Date published July 2010

 

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Therapeutic Protein Production: A Changing Landscape Report - Table of Contents

Author: K. John Morrow, Jr. Ph.D.

CHAPTER 1
INTRODUCTION 
1.1. Bioprocessing in the 21st Century 
A Word of Caution 
State of the Art 
What Is Bioprocessing? 
An Industry Committed to Mammalian Cell Expression Systems (Golden 2009, See Appendix) 
A Changing Landscape 
The Pipeline 
Antibodies Rule the Roost 
Corporate Strategies 
Pressures and Opportunities 
1.2. Bioprocessing Advances Are Incremental in Scope 
1.3. Range of the Industry Challenge  

CHAPTER 2
UPSTREAM PROCESSING 
2.1. Mammalian Cell Culture Expression Systems 
Historical Background  
Media Development and the Evolution of Therapeutic Antibodies 
Cell Line Development: Engineering for Better Performance 
Developing Overproducing Cell Lines 
Medarex’ Selection Procedure to Avoid Royalties 
Conventional Cell Lines: CHO, NSO, PER.C6, Other Types 
Chinese Hamster Ovary (CHO) Cells  
NSO Cells (Nonsecreting Mouse Myeloma) 
Per.C6 Cells (Golden 2009, See Appendix) (Primary Human Retinal Cells) 
Human Cell Lines 
Selection for Overproducers 
2.2. Mammalian Cell Culture Media  
Introduction to Mammalian Cell Culture Media Strategies  
Elimination of Serum From Mammalian Cell Culture Media  
Protein Hydrolysates 
Online Sources of Information 
Many Options for Cell Culture Media Optimization 
2.3. Post-Translational Modifications 
Glycosylation 
S-Glutathionylation 
Other Modifications 
2.4. Other Production Alternatives 
Bacteria 
Yeast 
Green Leafy Plants 
Chlamydomonas reinhardtii  
Microalgae 
Insect Cells 
Chesapeake PERL, Inc. 
Alternatives to Baculovirus for Insect Cell Protein Synthesis  
Protozoan Expression Hosts  
2.5. Bioreactors: Design and Function 
Computer Modeling of Bioreactor Performance 
Disposable Bioreactor Components 
Disposables and Rapid Response  
The Rise and Fall of Large Antibody Production Facilities 

CHAPTER 3
DOWNSTREAM PROCESSING 
3.1. Disposables, Reusables 

Disposable Technology Comes of Age 
Disposable Storage Options 
The Disposable Conundrum
The Future of Disposables 
3.2. Purification Strategies 
Fine-Tuning Contaminant Removal Through Filtration Technology  
Current Polishing Strategies: The Toolbox 
Single-Pass Tangential Flow Filtration (TFF) 
Recombinant Polyclonal Purification Challenges 
Filter Reconfiguration for Better Antibody Purification 
Affinity Tag Purification (Culp 2009 and Tomaselli 2009, See Appendix) 
Self-Cleaving Affinity Tag Purification  
Protein A 
Other Protein A Alternatives  
Trends in Downstream Bioprocessing from the European Union 
3.3. Monitoring Tools: HPLC-MS  

CHAPTER 4
OPTIMIZING BIOPROCESS DEVELOPMENT 
4.1. Time Is Money 

Avoiding Revenue Loss  
The Next Challenge  
The Example of Insulin 
Develop Processes That Will Survive Upscaling  
Economic Savings From Disposables 
Flexibility Generates Cost Savings 
Lean, Not Necessarily Mean 

CHAPTER 5
CURRENT REGULATORY STATUS OF BIOLOGICS 
5.1. The Biologics Problem 

European Guidelines on Biologics 
Canadian Regulatory Policy for Biologics 
Status of US Biosimilar Regulation  

CHAPTER 6
CONCLUSIONS DRAWN WHILE ON THE ROAD AHEAD; THOUGHTS ON THE FUTURE OF BIOPROCESSING 
6.1. Predicting the Future 
Small, Incremental Steps Will Guide Progress in Bioprocessing 
6.2. The Rise of Foreign Competition  
China’s Advance  
Drawbacks to China’s Advance 
Chinese Regulatory Policy 
United States and China: Price Competition 
Will the United States Throw Away Its Advantages in Bioprocessing? 
India 
The European Threat 
CMOs: Upsides and Downsides 
6.3. Marketing Issues; Costs 
Are Revolutionary Developments Possible in Bioprocessing? 
Disposables in the Ascendant 
Cell-Free Protein Production 
6.4. Options and Caveats 
Good News and Challenges Ahead 
Short-Term Trends in Bioprocessing 
R&D Is a Major Cost Driver 

REFERENCES 

APPENDIX 

COMPANY INDEX WITH WEB ADDRESSES