Contents 1 Fermentation Pilot Plant Yujiro Harada, Kuniaki Sakata, Seiji Sato and Shinsaku Takayama PROLOGUE(by Yujiro Harada) 1.0 MICROBIAL FERMENTATION (by Kuniaki Sakato 1.1 Fermentation Pilot Plant 1.2 Bioreactors and Culture Techniques 233 for microbial Processes 1. 3 Application of Computer Control and Sensing Technologies for Fermentation Process 1.5 Bioreactors for Recombinant DNA Technology.... 22 2.1 Introduction 2.2 Culture media 2.3 Microcarrier Culture and General Control Parameters. 26 2.4 Perfusion Culture Systems as a New High Density Culture Technolog 2.5 Sedimentation Column Perfusion Systems 2.6 High Density Culture Using a Perfusion Culture System with Sedimentation Column 2.7 Acknowledgment References and Bibliography (Section 2)
Contents 1 Fermentation Pilot Plant ........................................ 1 Yujiro Harada, Kuniaki Sakata, Seiji Sat0 and Shinsaku Takayama PROLOGUE (by Yujiro Harada) ................................................. 1 1 .O MICROBLAL FERMENTATION (by Kuniaki Sakato) ........ 2 ........... 3 ........... 3 1.1 Fermentation Pilot Plant ...... 1.2 Bioreactors and Culture Techniques 1.3 Application of Computer Control and 1.4 Scale-up ................................................... 1.5 Bioreactors for Recombinant DNA Technolo References (Section 1) ....................................... 2.0 MAMMALIAN CELL CULTURE SYSTEM (by 2.1 Introduction ............................... ......................... 25 2.2 Culture Media ........................................ 2.3 Microcarrier Culture and General Contro 2.4 Perfision Culture Systems as a New High Density for Microbial Processes ........................ Sensing Technologies for Fermentation Process ............... 8 Culture Technology ....................................................... 3 1 2.5 Sedimentation Column Perfision Systems ...................... 33 2.6 High Density Culture Using a Perfision Culture System with Sedimentation Column. 2.7 Acknowledgment ................. References and Bibliography (Se xiii
Contents 3.0 BIOREACTORS FOR PLANT CELL TISSUE AND ORGAN CULTURES (by Shinsaku Takayama)....41 3. 1 Background of the Technique--Historical Overview...41 3.2 Media Formulations 3.3 General applications 3.4 Bioreactors-Hardware Configuration 3.5 Bioreactor Size 3.6 Culture Period 3.7 Aeration and Agitation 3.8 Microbial Contamination 3.9 Characteristics 3.10 Manipulation 3. 11 Scale-up Problems 3. 12 Bioprocess Measurement and Control References( Section 3) 2 Fermentation Design.... 67 Allan C Soderberg L 0 INTRODUCTION 2.0 FERMENTATION DEPARTMENT, EQUIPMENT AND SPACE REQUIREMENTS......68 2. 1 The Microbiological Laboratories... 68 2.2 Analytical Support Laboratories 2.3 Production: Raw Material Storage…… 71 2.4 Media Preparation or Batching Area 2. 5 The Seed Fermenter Layout 2. 6 The Main Fermenter Layout 234 2.7 Nutrient Feed Tanks 2. 8 Sterile Filters ……75 2.9 Air Compressors 2.10 Valves(To Maintain Sterility) 2.11 Pumps 78 2. 12 Cooling Equipment 2. 13 Environmental Control 3.0 GENERAL DESIGN DATA 4.0 CONTINUOUS STERILIZERS 4. 1 A Justification for Continuous Sterilization 4.2 Support Equipment for a sterilizer 4.3 The Sterilizing Section 89 4.4 The Cooling Section 5.0 FERMENTER COOLING
xiv Contents 3.0 BIOREACTORS FOR PLANT CELL TISSUE AND ORGAN CULTURES (by Shinsaku Takayama) ...... 3.1 Background of the Technique-Historical Overview ..... .4 1 3.2 Media Formulations ............................. 3.3 General Applications ........................... 3.4 Bioreactors-Hardware Configuration.. 3.5 Bioreactor Size ..................................... 3.6 Culture Period ...................................... 3.7 Aeration and Agitation ....................... 3.8 Microbial Contamination .................... 3.9 Characteristics ...................................................... 3.10 Manipulation ................................... 3.11 Scale-up Problems .. 3.12 Bioprocess Measure References (Section 3) ............................................... .................... 55 2 Fermentation Design ............................................. 67 Allan C. Soderberg 1 .O INTRODUCTION ..................................... 2.0 FERMENTATION DEPARTMENT, EQUI AND SPACE REQUIREMENTS ............... 2.1 The Microbiological 2.2 Analytical S 2.3 Production: 2.4 Media Preparation or Batchin 2.5 The Seed Fermenter Layout .. 2.7 Nutrient Feed Tanks ............. 2.8 Sterile Filters ........... 2.9 Air Compressors ................ 2.10 Valves (To Maintain Steril 2.11 Pumps 78 2.12 Cooling Equipment .......... 2.13 Environmental Control ................................... 2.6 The Main Fermenter Layout .... ................... 74 3 .O GENERAL DESIGN DATA .......... 4.0 CONTINUOUS STERILIZERS ................. 4.1 A Justification for Continuo 4.2 Support Equipment for a St 4.3 The Sterilizing Section ..................... 4.4 The Cooling Section ....................................... ......................... 79 5.0 FERMENTER COOLING
Contents 6.0 THE DESIGN OF LARGE FERMENTERS (BASED ON AERATION 6. 1 Agitator Effectiveness 6.2 Fermenter Height 6. 3 Mixing Horsepower by Aeration 6.4 Air Sparger Design 107 6.5 Comparison of Shear of Air Bubbles by Agitators and Jets… 6.6 The Effect of Shear on Microorganisms 6. 7 Other Examples of Jet Air/Liquid Mixing 6.8 Mechanical Versus Non-mechanical Agitation l10 7.0 TROUBLE SHOOTING IN A FERMENTATION PLANTlll 8.0 GENERAL COMMENTS REFERENCES 120 3 Nutritional Requirements in Fermentation Processes 122 willem A Kampen L0 INTRODUCTION 20 NUTRITIONAL REQUIREMENTS OF THE CELL……125 3.0 THE CARBON SOURCE 128 0 THE NITROGEN AND SULFUR SOURCE 135 5.0 THE SOURCE OF TRACE AND ESSENTIAL ELEMENTS 6.0 THE VITAMIN SOURCE AND OTHER GROWTH FACTORS 7.0 PHYSICAL AND IONIC REQUIREMENTS 147 8.0 MEDIA DEVELOPMENT 9.0 EFFECT OF NUTRIENT CONCENTRATION ON GROWTH RATE REFERENCES 4 Statistical Methods For Fermentation Optimization 161 Edwin 0. Geiger 1.0 INTRODUCTION 161 2.0 TRADITIONAL ONE-VARIABLE-AT-A-TIME METHOD 3.0 EVOLUTIONARY OPTIMIZATION 162 4.0 RESPONSE SURFACE METHODOLOGY 166
Contents xv 6.0 THE DESIGN OF LARGE FERMENTERS (BASED ON AERATION) ................................................. 99 6.2 Fermenter Height ......................................................... 100 6.3 Mixing Horsepower by Aeration .................................. 10 1 by Agitators and Jets ................................................... 107 6.7 Other Examples of Jet Airkiquid Mixing .................... 109 6.8 Mechanical Versus Non-mechanical Agitation ............. 1 10 7.0 TROUBLE SHOOTING IN A FERMENTATION PLANT 11 1 8.0 GENERAL COMMENTS ................................................. 1 19 REFERENCES ................................................................... 120 6.1 Agitator Effectiveness ................................................... 99 6.4 Air Sparger Design ...................................................... 107 6.5 Comparison of Shear of Air Bubbles 6.6 The Effect of Shear on Microorganisms ....................... 109 3 Nutritional Requirements in Fermentation Processes .............................................................. 122 Willem H. Kampen 1 .O INTRODUCTION ............................................ 2.0 NUTRITIONAL REQUIREMENTS OF THE C 3 .O THE CARBON SOURCE ....................... 4.0 THE NITROGEN AND SULFUR SOUR 5.0 THE SOURCE OF TRACE AND ESSENTIAL ELEMENTS ....................... 6.0 THE VITAMIN SOURCE AND OTHER GROWTH FACTORS ............................................. 7.0 PHYSICAL AND IONIC REQUIREMENTS .......... 8.0 MEDIA DEVELOPMEN ......................................... 149 9.0 EFFECT OF NUTRIEN CENTRATION GROWTH RATE ............................................. REFERENCES ...... ........................................... 159 4 Statistical Methods For Fermentation Optimization ................................ 161 Edwin 0. Geiger 1 .O INTRODUCTION ............................................................ 16 1 2.0 TRADITIONAL ONE-VARIABLE-AT-A-TIME METHOD ................................................................... 16 1 3 .O EVOLUTIONARY OPTIMIZATION ............................... 162 4.0 RESPONSE SURFACE METHODOLOGY ..................... 166
xvi Contents 5.0 ADVANTAGES OF RSM 5. 1 Maximum Information from Experiments 169 5.2 Forces One To plan 170 5. 3 Know How Long Project Will Take 5.4 Interaction Between Variables 5.5 Multiple Responses 171 5.6 Design Data 171 6.0 DISADVANTAGES OF RSM 174 7.0 POTENTIAL DIFFICULTIES WITH RSM 174 7. 1 Correlation Coefficient 7. 2 Regression Coefficients 7.3 Standard Error of the Regression Coefficient…………176 7. 4 Computed T value 177 7.5 Standard Error of the Estimate 7. 6 analysis of variance 8.0 METHODS TO IMPROVE THE RSM MODEL 9.0 SUMMARY… REFERENCES 5 Agitation.....……181 James Y Oldshue 1.0 THEORY AND CONCEPTS 2.0 PUMPING CAPACITY AND FLUID SHEAR RATES 132 3.0 MIXERS AND IMPELLERS 183 1 Fluidfoil Impellers 191 4.0 BAFFLES 5.0 FLUID SHEAR RATES 203 5.1 Particles 206 5.2 Impeller Power Consumption 5.3 Mass Transfer Characteristics of Fluidfoil Impellers..217 6.0 FULL-SCALE PLANT DESIGN 6. 1 Some General Relationships in Large Scale Mixers Compared to Small Scale mixers 219 6. 2 Scale-Up Based on Data from Existing 22 6.3 Data Based on Pilot Plant Work 6. 4 Sulfite Oxidation Data 6.5 Oxygen Uptake Rate in the Broth 6.6 Some General Concepts 6.7 Reverse Rotation dual Power Impellers 228 7.0 FULL SCALE PROCESS EXAMPLE 229 8.0 THE ROLE OF CELL CONCENTRATION ON MASS TRANSFER RATE 231
mi Contents 5.0 ADVANTAGES OF RSM ................................................ 168 5.1 Maximum Information from Experiments .................... 169 5.2 Forces One To Plan ..................................................... 170 5.3 Know How Long Project Will Take ............................. 170 5.4 Interaction Between Variables ..................................... 170 5.5 Multiple Responses ............................... 5.6 Design Data .......................................... 6.0 DISADVANTAGES OF RSM .................... 7.0 POTENTIAL DIFFICULTIES WITH RSM ...................... 174 7.1 Correlation Coefficient ................................................ 176 7.2 Regression Coefficients ........................................ 7.3 Standard Error of the Regression Coefficient ............... 176 7.4 Computed T Value ....................................... 7.5 Standard Error of the Estimate ..................... 7.6 Analysis of Variance ................................................... 177 8.0 METHODS TO IMPROVE THE RSM MODEL .............. 178 9.0 SUMMARY ..................... ................................... 179 REFERENCES ..................... .................... 179 5 Agitation ....................... .............. ....................... 181 James I: Oldshue 1 . 0 THEORY AND CONCEPTS ......................... 2.0 PUMPING CAPACITY AND FLUID SHEAR RATES .... 182 3.0 MIXERS AND IMPELLERS ................... 183 3.1 Fluidfoil Impellers ...................................................... 191 4.0 BAFFLES ................................................................... 201 5.0 FLUID SHEAR RATES ........................... 5.1 Particles .................................................................. 206 5.2 Impeller Power Consumption ...... ............................ 207 5.3 Mass Transfer Characteristics of idfoil Impellers .... 217 6.1 Some General Relationships in Large Scale Mixers Compared to Small Scale Mixers ............................. 6.2 Scale-up Based on Data from Existing Production Plant ........................... ................... 220 6.3 Data Based on Pilot Plant Work ............... .. 223 6.4 Sulfite Oxidation Data ................................................. 226 6.5 Oxygen Uptake Rate in the Broth ......... ................... 227 227 6.7 Reverse Rotation Dual Power Impellers ....................... 228 .............. 229 ................... 231 6.0 FULL-SCALE PLANT DESIGN ................................ 6.6 Some General Concepts ................................. 7.0 FULL SCALE PROCESS EXAMPLE ......... 8.0 THE ROLE OF CELL CONCENTRATION MASS TRANSFER RATE
x 9.0 SOME OTHER MASS TRANSFER CONSIDERATIONS 235 10.0 DESIGN PROBLEMS IN BIOCHEMICAL ENGINEERING 236 11.0 SOLUTION-FERMENTATION PROBLEMS 238 LIST OF ABBREⅤ IATIONS 240 REFERENCES 6 Filtration.................... 242 Celeste todaro L0 INTRODUCTION 242 1. 1 Depth Filtration 243 2.0 CAKE FILTRATION 3.0 THEORY 243 3. 1 Flow Theory 243 3.2 Cake Compressibility 40 PARTICLE SIZE DISTRIBUTION 245 5.0 OPTIMAL CAKE THICKNESS 6.0 FILTER AID 247 70 FILTER MEDIA 248 8.0 EQUIPMENT SELECTION 250 8.1 Pilot testing………… 250 9.0 CONTINUOUS vS BATCH FILTRATION 251 100 ROTARY VACUUM DRUM FILTER 251 10.1 Operation and Applications 10.2 Optimization 258 110 NUTSCHES 258 ll.1 Applications… 258 11.2 Operation 260 11. 3 Maintenance 264 12.0 HP-HYBRID FILTER PRESS 12. 1 Applications 266 12.2 Operation 12. 3 Maintenance 269 13.0 MANUFACTURERS Rotary Drum Vacuum Filters 269 Nutsche 269 Hybrid Filter Press REFERENCES 270 7 Cross-Flow Filtration. Ramesh. bhave 1.0 INTRODUCTION 271
Contents xvii 9.0 SOME OTHER MASS TRANSFER CONSIDERATIONS235 10.0 DESIGN PROBLEMS IN BIOCHEMICAL ENGINEERING ............................................................... 23 6 1 1 .O SOLUTION-FERMENTATION PROBLEMS ............... 238 LIST OF ABBREVIATIONS .................................................... 240 REFERENCES ................................................................... 241 6 Filtration ............................................................. 242 1 .O INTRODUCTION ............................................................ 242 ................................................... 243 2.0 CAKE FILTRATION ....................................................... 243 3.0 THEORY ....................................... 3.1 Flow Theory ................................... 4.0 PARTICLE SIZE DISTRIBUTION ...... 5.0 OPTIMAL CAKE THICKNESS ........... 6.0 FILTER AID ................................................................... 247 7.0 FILTER MEDIA .............................. 8 .O EQUIPMENT SELECTION ............ 8.1 Pilot Testing ............................... Celeste L Todaro 1.1 Depth Filtration .... 3.2 Cake Compressibility ...................... .................... 244 10.1 Operation and Applications .............. ............................................ 258 11.1 Applications ......................... 11.2 Operation .................................................................. 260 11.3 Maintenance ............................................................. 264 12.0 HP-HYBRID FILTER PRESS .......................................... 266 12.1 Applications .......... ........................................ 266 12.2 Operation ........................................................ 267 12.3 Maintenance ......... ......................................... 269 13.0 MANUFACTURERS ............................ Rotary Drum Vacuum Filters ................. Nutsches .......................................... Hybrid Filter Press ............. REFERENCES ......... 7 Cross-Flow Filtration .......................................... 271 1 .O INTRODUCTION ............................................................ 27 1 Ramesh R. Bhave