Pharmaceutical Analysis for Small Molecules

Behnam Davani, PhD, has more than 25 years' experience in analytical chemistry, compendial and regulatory science, QC/QA and cGMPs. He is Principal Scientific Liaison in the General Chapters Group, Science Division of the United States Pharmacopeia (USP). In this role, he coordinates the identification and scientific development of compendial courses for stakeholders worldwide. He is also an active faculty for USP Global Education and Training department and teaches several compendial courses including method validation/verification/transfer, impurities in drug substances and products, compendial HPLC, residual solvents, stability studies for drug substances and products, and spectroscopy. He has taught these courses in the US as well as to international regulatory bodies and global pharmaceutical industries including in Europe, Canada, China, India, Russia, Korea, Latin America, Middle East, and North Africa.

About the Editor xvi List of Contributors xviii Preface xxi Acknowledgment xxv 1 Drug Approval Process and Regulatory Requirements 1 1.1 Introduction 1 1.2 The Regulatory Process for New Drug Entity 2 1.2.1 Preclinical Studies 2 1.2.2 Investigational New Drug Application (INDA) 2 1.2.2.1 Phase 1 Clinical 2 1.2.2.2 Phase 2 Clinical 3 1.2.2.3 Phase 3 Clinical 3 1.2.3 New Drug Application (NDA) 3 1.2.3.1 NDA Review by FDA 3 1.2.3.2 NDA Review Process 4 1.3 Good Laboratory Practice for Nonclinical Laboratory Studies 5 1.4 Validation of Analytical Procedures: Methodology 6 1.5 FDA Role in the Discovery and Development of New Drug Entities 7 1.5.1 INDA Analytical Requirements 7 1.5.2 NDA Analytical Requirements 8 1.5.3 Biotechnology]Derived Products Small Molecules 8 1.6 FDA Inspectors Role in Analytics Relative to Products in the Marketplace 9 1.6.1 FDA Compliance Program Guidance Manual (Implemented on 09/11/2015 with a Completion Date of 09/11/2016 Program 7356.002) 9 1.6.2 Guide for Inspection of Microbiological Pharmaceutical Quality Control Laboratories 10 1.6.3 Biotechnology Inspection Guide 11 1.7 Conclusions 12 References 12 2 Pharmacopeias and Compendial Approval Process 14 2.1 Introduction 14 2.2USP History 14 2.3 Evolution of the Mission of the USP 15 2.4 The USP Organization 16 2.4.1 The USP Convention 16 2.4.2 The Board of Trustees 16 2.4.3 The Council of Experts 16 2.4.4 Expert Panels to the Council of Experts 16 2.4.5 Stakeholder Forums and Project Teams 17 2.4.6 USP Staff 17 2.5 The USP-NF Revision Process 17 2.6 Publications of USP 18 2.6.1 USP]NF 18 2.6.2 Pharmacopeial Forum 18 2.6.3 Supplements 18 2.6.4 USP Spanish Edition 18 2.6.5 USP Reference Standards 18 2.6.6 Chromatographic Columns 18 2.6.7 USP Dictionary 18 2.6.8 USP Dietary Supplements Compendium 19 2.6.9 Food Chemical Codex 19 2.6.10 USP Medicines Compendium 19 2.7 Relationship between USP and FDA 19 2.8 USP and the Pharmacopoeias of Europe and Japan 20 2.8.1 The European Pharmacopoeia 20 2.8.2 The Pharmacopeia of Japan 21 2.9 Harmonization of Pharmacopeial Monographs and General Chapters 21 2.9.1 PDG Working Procedures 22 2.9.2 Status of the Pharmacopeial Harmonization Initiative 25 2.9.3 Roles and Responsibilities of Major Stakeholders in Pharmacopeial Harmonization 28 2.9.4 The Roles and Responsibilities of Industry in Pharmacopeial Harmonization 29 2.9.5 The Roles and Responsibilities of the Regulatory Agencies in Pharmacopeial Harmonization 30 2.9.6 The Roles and Responsibilities of the International Conference on Harmonization (ICH) in Pharmacopeial Harmonization 30 2.9.7 Advantages of Pharmacopeial Harmonization 31 2.9.8 Disadvantages of Pharmacopeial Harmonization 31 2.10 Comparisons between the PDG Process and the ICH Process in Harmonization 32 2.11 The Special Case of Pharmacopeial Harmonization of Excipients 33 2.12 Retrospective versus Forward Pharmacopeial Harmonization 33 2.13 Conclusions and Recommendations 34 2.14 Final Thoughts 35 List of Abbreviations 35 References 36 3 Common Methods in Pharmaceutical Analysis 37 3.1 Scope 37 3.2 Analytical Methods 37 3.2.1 Separation Methods 37 3.2.1.1 High]Performance Liquid Chromatography 37 3.2.1.2 Gas Chromatography 39 3.2.1.3 Thin]Layer Chromatography 39 3.2.1.4 Supercritical Fluid Chromatography 39 3.2.1.5 Capillary Electrophoresis 40 3.3 Spectroscopy Methods 40 3.3.1 Ultraviolet 40 3.3.2 Infrared 40 3.3.3 Raman Spectroscopy 40 3.3.4 Nuclear Magnetic Resonance 41 3.3.5 Mass Spectrometry 41 3.4 Other Spectroscopy Methods 41 3.4.1 Atomic Absorption Spectroscopy and Inductively Coupled Plasma Spectroscopy 41 3.5 Wet Chemistry Methods 42 3.5.1 Titration 42 3.5.2 Loss on Drying (LOD) 42 3.5.3 Loss on Ignition (LOI) 43 3.5.4 Residue on Ignition (ROI) or Sulfated Ash 43 3.5.5 Water Dete