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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, B a d ,B ioinfomatics 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~sc lass 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 witht he 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. l k s 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 1 GARY WALSH Abciximab: The First Platelet Glycoprotein IIb/IIIa Receptor Antagonist 35 ROBERTE . JORDAN, MARIAN T. NAKADAHA, RLAN F. WEISMAN Recombinant Coagulation Factor IX (BeneFixO) 73 JOHN EDWARDSN, EIL m y Biopharmaceutical Drug Development: A Case History 109 MARYANFNO OTE,A ND THOMASB OONE Follitropin beta (Puregon) 125 HENK J. OUT Insulin Lispro (Hmalog) 149 RONALD E. CHANCE, N. BRADLY GLAZER AND KATHLEENL . WISHNER i Contents 11 Interferon beta-lb - the first long-term effective treatment of relapsing- remittug and secondary progressive multiple sclerosis (MS) 173 R. HOROWSKI, J.-F. KAPP, M. S"MAYR, ST. STUERZEBECHER Reteplase, a recombinant plasminogen activator 185 MICHAEL WALLER AND ULRICH KOHNERT Stabilisation of biopharmaceutical products and finished product formulations 217 MA"DER S. HORA AND BAO-LUC HEN Patent Law for Biopharmaceuticals 249 R.S TEPHENC RESPI The development of new medicines: an overview 269 JOHNC. STINSON The EMEA and regulatory control of (bio)pharmaceuticals within the European Union 289 GARY WALSH Biopharmaceutical Validation: an overview 311 STEPHENS LATER Validation of Biopharmaceutical Chromatography Systems 337 K.F. WILLIAMS (*) AND C.J.A. DAVIS( **) Validation of Water for Injections (WFI) for Biopharmaceutical Manufacture 363 PASCHALB AKER AND WAELA LLAN Information retrieval and the biopharmaceutical industry: an introductory overview 3 89 PATRICIA O'DONNELL Information technology and the internet as a resource of biopharmaceutical information 405 J.P. JDWTH, D. FIELDHOUSEJ, .C.-M.Y U Marketing Issues for the (Bi0)pharmaceutical sector 42 1 SCOTT SPINKA