ENCYCLOPEDIA OF BIOPROCESS TECHNOLOGY: FERMENTATION, BIOCATALYSIS, AND BIOSEPARATION VOLUME 1 WILEY BIOTECHNOLOGY ENCYCLOPEDIAS

Encyclopedia of Bioprocess Technology: Fermentation, Biocatalysis, and Bioseparation Edited by Michael C. Flickinger and Stephen W. Drew Encyclopedia of Molecular Biology Edited by Thomas E. Creighton Encyclopedia of Cell Technology Edited by Raymond E. Spier Encyclopedia of Ethical, Legal, and Policy Issues in Biotechnology Edited by Thomas J. Murray and Maxwell J. Mehlman

ENCYCLOPEDIA OF BIOPROCESS TECHNOLOGY: FERMENTATION, BIOCATALYSIS, AND BIOSEPARATION EDITORIAL BOARD

Chairman Edward L. Cussler Elmer Gaden, Jr. University of Minnesota University of Virginia, Charlottesville Jonathan S. Dordick Rensselaer Polytechnic Institute Associate Editors Bryan Griffiths H.W. Blanch Centre for Applied Microbiology and Research University of California, Berkeley Lars Hagel Yusuf Chisti Amersham Pharmacia University of Almerı´a Zhao Kai Arnold Demain National Vaccine and Serum Institute Massachusetts Institute of Technology Subash B. Karkare Peter Dunnill AMGEN Advanced Centre for Biochemical Engineering Murry Moo-Young David Estell University of Waterloo Khepri Pharmaceuticals Tetsuo Oka Csaba Horvath Kyowa Hakko Kogyo Co., Ltd. Yale University Karl Schugerl Arthur E. Humphrey University of Hannover Pennsylvania State University Atsuo Tanaka Bjorn K. Lydersen Kyoto University Irvine Scientific Kathryn Zoon Poul B. Poulson U.S. Food and Drug Administration Novo Nordisk Dane Zabriskie Series Editor Biogen, Inc. Leroy Hood University of Washington Editorial Board Stuart E. Builder Editorial Staff Strategic Biodevelopment Publisher: Jacqueline I. Kroschwitz John R. Birch Managing Editor: Camille Pecoul Carter Lonza Biologics Editor: Glenn Collins Charles L. Cooney Massachusetts Institute of Technology Editorial Assistant: Hugh Kelly ENCYCLOPEDIA OF BIOPROCESS TECHNOLOGY: FERMENTATION, BIOCATALYSIS, AND BIOSEPARATION

VOLUME 1

Michael C. Flickinger University of Minnesota St. Paul, Minnesota

Stephen W. Drew Merck and Co., Inc. Rahway, New Jersey

A Wiley-Interscience Publication John Wiley & Sons, Inc. New York / Chichester / Weinheim / Brisbane / Singapore / Toronto This book is printed on acid-free paper. A

Copyright ᭧ 1999 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

Flickinger, Michael C. The encyclopedia of bioprocess technology : fermentation, biocatalysis, and bioseparation / Michael C. Flickinger, Stephen W. Drew. p. cm. Includes index. ISBN 0-471-13822-3 (alk. paper) 1. Biochemical engineering--Encyclopedias. I. Drew, Stephen W., 1945- . II. Title. TP248.3.F57 1999 660.6Ј03--dc21 99-11576 CIP

Printed in the United States of America.

10987654321 PREFACE

The Wiley Biotechnology Encyclopedias, composed of The third type of biological information arises from com- the Encyclopedia of Molecular Biology; the Encyclopedia of plex biological systems and networks. Systems informa- Bioprocess Technology: Fermentation, Biocatalysis, and tion is four dimensional because it varies with time. For Bioseparation; the Encyclopedia of Cell Technology; and example, the human brain has 1,012 neurons making ap- the Encyclopedia of Ethical, Legal, and Policy Issues in proximately 1,015 connections. From this network arise Biotechnology cover very broadly four major contemporary systems properties such as memory, consciousness, and themes in biotechnology. The series comes at a fascinating the ability to learn. The important point is that systems time in that, as we move into the twenty-first century, the properties cannot be understood from studying the net- discipline of biotechnology is undergoing striking para- work elements (e.g., neurons) one at a time; rather the col- digm changes. lective behavior of the elements needs to be studied. To Biotechnology is now beginning to be viewed as an in- study most biological systems, three issues need to be formational science. In a simplistic sense there are three stressed. First, most biological systems are too complex to types of biological information. First, there is the digital or study directly, therefore they must be divided into tracta- linear information of our chromosomes and genes with the ble subsystems whose properties in part reflect those of the four-letter alphabet composed of G, C, A, and T (the bases system. These subsystems must be sufficiently small to an- guanine, cytosine, adenine, and thymine). Variation in the alyze all their elements and connections. Second, high- order of these letters in the digital strings of our chromo- throughput analytic or global tools are required for study- somes or our expressed genes (or mRNAs) generates infor- ing many systems elements at one time (see later). Finally, mation of several distinct types: genes, regulatory machin- the systems information needs to be modeled mathemati- ery, and information that enables chromosomes to carry cally before systems properties can be predicted and ulti- out their tasks as informational organelles (e.g., centrom- mately understood. This will require recruiting computer eric and telomeric sequences). scientists and applied mathematicians into biology—just Second, there is the three-dimensional information of as the attempts to decipher the information of complete proteins, the molecular machines of life. Proteins are genomes and the protein folding and structure/function strings of amino acids employing a 20-letter alphabet. Pro- problems have required the recruitment of computational teins pose four technical challenges: (1) Proteins are syn- scientists. thesized as linear strings and fold into precise three-di- I would be remiss not to point out that there are many mensional structures as dictated by the order of amino acid other molecules that generate biological information: residues in the string. Can we formulate the rules for pro- amino acids, carbohydrates, lipids, and so forth. These too tein folding to predict three-dimensional structure from must be studied in the context of their specific structures primary amino acid sequence? The identification and com- and specific functions. parative analysis of all human and model organism (bac- The deciphering and manipulation of these various teria, yeast, nematode, fly, mouse, etc.) genes and proteins types of biological information represent an enormous will eventually lead to a lexicon of motifs that are the build- technical challenge for biotechnology. Yet major new and powerful tools for doing so are emerging. ing block components of genes and proteins. These motifs One class of tools for deciphering biological information will greatly constrain the shape space that computational is termed high-throughput analytic or global tools. These algorithms must search to successfully correlate primary tools can be used to study many genes or chromosome fea- amino acid sequence with the correct three-dimensional tures (genomics), many proteins (proteomics), or many shapes. The protein-folding problem will probably be cells rapidly: large-scale DNA sequencing, genomewide solved within the next 10–15 years. (2) Can we predict pro- genetic mapping, cDNA or oligonucleotide arrays, two- tein function from knowledge of the three-dimensional dimensional gel electrophoresis and other global protein structure? Once again the lexicon of motifs with their func- separation technologies, mass spectrometric analysis of tional as well as structural correlations will play a critical proteins and protein fragments, multiparameter, high- role in solving this problem. (3) How do the myriad of throughput cell and chromosome sorting, and high- chemical modifications of proteins (e.g., phosphorylation, throughput phenotypic assays. acetylation, etc.) alter their structures and modify their A second approach to the deciphering and manipulation functions? The mass spectrometer will play a key role in of biological information centers around combinatorial identifying secondary modifications. (4) How do proteins strategies. The basic idea is to synthesize an informational interact with one another and/or with other macromole- string (DNA fragments, RNA fragments, protein frag- cules to form complex molecular machines (e.g., the ribo- ments, antibody combining sites, etc.) using all combina- somal subunits)? If these functional complexes can be iso- tions of the basic letters of the corresponding alphabet, lated, the mass spectrometer, coupled with a knowledge of thus creating many different shapes that can be used to all protein sequences that can be derived from the com- activate, inhibit, or complement the biological functions of plete genomic sequence of the organism, will serve as a designated three-dimensional shapes (e.g., a molecule in a powerful tool for identifying all the components of complex signal transduction pathway). The power of combinational molecular machines. chemistry is just beginning to be appreciated. v vi PREFACE

A critical approach to deciphering biological informa- that influence behavior, cost of therapeutic drugs gener- tion will ultimately be the ability to visualize the function- ated by biotechnology, animal rights, and the nature and ing of genes, proteins, cells, and other informational ele- control of intellectual property. ments within living organisms (in vivo informational Clearly, the challenge is to educate society so that each imaging). citizen can thoughtfully and rationally deal with these is- Finally, there are the computational tools required to sues, for ultimately society dictates the resources and reg- collect, store, analyze, model, and ultimately distribute the ulations that circumscribe the development and practice of various types of biological information. The creation pres- biotechnology. Ultimately, I feel enormous responsibility ents a challenge comparable to that of developing new in- rests with scientists to inform and educate society about strumentation and new chemistries. Once again this the challenges as well as the opportunities arising from means recruiting computer scientists and applied mathe- biotechnology. These are critical issues for biotechnology maticians to biology. The biggest challenge in this regard that are developed in detail in the Encyclopedia of Ethical, is the language barriers that separate different scientific Legal, and Policy Issues in Biotechnology. disciplines. Teaching biology as an informational science The view that biotechnology is an informational science has been a very effective means for breeching these bar- pervades virtually every aspect of this science, including riers. discovery, reduction to practice, and societal concerns. The challenge is, of course, to decipher various types of These Encyclopedias of Biotechnology reinforce the emerg- biological information and then be able to use this infor- ing informational paradigm change that is powerfully po- mation to manipulate genes, proteins, cells, and informa- sitioning science as we move into the twenty-first century tional pathways in living organisms to eliminate or pre- to more effectively decipher and manipulate for human- vent disease, produce higher-yield crops, or increase the kind’s benefit the biological information of relevant living productivity of animals for meat and other foods. organisms. Biotechnology and its applications raise a host of social, ethical, and legal questions, for example, genetic privacy, Leroy Hood germline genetic engineering, cloning of animals, genes University of Washington CONTRIBUTORS

Nicholas R. Abu-Absi, University of Minnesota, St. Paul, Minnesota, Cell A.R. Bernard, Serono Pharmaceutical Research Institute, Geneva, Swit- Cycle, Eukaryotes zerland, Transient Expression Systems Luis A. Actis, Miami University, Oxford, Ohio, Plasmid DNA Replication Michael J. Betenbaugh, Johns Hopkins University, Baltimore, Maryland, Michael W.W. Adams, University of Georgia, Athens, Georgia, Enzymes, Insect Cells and Larvae, Gene Expression Systems Extremely Thermostable Kami Beyzavi, Bioprocessing Limited, Consett, County Durham, United P.S. Adams, Trudeau Institute, Saranac Lake, New York, Professional So- Kingdom, Adsorbents, Inorganic cieties, Association of Biomolecular Resource Facilities John R. Birch, Lonza Biologics PLC, Berkshire, , Suspen- William R. Adams, Merck Manufacturing Division, West Point, Pennsyl- sion Culture of Animal Cells vania, Adsorption, Protein, Batch H.D. Blasey, Serono Pharmaceutical Research Institute, Geneva, Switzer- Eduardo Agosin, Pontificia Universidad Cato´lica de Chile, Santiago, land, Transient Expression Systems Chile, Solid Substrate Fermentation, Automation Thomas Bley, Dresden University of Technology, Dresden, Germany, Flow Eric Ailor, Johns Hopkins University, Baltimore, Maryland, Insect Cells Cytometry and Larvae, Gene Expression Systems Lynda F. Bonewald, University of Texas Health Science Center, San An- Kazuo Aisaka, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan, Cholesterol tonio, Texas, Professional Societies, Association of Biomolecular Resource Oxidase Facilities Hiroyuki Akatsuka, Tanabe Seiyaku Co., Ltd., Osaka, Japan, Diltiazem C.J.-P. Boonaert, Universite´ Catholique de Louvain, Louvain-la-Neuve, Synthesis Belgium, Cell Separation, Flocculation Mohamed Al-Rubeai, University of Birmingham, Birmingham, England, Michelle K. Bothwell, Oregon State University, Corvallis, Oregon, Ad- Apoptosis; Cell Cycle sorption, Proteins with Synthetic Materials Seigo Amachi, Hokkaido University, Sapporo, Japan, Pyruvate, Produc- Joye Bramble, Merck and Company, West Point, Pennsylvania, Roller Bot- tion Using Defective ATPase Activity tle Culture, Mixing Teruo Amachi, Kyoto University, Kyoto, Japan, b-Galactosidase, Enzy- R. Bruttini, Criofarma Freeze-drying Equipment, Turin, Italy, Freeze- mology and Applications drying, Pharmaceuticals Graham Andrews, Idaho National Engineering and Environmental Lab- James D. Bryers, University of Connecticut, Farmington, Connecticut, oratory, Idaho Falls, Idaho, Bioreactors, Gas Treatment Biofilms, Microbial Ruth Hogue Angeletti, Albert Einstein College of Medicine, Bronx, New R. Buccholz, Technical University of Berlin, Berlin, Germany, Microen- York, Professional Societies, Association of Biomolecular Resource Fa- capsulation cilities Michael Butler, University of Manitoba, Winnipeg, Canada, Energy Me- William Apel, Idaho National Engineering and Environmental Labora- tabolism, Microbial and Animal Cells tory, Idaho Falls, Idaho, Bioreactors, Gas Treatment Eleanor Canova-Davis, Genentech, San Francisco, California, Profes- Frances H. Arnold, California Institute of Technology, Pasadena, Califor- sional Societies, Association of Biomolecular Resource Facilities nia, Enzymes, Directed Evolution Ningjun Cao, Purdue University, West Lafayette, Indiana, Hemicellulose David L. Aronson, Consultant, Bethesda, Maryland, Coagulation Factors, Conversion; Organic Compounds, Cellulose Conversion Therapeutic Christine L. Case, Skyline College, San Bruno, California, Professional Yasuhisa Asano, Toyama Prefectural University, Toyama, Japan, D- Societies, Society for Industrial Microbiology (SIM) Aminopeptidase, Alkaline D-Peptidase; Opine Dehydrogenase, Secondary S.A. Casnocha, Monsanto Co., St. Louis, Missouri, Media, Animal Cell Amine Dicarboxylic Acids; Phenylalanine Dehydrogenase; Mitsubishi Culture Chemical Co., Yokohama, Japan, Malate, D-Malate Francisco J. Castillo, Berlex Biosciences, Richmond, California, Hybrid- Yoshiro Ashina, Nitto Chemical Industry Co., Ltd., Tokyo, Japan, Nitrile oma, Antibody Production Hydratase Marvin Charles, Lehigh University, Bethlehem, Pennsylvania, Fermenter John Aunins, Merck and Company, West Point, Pennsylvania, Roller Bot- Design tle Culture, Mixing Peter S. J. Cheetham, Zylepsis, Ltd., Ashford, United Kingdom, Enzymes, Hans Axelsson, Alfa Laval Separation AB, Tumba, Sweden, Cell Separa- for Flavor Production tion, Centrifugation Shu-Jen D. Chiang, -Myers Squibb Company, Syracuse, New York, Irina Bagyan, University of Connecticut Health Center, Farmington, Con- Cephalosporins necticut, Gene Transfer, Gram-Positive Bacteria Yusuf Chisti, University of Almerı´a, Almerı´a, Spain, Mass Transfer; Shear Frederick S. Baker, Westvaco Corporation, Charleston, South Carolina, Sensitivity; Solid Substrate Fermentations, Enzyme Production, Food Activated Carbon, Decoloration of Pharmaceutical Products Enrichment Kym N. Baker, University of Kent, Canterbury, U.K., Glycosylation of Re- Jeffrey L. Cleland, Genentech, Inc., South San Francisco, California, For- combinant Proteins mulation and Delivery, Protein Pharmaceuticals Richard H. Baltz, CognoGen Enterprises, Indianapolis, Indiana, Muta- O. Colagrande, Universita` Cattolica Sacro Cuore, Piacenza, Italy, Wine genesis Production A. Baradarajan, Indian Institute of Technology–Madras, Chennai, India, Attilio Converti, Genoa University, Genoa, Italy, Biofilters Dextran, Microbial Production Methods Charles L. Cooney, Massachusetts Institute of Technology, Cambridge, Ana Paulina Barba de la Rosa, University of California, Irvine, Irvine, Massachusetts, Bioreactors, Continuous Stirred-Tank Reactors California, Crystallization, Bulk, Macromolecules Athel Cornish-Bowden, National Center for Scientific Research, Mar- Claudia Bardouille, ECACC CAMR Porton Down, Salisbury, Wiltshire, seilles, France, Kinetics, Enzymes United Kingdom, Animal Cells Used in Manufacturing Rosalie J. Cote, Becton Dickinson Microbiology Systems, Sparks, Mary- Ann-Kristin Barnfield Frej, Amersham Pharmacia Biotech, Uppsala, land, Media Composition, Microbial, Laboratory Scale; Medium Formu- Sweden, Adsorption, Expanded Bed lation and Design, E. coli and Bacillus spp. Jonathan Basch, Bristol-Myers Squibb Company, Syracuse, New York, John W. Crabb, Cleveland Clinic Foundation, Cleveland, Ohio, Profes- Cephalosporins sional Societies, Association of Biomolecular Resource Facilities J.W. Bennett, Tulane University, New Orleans, Louisiana, Aspergillus Steven M. Cramer, Rensselaer Polytechnic Institute, Troy, New York, Chro- I.S. Bentley, ABM Brewing and Enzymes Group/Rhone-Poulenc, Stock- matography, Ion Exchange port, United Kingdom, Enzymes, Starch Conversion Ronald L. Crawford, University of Idaho, Moscow, Idaho, Bioremediation vii viii CONTRIBUTORS

Jorge H. Crosa, Oregon Health Sciences University, Portland, Oregon, Craig J.L. Gershater, S. B. Pharmaceuticals, Harlow, Essex, England, Plasmid DNA Replication Inoculum Preparation John Cullum, LB Genetik, University of Kaiserslautern, Kaiserslautern, Robert L. Gherna, American Type Culture Collection, Rockville, Mary- Germany, Genetic Instability land, Culture Preservation, Bacteria, Fungi, Yeast, and Cell Lines; Me- Simon Cutting, Royal Holloway University of , Egham, Surrey, dium Formulation and Design, E. coli and Bacillus spp. United Kingdom, Gene Transfer, Gram-Positive Bacteria Siddartha Ghose, Aston University, Birmingham, United Kingdom, Pro- Hans von Do¨ hren, Technical University Berlin, Berlin, Germany, Peptide tein Adsorption, Expanded Bed Alessandro D’Aprano, University of Rome, La Sapienza, Rome, Italy, Barbara Ghrist, Genentech, San Francisco, California, Professional So- Conductivity cieties, Association of Biomolecular Resource Facilities W.-D. Deckwer, GBF-Gesellschaft fu¨ r Biotechnologische Forschung GmbH, M. Gluz, Ben-Gurion University of the Negev, Beer-Sheva, Israel, Bioreac- Braunschweig, Germany, Xanthan Gum tors, Airlift Reactors Michael L. Dekleva, Merck and Co., Inc., West Point, Pennsylvania, Vac- Francesc Go` dia, Universitat Auto`noma de Barcelona, Barcelona, Spain, cine Technology Bioreactors, Fluidized-Bed Arnold L. Demain, Massachusetts Institute of Technology, Cambridge, Victor Goetz, Merck Research Labs, West Point, Pennsylvania, Adsorption, Massachusetts, Metabolites, Primary and Secondary Protein, Batch P.B. Dengis, Universite´ Catholique de Louvain, Louvain-la-Neuve, Bel- C.S. Gong, Purdue University, West Lafayette, Indiana, Hemicellulose Con- gium, Cell Separation, Flocculation version; Organic Compounds, Cellulose Conversion C.P. Dillon, C.P. Dillon & Associates, St. Albans, West Virginia, Stainless Catherine Grassin, Gist-brocades, Seclin Cedex, France, Enzymes, Fruit Steels Juice Processing Dennis Dobie, Fluor Daniel, Marlton, New Jersey, Heating, Ventilating, Thomas P. Graycar, Genencor International Inc., Palo Alto, California, and Air Conditioning Proteolytic Cleavage, Reaction Mechanisms D. Dochain, Universite´ Catholique de Louvain, Louvain-La-Neuve, Bel- Lasse Greiner, Forschungszentrum Ju¨ lich GmbH, Ju¨ lich, Germany, En- gium, Process Control, Strategy and Optimization zymes, Immobilized, Reactors Ed Domanico, Tri-Clover, Valencia, California, Pumps, Industrial J. Bryan Griffiths, Scientific Consultancy & Publishing, Salisbury, United John Dougherty, Lilly Research Laboratories, Indianapolis, Indiana, Pro- Kingdom, Mammalian Cell Culture Reactors, Scale-Up fessional Societies, Association of Biomolecular Resource Facilities E. Molina Grima, University of Almerı´a, Almerı´a, Spain, Microalgae, Mass Alan Doyle, Centre for Applied Microbiology and Research, Salisbury, Culture Methods Wilts, United Kingdom, Culture Collections Tingyue Gu, Ohio University, Athens, Ohio, Chromatography, Radial Flow Y.F. Dufreˆne, Universite´ Catholique de Louvain, Louvain-la-Neuve, Bel- Maria J. Guardia, University of Minnesota, Minneapolis, Minnesota, gium, Cell Separation, Flocculation Mammalian Cell Bioreactors C.C. Dupont-Gillain, Universite´ Catholique de Louvain, Louvain-la- S. Guillouet, Massachusetts Institute of Technology, Cambridge, Massa- Neuve, Belgium, Cell Separation, Flocculation chusetts, Corynebacteria, Brevibacteria H. Dziallas, Technische Universita¨t Braunschweig, Braunschweig, Ger- H. Ha˚ kanson, Lund University, Lund, Sweden, Sampling Methods (Re- many, Scale-Up, Stirred-Tank Reactors actors, Contamination) Heinrich Ebner, Linz, Austria, Vinegar, Acetic Acid Production Daniel D. Hanle, Kendro Laboratory Products, Newtown, Connecticut, Centrifuges, Animal Cells G. Larry Eitel, Jacobs Engineering Group, Denver, Colorado, ASTM Stan- dards for Biotechnology Satoshi Hanzawa, TOSOH Corp., Ayase-shi, Japan, Aspartame; Tokyo Research Laboratory, Hayakawa, Japan, Thermolysin Lynda B.M. Ellis, University of Minnesota, Minneapolis, Minnesota, Bio- catalysis Databases Colin R. Harwood, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom, Bacillus Takakazu Endo, Nitto Chemical Industry Co., Ltd., Tokyo, Japan, Nitrile Junzo Hasegawa, Kaneka Corporation, Hyogo, Japan, Optically Active Hydratase 1,2-Diols, Microbial Production by Stereoinversion Larry E. Erickson, Kansas State University, Manhattan, Kansas, Anaer- Gary Hathaway, California Institute of Technology, Pasadena, California, obes Professional Societies, Association of Biomolecular Resource Facilities Bruno Fabiano, University of Genoa, Genoa, Italy, Corrosion, Microbial Holly Haughney, Pall Corporation, Long Island, New York, Filtration, Air; Pierre Fauquenberque, Gist-brocades, Seclin Cedex, France, Enzymes, Filtration, Cartridge Fruit Juice Processing J.J. Heijnen, Delft University of Technology, Delft, The Netherlands, Bio- Joseph Fernandez, Rockefeller University, New York, New York, Profes- energetics of Microbial Growth sional Societies, Association of Biomolecular Resource Facilities Martin Held, Swiss Federal Institute of Technology, Zu¨ rich, Switzerland, J.-L. Flores Candia, GBF-Gesellschaft fu¨ r Biotechnologische Forschung Pseudomonas, Process Applications GmbH, Braunschweig, Germany, Xanthan Gum Ulf Hellman, Ludwig Institute for Cancer Research, Uppsala, Sweden, Pro- Ian G. Fotheringham, NSC Technologies, Mount Prospect, Illinois, Phe- fessional Societies, Association of Biomolecular Resource Facilities nylalanine D.C. Hempel, Universita¨t Gesamthochschule Paderborn, Paderborn, Ger- Beth Fowler, Autoimmune, Inc., Lexington, Massachusetts, Professional many, Scale-Up, Stirred-Tank Reactors Societies, Association of Biomolecular Resource Facilities Diane L. Hevehan, Northwestern University, Evanston, Illinois, Hypoxia, Cornelius G. Friedrich, University of Dortmund, Dortmund, Germany, Effects on Animal Cells Waste Gas Cleaning, Biological S.M. Heydarian, University College London, London, United Kingdom, Roger Fuentes-Granados, Iowa State University, Ames, Iowa, Soybean Rheology of Filamentous Microorganisms, Submerged Culture (Fermentation, Meal Oil) Paula M. Hicks, North Carolina State University, Raleigh, North Caro- Daniel Y.C. Fung, Kansas State University, Manhattan, Kansas, Anaer- lina, Enzymes, Extremely Thermostable; Thermophilic Microorganisms obes Sophia Hober, Royal Institute of Technology, Stockholm, Sweden, Affinity Sean R. Gallagher, Motorola Phoenix Corporate Research Laboratories, Fusions, Gene Expression Tempe, Arizona, Electrophoresis of Proteins and Nucleic Acids Ann C. Horan, Schering Plough Research Institute, Kenilworth, New Jer- Subinay Ganguly, Smith Kline Beecham Pharmaceuticals, King of Prus- sey, Secondary Metabolite Production, Actinomycetes, Other Than Strep- sia, Pennsylvania, Expression Systems, Mammalian Cells tomyces F.A.P. Garcia, University of Coimbra, Coimbra, Portugal, Cell Disruption Daslav Hranueli, PLIVA d.d., Research Institute, Zagreb, Croatia, Genetic and Lysis Instability Alan R. Gardner, Smith Kline Beecham, King of Prussia, Pennsylvania, Tsu-An Hsu, Vaccine Pharmaceutical R&D, Merck & Co., Inc., West Point, Process Validation Pennsylvania, Insect Cells and Larvae, Gene Expression Systems Maria Gavrilescu, Research Centre for Antibiotics, Ias¸i, Romania, Static Wei-Shou Hu, University of Minnesota, Minneapolis, Minnesota, Mam- Mixing, in Fermentation Process malian Cell Bioreactors; Microcarrier Culture CONTRIBUTORS ix

Holger Huebner, Technical University of Berlin, Berlin, Germany, Mi- Udo Kragl, Forschungszentrum Ju¨ lich GmbH, Ju¨lich, Germany, Biotrans- croencapsulation formation, Engineering Aspects; Enzymes, Immobilized, Reactors Tony Hunt, Advanced Minerals Corporation, Santa Barbara, California, M.R.V. Krishnan, Anna University, Chennai, India, Citric Acid, Processes Filter Aids Maria-Regina Kula, Heinrich Heine University Du¨ sseldorf, Ju¨ lich, Ger- Takamitsu Iida, Niigata University, Niigata, Japan, Wastewater Treat- many, Protein Purification, Aqueous Liquid Extraction ment, Immobilized Cells Hidehiko Kumagai, Kyoto University, Kyoto, Japan, Dihydroxyphen- Yasuhiro Ikenaka, Kaneka Corporation, Hyogo, Japan, Aminohydrolases, ylalanine (4), Produced by Microorganisms; Tyrosine Phenol-lyase for Production of D-Amino Acids Hidetoshi Kutsuki, Kaneka Corporation, Hyogo, Japan, Optically Active Masayuki Inui, Mitsubishi Chemical Corporation, Ibaraki, Japan, L- 1,2-Diols, Microbial Production by Stereoinversion Isoleucine Andreas Lu¨ bbert, Martin Luther University, Wittenberg, Germany, Gas A.P. Ison, University College London, London, United Kingdom, Rheology Hold-Up of Filamentous Microorganisms, Submerged Culture David C. LaPorte, University of Minnesota, Minneapolis, Minnesota, Gly- Kathryn M. Ivanetich, University of California–San Francisco, San Fran- oxylate Bypass, Regulation cisco, California, Professional Societies, Association of Biomolecular Re- Xanthe M. Lam, Genentech, Inc., South San Francisco, California, For- source Facilities mulation and Delivery, Protein Pharmaceuticals Cornelius F. Ivory, Washington State University, Pullman, Washington, Per Larsen, Novo Nordisk A/S, Bagsvaerd, Denmark, Insulin, Purifica- Electrophoresis, Proteins, Batch and Continuous tion Mahendra K. Jain, MBI International, Lansing, Michigan, Anaerobes, Michael E. Laska, Massachusetts Institute of Technology, Cambridge, Industrial Uses Massachusetts, Bioreactors, Continuous Stirred-Tank Reactors David C. James, University of Kent, Canterbury, United Kingdom, Gly- Anh LeDuy, Laval University, Sainte-Foy, Canada, Pullulan, Microbial cosylation of Recombinant Proteins Production Methods Nigel Jenkins, Eli Lilly, Inc., Indianapolis, Indiana, Protein Glycosylation David Leak, Imperial College of Science, Technology, and Medicine, Lon- Steen Weber Jensen, Novo Nordisk A/S, Bagsvaerd, Denmark, Insulin, don, United Kingdom, Methylotrophs, Industrial Applications Purification Ann L. Lee, Merck Research Labs, West Point, Pennsylvania, Adsorption, Michael R. Johns, University of Queensland, Brisbane, Australia, Crys- Protein, Batch tallization, Proteins, Kinetics Gyun Min Lee, Korea Advanced Institute of Science and Technology, Tae- Alois Jungbauer, Institute of Applied Microbiology, Vienna, Austria, Chro- jon, Korea, Osmotic Stress, Secretion Rate matography, Computer-Aided Design P.A. Lessard, Massachusetts Institute of Technology, Cambridge, Massa- Beth H. Junker, Merck Research Laboratories, Rahway, New Jersey, Good chusetts, Corynebacteria, Brevibacteria Manufacturing Practice (GMP) and Good Industrial Large Scale Practice Andreas Liese, Forschungszentrum Ju¨ lich, Ju¨ lich, Germany, Biotransfor- (GLSP); Plants, Design and Operation mations, Engineering Aspects Oliver Kaltenbrunner, Institute of Applied Microbiology, Vienna, Austria, Carsten Lindemann, University of Hannover, Hannover, Germany, Fluo- Chromatography, Computer-Aided Design rescence Techniques for Bioprocess Monitoring Manohar Kalyanpur, Consultant, Bioseparations and Pharmaceutical M. Liu, Rutgers University, Piscataway, New Jersey, Roller Bottle Culture, Validation, Plaisir, France, Membrane Separations Mixing Per Ka˚ rsna¨s,Percreative, Go¨teborg, Sweden, Chromatography, Hydropho- David R. Lloyd, University of Birmingham, Birmingham, England, Cell bic Interaction Cycle R.S. Karthikeyan, Indian Institute of Technology–Madras, Chennai, In- Deryk T. Loo, Bristol-Myers Squibb Pharmaceutical Research Institute, dia, Dextran, Microbial Production Methods Seattle, Washington, Attachment Factors Michihiko Kataoka, Kyoto University, Kyoto, Japan, Aldehyde Reductase; Shun-ichi Maemoto, Kaneka Corporation, Hyogo, Japan, Optically Active Lactonohydrolase; Pantothenic Acid and Related Compounds 1,2-Diols, Microbial Production by Stereoinversion Yasuo Kato, Toyama Prefectural University, Toyama, Japan, Opine De- Savvas C. Makrides, PRAECIS Pharmaceuticals, Inc., Cambridge, Mas- hydrogenase, Secondary Amine Dicarboxylic Acids sachusetts, Expression Systems, E. coli Randal J. Kaufman, University of Michigan Medical School, Ann Arbor, Stefan Marose, University of Hannover,Hannover,Germany, Fluorescence Michigan, Secretion from Animal Cells Techniques for Bioprocess Monitoring Tetsuya Kawakita, Ajinomoto Co., Inc., Kanazawa, Japan, Amino Acids, R.E. Marquis, University of Rochester, Rochester, New York, Transport, Mi- Glutamate crobial Solute Uptake Takuo Kawamoto, Kyoto University, Kyoto, Japan, Cell Immobilization; Seiji Masuda, Kyoto University, Kyoto, Japan, Erythropoietin Organosilicon Compounds Jennie P. Mather, Rauen Biotechnologies, Inc., Mountain View, Califor- Robert M. Kelly, North Carolina State University, Raleigh, North Caro- nia, Culture Media, Animal Cells, Large Scale Production lina, Enzymes, Extremely Thermostable; Thermophilic Microorganisms Hiroaki Matsumae, Tanabe Seiyaku Co., Ltd., Osaka, Japan, Diltiazem Birgit Kessler, Institute of Biotechnology, Zu¨ rich, Switzerland, Synthesis Poly(3-Hydroxyalkanoates) Ryuichi Matsumo, Kyoto University, Kyoto, Japan, Glucosidases Shun-ichi Kidokoro, Sagami Chemical Research Center, Kanagawa, Ja- Tadashi Matsunaga, Tokyo University of Agriculture and Technology, To- pan, Thermolysin kyo, Japan, Algal Culture Shukuo Kinoshita, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan, Glutamic Ryuichi Matsuno, Kyoto University, Kyoto, Japan, Yeast, Baker’s Acid Producing Microorganisms; Production of L-Glutamic Acid B. Mattiasson, Lund University, Lund, Sweden, Sampling Methods (Re- Horst Kleinkauf, Technical University Berlin, Berlin, Germany, Peptide actors, Contamination) M.A. Klich, U.S. Department of Agriculture, New Orleans, Louisiana, As- Ian R. McDonald, , Coventry, United Kingdom, pergillus Methanotrophs Miki Kobayashi, Mitsubishi Chemical Corporation, Ibaraki, Japan, L- Joseph McGuire, Oregon State University, Corvallis, Oregon, Adsorption, Aspartic Acid Proteins with Synthetic Materials Arthur L. Koch, Indiana University, Bloomington, Indiana, Microbial Alexander McPherson, University of California, Irvine, Irvine, Califor- Growth Measurement, Methods nia, Crystallization, Bulk, Macromolecules Fragiskos N. Kolisis, National Technical University of Athens, Athens, J.C. Merchuk, Ben-Gurion University of the Negev, Beer-Sheva, Israel, Bio- Greece, Reverse Micelles, Enzymes reactors, Air-lift Reactors Hidenobu Komeda, Toyama Prefectural University, Toyama, Japan, D- Charles E. Miller, Westvaco Corporation, Charleston, South Carolina, Ac- Aminopeptidase, Alkaline D-Peptidase tivated Carbon, Decoloration of Pharmaceutical Products Tadashi Kometani, Toyama College of Technology, Toyama-shi, Japan, Stephen P. Miller, University of Minnesota, Minneapolis, Minnesota, Gly- Bioreduction; Yeast, Baker’s oxylate Bypass, Regulation x CONTRIBUTORS

William M. Miller, Northwestern University, Evanston, Illinois, Hypoxia, Nicolai S. Panikov, Institute of Microbiology, Russian Academy of Sci- Effects on Animal Cells ences, Moscow, Russian Federation, Kinetics, Microbial Growth Sheenah Mische, Rockefeller University, New York,New York, Professional Patrizia Perego, University of Genoa, Genoa, Italy, Corrosion, Microbial Societies, Association of Biomolecular Resource Facilities Madhusudan V. Peshwa, Dendreon Corp., Mountain View, California, Mi- David A. Mitchell, Universidade Federal do Parana, Curitiba, Brazil, crocarrier Culture Solid-State Fermentation, Microbial Growth Kinetics Joerg Peters, Bayer AG, Wuppertal, Germany, Cofactor Regeneration, Nic- Inger Mollerup, Novo Nordisk A/S, Bagsvaerd, Denmark, Insulin, Puri- otinamide Coenzymes fication David Pollard, Merck and Co., Inc., Rahway, New Jersey, Vent Gas Anal- Alison Moore, Amgen, Inc., Newbury Park, California, Culture Media, ysis Animal Cells, Large Scale Production Kaisa Poutanen, VTT Biotechnology and Food Research, Espoo, Finland, Vadim V. Mozhaev, University of Iowa, Iowa City, Iowa, Denaturation, Hemicellulases Proteins, Solvent Mediated Joan Qi Si, Novo Nordisk Ferment Ltd., Dittingen, Switzerland, Enzymes, Susann Mu¨ ller, University of Leipzig, Leipzig, Germany, Flow Cytometry Baking, Bread Making David W. Murhammer, University of Iowa, Iowa City, Iowa, Pluronic Poly- Bruce Ramsay, Queen’s University, Kingston, Ontario, Canada, ols, Cell Protection Polyhydroxyalkanoates, Separation, Purification, and Manufacturing J. Colin Murrell, University of Warwick, Coventry, United Kingdom, Meth- Methods anotrophs Juliana Ramsay, Queen’s University, Kingston, Ontario, Canada, Poly- F.J. Muzzio, Rutgers University, Piscataway, New Jersey, Roller Bottle hydroxyalkanoates, Separation, Purification, and Manufacturing Meth- Culture, Mixing ods Clayton Naeve, St. Jude Children’s Research Hospital, Memphis, Tennes- Douglas W. Rea, Cytogen Corp., Princeton, New Jersey, Antibody Purifi- see, Professional Societies, Association of Biomolecular Resource Facili- cation ties Kenneth F. Reardon, Colorado State University, Fort Collins, Colorado, Kazuhiro Nakanishi, Okayama University, Okayama, Japan, Membrane Fluorescence Techniques for Bioprocess Monitoring Surface Liquid Culture, Microorganisms, Fungi Matthias Redenbach, LB Genetik, University of Kaiserslautern, Kaisers- Toru Nakayama, Tohoku University, Sendai, Japan, b-Galactosidase, En- lautern, Germany, Genetic Instability zymology and Applications Hans Reichenbach, Gesellschaft fu¨ r Biotechnologische Forschung, Braun- M.P. Nandakumar, Lund University, Lund, Sweden, Sampling Methods schweig, Germany, Myxobacteria (Reactors, Contamination) Harold Reisman, Biotechnology Results, Weston, Connecticut, Economics Venkatesh Natarajan, Rensselaer Polytechnic Institute, Troy, New York, Albert J. Repik, Westvaco Corporation, Charleston, South Carolina, Ac- Chromatography, Ion Exchange tivated Carbon, Decoloration of Pharmaceutical Products Robert Newburgh, The Protein Society, Bethesda, Maryland, Professional Nadine Ritter, Abbott Laboratories, Abbott Park, Illinois, Professional So- Societies, The Protein Society cieties, Association of Biomolecular Resource Facilities Ronald L. Niece, University of California–Irvine, Irvine, California, Pro- Palmer Rogers, University of Minnesota, Minneapolis, Minnesota, Clos- fessional Societies, Association of Biomolecular Resource Facilities tridia, Solvent Formation Hans Ole Nielsen, DELTA Light&Optics, Lyngby, Denmark, Fluorescence Rodica-Viorica Roman, Chemical Pharmaceutical Research Institute, Techniques for Bioprocess Monitoring Ias¸i, Romania, Transfer Phenomena in Multiphase Systems in Mixing Jens Nielsen, Technical University of Denmark, Lyngby, Denmark, Fer- Vessels mentation Monitoring, Design and Optimization Charles M. Roth, Massachusetts General Hospital, Shriners Burns Hos- Zivko L. Nikolov, Iowa State University, Ames, Iowa, Soybean (Fermen- pital, and Harvard Medical School, Boston, Massachusetts, Chromatog- tation, Meal Oil) raphy, Size Exclusion Joakim Nilsson, Royal Institute of Technology, Stockholm, Sweden, Affin- P.G. Rouxhet, Universite´ Catholique de Louvain, Louvain-la-Neuve, Bel- ity Fusions, Gene Expression gium, Cell Separation, Flocculation Yasuo Ninomiya, Nitto Denko Company, Osaka, Japan, Insecticides, Mi- Joon Soo Ryu, Korea Advanced Institute of Science and Technology, Tae- crobial Production; Optical Resolution, Biocatalysis jon, Korea, Osmotic Stress, Secretion Rate Takuo Nishida, Tanabe Seiyaku Co., Ltd., Osaka, Japan, Diltiazem Syn- Peter Salmon, Merck and Co., Inc., Rahway, New Jersey, Vent Gas Anal- thesis, Microbial Asymmetric Reduction ysis P.T. Noble, Fluor Daniel GmbH, Wiesbaden, Germany, Sterilization-in- Gautam Sanyal, Astra Research Center Boston, Cambridge, Place Massachusetts, Thermal Unfolding, Proteins Per-A˚ ke Nygren, Royal Institute of Technology, Stockholm, Sweden, Affin- ity Fusions, Gene Expression Ryuzo Sasaki, Kyoto University, Kyoto, Japan, Erythropoietin Jun Ogawa, Kyoto University, Kyoto, Japan, Oils, Microbial Production Tadashi Sato, Tanabe Seiyaku Co., Ltd., Osaka, Japan, Enzymes, Immo- bilization Methods; Malic Acid, Production by Fumarase; Production of Masahiro Ogura, Kaneka Corporation, Hyogo, Japan, Optically Active L-Amino Acids by Aminoacylase 1,2-Diols, Microbial Production by Stereoinversion Catherine H. Schein, University of Texas Medical Branch, Galveston, Takehisa Ohashi, Kaneka Corporation, Hyogo, Japan, Optically Active Texas, Protein Aggregation, Denaturation; Protein Expression, Soluble 1,2-Diols, Microbial Production by Stereoinversion Thomas Scheper, University of Hannover, Hannover, Germany, Fluores- Hiromichi Ohta, Keio University, Yokohama, Japan, Lactones, Biocata- cence Techniques for Bioprocess Monitoring lytic Synthesis Tetsuo Oka, Kyowa Hakko Kogyo, Co., Ltd., Tokyo, Japan, Amino Acids, S. Schiewer, McGill University, Montreal, Canada, Biosorption, Metals Production Processes Andrew Schmid, Swiss Federal Institute of Technology, Zurich, Switzer- Hans Sejr Olsen, Novo Nordisk, Bagsvaerd, Denmark, Enzymes, Protein land, Pseudomonas, Process Applications Hydrolysis Ole Schou, Novo Nordisk A/S, Bagsvaerd, Denmark, Insulin, Purification Gustaf Olsson, Lund Institute of Technology, Lund, Sweden, Waste Treat- Robert Schwartz, Abbott Laboratories, North Chicago, Illinois, Profes- ment, Activated Sludge, Control Strategies sional Societies, Society for Industrial Microbiology (SIM) Tetsuo Omata, Nitto Denko Company, Osaka, Japan, Insecticides, Micro- Henry Schwartzberg, University of Massachusetts, Amherst, Massachu- bial Production; Optical Resolution, Biocatalysis setts, Food Process Engineering Sadettin S. Ozturk, Bayer Corporation, Berkeley, California, Ammonia James Searles, Merck and Company, West Point, Pennsylvania, Roller Toxicity, Animal Cells Bottle Culture, Mixing J. Ricardo Pe´rez-Correa, Pontificia Universidad Cato´lica de Chile, San- Katsuya Seguro, Food Research and Development Lab, Kawaski, Japan, tiago, Chile, Solid Substrate Fermentation, Automation Transglutaminase Philip Packer, Centre for Applied Microbiology and Research, Salisbury, Klaus Selber, Heinrich Heine University Du¨ sseldorf, Ju¨lich, Germany, Wilts, United Kingdom, Culture Collections Protein Purification, Aqueous Liquid Extraction CONTRIBUTORS xi

Sylvia Sellmer-Wilsberg, Bad Honnef, Germany, Vinegar, Acetic Acid Satomi Takahashi, Kaneka Corporation, Hyogo, Japan, Production Aminohydrolases, for Production of D-Amino Acids; Phenylglycines, D- Shuji Senda, Nitto Denko Company, Osaka, Japan, Insecticides, Microbial Phenylglycines Production; Optical Resolution, Biocatalysis Hiroyuki Takano, Chichibu Onoda Cement Corporation, Chiba- Pir M. Shah, De Montfort University, Leicester, United Kingdom, Protein prefecture, Japan, Algal Culture Glycosylation Haruko Takeyama, Tokyo University of Agriculture and Technology, To- P. Ayazi Shamlou, University College London, London, United Kingdom, kyo, Japan, Algal Culture Rheology of Filamentous Microorganisms, Submerged Culture Atsuo Tanaka, Kyoto University, Kyoto, Japan, Cell Immobilization Bhav P. Sharma, CV Therapeutics, Palo Alto, California, Cell Separation, Robert D. Tanner, Vanderbilt University, Nashville, Tennessee, Solid- Sedimentation State Fermentation, Microbial Growth Kinetics Allan R. Shatzman, SmithKline Beecham Pharmaceuticals, King of Prus- Maija Tenkanen, VTT Biotechnology and Food Research, Espoo, Finland, sia, Pennsylvania, Expression Systems, Mammalian Cells Hemicellulases Li Shi, Merck Research Laboratories, West Point, Pennsylvania, Thermal Masato Terasawa, Mitsubishi Chemical Corporation, Ibaraki, Japan, L- Unfolding, Proteins Aspartic Acid; L-Isoleucine Takeji Shibatani, Tanabe Seiyaku Co., Ltd., Osaka, Japan, Diltiazem Syn- Jo¨ rg Tho¨ mmes, Heinrich-Heine Universita¨tDu¨sseldorf, Ju¨ lich, Germany, thesis; Diltiazem Synthesis, Microbial Asymmetric Reduction Membrane Chromatography Sakayu Shimizu, Kyoto University, Kyoto, Japan, Aldehyde Reductase; Jules Thibault, Laval University, Sainte-Foy, Canada, Pullulan, Microbial Lactonohydrolase; Oils, Microbial Production; Pantothenic Acid and Re- Production Methods lated Compounds J.S. Tolan, Iogen Corporation, Ottawa, Canada, Enzymes, Pulp and Paper Suteaki Shioya, Osaka University, Osaka, Japan, Mixed Culture Processing M. S. Showell, Procter and Gamble, Cincinnati, Ohio, Enzymes, Detergent E. Donald Tolles, Westvaco Corporation, Charleston, South Carolina, Ac- Rabinder P. Singh, University of Birmingham, Birmingham, England, tivated Carbon, Decoloration of Pharmaceutical Products Apoptosis Marcelo E. Tolmasky, California State University, Fullerton, Fullerton, California, Plasmid DNA Replication Satinder K. Singh, University of Minnesota, Minneapolis, Minnesota, Gly- oxylate Bypass, Regulation Fusao Tomita, Hokkaido University, Sapporo, Japan, Pyruvate, Produc- tion Using Defective ATPase Activity A.J. Sinskey, Massachusetts Institute of Technology, Cambridge, Massa- chusetts, Corynebacteria, Brevibacteria Tetsuya Tosa, Tanabe Seiyaku Co. Ltd., Osaka, Japan, Enzymes, Immo- bilization Methods; Malic Acid, Production by Fumarase; Production of Augustine Smith, Abbott Laboratories, Abbott Park, Illinois, Professional L-Amino Acids by Aminoacylase Societies, Association of Biomolecular Resource Facilities R. Reid Townsend, University of California–San Francisco, San Fran- Thomas M. Smith, Smith Kline Beecham, King of Prussia, Pennsylvania, cisco, California, Professional Societies, Association of Biomolecular Re- Process Validation source Facilities Leo Snel, Novo Nordisk A/S, Bagsvaerd, Denmark, Insulin, Purification Mario R. Tredici, University of Florence, Florence, Italy, Bioreactors, Gail Sofer, BioReliance, Rockville, Maryland, Cleaning, Cleaning Valida- Photo tion G.T. Tsao, Purdue University, West Lafayette, Indiana, Hemicellulose Con- Carles Sola`, Universitat Auto`noma de Barcelona, Barcelona, Spain, Bio- version; Organic Compounds, Cellulose Conversion reactors, Fluidized-Bed Satoru Tsuda, Kaneka Corporation, Hyogo, Japan, Optically Active 1,2- Richard Sparling, University of Manitoba, Winnipeg, Canada, Energy Diols, Microbial Production by Stereoinversion Metabolism, Microbial and Animal Cells Radu Z. Tudose, Technical University Gh.Asachi Ias¸i, Ias¸i, Romania, Dave Speicher, Wistar Institute, Philadelphia, Pennsylvania, Professional Static Mixing, in Fermentation Process Societies, Association of Biomolecular Resource Facilities A.P.F. Turner, Cranfield Biotechnology Centre, Bedfordshire, United King- Koti Sreekrishna, Procter and Gamble Co., Ross, Ohio, Pichia, Optimi- dom, Process Monitoring zation of Protein Expression Makoto Ueda, Mitsubishi Chemical Co., Yokohama, Japan, Malate, D- Friedrich Srienc, University of Minnesota, St. Paul, Minnesota, Cell Cy- Malate cle, Eukaryotes Mathias Uhle´n,Royal Institute of Technology, Stockholm, Sweden, Affinity Stefan Sta˚ hl, Royal Institute of Technology, Stockholm, Sweden, Affinity Fusions, Gene Expression Fusions, Gene Expression Michiel E. Ultee, Cytogen Corp., Princeton, New Jersey, Antibody Purifi- Keith Stephenson, University of Newcastle upon Tyne, Newcastle upon cation Tyne, United Kingdom, Bacillus D.R. Unger, Rutgers University, Piscataway, New Jersey, Roller Bottle Cul- Kathryn Stone, Yale University, New Haven, Connecticut, Professional So- ture, Mixing cieties, Association of Biomolecular Resource Facilities Mahesh Uttamlal, Glasgow Caledonian University, Glasgow, Scotland, Bob Stover, Tri-Clover, Valencia, California, Pumps, Industrial Optical Sensors William R. Strohl, Merck Research Laboratories, Rahway, New Jersey, Robert van Reis, Genentech, Inc., South San Francisco, California, Pro- Secondary Metabolites, Antibiotics tein Ultrafiltration Daniel J. Strydom, Bio Nebraska, Inc., Lincoln, Nebraska, Professional James Vaughn, ARS, USDA, Beltsville, Maryland, Insect Cell Culture, Societies, Association of Biomolecular Resource Facilities Protein Expression Deidre M. Stuart, Queensland University of Technology, Brisbane, Aus- Liisa Viikari, VTT Biotechnology and Food Research, Espoo, Finland, tralia, Solid-State Fermentation, Microbial Growth Kinetics Hemicellulases John Stults, Genentech, San Francisco, California, Professional Societies, B. Volesky, McGill University, Montreal, Canada, Biosorption, Metals Association of Biomolecular Resource Facilities David B. Volkin, Merck Research Laboratories, West Point, Pennsylvania, Takeshi Sugai, Keio University, Yokohama, Japan, Lactones, Biocatalytic Thermal Unfolding, Proteins Synthesis Lawrence P. Wackett, University of Minnesota, Minneapolis, Minnesota, Masaru Suto, Nitto Chemical Industry Co., Ltd., Tokyo, Japan, Nitrile Biocatalysis Databases Hydratase David R. Walt, Tufts University, Medford, Massachusetts, Optical Sensors T. Swaminathan, Indian Institute of Technology–Madras, Chennai, India, Christian Wandrey, Forschungszentrum Ju¨ lich GmbH, Ju¨lich, Germany, Dextran, Microbial Production Methods Enzymes, Immobilized, Reactors P.D. Swanson, Rutgers University, Piscataway, New Jersey, Roller Bottle Sally Warburton, ECACC, Wiltshire, United Kingdom, Human and Pri- Culture, Mixing mate Cell Lines Kristine M. Swiderek, ZymoGenetics, Seattle, Washington, Professional Udo Werner, University of Dortmund, Dortmund, Germany, Waste Gas Societies, Association of Biomolecular Resource Facilities Cleaning, Biological xii CONTRIBUTORS

David White, Indiana University, Bloomington, Indiana, Electron Trans- Florian M. Wurm, Swiss Federal Institute of Technology, Lausanne, Swit- port zerland, Chinese Hamster Ovary Cells, Recombinant Protein Production S.F. White, Cranfield Biotechnology Centre, Bedfordshire, United Kingdom, Xinfa Xiao, Apotex Fermentation, Inc., Winnipeg, Canada, Energy Metab- Process Monitoring olism, Microbial and Animal Cells Erik M. Whiteley, Johns Hopkins University, Baltimore, Maryland, Insect Feng Xu, Novo Nordisk Biotech, Davis, California, Laccase Cells and Larvae, Gene Expression Systems Hideaki Yamada, Mitsubishi Chemical Co., Yokohama, Japan, Malate, D- Ken Williams, Yale University, New Haven, Connecticut, Professional So- Malate cieties, Association of Biomolecular Resource Facilities Tsuneo Yamane, Nagoya University, Nagoya, Japan, Monoacylglycerols L.B. Willis, Massachusetts Institute of Technology, Cambridge, Massachu- Martin L. Yarmush, Massachusetts General Hospital, Shriners Burns setts, Corynebacteria, Brevibacteria Hospital, and Harvard Medical School, Boston, Massachusetts, Chro- matography, Size Exclusion Jack Wilson, ABEC, Inc., Allentown, Pennsylvania, Fermenter Design Atsushi Yokota, Hokkaido University, Sapporo, Japan, Pyruvate, Produc- Patrick L. Wintrode, California Institute of Technology, Pasadena, Cali- tion Using Defective ATPase Activity fornia, Enzymes, Directed Evolution Hideaki Yukawa, Mitsubishi Chemical Corporation, Ibaraki, Japan, L- Bernard Witholt, Swiss Federal Institute of Technology, Zu¨ rich, Switzer- Aspartic Acid; L-Isoleucine land, Poly(3-Hydroxyalkanoates); Pseudomonas, Process Applications Dane W. Zabriskie, Smith Kline Beecham Pharmaceuticals, King of Prus- K.D. Wittrup, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan, Protein Secre- sia, Pennsylvania, Process Validation tion, Saccharomyces cerevisiae J. Gregory Zeikus, MBI International, Lansing, Michigan, Anaerobes, In- R.A. Wolfe, Monsanto Co., St. Louis, Missouri, Media, Animal Cell Culture dustrial Uses Kathy Wong, University of Minnesota, Minneapolis, Minnesota, Microcar- Mario Zilli, Genoa University, Genoa, Italy, Biofilters rier Culture Marko Zlokarnik, Graz, Austria, Dimensional Analysis, Scale-Up Marcel Wubbolts, Swiss Federal Institute of Technology, Zu¨ rich, Switzer- Andrew L. Zydney, University of Delaware, Newark, Delaware, Protein land, Pseudomonas, Process Applications Ultrafiltration COMMONLY USED ACRONYMS AND ABBREVIATIONS

ABS acrylonitrile-butadiene-styrene copolymer h hour(s) AISI American Iron and Steel Institute HACCP hazard analysis of critical control points ANSI American National Standards Institute HEPA high-efficiency particulate air (filter) APHIS Animal and Plant Health Inspection Service HEPES name of a buffer (of the USDA) HMSO Her Majesty’s Stationery Office API American Petroleum Institute hp horsepower; unit of power, 0.75 kW ASME American Society of Mechanical Engineers HVAC heating, ventilating, and air conditioning AS/RS automated storage and retrieval system ID inside diameter ASTM American Society for Testing and Materials IDF International Dairy Federation ATCC American Type Culture Collection INO Investigating new drug application (FDA) BLx biosafety level x IQ installation qualification BLx-Ls biosafety level x, large-scale ISS International Sanitary Standard BOD Biological oxygen demand Kla volumetric gas-liquid mass transfer BPVC Boiler and Pressure Vessel Code coefficient BSCC Biotechnology Science Coordinating L liter(s) Committee LAL Limulus amoebocyte lysate Btu British thermal unit (unit of energy) MAb monoclonal antibody CADD computer-aided design and drafting MAWP maximum allowable working pressure CBER Center for Biologics Evaluation & Research MF microfiltration (of FDA) MAW Ministry of Health & Welfare (Japan) CDER Center for Drug Evaluation & Research MWCO molecular weight cutoff CDW cell dry weight NAD, NADH, NADP, NADPH CFF cross-flow filtration nicotine adenine dinucleotides cfm cubic feet per minute NBS National Bureau of Standards CFR Code of Federal Regulations (U.S.) NDA new drug application (FDA) CFU colony-forming unit NEMA National Electrical Manufacturers cGMPs current good manufacturing practices Association CIP clean-in-place NIH National Institutes of Health COD chemical oxygen demand NIH/RAC National Institutes of Health Recombinant cP centipoise DNA Advisory Committee CPAC Central Pharmaceutical Affairs Council NIST National Institute of Standards and Testing (Japan) NPSH net positive suction head DCS distributed control system NPT National Pipe Taper (pipe thread) DI deionized (water) NSF National Science Foundation DIN Deutsches Institut fur Normung NWP normalized water permeability DNA deoxyribonucleic acid O&M operation and maintenance DOP dioctyl phthalate OD outside diameter DOT dissolved oxygen tension OECD Organization for Economic Cooperation and dP differential pressure Development DW dry weight OQ operational qualification DCW dry cell weight OSHA Occupational Safety and Health E&C engineering and construction Administration EDTA ethylenediaminetetraacetic acid PAB Pharmaceutical Affairs Bureau (Japan) EEC European Economic Community P&ID piping (or process) and instrumentation ELA Establishment License Application diagram EPA Environmental Protection Agency PFD process flow diagram EPDM ethylene-propylene-diene monomer PI proportional/integral EU endotoin unit PID proportional/integral/derivative FDA Food and Drug Administration PIEL pharmacologically insignificant exposure fpm feet per minute level GILSP good industrial large-scale practice PLA Product License Application GLSP good large-scale practice PLC programmable logic controller GMP good manufacturing practice PMN premanufacture notification gpm gallons per minute ppb parts per billion xiii xiv COMMONLY USED ACRONYMS AND ABBREVIATIONS ppm parts per million SVP small-volume parenteral PQ performance (or process) qualification T1/2 half-life psi pounds per square inch TDS total dissolved solids PTFE, polytetraflouroethylene ס QA quality assurance TFE QC quality control TFF tangential flow filtration R&D research & development TEL toxicologically insignificant exposure level Ra arithmetic average surface roughness TIG tungsten-inert-gas (welding) rDNA recombinant DNA TMP transmembrane pressure RH relative humidity TOC total organic carbon RO reverse osmosis TSCA Toxic Substances Control Act RODI reverse osmosis deionized water UF ultrafiltration ROI return on investment rpm, -s revolutions per minute, second UHPW ultra high purity water RTD resistance temperature device UK United Kingdom s second(s) UL Underwriters Laboratories SAL sterility assurance level USDA United States Department of Agriculture SAMA Scientific Apparatus Makers Association USP/NF United States Pharmacopoeia/National scfm standard cubic feet per minute Formulary SIP sterilization in place VVM volume per volume per minute SLPM standard liters per minute WFI Water for Injection STA slit-to-agar WHO World Health Organization CONVERSION FACTORS, ABBREVIATIONS, AND UNIT SYMBOLS

SI UNITS (Adopted 1960) The International System of Units (abbreviated SI), is being implemented throughout the world. This measurement system is a modernized version of the MKSA (meter, kilogram, second, ampere) system, and its details are published and controlled by an international treaty organization (The International Bureau of Weights and Measures). SI units are divided into three classes:

BASE UNITS SUPPLEMENTARY UNITS length meter† (m) plane angle radian (rad) mass solid angle steradian (sr) kilogram (kg) time second (s) electric current ampere (A) thermodynamic temperature‡ kelvin (K) amount of substance mole (mol) luminous intensity candela (cd)

Quantity Unit Symbol Acceptable equivalent volume cubic meter m3 cubic diameter dm3 L (liter) (5) cubic centimeter cm3 mL 1מwave number 1 per meter m 1מper centimeter cm 1

In addition, there are 16 prefixes used to indicate order of magnitude, as follows:

Multiplication factor Prefix Symbol 1018 exa E 1015 peta P 1012 tera T 109 giga G 106 mega M 103 kilo k 102 hecto ha 10 deka daa deci da 1מ10 centi ca 2מ10 milli m 3מ10 micro l 6מ10 nano n 9מ10 pico p 12מ10 femto f 15מ10 atto a 18מ10

aAlthough hecto, deka, deci, and centi are SI prefixes, their use should be avoided except for SI unit-multiples for area and volume and nontechnical use of centimeter, as for body and clothing measurement.

For a complete description of SI and its use the reader is referred to ASTM E380. A representative list of conversion factors from non-SI to SI units is presented herewith. Factors are given to four significant figures. Exact relationships are followed by a dagger. A more complete list is given in the latest editions of ASTM E380 and ANSI Z210.1.

†The spellings ‘‘metre’’ and ‘‘litre’’ are preferred by ASTM; however, ‘‘-er’’ is used in the Encyclopedia. ‡Wide use is made of Celsius temperature (t) defined by מ ס t T T0 ס where T is the thermodynamic temperature, expressed in kelvin, and T0 273.15 K by definition. A temperature interval may be expressed in degrees Celsius as well as in kelvin. xv xvi CONVERSION FACTORS, ABBREVIATIONS, AND UNIT SYMBOLS CONVERSION FACTORS TO SI UNITS To convert from To Multiply by 103 ן acre square meter (m2) 4.047 †10מ10 ן angstrom meter (m) 1.0 †102 ן are square meter (m2) 1.0 1011 ן astronomical unit meter (m) 1.496 105 ן atmosphere, standard pascal (Pa) 1.013 †105 ן bar pascal (Pa) 1.0 †28מ10 ן barn square meter (m2) 1.0 barrel (42 U.S. liquid gallons) cubic meter (m3) 0.1590 24מ ן e Bohr magneton ( B) J/T 9.274 10 103 ן Btu (International Table) joule (J) 1.055 103 ן Btu (mean) joule (J) 1.056 103 ן Btu (thermochemical) joule (J) 1.054 2מ10 ן bushel cubic meter (m3) 3.524 calorie (International Table) joule (J) 4.187 calorie (mean) joule (J) 4.190 calorie (thermochemical) joule (J) 4.184† †3מ10 ן centipoise pascal second (Pa s) 1.0 centistokes square millimeter per second (mm2/s) 1.0† 4מ10 ן cfm (cubic foot per minute) cubic meter per second (m3/s) 4.72 5מ10 ן cubic inch cubic meter (m3) 1.639 2מ10 ן cubic foot cubic meter (m3) 2.832 cubic yard cubic meter (m3) 0.7646 †1010 ן curie becquerel (Bq) 3.70 30מ10 ן debye coulomb meter (C m) 3.336 2מ10 ן degree (angle) radian (rad) 1.745 7מ10 ן denier (international) kilogram per meter (kg/m) 1.111 tex‡ 0.1111 3מ10 ן dram (apothecaries’) kilogram (kg) 3.888 3מ10 ן dram (avoirdupois) kilogram (kg) 1.772 6מ10 ן dram (U.S. fluid) cubic meter (m3) 3.697 †5מ10 ן dyne newton (N) 1.0 †3מ10 ן dyne/cm newton per meter (N/m) 1.0 19מ10 ן electronvolt joule (J) 1.602 †7מ10 ן erg joule (J) 1.0 fathom meter (m) 1.829 5מ10 ן fluid ounce (U.S.) cubic meter (m3) 2.957 foot meter (m) 0.3048† footcandle lux (lx) 10.76 2מ10 ן furlong meter (m) 2.012 †2מ10 ן gal meter per second squared (m/s2) 1.0 3מ10 ן gallon (U.S. dry) cubic meter (m3) 4.405 3מ10 ן gallon (U.S. liquid) cubic meter (m3) 3.785 5מ10 ן gallon per minute (gpm) cubic meter per second (m3/s) 6.309 cubic meter per hour (m3/h) 0.2271 4מ10 ן gauss tesla (T) 1.0 gilbert ampere (A) 0.7958 4מ10 ן gill (U.S.) cubic meter (m3) 1.183 2מ10 ן grade radian 1.571 5מ10 ן grain kilogram (kg) 6.480 2מ10 ן gram force per denier newton per tex (N/tex) 8.826 †104 ן hectare square meter (m2) 1.0 102 ן horsepower (550 ft • lbf/s) watt (W) 7.457 103 ן horsepower (boiler) watt (W) 9.810 †102 ן horsepower (electric) watt (W) 7.46 hundredweight (long) kilogram (kg) 50.80 hundredweight (short) kilogram (kg) 45.36 †2מ10 ן inch meter (m) 2.54 103 ן inch of mercury (32ЊF) pascal (Pa) 3.386 102 ן inch of water (39.2ЊF) pascal (Pa) 2.491 CONVERSION FACTORS, ABBREVIATIONS, AND UNIT SYMBOLS xvii CONVERSION FACTORS TO SI UNITS To convert from To Multiply by kilogram-force newton (N) 9.807 kilowatt hour megajoule (MJ) 3.6† 103 ן kip newton (N) 4.448 knot (international) meter per second (m/S) 0.5144 103 ן lambert candela per square meter (cd/m3) 3.183 103 ן league (British nautical) meter (m) 5.559 103 ן league (statute) meter (m) 4.828 1015 ן light year meter (m) 9.461 †3מ10 ן liter (for fluids only) cubic meter (m3) 1.0 †8מ10 ן maxwell weber (Wb) 1.0 †6מ10 ן micron meter (m) 1.0 †5מ10 ן mil meter (m) 2.54 103 ן mile (statute) meter (m) 1.609 †103 ן mile (U.S. nautical) meter (m) 1.852 mile per hour meter per second (m/s) 0.4470 102 ן millibar pascal (Pa) 1.0 †102 ן millimeter of mercury (0ЊC) pascal (Pa) 1.333 4מ10 ן minute (angular) radian 2.909 myriagram kilogram (kg) 10 myriameter kilometer (km) 10 oersted ampere per meter (A/m) 79.58 2מ10 ן ounce (avoirdupois) kilogram (kg) 2.835 2מ10 ן ounce (troy) kilogram (kg) 3.110 5מ10 ן ounce (U.S. fluid) cubic meter (m3) 2.957 ounce-force newton (N) 0.2780 3מ10 ן peck (U.S.) cubic meter (m3) 8.810 3מ10 ן pennyweight kilogram (kg) 1.555 4מ10 ן pint (U.S. dry) cubic meter (m3) 5.506 4מ10 ן pint (U.S. liquid) cubic meter (m3) 4.732 poise (absolute viscosity) pascal second (Pa • s) 0.10† pound (avoirdupois) kilogram (kg) 0.4536 pound (troy) kilogram (kg) 0.3732 poundal newton (N) 0.1383 pound-force newton (N) 4.448 103 ן pound force per square inch (psi) pascal (Pa) 6.895 3מ10 ן quart (U.S. dry) cubic meter (m3) 1.101 4מ10 ן quart (U.S. liquid) cubic meter (m3) 9.464 †102 ן quintal kilogram (kg) 1.0 †2מ10 ן rad gray (Gy) 1.0 rod meter (m) 5.029 4מ10 ן roentgen coulomb per kilogram (C/kg) 2.58 †6מ10 ן second (angle) radian (rad) 4.848 106 ן section square meter (m2) 2.590 slug kilogram (kg) 14.59 spherical candle power lumen (lm) 12.57 4מ10 ן square inch square meter (m2) 6.452 2מ10 ן square foot square meter (m2) 9.290 106 ן square mile square meter (m2) 2.590 square yard square meter (m2) 0.8361 stere cubic meter (m3) 1.0† †4מ10 ן stokes (kinematic viscosity) square meter per second (m2/s) 1.0 †6מ10 ן tex kilogram per meter (kg/m) 1.0 103 ן ton (long, 2240 pounds) kilogram (kg) 1.016 †103 ן ton (metric) (tonne) kilogram (kg) 1.0 102 ן ton (short, 2000 pounds) kilogram (kg) 9.072 102 ן torr pascal (Pa) 1.333 7מ10 ן unit pole weber (Wb) 1.257 yard meter (m) 0.9144†

†Exact.