biopharmaceuticals, an industrial perspective

BIOPHARMACEUTICALS, AN INDUSTRIAL PERSPECTIVE Edited by Gary Walsh University of Limerick, Limerick, Ireland and Brendan Murphy Limerick Institute of Technology, Limerick, Ireland KLUWER ACADEMIC PUBLISHERS DORDRECHT / BOSTON / LONDON Library of Congress Cataloging-in-Publication Data ISBN 0-7923-5746-9 Published by Kluwer Academic Publishers, P.O. Box 17, 3300 AA Dordrecht, The Netherlands. Sold and distributed in North, Central and South America by Kluwer Academic Publishers, 101 Philip Drive, Norwell, MA 02061, U.S.A. In all other countries, sold and distributed by Kluwer Academic Publishers, P.O. Box 322, 3300 AH Dordrecht, The Netherlands. Printed on acid-free paper All Rights Reserved 0 1999 Kluwer Academic Publishers No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner. Printed in the Netherlands Contributors Paschal Baker and Wael Allan, Raytheon Engineers & Constrqctors UK, Validation and GMP Compliance Group; Ronald E. Chance, N. Bradly Glazer and Kathleen L. Wishner, Eli Lilly and Company, hdanapolis, USA R. Stephen Crespi, European Patent Attorney, West Sussex, UK; John Edwards, Neil Jh-by, Genetics Institute Inc., 87 Cambridge Park Dnve, Cambridge, Mass.; Maryann Foote and Thomas Boone, Amgen Inc., USA; Maninder S. Hora and Bao-Lu Chen, Dept. of Formulation Development, Chron Corporation, 4560 Horton Street, Emeryville, Ca 94608, USA; R. Horowslu, J F. Kapp, M. Steinmayr, St. Stuerzebecher, Schering AG, SBU Therapeutics, D- 13342, Berlin, Germany; J.P Jenuth, D. Fieldhouse, J.C M. Yu, Bad, Bioinfomatics Inc.; Robert E. Jordan, Marian T. Nakada, Harlan F. Weisman, Centocor Inc., Malvern, Pensylvania, USA; Brendan Murphy, University of Limerick, Ireland; Patricia ODonnell, University of Limerick, Ireland; Henk J. Out, N.V. Organon, PO Box 20, 5340, BH OSS, The Netherlands; A. Rolland, S. Sullivan, K. Petrak, Gene Medicine Inc., 8301 New Trails Drive, The Woodlands, Texas, USA Stephen Slater, Raytherm Engneers and Constructors; Scott Spinka, CareMerica Inc., 16508 Kingspointe, Lake Lane, Chesterfield, Mo., USA; Dr. John C. Stinson, Leo Laboratories Ltd., Crumlin, Dublin 12, Ireland; V vi Biopharmaceuticals, an overview Dr Wchael Waller and Dr Ulrich Kohnert, Boehringer Mannheim Therapeutics, Mannheim and Penzberg, Germany; K.F. Williams, Validation Technologies (Europe) Ltd., Sutton Place, 49 Stoney St., Nottingham, NG1 lLX, UK and C.J.A. Davis, Tanvec Ltd., Alexandra Court, Carrs Road, Cheadle, SK8 2JY, UK; Dr. Gary Walsh, University of Limerick Acknowledgements The editors wish to thank the authors of individual chapters for providing such excellent contributions, and for their cooperation during the post writing phase of the publication process. A special word of thanks to Sandy Lawson, for her professionalism and efficiency in reformating the chapters to comply with publication requirements. Finally, thank you to Janet Hoffman and her colleagues at Kluwer for all their help. vii Preface The bwnning of the modern biotech era can be traced to the mid-l970s, with the development of recombinant DNA technology and hybridoma technology. Thus far, the most prominent applied impact of these technologes has been the successful development of biotech-derived therapeutic agents - the biopharmaceuticals. Th~s class of pharmaceutical product has rapidly become established. The first such product, Humulin (recombinant human insulin, Eli Lilly) was approved in the USA in 1982. Today there are in excess of 50 biopharmaceutical products approved for medical use, with almost another 400 undergoing clinical trials. While all the biopharmaceutical products approved to date are protein-based, nucleic acid- derived products are likely to gain regulatory approval with the next decade. Gven the undoubted scientific and commercial prominence of thls sector, relatively few books detailing biopharmaceutical products or issues of practical relevance to the biopharmaceutical industry have been published thus far. lks book aims to complement the previously published texts whch focus upon ths area. The initial chapters are largely concerned with specific biopharmaceutical products, whch have, in the main, gained regulatory approval in the relatively recent past. Subsequent chapters focus upon various issues of practical relevance to the biopharmaceutical industry, such as product stabilization, patenting and regulatory issues. The final two chapters focus upon gene therapy, a therapeutic approach currently at the cutting edge of pharmaceutical research and development. The book, whose contributors are largely drawn from industry, is primarily aimed at an industrial audience. However, it should also prove a useful reference source to research and educational personnel with a direct interest in thts field. 1x x Biopharmace uticals, an ove wiew In conclusion, the editors wish to thank all those who have contributed to the successful completion of ths book. Chief amongst these are the various chapter authors (and their employers), as well as Kluwer Academic Publishers, whose professionalism was much in evidence at all stages of the publication process. A special word of thanks is reserved for Sandy Lawson, whose patience and word processing slulls yet again proved to be second to none. Gary Walsh Brendan Murphy Limerick September 1998 Contents Contributors V Acknowledgements vii Preface ix Biopharmaceuticals, an overview GARY WALSH 1 Abciximab: The First Platelet Glycoprotein IIb/IIIa Receptor Antagonist 35 ROBERT E. JORDAN, MARIAN T. NAKADA, HARLAN F. WEISMAN Recombinant Coagulation Factor IX (BeneFixO) JOHN EDWARDS, NEIL my 73 Biopharmaceutical Drug Development: A Case History 109 MARYANN FOOTE, AND THOMAS BOONE Follitropin beta (Puregon) HENK J. OUT 125 Insulin Lispro (Hmalog) 149 RONALD E. CHANCE, N. BRADLY GLAZER AND KATHLEEN L. WISHNER i 11 Contents Interferon beta-lb - the first long-term effective treatment of relapsing- remittug and secondary progressive multiple sclerosis (MS) R. HOROWSKI, J F. KAPP, M. S"MAYR, ST. STUERZEBECHER 173 Reteplase, a recombinant plasminogen activator MICHAEL WALLER AND ULRICH KOHNERT 185 Stabilisation of biopharmaceutical products and finished product formulations 217 MA"DER S. HORA AND BAO-LU CHEN Patent Law for Biopharmaceuticals R. STEPHEN CRESPI The development of new medicines: an overview JOHNC. STINSON 249 269 The EMEA and regulatory control of (bio)pharmaceuticals within the European Union 289 GARY WALSH Biopharmaceutical Validation: an overview STEPHEN SLATER 311 Validation of Biopharmaceutical Chromatography Systems 337 K.F. WILLIAMS (*) AND C.J.A. DAVIS (**) Validation of Water for Injections (WFI) for Biopharmaceutical Manufacture 363 PASCHAL BAKER AND WAEL ALLAN Information retrieval and the biopharmaceutical industry: an introductory overview PATRICIA O'DONNELL Information technology and the internet as a resource of biopharmaceutical information J.P. JDWTH, D. FIELDHOUSE, J.C M. YU Marketing Issues for the (Bi0)pharmaceutical sector SCOTT SPINKA 3 89 405 42 1 [...]... is an effective and inexpensive anticoagulant, it can display a poorly predictable dose response and it can display a narrow benefit : risk ratio Dicoumarol and warfarin are low molecular weight, coumaran-based anticoagulants whch can prevent the post-translational modification of various clotting factors, thus also rendering them inactive Dr Gary Walsh 12 More recently, a protein-based anticoagulant... characteristic advantages and dsadvantages in terms of recombinant protein production Thus far, however, few recombinant biopharmaceuticals developed are produced in either yeast or fungal systems Two approved biopharmaceuticals are produced in Saccharomyces cerevisiae: Refludan (recombinant hrudin, an anticoagulant marketed by Behringwerke AG) and recombinant hepatitis B surface antigen, incorporated... the early start-up companies have successfully developed products and are now well established withn the biopharmaceutical sector Major examples include Genentech and Amgen A list of pharmaceutical companies who now manufacture and/or market biophannaceutical products is provided in Table 3 , Biopharmaceuticals, an overview 5 Table 3 (Bio)pharmaceutical companies which manufacture andor market biopharmaceutical... diseases, some forms of cancer and the management of bone marrow transplants (44, 45) Biopharmaceuticals, an overview 19 Table 8 Recombinant haemopoietic growth factors which have gained marketing approval, or are in clinical trials Data sourced from PhRMA (http://www.phrma.org) and the EMEA (http://www.eudra,org/emea/html) (Note: rEPO = recombinant erythropoietin, rGM-CSF = recombinant granulocyte-macrophage... stratwc alliances with them An example of the latter was the alliance formed between Genentech and Eli Lilly with regard to the development and marketing of recombinant human insulin Many of the original biopharmaceutical companies set up in the late 1970s and 1980s no longer exist In addition to mergers, acquisitions and alliances, many were forced out of business due to lack of capital, or disappointing... Anticoagulants The inappropriate formation of a blood clot (thrombus) w i t h a diseased blood vessel can have serious, if not fatal, medical consequences such as heart attacks and strokes Anticoagulants are substances which can prevent blood clot formation and, hence, are applied therapeutically in cases where hgh risk of inappropriate blood clot formation is diagnosed (23) Traditional anticoagulants... availability and accidental transmission of disease Genetic engneering essentially facilitates the production of limitless quantities of any protein of interest, whtle hybridoma technology allows production of limitless quantities of a chosen monoclonal antibody These biotechnologcal innovations, along with an increasing understanding of the molecular mechanisms underlining both health and disease,... thus by anaemia) Examples include renal failure, various cancers, AIDS and some other infectious diseases, as well as bone marrow transplantations and rheumatoid arthritis Many of those conditions appear responsive to administration of exogenous EPO, and recombinant EPO has been approved to treat various forms of anaemia (Table 8 ) (40, 41) Recombinant EPO preparations are usually produced in Chmese Hamster... USA andor the EU (Note: several of these companies have a presence in both regions) Company Company Company A m g e n (CA, USA) Cytogen (NJ, USA) Novo-Nordisk (NJ, USA) N.V Organon (The Eli Lilly (IN, USA) Bay& Corp (CT, USA) Netherlands) Baxter Healthcare Galenus Mannheim Ortho-biotech (NJ, USA) (Germany) (MA, USA) Behringwerke A.G Genentech (CA, USA) Ortho McNeil Pharmaceuticals (NJ, USA) (Germany)... an autocrine growth factor for Tlymphocytes and also enhances antibody production in activated B lymphocytes As such, it is a major regulator of both cell-mediated and humoral immunity IL-2 also promotes differentiation and activation of natural killer (NK) cells, which play an important role in the destruction of transformed cells and virally infected cells and clinical trials continue to assess its . BIOPHARMACEUTICALS, AN INDUSTRIAL PERSPECTIVE Edited by Gary Walsh University of Limerick, Limerick, Ireland and Brendan Murphy Limerick Institute of Technology, Limerick, Ireland. Crumlin, Dublin 12, Ireland; V vi Biopharmaceuticals, an overview Dr Wchael Waller and Dr Ulrich Kohnert, Boehringer Mannheim Therapeutics, Mannheim and Penzberg, Germany; K.F. Williams,. stratwc alliances with them. An example of the latter was the alliance formed between Genentech and Eli Lilly with regard to the development and marketing of recombinant human insulin. Many of