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BIOPROCESS ENGINEERING PRINCIPLES SECOND EDITION PAULINE M. DORAN AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA ...

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BIOPROCESS ENGINEERING PRINCIPLES SECOND EDITION PAULINE M. DORAN

AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier

Academic Press is an imprint of Elsevier 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK Copyright r 2013 Elsevier Ltd. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Doran, Pauline M. Bioprocess engineering principles / Pauline M. Doran. — 2nd ed. p. cm. Includes bibliographical references and index. ISBN 978-0-12-220851-5 (pbk.) 1. Biochemical engineering. I. Title. TP248.3.D67 2013 660.6’3—dc23 2012007234 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library. For information on all Academic Press publications visit our Web site at www.elsevierdirect.com Printed in the United Kingdom 12 13 14 15 16 10 9 8 7 6 5 4 3 2 1

Preface to the Second Edition

As originally conceived, this book is intended as a text for undergraduate and postgraduate students with little or no engineering background. It seeks to close the gap of knowledge and experience for students trained or being trained in molecular biology, biotechnology, and related disciplines who are interested in how biological discoveries are translated into commercial products and services. Applying biology for technology development is a multidisciplinary challenge requiring an appreciation of the engineering aspects of process analysis, design, and scaleup. Consistent with this overall aim, basic biology is not covered in this book, as a biology background is assumed. Moreover, although most aspects of bioprocess engineering are presented quantitatively, priority has been given to minimising the use of complex mathematics that may be beyond the comfort zone of nonengineering readers. Accordingly, the material has a descriptive focus without a heavy reliance on mathematical detail. Following publication of the first edition of Bioprocess Engineering Principles, I was delighted to find that the book was also being adopted in chemical, biochemical, and environmental engineering programs that offer bioprocess engineering as a curriculum component. For students with several years of engineering training under their belts, the introductory nature and style of the earlier chapters may seem tedious and

inappropriate. However, later in the book, topics such as fluid flow and mixing, heat and mass transfer, reaction engineering, and downstream processing are presented in detail as they apply to bioprocessing, thus providing an overview of this specialty stream of traditional chemical engineering. Because of its focus on underlying scientific and engineering principles rather than on specific biotechnology applications, the material presented in the first edition remains relevant today and continues to provide a sound basis for teaching bioprocess engineering. However, since the first edition was published, there have been several important advances and developments that have significantly broadened the scope and capabilities of bioprocessing. New sections on topics such as sustainable bioprocessing and metabolic engineering are included in this second edition, as these approaches are now integral to engineering design procedures and commercial cell line development. Expanded coverage of downstream processing operations to include membrane filtration, protein precipitation, crystallisation, and drying is provided. Greater and more in-depth treatment of fluid flow, turbulence, mixing, and impeller design is also available in this edition, reflecting recent advances in our understanding of mixing processes and their importance in determining the performance of cell cultures. More than 100 new illustrations and 150 additional problems

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PREFACE

and worked examples have been included in this updated edition. A total of over 340 problems now demonstrate how the fundamental principles described in the text are applied in areas such as biofuels, bioplastics, bioremediation, tissue engineering, site-directed mutagenesis, recombinant protein production, and drug development, as well as for traditional microbial fermentation. I acknowledge with gratitude the feedback and suggestions received from many users of the first edition of Bioprocess Engineering Principles over the last 15 years or so. Your input is very welcome and has helped shape the priorities for change and elaboration in the second edition. I would also like to thank Robert Bryson-Richardson and Paulina Mikulic for their special and much appreciated

assistance under challenging circumstances in 2011. Bioprocess engineering has an important place in the modern world. I hope that this book will make it easier for students and graduates from diverse backgrounds to appreciate the role of bioprocess engineering in our lives and to contribute to its further progress and development. Pauline M. Doran Swinburne University of Technology Melbourne, Australia

Additional Book Resources For those who are using this book as a text for their courses, additional teaching resources are available by registering at www.textbooks.elsevier.com.

C H A P T E R

1 Bioprocess Development An Interdisciplinary Challenge

Bioprocessing is an essential part of many food, chemical, and pharmaceutical industries. Bioprocess operations make use of microbial, animal, and plant cells, and components of cells such as enzymes, to manufacture new products and destroy harmful wastes. The use of microorganisms to transform biological materials for production of fermented foods has its origins in antiquity. Since then, bioprocesses have been developed for an enormous range of commercial products, from relatively cheap materials such as industrial alcohol and organic solvents, to expensive specialty chemicals such as antibiotics, therapeutic proteins, and vaccines. Industrially useful enzymes and living cells such as bakers’ and brewers’ yeast are also commercial products of bioprocessing.

Table 1.1 gives examples of bioprocesses employing whole cells. Typical organisms used are also listed. The table is by no means exhaustive; not included are processes for waste water treatment, bioremediation, microbial mineral recovery, and manufacture of traditional foods and beverages such as yoghurt, bread, vinegar, soy sauce, beer, and wine. Industrial processes employing enzymes are also not listed in Table 1.1: these include brewing, baking, confectionery manufacture, clarification of fruit juices, and antibiotic transformation. Large quantities of enzymes are used commercially to convert starch into fermentable sugars, which serve as starting materials for other bioprocesses. Our ability to harness the capabilities of cells and enzymes is closely related to advances in biochemistry, microbiology, immunology, and cell physiology. Knowledge in these areas has expanded rapidly; tools of modern biotechnology such as recombinant DNA, gene probes, cell fusion, and tissue culture offer new opportunities to develop novel products or improve bioprocessing methods. Visions of sophisticated medicines, cultured human tissues and organs, biochips for new-age computers, environmentally compatible pesticides, and powerful pollution-degrading microbes herald a revolution in the role of biology in industry. Although new products and processes can be conceived and partially developed in the laboratory, bringing modern biotechnology to industrial fruition requires engineering skills and know-how. Biological systems can be complex and difficult to control;

Bioprocess Engineering Principles, Second Edition

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© 2013 Elsevier Ltd. All rights reserved.

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1. BIOPROCESS DEVELOPMENT

TABLE 1.1 Examples of Products from Bioprocessing Product

Typical organism used

BIOMASS Agricultural inoculants for nitrogen fixation

Rhizobium leguminosarum

Bakers’ yeast

Saccharomyces cerevisiae

Cheese starter cultures

Lactococcus spp.

Inoculants for silage production

Lactobacillus plantarum

Single-cell protein

Candida utilis or Pseudomonas methylotrophus

Yoghurt starter cultures

Streptococcus thermophilus and Lactobacillus bulgaricus

BULK ORGANICS Acetone/butanol

Clostridium acetobutylicum

Ethanol (nonbeverage)

Saccharomyces cerevisiae

Glycerol

Saccharomyces cerevisiae

ORGANIC ACIDS Citric acid

Aspergillus niger

Gluconic acid

Aspergillus niger

Itaconic acid

Aspergillus itaconicus

Lactic acid

Lactobacillus delbrueckii

AMINO ACIDS Brevibacterium flavum

L-Arginine L-Glutamic

Corynebacterium glutamicum

acid

L-Lysine

Brevibacterium flavum

L-Phenylalanine

Corynebacterium glutamicum

Others

Corynebacterium spp.

NUCLEIC ACID-RELATED COMPOUNDS 50 -guanosine monophosphate (50 -GMP)

Bacillus subtilis

5 -inosine monophosphate (5 -IMP)

Brevibacterium ammoniagenes

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ENZYMES α-Amylase

Bacillus amyloliquefaciens

Glucoamylase

Aspergillus niger

Glucose isomerase

Bacillus coagulans

Pectinases

Aspergillus niger

Proteases

Bacillus spp.

Rennin

Mucor miehei or recombinant yeast

1. INTRODUCTION

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BIOPROCESS DEVELOPMENT

VITAMINS Cyanocobalamin (B12)

Propionibacterium shermanii or Pseudomonas denitrificans

Riboflavin (B2)

Eremothecium ashbyii

EXTRACELLULAR POLYSACCHARIDES Dextran

Leuconostoc mesenteroides

Xanthan gum

Xanthomonas campestris

Other

Polianthes tuberosa (plant cell culture)

POLY-β-HYDROXYALKANOATE POLYESTERS Alcaligenes eutrophus

Poly-β-hydroxybutyrate ANTIBIOTICS Cephalosporins

Cephalosporium acremonium

Penicillins

Penicillium chrysogenum

Aminoglycoside antibiotics (e.g., streptomycin)

Streptomyces griseus

Ansamycins (e.g., rifamycin)

Nocardia mediterranei

Aromatic antibiotics (e.g., griseofulvin)

Penicillium griseofulvum

Macrolide antibiotics (e.g., erythromycin)

Streptomyces erythreus

Nucleoside antibiotics (e.g., puromycin)

Streptomyces alboniger

Polyene macrolide antibiotics (e.g., candidin)

Streptomyces viridoflavus

Polypeptide antibiotics (e.g., gramicidin)

Bacillus brevis

Tetracyclines (e.g., 7-chlortetracycline)

Streptomyces aureofaciens

ALKALOIDS Ergot alkaloids

Claviceps paspali

Taxol

Taxus brevifolia (plant cell culture)

SAPONINS Ginseng saponins

Panax ginseng (plant cell culture)

PIGMENTS β-Carotene

Blakeslea trispora

PLANT GROWTH REGULATORS Gibberellins

Gibberella fujikuroi

INSECTICIDES Bacterial spores

Bacillus thuringiensis

Fungal spores

Hirsutella thompsonii (Continued)

1. INTRODUCTION

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1. BIOPROCESS DEVELOPMENT

TABLE 1.1 Examples of Products from Bioprocessing (Continued) Product

Typical organism used

MICROBIAL TRANSFORMATIONS D-Sorbitol to L-sorbose (in vitamin C production)

Acetobacter suboxydans

Steroids

Rhizopus arrhizus

VACCINES Diphtheria

Corynebacterium diphtheriae

Hepatitis B

Surface antigen expressed in recombinant Saccharomyces cerevisiae

Mumps

Attenuated viruses grown in chick embryo cell cultures

Pertussis (whooping cough)

Bordetella pertussis

Poliomyelitis virus

Attenuated viruses grown in monkey kidney or human diploid cells

Rubella

Attenuated viruses grown in baby hamster kidney cells

Tetanus

Clostridium tetani

THERAPEUTIC PROTEINS Erythropoietin

Recombinant mammalian cells

Factor VIII

Recombinant mammalian cells

Follicle-stimulating hormone

Recombinant mammalian cells

Granulocytemacrophage colony-stimulating factor

Recombinant Escherichia coli

Growth hormones

Recombinant Escherichia coli

Hirudin

Recombinant Saccharomyces cerevisiae

Insulin and insulin analogues

Recombinant Escherichia coli

Interferons

Recombinant Escherichia coli

Interleukins

Recombinant Escherichia coli

Platelet-derived growth factor

Recombinant Saccharomyces cerevisiae

Tissue plasminogen activator

Recombinant Escherichia coli or recombinant mammalian cells

MONOCLONAL ANTIBODIES Various, including Fab and Fab2 fragments

Hybridoma cells

THERAPEUTIC TISSUES AND CELLS Cartilage cells

Human (patient) chondrocytes

Skin

Human skin cells

1. INTRODUCTION

1.1 STEPS IN BIOPROCESS DEVELOPMENT: A TYPICAL NEW PRODUCT FROM RECOMBINANT DNA

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nevertheless, they obey the laws of chemistry and physics and are therefore amenable to engineering analysis. Substantial engineering input is essential in many aspects of bioprocessing, including the design and operation of bioreactors, sterilisers, and equipment for product recovery, the development of systems for process automation and control, and the efficient and safe layout of fermentation factories. The subject of this book, bioprocess engineering, is the study of engineering principles applied to processes involving cell or enzyme catalysts.

1.1 STEPS IN BIOPROCESS DEVELOPMENT: A TYPICAL NEW PRODUCT FROM RECOMBINANT DNA The interdisciplinary nature of bioprocessing is evident if we look at the stages of development of a complete industrial process. As an example, consider manufacture of a typical recombinant DNA-derived product such as insulin, growth hormone, erythropoietin, or interferon. As shown in Figure 1.1, several steps are required to bring the product into commercial reality; these stages involve different types of scientific expertise. The first stages of bioprocess development (Steps 111) are concerned with genetic manipulation of the host organism; in this case, a gene from animal DNA is cloned into Escherichia coli. Genetic engineering is performed in laboratories on a small scale by scientists trained in molecular biology and biochemistry. Tools of the trade include Petri dishes, micropipettes, microcentrifuges, nano- or microgram quantities of restriction enzymes, and electrophoresis gels for DNA and protein fractionation. In terms of bioprocess development, parameters of major importance are the level of expression of the desired product and the stability of the constructed strains. After cloning, the growth and production characteristics of the recombinant cells must be measured as a function of the culture environment (Step 12). Practical skills in microbiology and kinetic analysis are required; small-scale culture is carried out mostly using shake flasks of 250-ml to 1-litre capacity. Medium composition, pH, temperature, and other environmental conditions allowing optimal growth and productivity are determined. Calculated parameters such as cell growth rate, specific productivity, and product yield are used to describe the performance of the organism. Once the culture conditions for production are known, scale-up of the process starts. The first stage may be a 1- or 2-litre bench-top bioreactor equipped with instruments for measuring and adjusting temperature, pH, dissolved oxygen concentration, stirrer speed, and other process variables (Step 13). Cultures can be more closely monitored in bioreactors than in shake flasks, so better control over the process is possible. Information is collected about the oxygen requirements of the cells, their shear sensitivity, foaming characteristics, and other properties. Limitations imposed by the reactor on the activity of the organism must be identified. For example, if the bioreactor cannot provide dissolved oxygen to an aerobic culture at a sufficiently high rate, the culture will become oxygenstarved. Similarly, in mixing the broth to expose the cells to nutrients in the medium, the stirrer in the reactor may cause cell damage. Whether or not the reactor can provide conditions for optimal activity of the cells is of prime concern. The situation is assessed using measured and calculated parameters such as mass transfer coefficients, mixing time, gas

1. INTRODUCTION

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1. BIOPROCESS DEVELOPMENT

4. Gene cut from chromosome

Gene 1. Biochemicals

9. Insertion into microorganism

3. Part of animal chromosome

2. Animal tissue

8. Recombinant plasmid 5. Microorganism such as E. coli

6. Plasmid

7. Cut plasmid

14. Pilot-scale bioreactor

15. Industrial-scale operation

10. Plasmid multiplication and gene expression

13. Bench-top bioreactor

16. Product recovery

12...