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Preface
consumers. It also elaborates on how these key stakeholders can work together to achieve a win-win outcome via ongoing national, regional, and global partnerships, collaborations and harmoniza­tion, and reliance initiatives.
Some chapters of the book are based on articles which have been peer-reviewed and published by the authors (with their students and collaborators) in reputable international scientific journals. We believe these articles will be of practical value to the academia and professionals from the global pharmaceutical and biopharma­ceutical industry, as well as the drug regulatory authorities. Some chapters have also incorporated our lectures which have been reg­ularly updated and delivered over the years to undergraduate and post-graduate students at the National University of Singapore. They include educational materials on pharmaceutical dosage forms, good manufacturing practices, ASEAN harmonization on phar­maceutical inspection, regulatory compliance and emerging issues relating to online pharmacies and medicinal product e-commerce, quality by design, continuous manufacturing and Industry 4.0. We believe these lecture materials and accompanying anecdotes will also be of interest to any avid reader and lay consumers of medicinal and healthcare products. In essence, this book is a collection of pub­lished and unpublished articles as well as training and educational materials that will serve as a one-stop resource and reference for all interested readers.
xi
The book begins with an introduction to the evolution of the pharmaceutical inspection system in Singapore to become the first Asian member of the international Pharmaceutical Inspec­tion Co-operation Scheme (PIC/S). Closely related developments, in particular the ASEAN harmonization on pharmaceutical GMP
xii
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
inspection and the PIC/S and WHO reliance programs, are included. Not many in the pharmaceutical industry are aware of this wide range of regional and international harmonization programs and reliance initiatives. Hence, the missions and modus operandi of these supranational partnerships are compiled in this book for gen­eral knowledge, ease of reference, and to highlight the many collab­orations among pharmaceutical regulatory authorities across the world. The co-author (Sia Chong Hock) was actively involved and represented Singapore, a small and young nation, in these historic journeys. These topics are covered in the first few chapters, where he shares his insights, untold stories and his resolute dedication with a personal touch. Many photographs and snapshots of information and milestones are provided wherever possible for clearer illustra­tions and a more enjoyable read. As these pictures and images are included for illustrative purposes, they may not be given a number and formal title (which is normally the case). A large portion of the book is devoted to the manufacture, quality assurance, supply chain integrity, science and regulation of a broad range of medicinal prod­ucts and related healthcare products. Contamination, adulteration, counterfeiting and falsification of medicinal products during man­ufacture, distribution and supply, and their risks and challenges, are also discussed at length.
Last but not least, this book has also incorporated the emerging top­ics of good documentation practice and pharmaceutical data integ­rit y, parametric release and quality by design, continuous manufac­turing, online pharmacies and medicinal product e-commerce. The impact to pharmaceutical manufacturing and regulation posed by Industry 4.0, the increasing use of computerized systems and digital transformation, the advent of biotechnology and emergence of dis­ruptive technologies have also been addressed as much as possible.
Preface
The book concludes with a peek into the future of pharmaceuti­cal inspection, together with an outline of the hard and soft skills, and mindsets needed by the pharmaceutical workforce as we march forward into Industry 4.0 and a volatile, uncertain, complex and ambiguous (VUCA) world.
We hope that this book will appeal to a very wide range of read­ers, including university professors and researchers, undergraduate and post-graduate students, regulators of medicinal and healthcare products, such as the inspectors, reviewers, laboratory analysts, vigilance and law enforcement ocers, as well as manufacturing and quality assurance professionals from the global pharmaceutical industry. And not forgetting all consumers who will get to make a more informed decision on the medicinal and healthcare products which they are taking, after reading this book. To one and all, we wish you an immense reading pleasure!
xiii

Acknowledgements

xv
The authors would like to express our heartfelt gratitude and indebt­edness to the following individuals:
Shaun Tan Yi Jie — Acquisitions Assistant Director, World Sci-
entific Publishing Company, for the very close collaboration,
editing and facilitation of this book project.
Robert (Bob) Tribe — ISPE Asia-Pacific Regulatory Advisor,
PIC/S Chairman (2000–2001) and Former Chief GMP Inspec­tor, TGA Australia, for his sincere and generous mentorship
over more than two decades, and for reviewing the book.
Maurizio D’Incalci — Emeritus Professor of Pharmacology,
Humanitas University, Italy, for providing an invaluable, suc-
cinct, yet comprehensive review of the book.
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Vimal Sachdeva — Senior Inspector, World Health Organiza- tion, for the opportunities to participate in many WHO pre-
qualification inspections (in India, China and Singapore), and for reviewing the book.
Lasia Tang — Co-founder, Generics and Biosimilars Initia- tive (GaBI), Belgium, for the strong and generous support in
co-organizing the ASEAN-GaBI Educational Workshops on Biopharmaceuticals and Biosimilars for ASEAN inspectors and reviewers.
Our families, like-minded friends and colleagues, for their unwavering support from behind the scenes.
The authors would also like to express our sincere thanks to all National University of Singapore Pharmacy students with whom we had the pleasure of working together over the years on many interesting final-year projects. Collectively, we have had countless moments of intellectually stimulating and productive discussions on the manufacture, supply, science and regulation of multiple cat­egories of medicinal products:
Yan Mei Ying
Constance Neo Xue Rui
Tan Kiat Yun
Katherine Loh Kai Xin
Sean Lee Ji Yang
Benjamin Tan Zhi Yang
Loo Shang Jun
Mervyn Lee Ming Xuan
Sia Ming Kian
Vernon Tay Keat Hong
Adelia Pheh
Christine Koh Hua Yue
Tan Ying Ting
Teh Kee Siang
Hong Sheu Dong
Jerrick Teo Chan Rui

Contents

xvii
About the Authors v Preface ix Acknowledgements xv
Part I Journey Towards Being 1st Asian PIC/S Member
and Beyond 1
Chapter 1 Evolution of Pharmaceutical Inspection in
Singapore and Benchmarking to PIC/S 3
Chapter 2 ASEAN Harmonization on Pharmaceutical
Inspection and Mutual Recognition Arrangement Implementation 41
Chapter 3 Developing a Training and Continuous
Training Program for ASEAN Inspectors 67
xviii
Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Chapter 4 WHO Listed Authority and Other International
Reliance and Harmonization Initiatives 92
Part II GMP Compliance and Manufacture of
High-Quality Medicinal Products 137
Chapter 5 Compliance of Pharmaceutical Manufacturers
to Good Manufacturing Practice Standards 139
Chapter 6 Manufacturing High-Quality Medicinal
Products 175
Chapter 7 Stability and Shelf-Life Testing of Medicinal
Products 204
Chapter 8 Good Documentation Practice and
Pharmaceutical Data Integrity 225
Part III Manufacture and Supply, Science and
Regulation of Medicinal Products 259
Chapter 9 Manufacture and Supply, Science and
Regulation of Biopharmaceutical Products 261
Chapter 10 Manufacture and Supply, Science and
Regulation of Nanomedicines 297
Chapter 11 Novel and Traditional Vaccines 310
Chapter 12 Cells, Tissues, and Gene Therapy Products 344
Chapter 13 Hand Sanitizers 393
Chapter 14 Pharmaceutical Dosage Forms 427
Part IV Assuring Quality and Supply Chain Integrity
of Starting Materials and Other Health Products 479
Chapter 15 Assuring Quality and Supply Chain Integrity
of Active Pharmaceutical Ingredients 481
Contents
Chapter 16 Assuring Quality and Supply Chain Integrity
of Pharmaceutical Excipients 490
Chapter 17 Assuring Quality and Supply Chain Integrity
of Traditional and Herbal Medicinal Products 501
Chapter 18 Assuring Quality and Supply Chain Integrity
of Health Supplements 531
Chapter 19 Assuring Quality and Supply Chain Integrity of
E-Commerce Medicinal Products 543
Chapter 20 Assuring Supply Chain Integrity of Psychotropic
Substances and Narcotic Drugs 555
Part V Contaminated, Adulterated, Counterfeit,
Falsified and Substandard Medicinal Products 577
Chapter 21 Looks Are Deceiving: Adulterated, Counterfeit,
Contaminated and Falsified Medicinal Products 579
xix
Chapter 22 Nitrosamine Saga and Control of Impurities
in Active Pharmaceutical Ingredients and Pharmaceutical Products 595
Chapter 23 Lapses in Global Good Manufacturing Practice
Compliance and Impact on Product Quality 611
Part VI Industry 4.0 and Emerging Pharmaceutical
Technologies 61 9
Chapter 24 Making Vaccines for Supply to the Whole World:
Challenges and Benefits 621
Chapter 25 Industry 4.0 and Emerging Trends in
Pharmaceutical Manufacturing 647
Chapter 26 Quality by Design and Process Analytical
Technology 680
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Manufacture and Supply, Science and Reg ulation Towards High-Qua lity Medicinal Products
Chapter 27 Continuous Manufacturing 704
Chapter 28 The Future of Pharmaceutical Inspections 743
Conclusion: Skills and Mindsets Needed by Manufacturers and Inspectors in Industry 4.0 757
Bibliography 763 Index 766
Part I
Journey Towards Being 1st Asian
PIC/S Member and Beyond