – Subpart B2.3.1      Responsibilities of Quality Control Unit2.3.2      Personnel Qualifications and Responsibilities2.4         Equipment – Subpart D2.4.1      Metrology Functions2.4.2      Qualification Phases2.5         Laboratory Controls – Subpart I2.5.1      General Requirements2.5.2      Testing and Release for Distribution2.5.3      Stability Program2.5.4      Retention Program2.6         Records and Reports2.7         Pharmaceutical Quality2.7.1      Quality Manual2.7.2      Quality Risk Management2.7.3      Product Quality Review2.7.4      Pharmaceutical Quality SystemsReferencesList of Abbreviations  Chapter 3 – Analytical Techniques Used in the GMP Laboratory3.1         Introduction3.2         Definitions3.2.1      Raw Data and Analytical Data3.2.2      Analyses3.2.3      Analytical Documents3.3         Basic Laboratory Procedures3.3.1      Balances3.3.2      Volumetric Glassware3.3.3      Potentiometry (ion-selective electrode) and pH Test3.3.4      The Density Test3.3.5      The Friability Test3.3.6      The Hardness Test3.3.7      The Titration Test3.3.8      The Karl Fischer Titration – Water Determination3.3.9      Loss on Drying3.3.10    Residue on Ignition/Sulfated Ash3.3.11    Thermal Gravimetric Analysis3.3.12    Differential Scanning Calorimetry3.3.13    The Disintegration Test3.3.14    Particulate Matter3.3.15    Osmolality3.4         Chromatography3.4.1      High-Performance Liquid Chromatography3.4.1.1  Normal Phase Separation Mode3.4.1.2  Reversed-Phase Separation Mode3.4.1.3  Other HPLC Separation Modes3.4.2      Ultra-High Pressure Liquid Chromatography3.4.3      Detectors of Liquid Chromatography3.4.4      System Suitability Tests for Chromatographic Methods3.4.5      Maintenance of HPLC and UHPLC3.4.6      Gas Chromatography3.4.6.1  Residual Solvents3.4.6.2  Hyphenated Technologies3.4.7      Thin Layer Chromatography3.4.8      Bio-Pharmaceutical Separations3.4.8.1  Capillary Zone Electrophoresis3.4.8.2  Isoelectric focusing3.4.8.3  Sodium dodecyl sulfate-Polyacrylamide Gel electrophoresis (SDS-Page)3.5         Spectroscopic Sciences3.5.1      Ultraviolet-Visible3.5.2      Infrared Absorption3.5.3      Mass Spectroscopy3.5.4      Atomic Absorption, Inductively-Coupled Plasma, Inductively Coupled Plasma/Mass Spectrometry, and Inductively Coupled Plasma/Optical Emission Spectrometry3.5.5      Nuclear Magnetic Resonance Spectroscopy3.5.6      X-ray Absorption and X-ray Emission Spectrometry3.6         Uniformity of Dosage Units3.6.1      Weight Variation3.6.2      Acceptance Criteria per USP <905>3.7         Elemental Analysis3.8         Appearance3.9         Visual Inspection3.10       Microbiological Testing3.10.1    Microbial Limits3.10.2    Sterility3.10.3    Bacterial Endotoxin3.10.4    Antimicrobial Effectiveness Testing3.11       SummaryReferencesList of Abbreviations  Chapter 4 – Control Strategies for Pharmaceutical Development4.1         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 substance4.4.2.     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 criteria4.4.4.1. 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 Procedures5.1         Introduction5.2         Method Development5.2.1      Physical, Chemical, and Microbiological Procedures5.3         Qualification, Validation, and Verification5.3.1      Qualification5.3.2      Validation5.3.3      Verification5.3.4      Frequency of Study5.4         Validation Parameters5.4.1      Accuracy5.4.2      Precision5.4.3      Specificity           5.4.4      Quantitation and Detection Limits5.4.5      Linearity5.4.6      Range5.4.7      Robustness5.4.8      Suitability System Testing5.4.9      Sample Stability during Analysis5.4.10    Tie the Pieces Together5.5         Validation for Physical, Chemical, Biotechnological and Microbiological Procedures5.6         Validation for In-process, Environmental, Release and Stability Procedures5.6.1      In-Process Procedures5.6.2      Environmental Procedures5.6.3      Release and Stability Procedures              5.7         Other Procedures5.7.1      Process Analytical Technology (PAT)5.7.2      Parametric Release and Real-Time Release5.8         Validation of Procedures in Continuous and Batch Manufacturing5.9         SummaryReferencesList of Abbreviations  Chapter 6 – Transfer of Analytical Procedures6.1         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 Transfer6.4.3      Method Training Phase6.4.3.1  Method Familiarization6.4.3.2  Method Demonstration               6.4.4      Method Qualification Phase       6.5         Transfer Protocol                           6.5.1      Content of a Transfer Protocol6.5.2      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 Lab6.5.5      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 Deviation6.6         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 Failures6.9         Transfer to a Contract Lab           6.10       Transfer to an International Site6.11       Summary                          ReferencesList of Abbreviations  Chapter 7 – Dissolution Testing in the Pharmaceutical Laboratory7.1 Introduction7.2 Regulatory and Compendial Role in Dissolution Testing7.3 Theory7.4 Equipment Operation and Sources of Error7.5 Common Errors of Dissolution Apparatus7.6 Dissolution Method Considerations7.7 Method Development7.8 Poorly Soluble Drugs7.9 Setting Specifications7.10 Harmonization7.11 Method Validation7.12 Validation of Product Performance Parameters7.13 Validation of the Analytical finish7.14 Method Transfer Considerations7.15 Good Manufacturing Practices in the Dissolution Testing Laboratory7.16 Summary7.17 ResourcesReferencesList of Abbreviations  Chapter 8 – Analytical Records and the Documentation System8.1         Introduction8.1.1      Types of Documents8.2         GMP for Records and Reports–Subpart J8.2.1      General Requirements8.2.2      Equipment Cleaning and Use Log8.2.3      Component, Drug Product Container, Closure, and Labeling Records8.2.4      Master Production and Control Records8.2.5      Batch Production and Control Records8.2.6      Production Record Review8.2.7      Laboratory Records8.3         Keeping Good Records8.3.1      Writing Good Procedures8.3.2      Following Procedures8.4         Raw Data Documentation8.4.1      Data Recording Practices8.4.2      Witness Responsibilities8.4.3      Changes in Notebook8.4.4      Recording Date and Time8.4.5      Voiding and Restoring GMP Records8.4.6      Computer Collected Data8.4.7      Reporting Analytical Results8.4.7.1 Decimal Places and Significant Figures8.4.7.2  Mathematical Operations8.4.7.3  Rounding Rules8.4.7.4  Reporting Impurity Results8.5         Sampling, Reagents, Standards, Reference standards8.5.1      Samples8.5.2      Reagents8.5.3      Analytical Standards8.5.4      Reference Standards8.6         Drug Substance Analysis8.7         Drug Product Analysis8.8         Batch Release8.8.1      Batch Packaging Record8.8.2      Batch Processing Record8.8.3      Distribution Record8.9         Establishment of Specifications8.9.1      Content of Specifications8.9.2      Setting Specifications8.9.3      Periodic Revisions8.9.4      Test Procedures8.10       Out-of-Specification Results8.10.1   Lab Phase Investigation8.10.1.1               Identifying an OOS Result8.10.1.2               Laboratory Error8.10.1.3               Determining Root Cause8.10.1.4               Retesting8.10.1.5               Outlier Test8.10.1.6               Averaging Results8.10.1.7               Field Alert Report8.10.2    Full Scale Investigation8.11       Compendial Testing8.11.1   Validation and Verification of Compendial Procedures8.11.2   USP Reference Standards8.12       Standard Operating Procedures8.12.1   Control of SOPs8.12.2   Format of SOPs8.12.3   Flow of documents8.13       Analytical Documents8.13.1   Hierarchy of Documentation System8.13.2   Analytical Protocols8.13.3   Analytical Reports8.13.4   Annual Product Review8.13.5    Change of documentation8.14       Quality Assurance8.14.1   Six Quality Systems and Supporting Programs8.14.2   Quality System Performance8.14.3    Lifecycle Management Approach for Analytical Procedures8.14.4   Audit and Inspection Program8.15       SummaryReferencesList of Abbreviations  Chapter 9 – The Stability Program9.1.        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            ReferencesList of Abbreviations  Chapter 10 – Laboratory Information Management System (LIMS) and Electronic Data10           Introduction      10.1       Analytica Data to Support Quality decisions10.2       Quality System  10.3       Metrics in Quality Management10.4       Material Management   10.5       Product Release              10.6       Stability Studies10.7       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 Data10.20     Benefits of Computerized Systems10.21     Big Data              ReferencesList of Abbreviations  Index