Therapeutic Monoclonal Antibody Production

Report Summary

Bioprocessing is the branch of biotechnology dealing with the production and purification of biological materials of commercial interest. This report focuses on the wide ranging disciplines applied to the goal of rapidly, accurately and economically complex monoclonal antibody molecules. While most antibody biologics are anti-cancer agents, there are a number of other areas of disease management to which biologics in this class are starting to play a significant role. These indications include immune dysfunction, infectious disease and mental illness.

Trends in the upstream and the downstream areas of monoclonal antibody production are encouraging, and should provide help in holding down the costs of these very expensive biological molecules. As indicated in this report, the large expansion in the use of disposables in upstream and downstream unit operations of the production chain is underway. This shift away from fixed, reusable equipment is causing monumental changes in the industry, making available workable product quantities at affordable cost to cash strapped small companies while allowing clinical trials of promising but higher risk, second tier candidates to proceed. The exploding availability of disposables has caused major biotech companies to question their strategy of large capital investments in massive plants and reusable equipment.

This report identifies the continuing upstream versus downstream gap problem for the industry. Specifically, progress toward producing more protein per unit volume of culture medium has moved more rapidly to put pressure on the rates at which these materials can be purified on the downstream end. This overall expansion has motivated law-making bodies in Europe to redefine intellectual property guidelines and rules governing biogenerics. Legislation governing biosimilars has been passed in the US as part of the recent 2010 health care legislation.

This report also evaluates rising concern over the threat of Asian and European competition to the American bioprocessing industry.

• The pros and cons of animal cell culture
• Development of alternative production cell lines
• Improving MAb production per volume of culture media
• Impact of disposables on cost and availability of MAb’s
• Bottlenecks appear on the downstream side of production
• The shift in capital spending on fixed, reusable infrastructure
• Tackling biogenerics regulatory questions
• The dimensions of Asian and EU competition

Table of Contents

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
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.6, other types
Chinese Hamster Ovary (CHO) Cells
NSO Cells
Per.C6 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
BioLexis; Duckweed.
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
Recombinant Polyclonal Purification Challenges
Filter reconfiguration for Better Antibody Purification
Affinity tag purification.
Self Cleaving Affinity tag purification
Protein A
Other Protein A Alternatives
Trends in Bioprocessing from the EU

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
Effective project management tools
Lean, Not Necessarily Mean

Chapter 5 Current Regulatory Status of Biologics

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
US and China: Price Competition
Will the US thrown away its advantages in bioprocessing?
The European threat
CMOs: Upsides and Downsides

6.3 Marketing Issues; Costs

Are Revolutionary Developments Possible in Bioprocessing?
Disposables in the Ascendant.

6.4 Options and Caveats

Good News and Challenges Ahead.
Short Term Trends in Bioprocessing
R&D is a major cost driver

Chapter 7 References