PUTTING BIOTECHNOLOGY TO WORK BIOPROCESS ENGINEERING

Committee on Bioprocess Engineering

Board on Biology

Commission on Life Sciences

National Research Council

NATIONAL ACADEMY OF SCIENCES
Washington, D.C.
1992



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Putting Biotechnology to Work Bioprocess Engineering PUTTING BIOTECHNOLOGY TO WORK BIOPROCESS ENGINEERING Committee on Bioprocess Engineering Board on Biology Commission on Life Sciences National Research Council NATIONAL ACADEMY OF SCIENCES Washington, D.C. 1992

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Putting Biotechnology to Work Bioprocess Engineering NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. This Board on Biology study was supported by the National Science Foundation, the Department of Energy, the U. S. Department of Agriculture, the National Aeronautics and Space Administration, the National Institute of Standards and Technology, and the National Academy of Engineering. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the sponsors of this report. Library of Congress Catalog Card Number 92-61717 International Standard Book Number 0-309-04785-4 Additional copies of this report are available from: National Academy Press 2101 Constitution Avenue, N.W. Washington, D.C. 20418 B-019 Copyright 1992 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Putting Biotechnology to Work Bioprocess Engineering COMMITTEE ON BIOPROCESS ENGINEERING Michael R. Ladisch (Chairman), Purdue University, West Lafayette, Indiana Charles L. Cooney, Massachusetts Institute of Technology, Cambridge, Massachusetts Robert C. Dean, Jr., Dean Technology, Inc., Lebanon, New Hampshire Arthur E. Humphrey, Pennsylvania State University, State College, Pennsylvania T. Kent Kirk, U.S. Department of Agriculture, Madison, Wisconsin Larry V. McIntire, Rice University, Houston, Texas Alan S. Michaels, Alan Sherman Michaels, Sc.D., Inc., Chestnut Hill, Massachusetts Paula Myers-Keith, Pitman-Moore, Inc., Terre Haute, Indiana Dewey D.Y. Ryu, University of California, Davis, California James R. Swartz, Genentech, Inc., San Francisco, California Daniel I.C. Wang, Massachusetts Institute of Technology, Cambridge, Massachusetts Janet Westpheling, University of Georgia, Athens, Georgia George M. Whitesides, Harvard University, Cambridge, Massachusetts National Research Council Staff: John E. Burris, Study Director Oskar Zaborsky, Study Director (until April 1992) Marietta Toal, Administrative Secretary Norman Grossblatt, Editor

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Putting Biotechnology to Work Bioprocess Engineering BOARD ON BIOLOGY Harold E. Varmus (Chairman), University of California, San Francisco, California Ananda M. Chakrabarty, University of Illinois Medical Center, Chicago, Illinois Michael T. Clegg, University of California, Riverside, California Richard E. Dickerson, University of California, Los Angeles, California Gerald D. Fischbach, Harvard Medical School, Boston, Massachusetts Richard E. Lenski, Michigan State University, East Lansing, Michigan Barbara J. Mazur, E. I. du Pont de Nemours & Company, Wilmington, Delaware Daniel E. Morse, University of California, Santa Barbara, California Philip Needleman, Monsanto Company, St. Louis, Missouri Mary Lou Pardue, Massachusetts Institute of Technology, Cambridge, Massachusetts Michael E. Soulé, University of California, Santa Cruz, California Geerat J. Vermeij, University of California, Davis, California National Research Council Staff: John E. Burris, Study Director Oskar Zaborsky, Study Director (until April 1992) Marietta Toal, Administrative Secretary

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Putting Biotechnology to Work Bioprocess Engineering COMMISSION ON LIFE SCIENCES Bruce M. Alberts (Chairman), University of California, San Francisco, California Bruce N. Ames, University of California, Berkeley, California J. Michael Bishop, University of California Medical Center, San Francisco, California David Botstein, Stanford University School of Medicine, Stanford, California Michael T. Clegg, University of California, Riverside, California Glenn A. Crosby, Washington State University, Pullman, Washington Leroy E. Hood, California Institute of Technology, Pasadena, California Marian E. Koshland, University of California, Berkeley, California Richard E. Lenski, Michigan State University, East Lansing, Michigan Steven P. Pakes, University of Texas Southwestern Medical Center, Dallas, Texas Emil A. Pfitzer, Hoffmann-La Roche Inc., Nutley, New Jersey Malcolm C. Pike, University of Southern California School of Medicine, Los Angeles, California Thomas D. Pollard, Johns Hopkins University Medical School, Baltimore, Maryland Paul G. Risser, University of New Mexico, Albuquerque, New Mexico Jonathan M. Samet, University of New Mexico School of Medicine, Albuquerque, New Mexico Harold M. Schmeck, Jr., Armonk, New York Carla J. Schatz, University of California, Berkeley, California Susan S. Taylor, University of California, San Diego, La Jolla, California Roy P. Vagelos, Merck & Company, Inc., Rahway, New Jersey Torsten N. Wiesel, Rockefeller University, New York, New York National Research Council Staff: John E. Burris, Executive Director

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Putting Biotechnology to Work Bioprocess Engineering The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Frank Press is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government, The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Robert M. White is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an advisor to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and of advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Frank Press and Dr. Robert M. White are chairman and vice chairman, respectively, of the National Research Council.

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Putting Biotechnology to Work Bioprocess Engineering Preface Biotechnology is broadly defined in a 1991 Office of Technology Assessment report as "any technique that uses living organisms (or parts of organisms) to make or modify products, to improve plants or animals, or to develop microorganisms for specific uses." This technology has been instrumental in the development and implementation of processes for the manufacture of antibiotics and other pharmaceuticals, industrial sugars, alcohols, amino acids and other organic acids, foods, and specialty products through the application of microbiology, fermentation, enzymes, and separation technology. Engineers, working with life scientists, often achieved scale-up to industrial production in remarkably short periods. A relatively small number helped to catalyze, over a period of 50 years, the growth of the pharmaceutical, food, agricultural-processing, and specialty-product sectors of the U.S. economy to the point where sales now exceed $100 billion/year. The introduction of the new biotechnology since 1970 enabled directed manipulation of the cell's genetic machinery through recombinant-DNA techniques and cell fusion. Its application on an industrial scale since 1979 has fundamentally expanded the utility of biological systems and positioned a number of industries for explosive global growth. Scientists and engineers can now change the genetic makeup of microbial, plant, and animal cells to confer new characteristics. Biological molecules, for which there is no other means of industrial production, can now be generated. Existing industrial organisms can be systematically altered (i.e., engineered) to enhance their function and to produce useful products in new ways. The new biotechnology, combined with the existing industrial, government, and university infrastructure in biotechnology and the pervasive influence of biological substances in everyday life, has set the stage for unprecedented growth in products, markets, and expectations.

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Putting Biotechnology to Work Bioprocess Engineering Substantial manufacturing capability will be needed to bring about the full application of biotechnology for the benefit of society. A wide array of engineering fundamentals applied to biological systems will be required to produce and purify biological products on a commercial scale. Bioprocess engineers will be essential for translating the discoveries of biotechnology into tangible commercial products, thereby putting biotechnology to work. The Committee on Bioprocess Engineering was convened in the National Research Council's Board on Biology to address issues that are of critical importance if the nation is to reap the full benefits of its success in fundamental biotechnology research: What discoveries and concepts in biology and chemistry are important to bioprocess engineering? What barriers to their exploitation exist? What is the position of the United States in relation to other countries' efforts in bioprocess engineering, especially those of Japan and Germany? What actions are required to ensure that research and training are adequately organized and supported so that the United States can maintain and improve its position? The committee met five times from May 1991 to May 1992 and found that much needs to be done, and done quickly. This report represents a consensus of the committee, which hopes to impart a sense of urgency to the planning for bioprocess-engineering needs in biotechnology manufacturing in the United States. The committee carefully considered the best way to present its findings and to organize the report, given the wide range of products, services, and needs that will be affected by bioprocess engineering and the diverse backgrounds of those who will read this report. The committee decided that the reader should first be provided a definition of bioprocess engineering, a discussion of its economic impact on biotechnology, and a summary of major barriers to the exploitation of biotechnology. Further definitions and a historical perspective were to be addressed in Chapter 2, to illustrate the role of bioprocess engineering in a substantial portion of the economic sectors of the United States. We decided to present the current status of U.S. capabilities, and those of Japan and Europe next, because of the importance of international competitiveness for U.S. economic activities, particularly those affected by bioprocessing. The many areas already affected by bioprocess engineering are presented in Chapter 4, to help the reader become more aware of the language and technologies encompassed by biotechnology. Having "set the stage," the committee chose to present, in Chapter 5, what needs to be done now to address needs that will not be fully understood for some years to come. Chapter 6 addresses future scenarios of biotechnology development and how the education, training, research, and technology-transfer issues related to current opportunities (described in Chapter 5) will prepare bioprocessing to address future needs. The committee thanks those who contributed to its work and shared their expertise at our meetings. In particular, we would like to thank the Nation-

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Putting Biotechnology to Work Bioprocess Engineering al Science Foundation (NSF) Directorate for Engineering (Biotechnology Program and Divisions of Biological and Critical Systems, Engineering Education Centers, and Chemical and Thermal Systems), the NSF Directorate for Biological Sciences (Divisions of Behavioral and Cognitive Sciences, Biological Instrumentation and Resources, Social and Economic Science, and Molecular Biosciences), the Department of Energy (offices of Industrial Technologies, Fossil Energy, and Alcohol Fuels), the Department of Agriculture (Office of the Assistant Secretary for Science and Education and Agricultural Research Service), the National Aeronautics and Space Administration (Life Sciences Division, Microgravity Science Division, and Office of Commercial Programs), the Department of Commerce (National Institute of Standards and Technology, Chemical Science and Technology Laboratory), and the National Academy of Engineering for funding this study. Duane Bruley, Luther Williams, and Carl Hall of NSF deserve special mention for their support of this study in its early stages and Fred Heineken of NSF for serving as the contact person of the lead agency on logistic matters. The chairman thanks Purdue University for making time available to carry out the tasks associated with the committee's work, Carolyn Wasson for excellent assistance in preparing the various drafts of this report, and Norma Leuck for coordinating the numerous communications with committee members. The chairman also thanks Michael Shuler of Cornell University for making his expertise available and contributing to the technical completeness of the report; Charles Scott of Oak Ridge National Laboratories for comments on bioprocess-engineering needs; Edith Munroe of the Corn Refiners Association, Inc., and Matthew Rendlemen and Betsy Kuhn of the Department of Agriculture Economic Research Service for helpful information on value-added products from corn; and Karl H. Kroner of the German National Research Center for Biotechnology (GBF) for providing information on German bioprocess engineering. The committee thanks Donald Henninger, Doug Ming, and Glenn Spaulding of the National Aeronautics and Space Administration Johnson Space Center for arranging a subcommittee visit to the center and is indebted to Marietta Toal of the Board on Biology for her excellent assistance with committee meetings. The committee also thanks numerous individuals and organizations that rapidly responded to inquiries from the committee. Norman Grossblatt, of the National Research Council's Commission on Life Sciences, edited the report. Special thanks are due to Oskar Zaborsky, director of the Board on Biology, whose vision, hard work, and many capabilities enabled this study to be initiated and carried out in a timely manner, and to him and John Burris, executive director of the Commission on Life Sciences, for the long hours they spent in guiding this report through many drafts to its successful conclusion. Michael R. Ladisch, Chairman, Committee on Bioprocess Engineering

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Putting Biotechnology to Work Bioprocess Engineering Contents     Executive Summary   1 1   Introduction   9     1.1 Biotechnology: The Challenge of the Twenty-First Century   9     1.2 What is Bioprocess Engineering?   9     1.3 The Committee's Approach   10     1.4 Economic Impact of Biotechnology   10     1.5 Role of Bioprocess Engineering   11     1.6 Barriers to Exploitation of Biotechnology   11 2   The Challenge   13     2.1 Translating Science into Products   13     Vignette 1: The Scaleup of Penicillin Production—Parallels to the New Biotechnology?   15     2.2 Biopharmaceuticals   16     Vignette 2: Bioprocess Engineering for Early Biopharmaceuticals   17     2.3 The Environment   23     2.4 Conversion of Renewable and Nonrenewable Resources   23     Vignette 3: Pulp and Paper Bioprocessing   25     Vignette 4: Bioprocess Engineering for High-Volume Products: The Case of Corn and the Wet-Milling Industry   27     2.5 Space   32     2.6 Biotechnology-Research Initiative Given by Federal Coordinating Council for Science, Engineering, and Technology (FCCSET)   33

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Putting Biotechnology to Work Bioprocess Engineering     2.7 Summary   34     2.8 References   35 3   Benchmarking: Status of U. S. Bioprocessing and Biotechnology   38     3.1 Bioprocess Engineering in Japan   38     3.2 Bioprocess Engineering in Germany and Europe   41     3.3 Bioprocess Engineering in United States   44     Vignette 5: Bioprocess-Industry Needs: A Moving Target   46     3.4 Summary   48     3.5 References   48 4   Current Bioprocess Technology, Products, and Opportunities   50     4.1 Biopharmaceuticals   50     4.2 Specialty Bioproducts and Industrial Chemicals   66     4.3 Environmental Applications   69     4.4 References   75 5   Needs: What Must Be Done to Meet the Challenges   77     5.1 Education and Training   77     5.2 Research   80     5.3 Technology Transfer   83     5.4 References   85 6   The Future   86     6.1 Opportunities   86     Vignette 6: Cell-Transplantation Therapy   88     6.2 Defense and National Security   97     6.3 Needs   99     6.4 Recommendations   100     6.5 References   101     Bibliography   102 Appendix A:   Biographical Sketches of Committee Members   105 Appendix B:   Invited Speakers at Committee Meetings   112     Index   115