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.

CHAPTER 1: INTRODUCTION TO BIOPROCESSING

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

CHAPTER 2: GROWTH OPERATIONS

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

CHAPTER 3: RECOVERY & DOWNSTREAMS PROCESSING

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

CHAPTER 4: SUPPORT 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

CHAPTER 5: BIOPROCESS DESIGN

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

CHAPTER 6: PROCESS SIMULATION

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

CHAPTER 7: COST MODELLING

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

CHAPTER 8: SAMPLE PROCESSES

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

CHAPTER 9: DISPOSABLES

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

CHAPTER 10: REGULATORY ENVIRONMENT

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

LIST OF TABLES

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

LIST OF FIGURES

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