Production of Plasma Proteins for Therapeutic Use

Sets forth the state of the science and technology in plasmaprotein production

With contributions from an international team of eighty leadingexperts and pioneers in the field, Production of Plasma Proteinsfor Therapeutic Use presents a comprehensive overview of thecurrent state of knowledge about the function, use, and productionof blood plasma proteins. In addition to details of the operationalrequirements for the production of plasma derivatives, the bookdescribes the biology, development, research, manufacture, andclinical indications of essentially all plasma proteins withestablished clinical use or therapeutic potential.

Production of Plasma Proteins for Therapeutic Use coversthe key aspects of the plasma fractionation industry in fivesections:

Section 1: Introduction to Plasma Fractionationinitially describes the history of transfusion and then covers theemergence of plasma collection and fractionation from its earliestdays to the present time, with the commercial and not–for–profitsectors developing into a multi–billion dollar industry. Section 2: Plasma Proteins for Therapeutic Use contains24 chapters dedicated to specific plasma proteins, includingcoagulation factors, albumin, immunoglobulin, and a comprehensiverange of other plasma–derived proteins with therapeuticindications. Each chapter discusses the physiology, biochemistry,mechanism of action, and manufacture of each plasma proteinincluding viral safety issues and clinical uses. Section 3: Pathogen Safety of Plasma Products examinesissues and procedures for enhancing viral safety and reducing therisk of transmissible spongiform encephalopathy transmission. Section 4: The Pharmaceutical Environment Applied to PlasmaFractionation details the requirements and activitiesassociated with plasma collection, quality assurance, compliancewith regulatory requirements, provision of medical affairs support,and the manufacture of plasma products. Section 5: The Market for Plasma Products and the Economicsof Fractionation reviews the commercial environment andeconomics of the plasma fractionation industry including futuretrends, highlighting regions such as Asia, which have the potentialto exert a major influence on the plasma fractionation industry inthe twenty–first century.

PREFACE ix

CONTRIBUTORS xi

SECTION 1 INTRODUCTION TO PLASMA FRACTIONATION

1 The History and Development of the Plasma ProteinFractionation Industry 3
John Curling, Neil Goss, and Joseph Bertolini

SECTION 2 PLASMA PROTEINS FOR THERAPEUTIC USE

2 Production and Clinical Profile of Human Plasma CoagulationFactor VIII 31
Sami Chtourou

3 Production and Clinical Profile of Human Plasma–Derived VonWillebrand Factor 41
Sami Chtourou and Michel Poulle

4 Factor Eight Inhibitor Bypassing Activity 49
Peter Turecek and Hans Peter Schwarz

5 Prothrombin Complex 65
Jürgen Römisch and Katharina Pock

6 Factor IX 81
Salvador Grancha, Steven Herring, Antonio Pa´ez, PereRistol, and Juan Ignacio Jorquera

7 Factor XI 93
Sami Chtourou and Michel Poulle

8 Factor XIII and Factor X 101
Peter Feldman

9 Fibrinogen: Science and Biotechnology 117
Gerard Marx

10 Fibrin Glues and Bandages 137
Hans Christian Hedrich and Heinz Gulle

11 Production and Clinical Use of Plasma Antithrombin III147
Andrea Morelli

12 Human Serum Albumin: A Multifunctional Plasma Protein159
John More and Mark Bulmer

13 IntravenousImmunoglobulinGfromHumanPlasma PurificationConcepts and Important QualityCriteria 185
Andrea Buchacher and Waltraud Kaar

14 Hyperimmune Immunoglobulin G 207
Hugh Price, Maurice Genereux, and Christopher Sinclair

15 Rh (D) Immunoglobulin 217
Maurice Genereux, Jodi Smith, William Bees, and ChristopherSinclair

16 Alpha1–Proteinase Inhibitor: The Disease, the Protein, andCommercial Production 227
Wytold Lebing

17 C1–Inhibitor 241
Jan Over, Christine Kramer, Anky Koenderman, Diana Wouters, andSacha Zeerleder

18 Acid–Stabilized Plasmin as a Novel Direct–Acting Thrombolytic259
Valery Novokhatny, James Rebbeor, Philip Scuderi, and StephenPetteway Jr.

19 Reconstituted, Plasma–Derived High–Density Lipoprotein273
Peter Lerch

20 Plant–Derived Manufacturing of Apolipoprotein AIMilano:Purification and Functional Characterization 283
Cory Nykiforuk, Yin Shen, Elizabeth Murray, Joseph Boothe, andMaurice Moloney

21 Transferrin 301
Leni von Bonsdorff, Hennie ter Hart, Ingrid Prins–de Nijs, AnkyKoenderman, Jan Over, and Jaakko Parkkinen

22 Plasminogen: Its Role in the Therapy of LigneousConjunctivitis 311
Claudia Nardini

23 Haptoglobin 321
Joan Dalton and Azubuike Okemefuna

24 Ceruloplasmin: Biology, Manufacture, and Clinical Use337
Aron Berkovsky and Vladimir Vaschenko

25 Solvent/Detergent Plasma 345
Tor–Einar Svae, Andrea Heger, Lothar Biesert, AndreaNeisser–Svae, and Wolfgang Frenzel

SECTION 3 PATHOGEN SAFETY OF PLASMA PRODUCTS

26 Ensuring Virus Safety of Plasma Products 361
Herbert Dichtelmu¨ller

27 Transmissible Spongiform Encephalopathies and Plasma Products369
Luisa Gregori, David Asher, and Dorothy Scott

SECTION 4 THE PHARMACEUTICAL ENVIRONMENT APPLIED TO PLASMAFRACTIONATION

28 Quality Assurance Requirements in Plasma Product Manufacture383
Jens Jesse

29 Regulatory Activities Associated with Production andCommercialization of Plasma Protein Therapeutics 403
Nancy Kirschbaum and Timothy Lee

30 The Emerging Role of Global Medical Affairs in theTwenty–First Century 413
Hartmut Ehrlich, David Perry, David Gelmont, and RaminFarhood

31 Plasma for Fractionation 423
Joseph Bertolini and Timothy Hayes

32 The Pharmaceutical Manufacturing Environment 437
Ernst Hetzl

SECTION 5 THE MARKET FOR PLASMA PRODUCTS AND THE ECONOMICS OFFRACTIONATION

33 The Economics of Plasma Fractionation 451
Neil Goss and John Curling

34 Future Trends in the Plasma Products Market 461
Paolo Marcucci

INDEX 471

JOSEPH BERTOLINI, BSc (HONS.), MSc, PhD, is R&DManager at CSL Bioplasma where he has been closely involved in thetechnical development and improvement of immunoglobulin and albuminproducts. He is active in national and international conferencesand industry organizations and is a strong advocate for theadvancement of bioprocessing.

NEIL GOSS, BSc (HONS.), PhD, is Executive Director atFurther Options Pty Ltd., a consulting company specializing inbiotechnology and the plasma fractionation industry. He waspreviously Director of R&D, CSL Bioplasma and is the foundingorganizer for both the Plasma Product Biotechnology Meeting seriesand the BioProcessing Network.

JOHN CURLING, BSc, is a consultant in bioseparations andprotein purification whose clients have included numerousbiopharmaceutical, biotechnology, and vendor companies. Hepioneered the development of chromatographic methods of plasmafractionation and was the President of the Process SeparationDivision of Pharmacia. He has acted as an advisor to the WorldHealth Organization.