Agitator Design for Gas–Liquid Fermenters and Bioreactors

Agitator Design for Gas–Liquid Fermenters and Bioreactors

Gregory T. Benz

Benz Technology International, Inc.,Clarksville, OH, USA

Copyright © 2021 by the American Institute of Chemical Engineers, Inc. All rights reserved.

A Joint Publication of the American Institute of Chemical Engineers and John Wiley & Sons, Inc.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.

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Library of Congress Cataloging-in-Publication Data

Names: Benz, Gregory T., author. Title: Agitator design for gas–liquid fermenters and bioreactors / Gregory

T. Benz, Benz Technology International, Inc., Ohio, US. Description: First edition. | Hoboken, NJ, USA : Wiley, 2021. | Includes

bibliographical references and index. Identifiers: LCCN 2020051152 (print) | LCCN 2020051153 (ebook) | ISBN

9781119650492 (hardback) | ISBN 9781119650508 (adobe pdf) | ISBN 9781119650539 (epub)

Subjects: LCSH: Bioreactors–Equipment and supplies. | Fermentation–Equipment and supplies. | Mixing machinery–Design and construction. | Gas-liquid interfaces.

Classification: LCC TP248.25.B55 B46 2021 (print) | LCC TP248.25.B55 (ebook) | DDC 660/.28449–dc23

LC record available at https://lccn.loc.gov/2020051152LC ebook record available at https://lccn.loc.gov/2020051153

Cover Design: WileyCover Image: © Courtesy Gregory T. Benz

Set in 9.5/12.5pt STIXTwoText by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1

I dedicate this book to my late father-in-law, Richard Durchholz, for inspiring me as an engineer and a person; to Wayne Ramsey, for mentoring me and giving me the opportunity to design the largest fermenters built by Chemineer up to that point; to Ms. Jian Li, my colleague and friend, for helping me to succeed in managing the China office and understanding Chinese culture, and my wife, Kim Benz, for encouraging me and supporting me in the massive undertaking of writing this book.

vii

Preface xixForeword xxiForeword for Greg Benz xxiii

1 Purposeof AgitatorDesign 1­References­ 2

2 MajorStepsin SuccessfulAgitatorDesign 3­Define­Process­Results­ 3­Define­Process­Conditions­ 5­Choose­Tank­Geometry­ 6­Calculate­Equivalent­Power/Airflow­Combinations­for Equal­­Mass­Transfer­Rate­ 7­Choose­Minimum­Combined­Power­ 7­Choose­Shaft­Speed;­Size­Impeller­System­to Draw­Required­­Gassed­Power­ 7­Decision­Point:­D/T­and Gassing­Factors­OK?­ 8­Mechanical­Design­ 8­Decision­Point:­Is­the Mechanical­Design­Feasible?­ 8­Repeat­to Find­Lowest­Cost­ 8­Repeat­for Different­Aspect­Ratios­ 9­Repeat­for Different­Process­Conditions­ 9­Finish­ 9­Summary­of Chapter­ 10List­of­Symbols­ 10­References­ 10

Contents

Contentsviii

3 AgitatorFundamentals 11­Agitated­Tank­Terminology­ 11­Prime­Mover­ 11­Reducer­ 13­Shaft­Seal­ 13­Wetted­Parts­ 13­Tank­Dimensions­ 14­How­Agitation­Parameters­Are­Calculated­ 14­Reynolds­Number­ 15­Power­Number­ 16­Pumping­Number­ 17­Dimensionless­Blend­Time­ 17­Aeration­Number­ 18­Gassing­Factor­ 18­Nusselt­Number­ 18­Froude­Number­ 19­Prandtl­Number­ 19­Geometric­Ratios­ 20­Baffle­Number­ 20­Dimensionless­Hydraulic­Force­ 20­Thrust­Number­ 21­Typical­Dimensionless­Number­Curves­ 21­A­Primer­on Rheology­ 25­Newtonian­Model­ 26­Pseudoplastic­or­Shear­Thinning,­Model­(Aka­Power­Law­Fluid)­ 27­Bingham­Plastic­ 27­Herschel–Bulkley­ 27­Impeller­Apparent­Viscosity­ 29­A­Bit­of Impeller­Physics­ 29­Summary­of Chapter­ 31List­of­Symbols­ 31Greek­Letters­­ 32­References­ 32

4 AgitatorBehaviorunderGassedConditions 35­Flooding­ 35­kla­Method­ 35­Power­Draw­Method­ 36­Visual­Flow­Pattern­Method­ 37­Effect­on Power­Draw­ 38­Holdup­ 39

Contents ix

­Example­of Holdup­Calculation­ 40­Holdup­“War­Story”­ 40­Variable­Gas­Flow­Operation­ 40­Mechanical­Effects­ 42­Summary­of Chapter­ 42List­of­Symbols­ 42­References­ 43

5 ImpellerTypesUsedin Fermenters 45­Impeller­Flow­Patterns­ 45

Axial­Flow­ 46Radial­Flow­ 47Mixed­Flow­ 47Chaos­Flow­ 48

­Examples­of Axial­Flow­Impellers­ 49Low­Solidity­ 49High­Solidity­ 52Up-pumping­vs.­Down­Pumping­ 55

­Examples­of Radial­Flow­Impellers­ 56Straight­Blade­Impeller­ 56Disc,­aka­Rushton,­Turbines­ 57Smith­Turbines­ 62CD-6­Turbine­by­Chemineer;­aka­Smith­Turbine­by­Many­Manufacturers­ 62Deeply­Concave­Turbines­ 66Deep­Asymmetric­Concave­Turbine­with Overhang­(BT-6)­ 68

­Examples­of Mixed­Flow­Impellers­ 73­Examples­of Chaos­Impellers­ 74

Shear­Effects­ 76Specialty­Impellers­ 78

­Summary­of Chapter­ 80List­of­Symbols­ 80­References­ 81

6 ImpellerSystems 83­Why­Do­We Need­a System?­ 83

Reaction­Engineering­ 83Fermenter­History­ 84

­Steps­to Impeller­System­Design­ 85­Choose­Number­of Impellers­ 86­Choose­Placement­of Impellers­ 86

Contentsx

­Choose­Type(s)­of Impellers­ 87­Choose­Power­Split­or­Distribution­Among­Impellers­ 93­Choose­D/T­and/or­Shaft­Speed­ 93

D/T­Effects­with Variable­Gas­Flowrates­ 96Conclusions­on D/T­Ratio­ 98

­Design­to Minimize­Shear­Damage­ 99­Sparger­Design­ 100

Ring­Sparger­ 100Pre-dispersion­ 103Fine­Bubble­Diffuser­ 104

­Summary­of Chapter­ 105List­of­Symbols­ 106­References­ 106

7 Pilotingfor MassTransfer 109­Why­Pilot­for Mass­Transfer­ 109­Methods­for­Determining­kla­ 112

Sulfite­Method­ 112Dynamic­Method;­aka­Dynamic­Gassing/Degassing­Method­ 112Steady-State­Method;­aka­Mass­Balance­Method­ 113Combined­Dynamic­and Steady-State­Method­ 114

­Equipment­Needed­for Scalable­Data­ 114Data­Gathering­Needs­ 120

­Experimental­Protocol­ 121­Summary­of Chapter­ 128List­of­Symbols­ 128­References­ 129

8 Powerand GasFlowDesignand Optimization 131­What­This­Chapter­Is­about­ 131­Where­We Are­in Terms­of Design­ 131­Design­with no­Data­ 131­Design­with Limited­Pilot­Data­ 133­Design­with Full­Data­ 135­Choose­Minimum­Combined­Power­ 136­State­of Design­Completion­ 141­Additional­Considerations­ 142­Summary­of Chapter­ 142List­of­Symbols­ 142­References­ 142

Contents xi

9 OptimizingOperationfor MinimumEnergyConsumptionperBatch 145­Purpose­of This­Chapter­ 145­Prerequisite­ 145­Conceptual­Overview­ 145­Detailed­Procedure­ 146Minimizing­Total­Energy­Usage­ 150­Practical­Design­ 150­Additional­Considerations­ 150­Summary­of Chapter­ 152List­of­Symbols­ 152­References­ 153

10 HeatTransferSurfacesand Calculations 155­Purpose­of This­Chapter­ 155­Design­Philosophy­ 155­Overview­of the Problem­ 156­Heat­Sources­ 156­Cooling­Sources­ 157­Heat­Exchange­Surface­Overview­ 158­Principle­of Heat­Transfer­Calculation­ 164­Calculations­By­Type­of Surface­ 166

Vessel­Jacket,­Agitated­Side­ 166Simple­Unbaffled­Jacket,­Jacket­Side­ 167Dimple­Jacket,­Jacket­Side­ 167Half-Pipe­Coil,­Jacket­Side­ 169Helical­Coil,­Inside­ 171Helical­Coil,­Process­Side­ 171Vertical­Tube­Bundle,­Inside­ 173Vertical­Tube­Bundle,­Process­Side­ 174Plate­Coil,­Inside­ 175Plate­Coil,­Process­Side­ 176

­Example­Problem:­Vertical­Tube­Bundle­ 176Problem­Statement­ 176Problem­Solution­ 177

­Additional­Consideration:­Effect­on Power­Draw­ 182­Additional­Consideration:­Forces­on Heat­Exchange­Surfaces­Used­as Baffles­ 183­Additional­Consideration:­Wall­Viscosity­ 184­Additional­Consideration:­Effect­of Gas­ 185­External­Heat­Exchange­Loops­ 186­Summary­of Chapter­ 187

Contentsxii

List­of­Symbols­ 187References­ 189Further­Readings­ 189

11 GassesOtherThanAirand LiquidsOtherThan Water 191­General­Principle­ 191­Comments­on Some­Specific­Gasses­ 191

Ammonia­ 191Carbon­Dioxide­ 192Carbon­Monoxide­ 192Hydrogen­ 192Methane­ 192Oxygen­ 192

­Economic­Factors­ 192­Disposal­Factors­ 193­Effects­of­Different­Gasses­on­kla­ 193­Effects­of Different­Gasses­on Driving­Force­ 195­Operating­Condition­Effects­ 195­Constraints­on Outlet­Concentration­ 196­Safety­ 196­Liquids­Other­Than­Water­ 198­Summary­of Chapter­ 198List­of Symbols­ 198­References­ 199

12 ViscousFermentation 201­General­Background­ 201­Sources­of Viscosity­ 201­Viscosity­Models­for Broths­ 202­Effect­of Viscosity­on Power­Draw­ 203

Example­Problem­ 204Example­Problem­Answer­ 204

­Effect­of­Viscosity­on­kla­ 205­Effect­of Viscosity­on Holdup­ 207­Effect­of Viscosity­on Blend­Time­ 207­Effect­of Viscosity­on Flooding­ 209­Caverns­ 209

Estimating­Cavern­Size­ 211­Xanthan­and Gellan­Gums­ 212

Viscosity­Models­for Gums­ 213Installation­Survey­ 214

Contents xiii

­Effect­of D/T­and No.­and Type­of Impellers­on Results­­in Xanthan­Gum­ 217

Production­Curve­ 218Heat­Transfer­ 218All-Axial­Impeller­Design­ 218Invisible­Draft­Tube­vs.­Axial/Radial­Combination­ 222

­Mycelial­Broths­ 223Typical­Viscosity­Model­ 224Morphology­Effects­ 224

­Recommendations­ 225­Summary­of Chapter­ 227List­of Symbols­ 227­References­ 228

13 ThreePhaseFermentation 231­General­Problem­ 231­Effect­on Mass­Transfer­ 231­Effect­on Foam­ 233­Emulsion­vs.­Suspension­ 233­Complexity:­How­to Optimize­Operation­ 233­Summary­of Chapter­ 234List­of­Symbols­ 234­References­ 234

14 UseofCFDinFermenterDesign 237­Purpose­of This­Chapter­ 237­Basic­Theory­ 237­Methods­of Presenting­Data­ 239­Velocity­Distribution­ 240­Cavern­Formation­ 240­Blending­Progress­ 242­Flow­Around­Coils­ 245­Bubble­Size,­kla,­Holdup­ 247­DO­Distribution­ 248­Summary­of Chapter­ 250List­of­Symbols­ 250­References­ 250

15 AgitatorSealDesignConsiderations 251­Introduction­ 251­Terminology­ 251

Contentsxiv

­Main­Functions­of Fermenter­Shaft­Seals­ 252­Common­Types­of Shaft­Seals­ 254­Material­Considerations­ 265­Methods­of Lubricating­Seals­ 267­Seal­Environmental­Control­and Seal­Support­System­ 267­Seal­Life­Expectations­ 272­Special­Process­Considerations­ 272­Summary­of Chapter­ 275­Reference­ 275

16 FermenterAgitatorMountingMethods 277­Introduction­ 277­Top­Entering­Methods­ 277

Direct­Nozzle­Mount­ 278Beam­Gear­Drive­Mount­with Auxiliary­Packing­or­Lip­Seal;­Beams­Tied­into­Vessel­Sidewall­ 281Beam­Gear­Drive­Mount­with Auxiliary­Mechanical­Seal;­Beams­Tied­into­Vessel­Sidewall­ 283Beam­Gear­Drive­Mount­with Auxiliary­Mechanical­Seal;­Beams­Tied­into­Building­Structure­ 284Complete­Drive­and Seal­Mount­to Beams­Tied­into­Vessel­Sidewall,­with Bellows­Connector­ 285Complete­Drive­and Seal­Mount­to Beams­Tied­into­Building­Structure,­with Bellows­Connector­ 287

­Bottom­Entering­Methods­ 287Direct­Nozzle­Mount­ 288Floor­Gear­Drive­Mount­with Auxiliary­Packing­or­Lip­Seal­ 288Floor­Gear­Drive­Mount­with Auxiliary­Mechanical­Seal­ 289Floor­Integrated­Drive­and Seal­Mount­with Bellows­Connector­ 291

­Summary­of Chapter­ 292­References­ 292

17 MechanicalDesignof FermenterAgitators 293­Introduction­ 293

Impeller­Design­Philosophy­ 294Discussion­on Hydraulic­Force­ 295Shaft­Design­Philosophy­ 297Shaft­Design­Based­on Stress­ 298

­Simple­Example­Problem­ 302­Sample­Problem­with Steady­Bearing­ 304

Shaft­Design­Based­On Critical­Speed­ 304

Contents xv

­Cantilevered­Designs­ 306­Example­Problem­ 308­Units­with Steady­Bearings­ 311

Solid­Shaft­vs.­Hollow­Shaft­ 315Role­of FEA­in Overall­Shaft­Design-Simplified­Discussion­ 319Agitator­Gear­Drive­Selection­Concepts­ 319

­Early­History­ 320­Loads­Imposed­ 320­Handle­or­Isolate­Loads?­ 323­Handle­Loads­Option­1:­Oversized­Commercial­Gear­Drive­ 323­Handle­Loads­Option­2:­Purpose-Built­Agitator­Drive­ 324­Isolate­Loads­Option­1:­Hollow­Quill­Integrated­Drive­with Flexibly­­Coupled­Extension­Shaft­ 325­Isolate­Loads­Option­2:­Outboard­Support­Bearing­Module­ 328

Bearing­Life­Considerations­ 329Noise­Considerations­ 330Torsional­Natural­Frequency­ 332

­Important­or­Useful­Mechanical­Design­Features­ 332Summary­of Chapter­ 333List­of Symbols­ 333Greek­Letters­ 334­References­ 334

18 SanitaryDesign 335­Introduction­ 335­Definitions­ 336­Construction­Principles­ 336­Wetted­Parts­Construction­Methods­ 336

Welded­Construction­ 336In-Tank­Couplings­ 338Mounting­Flange­Area­ 341Axial­Impellers­ 344Radial­Impellers­ 345

­Bolts­and Nuts­ 347­Steady­Bearings­ 348

Use­of Castings,­3-D­Printing­ 349­Polishing­Methods­and Measures1:­Polishing­vs.­Burnishing­ 350­Polishing­Methods­and Measures2:­Lay­ 351­Polishing­Methods­and Measures3:­Roughness­Average­ 353­Electropolish­ 355­Passivating­ 357

Contentsxvi

­Effect­on Mechanical­Design­ 357­Summary­of Chapter­ 357­Additional­Sources­of Information­ 358List­of­Symbols­ 358­References­ 358

19 AspectRatio 359Acknowledgment­ 359­Definition­and Illustration­of Aspect­Ratio­ 359­What­Is­the Optimum­Aspect­Ratio?­ 360­Effects­of Z/T­on Cost­and Performance­at­a Given­Working­Volume­ 361

Vessel­Cost­ 361Agitator­Shaft­Design­Difficulty­ 361Power­Required­for Mass­Transfer­ 361Agitator­Cost­ 362Airflow­Requirements­ 362Compressor­Power­ 362DO­Uniformity­ 362Heat­Transfer­Capability­ 363Real­Estate/Land­Usage­Issues­ 363Building­Codes;­Noise­ 363

­Illustrative­Problem­Number­1­ 363Vessel­Dimensions­ 364Airflow­and Power­ 366Heat­Transfer­Data­and Assumptions­ 367Heat­Transfer­Results­ 369Blend­Time,­DO­Uniformity­ 371Capital­Cost­(Agitator­Plus­Vessel­Only)­ 372Other­Operating­Costs­ 372So­What­Is­the Optimum­Aspect­Ratio­for This­Problem?­ 373

­Illustrative­Problem­Number­2­ 373­Illustrative­Problem­Number­3­ 376­Summary­of Chapter­ 380List­of­Symbols­ 381­References­ 381

20 VendorEvaluation 383­Product­Considerations­ 383­Gear­Drive­Ruggedness­ 384­Design­Technology­ 384­Impeller­Selection­ 384

Contents xvii

­Shaft­Design­ 385Company­Considerations­ 385

­Reputation­with Customers­ 385­Company­Size­ 386­Years­in Business­ 386­Years­Under­New­Ownership­ 386­Employee­Turnover­ 387­Vertical­Integration­ 387­R&D­Program­and Publications­ 388­Depth­of Application­Engineering­ 389­Testing­Laboratory­ 389­ISO­Certification­(Necessary­vs­Sufficient)­ 391­Quality­Control­Program­(Not­Lot­Sample;­100%)­ 391­Rep­vs­Direct­Sales­(a­Good­Rep­Annoys­the Manufacturer)­ 392­Service­Capability­ 393­Typical­Delivery­Times­and Performance­ 393­Parts­Availability­ 394­Price­(Least­Important)­ 395­Willingness­to Work­with Consultants­ 395­Vendor­Audit­Checklist­ 396

Use­of an Outside­Consultant­ 397­Summary­of Chapter­ 399List­of­Symbols­ 399­References­ 400A.­Appendix­to­Chapter­20­ 400

21 InternationalPractices 401­Introduction­ 401­North­America­ 401

Vendors­ 401Design­Practices­ 402Selling/Buying­Practices­ 402Degree­of Vertical­Integration­ 403Role­of Design­Firms­ 403R&D­ 404Culture­ 404

­EU­ 405Vendors­ 405Design­Practices­ 405Selling/Buying­Practices­ 405Degree­of Vertical­Integration­ 406

Contentsxviii

Role­of Design­Firms­ 406R&D­ 406Culture­ 407

­Japan­ 407Vendors­ 407Design­Practices­ 407Selling/Buying­Practices­ 407Degree­of Vertical­Integration­ 408Role­of Design­Firms­ 408R&D­ 408Culture­ 408

­China­ 409Vendors­ 409Design­Practices­ 409Selling/Buying­Practices­ 411Degree­of Vertical­Integration­ 412Role­of Design­Firms­ 412R&D­ 412Culture­ 413

­Summary­of Chapter­ 413­Cultural­Resources­ 413

Afterword 415Index 417

xix

This is a book about fluid agitation, as applied to gas–liquid systems such as fermenters or bioreactors (We will use those terms interchangeably in this text.). The specific focus is on mechanically agitated systems, consisting of a closed vessel with a rotating shaft and impellers, as this is the most common and versa-tile way to achieve process objectives in a gas–liquid system. Though airlift and bubble columns have also been used, they will not be discussed in any detail here, as that is not the focus of this book.

Many books have been written about fluid agitation. Many books have also been written about fermentation. Much, though not all, of the material in this book has been covered in such books. However, all such books cover much more than agita-tor design for bioreactors. For example, typical books on agitation cover topics such as solids suspension (almost never an issue in fermentation), highly viscous systems (>50 000 cP), specialized impellers such as helical ribbons, anchors, augers, and others that have no use in fermenters, mixing in high-yield stress flu-ids such as paper stock, etc. Likewise, books on fermenter design usually cover some topics on agitator design but also cover feeding strategies, reaction kinetics, cell metabolism, sensitivity to concentration and temperature changes, product recovery, and a whole host of other topics. Little has been published in such books about how to acquire the proper pilot data for agitator design, or how to minimize energy consumption.

The main purpose of this book is to be a single-source reference on all the major issues related to agitator design for bioreactors. It is intended to save the reader time by avoiding the need to consult multiple references or sift through many pages of text to find what is needed specifically for fermenter agitator design. This book will also cover important related topics such as heat transfer, power cost, basic agitator mechanical design, and vendor bid evaluation.

Though some introductory fundamental theory is included, the main focus is on practical application of theory to real-world agitator design. This book is more of a how-to book than an academic treatise. The relative brevity of the book is

Preface

Prefacexx

intentional. It is hoped that the brevity will encourage people to actually read the entire book, not just skim an occasional page or chapter.

This book is intended to be useful for a variety of people. Since it is primarily a technical document, most readers will have a science or engineering degree. Many will be Chemical Engineers. Some will be chemists or microbiologists tasked with operating facilities in a way that can produce scalable data. Academic degrees among readers will vary from Bachelor up through Post-Doc. Most readers will be employed by companies using bioprocessing to make valuable products as well as many making commodity products. Some will work for agitator manufacturers. If used as a course supplement, some will be college students or professors. Top-level managers may want to skim the contents to make sure their teams are prop-erly staffed and have a high-level view of what their team should be doing. They will find the overview and flow chart described in Chapter 2 especially useful. Chapters on energy use optimization will also be of interest to business unit man-agers. Information on bid evaluation should be of interest to procurement profes-sionals. Although written primarily for users of agitation equipment and operators of fermentation facilities, engineers employed by agitator manufacturers will likely find it of interest as it provides a deeper window into the details of these applications than they are accustomed to, as well as how their bids may be viewed in a competitive environment.

A note about symbols: rather than make the reader refer to a list of symbols in the appendix, each chapter has the symbols used in that chapter at the end. That should save the reader some time. Also, it lets the author use the same symbol for different purposes in different contexts, reducing the number of symbols needed. For example, C means off bottom impeller clearance in most cases, but in the context of mass transfer correlations, it is used as an exponent, and it can also mean dissolved gas concentration.

Most of the book is focused on gas–liquid agitation, as that is the controlling parameter for most bioreactors. By that I mean the agitator is primarily designed to disperse gasses into liquids. This does not mean evolving gas from solution, which is a separate case. The fundamentals presented are applicable to other pro-cesses as well, such as miscible liquid blending, but design procedures for these problem categories are not presented here.

Gregory T. BenzBenz Technology International, Inc.

xxi

Genetic modification, microbiome, green technology, renewable fuels and chemi-cals, bio-degradable plastic, pandemic recovery, prebiotics, probiotics, agricul-tural biologics, world food shortage, meatless meat, animal free dairy, human and animal health. What do these important concepts have in common? They all rely on the use of bioreactors to realize the ultimate benefit to current and future generations.

The most powerful of these products utilized in human and animal health can generate the world supply in quantities measured in pounds. Vaccines, antibiot-ics, probiotics, prebiotics, and others have a large portion of their cost included in research and development, clinical trials, and regulatory approval processes that bring challenge to this business space. In these cases, the bioreactors capital and operational cost impact to the cost of goods sold is small compared to the margins and returns of a successful product launch. These applications historically required a focus on agitation and reactor design with a focus on functionality versus a minimization of operating cost. These products are apportioned in quan-tities measured in microgram to gram quantities with price measured in millions of dollars per pound in some cases.

On the other end of the spectrum are commodity products utilized every day in quantities measured in tens to hundreds of millions of tons per year. Fuel, poly-mers, industrial chemicals, animal feed ingredients, and the like. These products’ sales prices are measured in pennies to dollars per pound and operate on tight margins. Making these products in bioreactors is more challenging as a result requiring a focus on things such as reactor design, power optimization between the agitator and air compressor can be a competitive advantage or define the success or failure of a venture.

The teams I worked with directly had the pleasure of working with Greg Benz for the past 15 years on commodity products. From development to commerciali-zation, the details of reactor design mattered significantly in these projects. The information provided in this book allowed the proper questions to be asked during

Foreword

Forewordxxii

process design. Bench, pilot, and demonstration trials were designed to be commercially applicable as a result. This allowed for realistic process design, rate, titer, and yield demonstrations to be applied to financial and process modeling early in the process. It also prevented mistakes that saved hundreds of thousands of dollars through effective understanding prior to spending significant develop-ment dollars.

Our team worked with the smallest start-ups to the largest most established biotech companies in the world as a contract research and manufacturing opera-tion. Each time agitation questions are asked, Greg is the go-to expert that every-one already knows and has positive experiences with. Greg’s knowledge and experience in this area is of significant importance to realizing the benefit of mod-ern biological technology. I am happy to see that he has decided to put his knowl-edge and experience in a more detailed writing as I have referenced his course materials hundreds of times in the past 15 years. Thank you to Greg, the biotech-nology industries favorite “Professional Agitator.”

Jeremy Javers PhDSt. Joseph, MO

1 September 2020

xxiii

­Foreword­for Greg­Benz

Bioreactor agitator engineering is a broad mosaic. The image is simple and clear from a distance, but as the viewer moves closer, a multitude of distinct individual pieces come into view. Likewise, several diverse disciplines converge in this spe-cialized field: microbiology, transport phenomena, machine design, metallurgy, and reliability engineering. During a project, this list is expanded to include man-ufacturing and procurement. For the practitioner, the challenge is significant. What information is important? What solutions are time-tested? What are the common pitfalls? How should all of these pieces be assembled into a unified design?

There are many books and articles available on the design of agitators and bio-reactors. However, when the time comes to prepare drawings and make purchases for an actual project, it becomes apparent that those resources are missing large swaths of practical information to guide the reader’s design choices. How are bio-reactor agitators designed in real life? This comprehensive book addresses both the broad background and the small details needed to deliver a good project, from design through delivery.

I was excited to learn that Greg Benz was writing this book. We have worked together for many years designing equipment for bioprocessing facilities, from cellulosic ethanol to enzyme production to hydrogen-rich gas fermentation. He has been a trusted mentor and a patient teacher.

Greg is an accomplished practitioner, a true craftsman. His career has spanned the full scope of the design, manufacturing, and operation of mixing systems, with a special focus on gas–liquid systems for bioreactors. Through his years at Chemineer, and later as a well-known and respected mixing consultant, he has perhaps overseen more bioreactor agitator designs than anyone in the field. His expertise helped to establish industrial biotechnology as a mature industry.

During our years working together, Greg has offered insight on many questions not generally answered in fermentor design books, such as: What is the best way to seal a shaft? What is better: small, fast agitators or big and slow? What are the

­ForeFord For oreg renxxiv

most common failure modes? Is metal surface polishing really necessary in comparison with other contamination sources? How much polish? What are the most common failure modes? How much overdesign should be included? Bubble columns versus stirred tanks? What are the latest innovations? How does fed-batch impact agitation design? What information should we gather at pilot scale to ensure commercial-scale success? How should the fermenter be controlled to maintain a dissolved oxygen level: vary the air or vary the motor speed? How do agitation performance and power draw change if the mixer is on speed control? How are baffles designed? How do we clean underneath an impeller? How can thermal expansion be handled during cleaning and steam-in-place? What heat transfer coefficient should we expect from internal coils? External jackets? What vendors are reliable? How do we install this equipment, anyway?

Until now, answers to these questions have been difficult to find, making this book a treasure trove for a practicing engineer. Additionally, this valuable infor-mation will fuel the progress of biotechnology, which provides food and energy resources to people around the world.

Few engineers possess Greg’s wealth of expertise and fewer still take the time to meticulously summarize their knowledge for the benefit of future generations. That he did so makes me very glad.

Keith Flanegan, P.E.IdeaCHEM, Inc.September 2020

Agitator Design for Gas–Liquid Fermenters and Bioreactors, First Edition. Gregory T. Benz. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc.

1

The purpose of using the agitator design principles in this book is to ensure, to the extent possible, that the user of agitation equipment achieves the process objectives and does so in a reliable and economical manner.

Agitators are employed in many different industries. The process results/ objectives desired from the agitators vary by industry and by application within each industry. Since an agitator is ultimately nothing more than a kind of pump, and the agitated tank is essentially a deadheaded pump, it would be ideal if the objectives could be stated in purely physical terms, mostly related to flow and head. For example, some would describe agitation in terms of pumping capacity, characteristic fluid velocity [1], G-value [2], or other physical terms.

Some process results correlate well with simple physical measurements of agi-tation. For example, the ability to overcome density differences or viscosity ratios correlates well with characteristic fluid velocities  [1]. However, many other process objectives do not correlate well with such simple measures. Examples of process results that have complex relationships to agitation and do not correlate well with pumping capacity, fluid velocity, or other simple measures would include blend time, mass transfer rate, heat transfer rate, off-bottom solids sus-pension, solids suspension degree of uniformity, solids suspension cloud height, rate of particle attrition or shear damage, dissolved oxygen spatial distribution, reaction rate, reaction product distribution, and many others.

Since this book is about agitator design for fermenters/bioreactors, we will focus on the attributes of agitator design most important for those applications. The most important process result is normally the mass transfer rate (MTR), often called the OTR, or oxygen transfer rate, when oxygen is the species being trans-ferred. This is generally the dominant design requirement.

The mass transfer rate depends on more than just agitation, of course. It also depends on the airflow, the properties of the broth, the organism’s ability to absorb the transferred gas (OUR, or oxygen uptake rate for aerobic systems), and a host

1

Purpose of Agitator Design

Purpose of Agitator Design2

of other factors. The principle agitation parameter for a given system is the power invested under gassed conditions. Therefore, the principle purposes of agitator design in this book are enumerated below and expanded upon in subsequent chapters. In most chapters, we will describe results based on the gas being oxygen. Chapter 11 will delve into how to handle other gasses.

● Provide sufficient power input to facilitate the required mass transfer rate. This will vary with tank geometry, scale of operation, pressure, temperature, allow-able minimum dissolved gas concentration, and gas flowrate.

● Use an impeller system designed to maximize fluid mixing and thereby mini-mize concentration gradients, while still dispersing gas.

● Provide sufficient overall mixing. Usually, the agitation required to disperse gas is more than ample for other mixing requirements.

● Optimization of power used. The same mass transfer rate can be achieved with different combinations of airflow and agitator power. The total power of agita-tor and compressor goes through a minimum. Ideally, the design should use that minimum unless other factors override this desire.

● Optimization of capital cost. Within a certain design power, there is a range of acceptable agitator designs. But there can be differences in capital cost among different designs.

● Optimization of total batch cycle energy costs. Since batch processes have dif-ferent OTR requirements at different stages of the batch cycle, the power costs can be optimized at each stage, thereby minimizing total energy used per batch.

● Optimization of total system economics. Tank geometry affects capital and energy costs of both the tank itself and the agitator

● Assure the final design has the utmost in mechanical integrity. This includes the tank and the mounting arrangement. Historically, agitators for gas–liquid contacting have had higher mechanical failure rates than those used for simple liquid blending, yet the cost of downtime can be very high. We aim to remedy that by promoting design principles that lead to minimal downtime.

● Choose vendors that not only build a good product, but can support it in the field.

References

1 Hicks, R.W., Morton, J.R., and Fenic, J.G. (1976). How to design agitators for desired process response. Chemical Engineering Magazine: 22–30.

2 Benz, G.T. (2007). The G-value for agitator design: time to retire it? Chemical Engineering Progress 103: 43–47.

Agitator Design for Gas–Liquid Fermenters and Bioreactors, First Edition. Gregory T. Benz. © 2021 John Wiley & Sons, Inc. Published 2021 by John Wiley & Sons, Inc.

3

This chapter presents an overview of the main steps and logic required to achieve the best agitation system design. Subsequent chapters will provide more technical details and fundamental concepts so that each step can be undertaken. Figure 2.1 provides a graphic summary of these steps. We will describe each one in more detail in the following paragraphs. The flow chart concept used here was inspired by the procedures in Ref. [1], but is expanded upon in more detail here specifically for bioreactor design.

Define Process Results

The first step in agitator design, or, for that matter, the design of any kind of pro-cess equipment, is to define the expected process result. For agitators, that could be a number of different things, such as degree of solids suspension, blend time to some specified degree of uniformity, characteristic fluid velocity, heat transfer coefficient, etc. While some or all of these process results may be needed or appli-cable to bioreactor design, in general, the requirement for a certain mass transfer rate is the most important and difficult to achieve. In other words, when an agita-tor is designed for mass transfer, the other process requirements are normally exceeded.

There are two exceptions to this. One is when the mass transfer requirement is very low (say, less than 10 mmol/l-h). This is sometimes called micro-aeration. In such a case, there may be minimum liquid velocities or blend time requirements. However, we feel that such cases are covered well in the general literature, such as in Refs.  [1,2]. Therefore, we will not describe agitator design where velocity or blend time is the required results for low viscosity liquids. By “low viscosity,” we typically mean that the viscosity is less than 1000 cP. Viscosities less than 1000 cP typically have little effect on power draw or blending performance. However, heat

2

Major Steps in Successful Agitator Design

Major Steps in Successful Agitator Design4

transfer is affected at all viscosities, and mass transfer is affected when viscosity gets above approximately 50–80 cP.

The other exception is fermentation of highly viscous liquids, such as Xanthan gum or Gellan gum. At peak concentrations in the broth, such materials may have

Yes

Start

No

Define process results(e.g., OTR)

Yes

Define process conditions

Choose tank geometry/aspect ratio

Calculate equivalent power/airflow combinations

Choose minimum combined power

Choose shaft speed

Choose/size impeller system

D/T and gassing factors OK?

Mechanical design

Feasible?

Repeat to find lowest cost

Repeat for different aspect ratios-optimize

Repeat for different process conditions-optimize Finish

No

Figure 2.1 Agitator design flow chart.