A Practical Guide to Biopharmaceutical Manufacturing

Publication Date	January 2006
Publisher	Scrip Reports
Product Type	Report
Pages
ISBN Number	not applicable
Product Code	SCR00002

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Summary

The first version of this aid to understanding pharmaceutical R&D was published in 2003 and updated in 2005. It concentrated on small molecule drugs (molecular weights usually below 500 daltons) and the dangers of failing to integrate their discovery with the developmental demands of clinical research (pharmaceutics, pharmacokinetics and safety, for example).

Aimed at no particular specialists, it sought to inform all those involved with pharmaceutical R&D, however loosely, how each of the necessary disciplines fit together to take a new medicine from discovery to market launch. Feedback was positive but with one consistent request: to increase the detail on regulatory procedures and clinical evaluation. Version 2 was published in 2005 with this aim.

A second update is timely from several standpoints. True, the principles of R&D have not changed markedly in the intervening years, but like any industry, Pharma has been forced to take stock of the manner in which it operates. Analysis of financial profits and losses consistently shows that increasingly greater investment is required for reduced numbers of marketed products. Despite the introduction of new technologies aimed at faster and more innovative drug discovery, the number of new introductions with novel mechanisms of action has remained constant. And threats to public safety, whilst rare, demand ever more stringent regulatory procedures.

The industry continues to consolidate through M&A. Although these activities in themselves rarely bring long-term growth, they provide an opportunity to divest activities no longer considered essential for in-house ownership. From this has sprung the need for contract organisations, specialist companies with expertise in particular phases of pharmaceutical R&D ranging from the supply of drug targets and chemical building blocks through non-clinical development and on to clinical evaluation and regulatory affairs.

Innovation in the industry is not at a standstill: it has changed direction.

Where once small molecule research provided the mainstay, biological drugs are now making their presence felt. While the range of genomic sciences waits to make its impact, biologicals are providing the current focus for novel discovery. This move doesn't come without a price. Biologicals do not behave like small molecules: they have large molecular weights and are most usually species specific. The rules for their development are different and often little understood: witness the tragedy which occurred at Northwick Park following the administration of an immune activator to healthy volunteers in March 2006.

The 2007 update to 'How Drugs are Developed' responds to these changes.

Sections which previously focused on small molecules have been expanded where necessary to describe the corresponding processes for biologicals.

And there are two new chapters. The first deals with project management: the fundamentals of managing multidisciplinary teams and the ways in which the role is changing to encompass external as well as internal interfaces. The second concerns the growing interest in translational research, the ways in which laboratory concepts can be converted into medical advances.

In 2003, the impact of sequencing the human genome was just being felt throughout the industry. Now, in 2007, it is apparent that while providing promise for the future, there will be no 'quick fix' for the industry and it must pursue an ever wider range of opportunities to achieve its goals. The result is a networked industry without historical parallel.

Content

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)157
- 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