Handbook of Biogeneric Therapeutic Proteins

Regulatory, Manufacturing, Testing, and Patent Issues

Sarfaraz K. Niazi

• Publisher: CRC Press
• Year: 2002
• eBook ISBN: 9781000611328
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

More than 20 billion dollars worth of biopharmaceuticals are scheduled to go off-patent by 2006. Given the strong political impetus and the development of technological tools that can answer the questions regulatory authorities may raise, it is inevitable that the FDA and EMEA will allow biogeneric or biosimilar products. Even with all the regulato

1 The Frontiers of Biotechnology

Introduction

Man has done well utilizing other life forms to his own advantage. From the taming of the cattle to making recombinant therapeutic proteins using yeast, the history of man interacting with nature is full of great and exciting surprises, genius exploitation, and pursuit of solutions to problems of mankind in nature. The first wave of this interaction began very early when man fermented food articles to make bread, wine, cheese, and yogurt long before he had any knowledge of the invisible, microbial world. The thesis that technology does not necessarily depend on science is well proven here. The next wave arrived when man learned the scientific basis of the biological world and began manufacturing drugs and other essential components from biological tissues; the discovery of penicillin opened the way for this research. Antibiotics were then routinely manufactured by the process of fermentation. The third wave of technologic and scientific breakthrough came in the late 1970s and 1980s when the new technology related to cell culture, fusion, bioprocessing, and genetic engineering took roots in the industry. Today, prokaryotes, eukaryotes algae, glycophytes, and halophytes are all likely to contribute to products of the future. The techniques of DNA manipulation, monoclonal antibody preparation, tissue culture, protoplast fusion, protein engineering, immobilized enzymes, cell catalysis, antisense DNA, and so forth are the leading technology helping mankind find solutions to his problems, what began with a glass of brewed grape juice that made man feel good.

Biotechnology is the application of biological systems and organisms to technical and industrial processes. In its broadest definition, biotechnology refers to the use of living organisms, including isolated mammalian cells, in the production of products having beneficial use. This places alcohol brewing, antibiotic production, and dairy processing, for example, within the scope of biotechnology. The use of yeast to ferment grain into alcohol has been ongoing for centuries. Likewise, farmers and breeders use a form of “genetic engineering” to produce improved crops and stock by selecting for desirable characteristics in plants and animals. Only recently have “new” biotechnology techniques enabled scientists to modify an organism’s genetic material at the cellular or molecular level. These methods are more precise, but the results are similar to those produced with classical genetic techniques involving whole organisms. Biotechnologically derived products are those derived from the new biotechnology techniques. The development of these products offers many challenges, integration of many sciences, and an almost art-like implementation of technology to achieve consistent results.

However, the current interest in biotechnology is a result primarily of two major advances:

1. The development of recombinant DNA (rDNA) technology, which allowed the genes of one species to be transplanted into another species (gene coding). Thus, gene coding for the expression (production) of a desired protein (usually human) could be inserted into a host prokaryotic (e.g., bacteria) or eukaryotic (e.g., mammalian) cell in such a manner that the host cell would then express (yield) usable (commercially) quantities of the desired protein.
2. The development of techniques for producing large quantities of monoclonal antibodies (i.e., antibodies arising from a single lymphocyte).

TABLE 1.1
Global Definitions of Biotechnology

Country/Region (Source)	Definition	Analysis
British (British Biotechnologist)	Application of biological organisms, systems, or processes to manufacturing and service industries.	Broad, noncommittal, technology driven, bureaucratic differentiating manufacturing and services industries.
European (European Federation of Biotechnology)	The integrated use of biochemistry, microbiology, and engineering sciences in order to achieve technological (industrial) applications of the capabilities of microorganisms, cultured tissue cells, and parts thereof.	Legal deconstruction of the term defining components and targets and beginning with “integrated,” to reflect the union.
Japan (Japanese Biotechnologists)	A technology using biological phenomena for copying and manufacturing various kinds of useful substances.	Pure technologic exploitation; the use of “copying” and “various kinds” is significant as it is leading to “useful” substances.
USA (National Science Foundation)	The controlled use of biological agents, such as microorganisms or cellular components, for beneficial use.	Control, concern about its unlawful exploitation, and deleterious effects using microorganisms is obvious.

The definition of “biotechnology” is relatively new and how it is accepted worldwide is worth examining as it reflects how the regulatory controls of biotechnology derived products would be evaluated. Table 1.1 lists the definitions of the world’s major regulatory regions. Later, we will analyze how different regulatory agencies label “biogeneric,” from what it should be to all types of variations like, “follow-on,” “biosimilar,” or “generic biologicals,” all reflecting a bias, a disbelief (or perhaps amazement) at how fast the age of biogenerics products has arrived.

As we get closer to regulatory approvals of the first biological products in their “generic” forms, the above differences in how different countries view biotechnology are beginning to become obvious. For example, Europeans would prefer to call the products marketed by competitors after the expiry of patents as “follow-on biologicals,” “similar biologicals,” whereas the push in the U.S. is to call it “biogeneric,” as it is a generic product. Billions of dollars are riding on the hair splitting differences between these interpretations. Lobby groups like Biotechnology Industry Organization (BIO) in the U.S. are supported by the big pharmaceutical companies and they work incessantly to block the introduction of biogeneric products, whereas the legislature, the generic companies, and government-supported Medicare are insisting on cheaper biological products — the biogenerics. These differences will be further discussed in Chapter 11.

Biotechnology Frontiers

“Biotechnology, the combination of biology and technology, includes biologic applications, diagnostic tools and businesses that improve everyday life by providing solutions to some of life’s most vexing problems,” describes the BIO. Since 1982, hundreds of millions of people have been helped by about 200 biotechnology drugs and vaccines, with many more in the pipeline treating diseases that were just a couple of decades ago were considered untreatable, from AIDS to Alzheimer’s disease to stroke prevention. Prevention of diseases like cancer appears possible within a short time. Many enzymes used to make food products are likely to be produced by recombinant techniques, as are the ingredients in most processed foods. A newer generation of oils without trans fats and cholesterol are now available that reduce the incidence of heart disease; “golden rice” fortified with vitamins and allergen-free foods is now common as are safer meats.

Today, over 2500 biologicals are used to fight nearly 200 different animal diseases. To make animal products safe, products are made to keep animals free of infectious bacteria (e.g., E. col...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Dedication
• Foreword
• Preface
• About the Author
• Author’s Comments
• List of Figures
• List of Tables
• Table of Contents
• Chapter 1 The Frontiers of Biotechnology
• Chapter 2 Marketing Opportunities
• Chapter 3 Manufacturing Overview
• Chapter 4 Genetically Modified Cells
• Chapter 5 Upstream Processing
• Chapter 6 Manufacturing Systems
• Chapter 7 Downstream Processing
• Chapter 8 Purification Techniques
• Chapter 9 Quality Assurance Systems
• Chapter 10 Quality Control Systems
• Chapter 11 Regulatory Affairs
• Chapter 12 Intellectual Property Issues
• Appendix I: Recombinant DNA and Monoclonal Antibody Products Approved by FDA
• Appendix II: Glossary of Terms
• Appendix III: Bibliography
• Index