Manufacturing of pharmaceutical proteins : from technology to economy

Cover
Title Page
Copyright
Contents
Preface to Third Edition
Preface to First Edition
List of Abbreviations
Part I Introduction
	Chapter 1 Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction
		1.1 Role of Production in Pharmaceutical Biotechnology
			1.1.1 Relationship Between Production and Development
			1.1.2 Relationship Between Production and Marketing
		1.2 Product Groups
			1.2.1 Vaccines
			1.2.2 Pharmaceuticals from Blood and Organs
			1.2.3 Recombinant Therapeutic Proteins
			1.2.4 Cell and Gene Therapeutics
			1.2.5 Antibiotics
		1.3 Basics of Biology
			1.3.1 Cells and Microorganisms
				1.3.1.1 Structure and Types of Cells
				1.3.1.2 Metabolism
				1.3.1.3 Reproduction and Aging
				1.3.1.4 Viruses and Bacteriophages
				1.3.1.5 Protein Biosynthesis
			1.3.2 The Four Molecular Building Blocks of Biochemistry
				1.3.2.1 Proteins
				1.3.2.2 Nucleic Acids
				1.3.2.3 Polysaccharides
				1.3.2.4 Lipids
Part II Technology
	Chapter 2 Manufacturing Process
		2.1 Role of the Manufacturing Process in Biotechnology
		2.2 Process Schematic and Evaluation
			2.2.1 Drug Substance Manufacturing
			2.2.2 Drug Product Manufacturing
			2.2.3 Key Factors for Process Evaluation
		2.3 Cell Bank
			2.3.1 Expression Systems
			2.3.2 Microbial Systems
				2.3.2.1 Mammalian Systems
				2.3.2.2 Transgenic Systems
			2.3.3 Manufacturing and Storage of the Cell Bank
		2.4 Fermentation
			2.4.1 Basic Principles
				2.4.1.1 Cell Growth and Product Expression
				2.4.1.2 Comparison of Batch and Continuous Processes
				2.4.1.3 Sterility and Sterile Technology
				2.4.1.4 Comparison of Fermentation with Mammalian Cells and Microorganisms
			2.4.2 Technologies and Equipment
				2.4.2.1 Fermentation in Suspension Culture
				2.4.2.2 Adherent Cell Cultures
				2.4.2.3 Transgenic Systems
			2.4.3 Raw Materials and Processing Aids
				2.4.3.1 Nutrient Media
				2.4.3.2 Water, Gases, and Other Processing Aids
			2.4.4 Overview of Fermentation
		2.5 Purification
			2.5.1 Basic Principles
				2.5.1.1 Basic Pattern of Purification
				2.5.1.2 Types of Impurities
				2.5.1.3 Principles of Separation Technologies
			2.5.2 Technologies for Cell Separation and Product Isolation
				2.5.2.1 Cell Separation
				2.5.2.2 Cell Disruption, Solubilization, and Refolding
				2.5.2.3 Concentration and Stabilization
			2.5.3 Technologies for Final Purification
				2.5.3.1 Chromatographic Processes
				2.5.3.2 Precipitation and Extraction
				2.5.3.3 Sterile Filtration and Virus Removal
			2.5.4 Raw Materials and Processing Aids
				2.5.4.1 Gels for Chromatography
				2.5.4.2 Membranes for TFF
			2.5.5 Overview of Purification
		2.6 Formulation and Filling
			2.6.1 Basic Principles
			2.6.2 Freeze‐Drying
		2.7 Labeling and Packaging
	Chapter 3 Analytics
		3.1 Role of Analytics in Biotechnology
		3.2 Product Analytics
			3.2.1 Identity
			3.2.2 Content
			3.2.3 Purity
			3.2.4 Activity
			3.2.5 Appearance
			3.2.6 Stability
			3.2.7 Quality Criteria of Analytical Methods
			3.2.8 Analytical Methods
				3.2.8.1 Amino Acid Analysis
				3.2.8.2 Protein Sequencing
				3.2.8.3 Peptide Mapping
				3.2.8.4 Protein Content
				3.2.8.5 Electrophoresis
				3.2.8.6 Western Blot
				3.2.8.7 HCP Enzyme‐Linked Immunosorbent Assay (ELISA)
				3.2.8.8 Analytical Chromatography
				3.2.8.9 Infrared (IR) Spectroscopy
				3.2.8.10 UV/Vis Spectroscopy
				3.2.8.11 Mass Spectrometry
				3.2.8.12 Glycoanalytics
				3.2.8.13 PCR
				3.2.8.14 DNA/RNA Sequencing
				3.2.8.15 Endotoxins and Pyrogen Testing
				3.2.8.16 Bioburden Test
				3.2.8.17 Virus Testing
				3.2.8.18 TEM
				3.2.8.19 Circular Dichroism
				3.2.8.20 Differential Scanning Calorimetry
		3.3 Process Analytics
			3.3.1 Fermentation
			3.3.2 Purification
			3.3.3 Formulation and Packaging
		3.4 Environmental Monitoring
		3.5 Raw Material Testing
		3.6 Product Comparability
Part III Pharmacy
	Chapter 4 Pharmacology and Drug Safety
		4.1 Action of Drugs in Humans
			4.1.1 Pharmacokinetics
			4.1.2 Pharmacodynamics
				4.1.2.1 Principles of Phenomenological Effects
				4.1.2.2 Parameters of Drug Effects
		4.2 Routes and Forms of Administration
		4.3 Drug Study
			4.3.1 Pre‐Clinical Study
			4.3.2 Clinical Study
				4.3.2.1 Phases of Clinical Studies
				4.3.2.2 Design and Conduct of Clinical Trials
		4.4 Path of the Drug from the Manufacturer to Patients
		4.5 Drug Safety
			4.5.1 Causes and Classification of Side Effects
			4.5.2 Methods for Supervising Drug Safety (Pharmacovigilance)
			4.5.3 Measures upon Incidence of Adverse Reactions
Part IV Quality Assurance
	Chapter 5 Fundamentals of Quality Assurance
		5.1 Basic Principles
		5.2 Benefit of Quality Assurance Activities
		5.3 Quality Management According to ISO 9000
			5.3.1 Fields of Activity
		5.4 Structure of Quality Management Systems
		5.5 Quality Management System Components in the Pharmaceutical Area
			5.5.1 Documentation
			5.5.2 Failure Prevention and Correction
			5.5.3 Responsibility of Management and Training of Personnel
			5.5.4 Audits
			5.5.5 External Suppliers
			5.5.6 Contract Review
		5.6 Quality Assurance in Development
	Chapter 6 Quality Assurance in Manufacturing
		6.1 GMP
			6.1.1 Personnel
			6.1.2 Premises and Equipment
				6.1.2.1 Measures to Avoid External Contamination
				6.1.2.2 Measures to Avoid Cross‐Contamination and Product Confusion
			6.1.3 Equipment Qualification
			6.1.4 Process Validation
			6.1.5 Computer Validation
			6.1.6 Documentation
		6.2 Operative Workflows under GMP Conditions
			6.2.1 Product Release and Deviation Management
			6.2.2 Changes in the Manufacturing Process
		6.3 Production of Investigational Drugs
	A Case Study Part IV: Warning Letters by FDA
Part V Pharmaceutical Law
	Chapter 7 Pharmaceutical Law and Regulatory Authorities
		7.1 Fields of Pharmaceutical Law
		7.2 Bindingness of Regulations
		7.3 Authorities, Institutions, and Their Regulations
			7.3.1 FDA
			7.3.2 EMA
			7.3.3 German Authorities
			7.3.4 Japanese Authorities
			7.3.5 Authorities of Growth Markets
				7.3.5.1 China: National Medical Products Administration (NMPA)
				7.3.5.2 Brazilian Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency, ANVISA)
			7.3.6 Other Important Institutions
				7.3.6.1 US Pharmacopoeia
				7.3.6.2 ICH
				7.3.6.3 ISO
				7.3.6.4 WHO
				7.3.6.5 PIC/S
				7.3.6.6 ISPE
				7.3.6.7 PDA
		7.4 Official Enforcement of Regulations
		7.5 Drug Approval
	B Case Study Part V: Clinical Trials for Protein Products
		B.1 Mabthera®/Rituxan®
		B.2 Enbrel®
			B.2.1 Adult Patients with Rheumatoid Arthritis
		B.3 Remicade® Infliximab
			B.3.1 Adult Rheumatoid Arthritis
		B.4 Humira® 40 mg
		B.5 Lucentis®
			B.5.1 Treatment of Wet AMD
		B.6 Zaltrap®
Part VI Production Facilities
	Chapter 8 Facility Design
		8.1 Basic Principles
		8.2 GMP‐Compliant Plant Design
			8.2.1 Production Flow Diagram
			8.2.2 Conceptual Plant Layout
				8.2.2.1 Is the Facility Fit for the Intended Purpose?
				8.2.2.2 Is the Facility cGMP Compliant?
				8.2.2.3 Is the Facility Flexible?
				8.2.2.4 Can the Facility Be Expanded?
				8.2.2.5 Is It Possible to Separate the Core Process from the Support Functions?
				8.2.2.6 Is the Plant Capacity Optimized and Are Synergies with Existing Facilities Used?
			8.2.3 GMP Flow Analysis
			8.2.4 Zoning Concept
		8.3 Basic Concepts for Production Plants
			8.3.1 Single‐ and Multiproduct Plants
			8.3.2 Fractal and Integrated Configuration
			8.3.3 Flexible and Fixed Piping
			8.3.4 Steel Tanks and Disposable Equipment
		8.4 Clean and Plant Utilities
			8.4.1 Clean Utilities
				8.4.1.1 Water
				8.4.1.2 Clean Steam
				8.4.1.3 Gases and Process Air
			8.4.2 Plant Utilities
			8.4.3 Waste Management
		8.5 Equipment Cleaning
		8.6 Clean Rooms
			8.6.1 Separation of Zones by Clean Room Design
			8.6.2 Finishing of Floors, Walls, and Ceilings
			8.6.3 HVAC Installations
			8.6.4 Qualification
		8.7 Automation
		8.8 QC Laboratories
		8.9 Location Factors
			8.9.1 Cost
			8.9.2 Personnel
			8.9.3 Permitting
			8.9.4 Synergies with Existing Facilities or Units
			8.9.5 Logistics
			8.9.6 Know‐How and Intellectual Property Protection
			8.9.7 Other Risks
			8.9.8 Market Access
			8.9.9 Language and Culture
	Chapter 9 Planning, Construction, and Commissioning of a Manufacturing Plant
		9.1 Steps of the Engineering Project
			9.1.1 Planning
			9.1.2 Construction
			9.1.3 Commissioning, Qualification, Validation
		9.2 Project Schedules
		9.3 Cost Estimates
		9.4 Organization of an Engineering Project
			9.4.1 Expert Groups Involved
			9.4.2 Role and Selection of Contractors
			9.4.3 Contracts and Scope Changes
		9.5 Successful Execution of an Engineering Project
		9.6 Legal Aspects of Facility Engineering
			9.6.1 Health, Safety, and Environmental Law
			9.6.2 Building Law
Part VII Economy
	Chapter 10 Production Costs
		10.1 Drug Life Cycle
		10.2 Position of the Manufacturing Costs in the Overall Cost Framework
		10.3 Basic Principles of Cost Calculation
			10.3.1 Nominal Accounting – Actual Accounting
			10.3.2 Cost Accounting – Profit and Loss Accounting
			10.3.3 Direct Costs – Indirect Costs
			10.3.4 Fixed Costs – Variable Costs
			10.3.5 Relevant and Irrelevant Costs
			10.3.6 Cost Type, Cost Center, and Cost Unit
		10.4 Costs of Biotechnological Manufacturing Processes
			10.4.1 Capital Costs
			10.4.2 Operating Costs
		10.5 Accounting Methods
			10.5.1 Cost Accounting
			10.5.2 Profit and Loss Accounting
	Chapter 11 Investments
		11.1 Basic Principles
			11.1.1 Investment Targets
			11.1.2 Types of Investments
				11.1.2.0 Classification According to the Object of Investment
				11.1.2.0 Classification According to the Effect of Investment
				11.1.2.0 Classification According to Other Criteria
			11.1.3 Decision Processes
		11.2 Value–Benefit Analysis
		11.3 Investment Appraisal
			11.3.1 Static Methods
				11.3.1.1 Cost Comparison
				11.3.1.2 Profit Comparison
				11.3.1.3 Profitability Comparison
				11.3.1.4 Static Payback Time
			11.3.2 Dynamic Methods
				11.3.2.1 Capital Value
				11.3.2.2 Internal Rate of Return
				11.3.2.3 Annuity
		11.4 Dynamic Payback Time
	Chapter 12 Production Concept
		12.1 Capacity Planning
		12.2 Dilemma of In‐House Manufacturing
		12.3 Aspects of Manufacturing Outsourcing
			12.3.1 Types of Cooperation
			12.3.2 Contractual Agreements
			12.3.3 Technology Transfer
			12.3.4 Time Schedules
		12.4 Make‐or‐Buy Analysis
		12.5 Process Optimization
			12.5.1 Comparability of the Product
			12.5.2 Operational Excellence
				12.5.2.1 Lean Management
				12.5.2.2 Six‐Sigma
		12.6 Supply‐Chain Management
			12.6.1 Security of Supply
			12.6.2 Performance Management
	C Examples Part VII: Manufacturing Cost Calculation
		C.1 Introduction
		C.2 Basic Assumptions for Both Production Processes
		C.3 Step 1: Production of Product 1 in Dedicated Facility
			C.3.1 Cost Structure
			C.3.2 Product Costs
			C.3.3 Idle Costs
			C.3.4 Unit Price Based on Facility Usage
		C.4 Step 2: Addition of a Second Product
			C.4.1 Costs of Products
			C.4.2 Evaluation of Manufacturing Options
Part VIII Production Organization and Digitalization
	Chapter 13 Organization of a Manufacturing Facility
		13.1 Functional Setup of a Manufacturing Plant
		13.2 Development of a Plant Organization
		13.3 Organizational Charts and Cooperation Pathways
		13.4 Cultural Aspects: The Human Factor
	Chapter 14 Digitalization
		14.1 Operational and Digital Perspective
		14.2 Digital Maturity
		14.3 Integration and IT Architecture
		14.4 Digital Transformation
		14.5 Digital Applications in the GMP Environment
References
Index
EULA