Kim Huynh-Ba, [...]., 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))

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

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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

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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

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

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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

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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

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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