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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5855_Библиотеки_им_академика_М_И_Перельмана.pdf
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- •About the Authors
- •Preface
- •Acknowledgements
- •Contents
- •1.1. Singapore as a British Colony
- •1.5.1. Levelling Up the Pharmaceutical Inspection System of Singapore
- •1.5.2. Advantages of PIC/S Membership to Singapore and Other Participating Authorities
- •1.6. Emergence of MNC Pharmaceutical Manufacturing Industry in Singapore
- •1.6.1. Why do MNC Pharmaceutical Manufacturers Set Up Facilities in Singapore?
- •2.2. Geographical Background of ASEAN vis-à-vis Asia and the Rest of the World
- •2.4. Formation of an ASEAN MRA Taskforce on GMP Inspection
- •2.5. Signing of ASEAN Sectoral MRA on GMP Inspection
- •2.6. Formation of ASEAN JSC on GMP Inspection and Establishing Register of ASEAN LIS
- •2.8. Assessment of FDA Philippines by ASEAN PoE
- •2.9. Register of ASEAN Listed Inspection Services (LIS)
- •3.1. Introduction: Urgency of Training ASEAN Inspectors
- •3.3. Collaboration with Korea Ministry of Food and Drug Safety (MFDS)
- •3.4. Collaboration with the Generics and Biosimilars Initiative (GaBI)
- •3.5. Pre-employment Training in Pharmacy and Pharmaceutical Science Schools
- •4.1. Introduction
- •4.2. Historical Context to WHO Reliance Initiative
- •4.3. The First NRAs to Achieve ML4 and WLA Status
- •4.5. Other International Reliance and Harmonization Initiatives
- •4.5.1. Access Consortium
- •4.5.2. Association of Southeast Asian Nations (ASEAN)
- •4.5.3. East African Community (EAC)
- •4.5.4. European Medicines Agency (EMA)
- •4.5.6. International Council for Harmonization (ICH)
- •4.5.6.1. Introduction
- •4.5.6.2. ICH Members and Observers
- •4.5.6.3. Future Direction
- •4.5.7.1. Introduction
- •4.5.7.2. Addressing Common Regulatory Issues
- •4.5.7.3. ICMRA Pilot Program for Collaborative Hybrid Inspection
- •4.5.8. International Pharmaceutical Regulators Program (IPRP)
- •4.5.9. Latin America
- •4.5.10. Pharmaceutical Inspection Co-operation Scheme (PIC/S)
- •4.5.10.1. Introduction
- •4.5.10.2. PIC/S Participating Authorities
- •4.5.11. WHO Collaborative Registration Procedure for Medical Products (CRP)
- •4.5.12.1. Introduction
- •4.5.12.3. WHO Inspection Report
- •4.5.13. ZaZiBoNa
- •4.6. Conclusion
- •5.1. Introduction to GMP
- •5.2. Overview of the PIC/S GMP Standard
- •5.3. How is an On-site GMP Inspection Conducted?
- •5.3.1. Why is the Warehouse Inspected?
- •5.3.3. Why are the Production Areas Inspected?
- •5.3.4. Why are the Packaging Areas Inspected?
- •5.3.5. Why are the QC Laboratories Inspected?
- •5.3.6. Why do GMP Inspectors Visit Other Miscellaneous Areas?
- •5.3.8. Why is there a Need to Conduct Documentation Audit/Review?
- •5.3.8.1. Assessing Product Quality Review
- •5.3.8.3. Assessing Self-Inspection Program
- •5.4. The 20 Annexes of PIC/S GMP Standard
- •5.5. PIC/S Inspection System: A Risk-based Approach
- •5.5.1. Whom can the GMP Inspector Interview?
- •5.5.2.1. Inspector’s Expectations of a Manufacturer
- •5.5.2.2. Manufacturer’s Expectations of an Inspector
- •5.6. Who Inspects the Inspectors?
- •6.1. Historical Development of Pharmaceutical Quality
- •6.2. What is a High-Quality Medicinal Product?
- •6.3. Purity of a Medicinal Product: Elimination of Impurities and Contaminants
- •6.3.1. What is a Contaminated Medicinal Product?
- •6.3.2. Why is There a Need to Control Impurities?
- •6.3.2.1. Types of Impurities from APIs
- •6.3.2.2. Types of Impurities from Container-Closure System
- •6.3.3. Control of Intrinsic Contaminants
- •6.3.4. Control of Extrinsic Contaminants
- •6.3.5. General Assessment of Cross-Contamination Risks
- •6.4. Stability and Shelf-Life Testing of a Medicinal Product
- •6.4.1. Why is Proper Storage, Distribution and Handling of a Medicinal Product Important?
- •6.6. Summary of High-Quality Medicinal Products
- •7.1. Introduction to Stability and Quality
- •7.3.1. Why is Proper Storage Important?
- •7.3.2. Why is Proper Transportation of a Medicinal Product Important?
- •7.3.3. Why is Proper Handling of a Medicinal Product during Use Important?
- •7.4.1. Number and Size of Batches
- •7.4.2. Testing Frequency
- •7.4.3. Storage Conditions
- •7.4.4. Test Methods
- •7.4.5. Container-Closure Systems
- •7.5. Stability Study Schedule and Report
- •7.6. Temperature Excursions and Product Stability
- •7.8. Cold Chain Products and Temperature Excursions
- •7.11. Conclusion
- •8.1. Christopher Columbus versus the Vikings
- •8.4. Pharmaceutical Data Integrity and ALCOA
- •8.5. Article(s) on Pharmaceutical Data Integrity
- •Introduction
- •Current trends
- •Reasons for Data Integrity violations (inadvertent and intentional)
- •Assuring and promoting Data Integrity via legislation and guidance documents
- •Legislation
- •Guidance documents
- •Proposed Solutions to Better Promote and Assure Data Integrity
- •Culture of integrity
- •Database management systems
- •Robust quality agreements
- •Collaboration between countries
- •Computerized systems validation
- •List of abbreviations
- •Conclusion
- •Authors
- •References
- •9.1. Pharmaceuticals versus Biopharmaceuticals
- •9.2. Transcription and Translation: Central Dogma of Genetics
- •9.3. Biotechnology-derived Medicinal Products: Microbial versus Mammalian Substrates
- •9.4. Manufacture of Biotechnology-derived Medicinal Products: Key Processes
- •Introduction
- •Manufacture of biopharmaceuticals — an overview
- •Procurement and testing of biological starting materials
- •Generation and characterization of cell banks/seed lots
- •Cell culturing
- •Challenges concerning manufacture of biopharmaceuticals
- •Extensive process and product understanding required
- •Inherent variability of host cells
- •Downstream processing remains a key bottleneck
- •Review of current GMP frameworks for biopharmaceuticals
- •Challenges in the regulation of biopharmaceuticals
- •Resource-intensive evaluation of biosimilarity
- •Growing number of data integrity lapses
- •Proposed solutions to challenges of biopharmaceuticals
- •Optimizing biopharmaceutical manufacturing with Industry 4.0
- •Enhancing data integrity with a culture of quality (quality culture)
- •Conclusion
- •List of abbreviations
- •Authors
- •References
- •10.1. Introduction
- •10.2. Advantages of Nanomedicines
- •10.3. Types of Nanomedicines
- •10.3.1. Nanocarrier Systems
- •10.3.2. Nanosuspensions
- •10.4. Future of Nanomedicines
- •10.5. GMP Requirements Governing Nanomedicines and Challenges
- •10.5.1. Lack of Trained Personnel to Operate Manufacturing Processes
- •10.5.2. Lack of Safety Protocol for Manufacturing Personnel
- •10.5.3. Challenges in Controlling for Nanoparticle Contamination
- •10.6. Conclusion
- •11. Novel and Traditional Vaccines
- •11.1. Historical Development and Evolution of Traditional and Novel Vaccines
- •11.2. Traditional Vaccines Versus Novel Vaccines
- •Introduction
- •Traditional vaccines
- •Novel vaccines
- •Vaccine manufacture
- •Vaccine storage, transport and distribution
- •Regulatory controls
- •Challenges, safety and quality issues and possible solutions
- •Conclusion
- •Authors
- •References
- •12.1. Cells and Tissues
- •12.2. Gene Therapy Products
- •12.3. Published Article on CTGTPs
- •Introduction
- •CTGTPs and their principles of action
- •Manufacturing of CTGTPs
- •Premises and equipment
- •Materials and processing
- •Starting material
- •Quality control
- •Cryopreservation
- •Human resource and accreditation
- •Potential solutions to the challenges encountered in manufacturing
- •Outsourcing
- •Technology
- •Control of CTGTPs
- •Current regulatory framework
- •Risk-based approach
- •Conclusion
- •Authors
- •References
- •13. Hand Sanitizers
- •13.1. What are Hand Sanitizers?
- •13.4. Published Article and Commentary on Hand Sanitizers
- •Introduction
- •The microbiology of bacteria, fungi and viruses
- •Antimicrobial compounds and their applications in hand sanitizers
- •FDA policy for testing of alcohol and USP limits for methanol
- •Common myths about hand sanitizers
- •A lack of regulatory framework
- •Proposed solutions
- •Tightening the regulatory framework
- •Training pharmacists on hand sanitizer vigilance
- •Public Education
- •Conclusion
- •Authors
- •References
- •14. Pharmaceutical Dosage Forms
- •14.1. Introduction
- •14.2. What Are Pharmaceutical Dosage Forms?
- •14.4.1. Routes of Administration
- •14.4.1.1. Oral Dosage Forms — Solids
- •14.4.1.2. Oral Dosage Forms — Liquids
- •14.4.1.3. Topical Dosage Forms
- •14.4.1.5. Inhaled Dosage Forms
- •14.4.1.6. Ophthalmic Dosage Forms
- •14.4.1.7. Nasal Dosage Forms
- •14.4.1.8. Otic Dosage Forms
- •14.4.1.9. Rectal Dosage Forms
- •14.4.1.10. Vaginal Dosage Forms
- •14.4.1.11. Transdermal Patch
- •14.4.2. Physical Forms
- •14.4.2.1. Solid Dosage Forms
- •14.4.2.2. Liquid Dosage Forms
- •14.4.2.3. Semi-solid Dosage Forms
- •14.4.2.4. Gaseous or Aerosol Dosage Forms
- •14.5. Manufacture and Important Characteristics of Common Pharmaceutical Dosage Forms
- •14.5.1. Tablets
- •14.5.2. Capsules
- •14.5.3. Solutions
- •14.5.4. Suspensions
- •14.5.5. Emulsions
- •14.5.6. Creams
- •14.5.7. Ointments
- •14.5.8. Metered Dose Inhalers
- •14.6. Overall Summary of the Manufacture of a Pharmaceutical Dosage Form
- •15.1. Introduction

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 ocers, 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.

xvi
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

xx
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
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