バイオ医薬品製造の実践ガイド

Biomanufacturing is an exciting and fundamentally new science that is constantly changing and yielding novel products from emerging technologies. This report A Practical Guide to Biopharmaceutical Manufacturing, provides an excellent introduction for anyone interested in developing an in-depth understanding of the biopharmaceutical industry. The report is written to highlight the production technologies and operations that occur in the manufacturing facility.

Table of Contents

• 1.1 Introduction
  • 1.1.1 Special considerations
• 1.2 The biopharmaceutical development process
  • 1.2.1 Drug discovery
  • 1.2.2 Process development
  • 1.2.3 Clinical Trials
  • 1.2.4 Time-to-market
• 1.3 The biopharmaceutical manufacturing process
  • 1.3.1 Manufacturing capacity
  • 1.3.2 Scale-up of production processes
• 1.4 Demand for biologics
  • 1.4.1 Historical growth
  • 1.4.2 Biologics in clinical trials
  • 1.4.3 Approved biological products
• 1.5 Contract manufacturing organisations
  • 1.5.1 Clinical Trials Directive
  • 1.5.2 CMO Entrant

• 2.1 EXPRESSION SYSTEMS
  • 2.1.1 Host organisms
  • 2.1.2 Transgenic hosts
• 2.2 Culture type
  • 2.2.1 Suspension culture
  • 2.2.2 Attachment dependent
• 2.3 Growth characterisitics
  • 2.3.1 Product formation
  • 2.3.2 Scale-up
  • 2.3.3 Culture media
  • 2.3.4 Process monitoring and control
• 2.4 Modes of operation
  • 2.4.1 Batch operation
  • 2.4.2 Fed-batch operation
  • 2.4.3 Media exchange operation
  • 2.4.4 Perfusion operation
  • 2.4.5 Solera

• 3.1 Recovery
  • 3.1.1 Centrifugation
  • 3.1.2 Lysis
  • 3.1.3 Filtration
• 3.2 Purification
  • 3.2.1 Solubilisation and refolding
  • 3.2.2 Chromatography
  • 3.2.3 Precipitation
  • 3.2.4 Viral clearance
• 3.3 Sterile filtration
• 3.4 Formulation, fill and finish
  • 3.4.1 Pre-formulation
  • 3.4.2 Stabilisation and formulation
  • 3.4.3 Fill finish operations

• 4.1 Process equipment
  • 4.1.1 Standard vessels
  • 4.1.2 Jacketed vessels
  • 4.1.3 Disposables
  • 4.1.4 Pipework
  • 4.1.5 Manifolds
• 4.2 Process solutions and waste
  • 4.2.1 Process solutions
  • 4.2.2 Sampling
  • 4.2.3 Waste
• 4.3 Cleaning and sterilisation
  • 4.3.1 Clean-in-place (CIP)
  • 4.3.2 Sterilisation
• 4.4 Process utilities
  • 4.4.1 Purified water (PW)
  • 4.4.2 Water for injection (WFI)
  • 4.4.3 Clean steam
  • 4.4.4 Utility distribution

• 5.1 Introduction
• 5.2 Bioprocess design
  • 5.2.1 Process description
  • 5.2.2 GMP philosophy
  • 5.2.3 Mass balance
  • 5.2.4 Block flow diagrams and process flowsheets
  • 5.2.5 Process Simulation
  • 5.2.6 Equipment List
  • 5.2.7 Piping and instrumentation diagram
  • 5.2.8 Process control
  • 5.2.9 Scale-up/Scale-down
• 5.3 Facility design
  • 5.3.1 Facility products
  • 5.3.2 Plant layout
  • 5.3.3 Room classifications and HVAC zoning
  • 5.3.4 Clean air
  • 5.3.5 People, material and waste flows
  • 5.3.6 Change rooms and airlocks
  • 5.3.7 Waste management
• 5.4 Design lifecycle
  • 5.4.1 Conceptual design
  • 5.4.2 Front end engineering
  • 5.4.3 Detail design
  • 5.4.4 Construction
  • 5.4.5 Commissioning and qualification

• 6.1 Introduction
  • 6.1.1 Simulation models
  • 6.1.2 Simulation study
• 6.2 Overview of process simulation
  • 6.2.1 Challenges of bioprocess simulation
  • 6.2.2 Benefits of process simulation
  • 6.2.3 Simulators for the bioprocess industry
• 6.3 Bioprocess simulation
  • 6.3.1 Domain description
  • 6.3.2 Modelling scope of a bioprocess simulator
  • 6.3.3 Bioprocess simulation software packages
• 6.4 A simulation case study
  • 6.4.1 An example of a modelling framework
  • 6.4.2 Case study set-up
  • 6.4.3 Simulation results and discussion
  • 6.4.4 Conclusion

• 7.1 Introduction
• 7.2 Cost performance metrics
  • 7.2.1 Capital costs
  • 7.2.2 Operating costs
  • 7.2.3 Net Present Value (NPV)
• 7.3 Framework of a cost model
  • 7.3.1 An example of a cost model framework
  • 7.3.2 Data collection
  • 7.3.3 COG modules
• 7.4 A COG case study
  • 7.4.1 Case study set-up
  • 7.4.2 Simulation results and discussion

• 8.1 Therapeutic proteins
  • 8.1.1 Monoclonal antibodies (MAbs)
  • 8.1.2 Recombinant interferons
  • 8.1.3 Recombinant interleukins
  • 8.1.4 Recombinant hormones
  • 8.1.5 Recombinant growth factors
  • 8.1.6 Monoclonal antibodies
  • 8.1.7 Growth
  • 8.1.8 Recovery
  • 8.1.9 Purification
• 8.2 Vaccines
  • 8.2.1 Types of vaccines
  • 8.2.2 Whooping cough
  • 8.2.3 Growth and Recovery
  • 8.2.4 Solid Fraction Lysis and Purification
  • 8.2.5 Supernatant Purification
  • 8.2.6 Polishing and combined purification
• 8.3 Gene therapy
  • 8.3.1 Genetic Vectors
  • 8.3.2 Growth
  • 8.3.3 Recovery
  • 8.3.4 Purification
• 8.4 Cellular therapy
  • 8.4.1 Dendritic white blood cells
  • 8.4.2 Purification & transformation
  • 8.4.3 Recovery and Growth

• 9.1 Disposable application evaluation
  • 9.1.1 Quantitative analysis
  • 9.1.2 Benefits of disposable technology
  • 9.1.3 Disadvantages of disposable technology
• 9.2 Design guide: bag handling
  • 9.2.1 Empty bioprocess bags & disposable equipment
  • 9.2.2 Filled bioprocess bags
  • 9.2.3 Tubing
• 9.3 Systems
  • 9.3.1 Cell culture
  • 9.3.2 Chromatography
  • 9.3.3 Mixer systems
  • 9.3.4 Freezing systems
• 9.4 Components
  • 9.4.1 Bags
  • 9.4.2 Connectors
  • 9.4.3 Rapid transfer ports
  • 9.4.4 Tubing
  • 9.4.5 Filling
• 9.5 Instrumentation and control

• 10.1 Product licensing
  • 10.1.1 Clinical development and product approval
  • 10.1.2 Clinical trials
  • 10.1.3 Regulatory authorities
• 10.2 Good manufacturing practice
  • 10.2.1 Defining the regulatory requirements
  • 10.2.2 Regulatory framework
  • 10.2.3 Scope Process areas
  • 10.2.4 Assessing requirements
  • 10.2.5 Design considerations
  • 10.2.6 Viral clearance of biotechnology products
  • 10.2.7 Good Automated Manufacturing Practices (GAMPs)
• 10.3 Biosafety
  • 10.3.1 Defining the regulatory requirements
  • 10.3.2 Risk
  • 10.3.3 Biosafety & GMP
• 10.4 Validation approach
  • 10.4.1 Validation requirements
  • 10.4.2 Validation life cycle
• 10.5 Quality: The role of QA/QC
  • 10.5.1 Quality Assurance
  • 10.5.2 Quality Control

• Table 1.1 Average figures for number of subjects, success rates and trial durations in clinical phases
• Table 1.2 Mean total phase lengths for biopharmaceuticals
• Table 1.3 Typical dosage figures for a selection of approved products
• Table 1.4 Typical therapeutic antibodies approved, and their indications
• Table 4.1 Typical mixing time for media and buffer preparation
• Table 4.2 System requirements for solution preparation stations
• Table 5.1 Environmental classification
• Table 5.2 Classification of cleanrooms
• Table 6.1 Comparison of SuperPro/SchedulePro Designer and BPS Simulation
• Table 6.2 Major equipment specification
• Table 7.1 A typical worksheet for presenting the annual cash flow, the discounted present value and the net present value of a project
• Table 7.2 An example of a production worksheet
• Table 7.3 An example of an equipment list worksheet
• Table 7.4 Cost factors included in the capital charge
• Table 7.5 Lang factors used in the capital estimate (contingencies excluded)
• Table 7.6 Labour benchmarking factors and estimated headcount
• Table 7.7 Capital breakdown for the traditional and concept facility
• Table 7.8 Cost of goods (COG) comparison (including capital) (€ /g)
• Table 9.1 Tubing pass-through options
• Table 9.2 Disposable bioreactors
• Table 9.3 Disposable flasks, bottles and other containers
• Table 9.4 Mixer systems
• Table 9.5 Disposable connectors
• Table 9.6 Instrumentation and control components
• Table 10.1 Average figures for number of subjects, success rates and trial durations in clinical phases
• Table 10.2 Regulatory bodies
• Table 10.3 ICH documents
• Table 10.4 EU Directives and Guidelines
• Table 10.5 US Regulations and Guidelines
• Table 10.6 System Classifications

• Figure 1.1 Scale-up of biopharmaceutical production process to generate product for initial R&D clinical trials and commercialisation
• Figure 1.2 IND applications in US
• Figure 1.3 Breakdown of clinical trials by expression system
• Figure 1.4 Breakdown of clinical trials per phase by expression system
• Figure 1.5 Breakdown of clinical trials by product type
• Figure 1.6 Breakdown of clinical trials by location of trials
• Figure 1.7 Breakdown of clinical trials by location of companies
• Figure 1.8 Contract manufacturing organisations (CMOs)
• Figure 2.1 An airlift bioreactor
• Figure 2.2 Stirred tank bioreactor
• Figure 2.3 T-flasks
• Figure 2.4 Nalgene cell factories
• Figure 2.5 A schematic of a hollow fibre bioreactor
• Figure 2.6 A packed bed bioreactor
• Figure 2.7 The different phases during the growth of an organism
• Figure 2.8 Typical scale-up trajectory
• Figure 3.1 Operation of disk stack centrifuge
• Figure 3.2 Operation of a tubular bowl centrifuge
• Figure 3.3 Different types of filtration based on the particle size range
• Figure 3.4 Considerations for process selection
• Figure 3.5 Interaction between matrix and product in affinity chromatography
• Figure 3.6 Interaction between matrix and product in ion exchange chromatography
• Figure 3.7 Diffusion-based process that uses a porous matrix where species within the feed can diffuse
• Figure 3.8 Sterile filtration steps in media preparation
• Figure 4.1 Commonly installed ports in a standard vessel
• Figure 4.2 Commonly installed ports in a jacketed vessel
• Figure 4.3 An illustration of a CIP system
• Figure 4.4 CIP skid system
• Figure 4.5 Typical duration of activities in an SIP operation
• Figure 4.6 The sequences for preparing purified water
• Figure 4.7 The operation of a clean steam generator
• Figure 5.1 Using operation yields to calculate the scale of operation
• Figure 5.2 An example of a section of a block flow diagram
• Figure 5.3 Graphical representation of the process
• Figure 5.4 P&ID of a typical temperature loop with valve positioner
• Figure 5.5 An example of a control system for bioreactor temperature
• Figure 5.6 Operating boundaries for process scale-up
• Figure 5.7 Single product facility
• Figure 5.8 Single product facility with pre- and post-viral segregation
• Figure 5.9 The use of airflows and HEPA filters in a facility
• Figure 5.10 The movement of people and equipment
• Figure 5.11 Waste disposal
• Figure 6.1 Steps in a simulation study
• Figure 6.2 The modelling framework for the simulation tool
• Figure 6.3 A downstream purification flowsheet simulation diagram
• Figure 6.4 Gantt chart of a process schedule
• Figure 6.5 Process flow diagram of the case study: Production of a therapeutic MAb from mammalian cell culture using batch culture
• Figure 6.6 Gantt chart - process scheduling
• Figure 6.7 Gantt chart - Vessel utilisation
• Figure 6.8 Gantt chart - CIP skid utilisation
• Figure 6.9 Utility plots for (a) WFI storage and (b) supply/demand
• Figure 7.1 Cost of goods (COG) spreadsheet structure
• Figure 7.2 The mass balance table and a detailed breakdown of the sub unit operations
• Figure 7.3 The layout of a COG summary worksheet
• Figure 7.4 Disposable application savings (€ /g)
• Figure 8.1 Sample flowsheet for a typical MAb production process
• Figure 8.2 Sample process flowsheet for the production of vaccines
• Figure 8.3 Recovery steps for the culture of Bordetella pertussis cells
• Figure 8.4 Sample process flowsheet for gene therapy
• Figure 8.5 Growth pattern for the production of viruses
• Figure 8.6 Scale-out over scale-up
• Figure 8.7 Sample process flowsheet for cellular therapy
• Figure 9.1 The relative proportions of direct materials costs associated with the application of disposables
• Figure 9.2 Single-head Acerta disposable filling system
• Figure 10.1 From discovery to launch
• Figure 10.2 Validation document structure