Fermentation and Biochemical Engineering Handbook. Principles, Process Design, and Equipment

807 Pages·1996·10.342 MB·English

by  Henry C. Vogel and Celeste L. Todaro (Eds.)

Preface to the
Second Edition
ThesecondeditionoftheFermentationandBiochemicalEngineer
ing Handbook, likethe previous edition,is intendedto assist the develop
ment, design and production engineerwho is engaged inthe fermentation
industry. Particularemphasisisgivetothoseunitoperationsmostfrequently
encounteredinthecommercialproductionofchemicalsandpharmaceuticals
via fermentation, separation, and purification.
Sometheory isincludedto provide the necessaryinsightintothe
unit operation but isnot emphasized. Rather, the emphasis is placed on
the practical aspects of development, design and operation-how one
goesaboutcollectingdesign data,what arethescale-upparameters,how
to select the right piece ofequipment, where operating problems arise,
and how to troubleshoot.
Thetext iswrittenfrom apracticaland operatingviewpoint,and
all of the contributing authors have been chosen because of their
industrial background and orientation. Several ofthe chapters which
were in the first edition have been either deleted or replaced by other
chapters which are more germane to current fermentation practice.
Those chapters which were retained have been updated or have been
rewritten to reflect current practice. Several new chapters were intro
duced to reflect current emphasis on cell cultures, nutritional require
ments, statistical methods for fermentation optimization, cross-flow
filtration, environmental concerns, and plant design
vi
PrefacetotheSecondEdition vii
TheeditorswishtoexpresstheirgratitudetoMrs. ConnieGaskill
ofHeinkel FilteringSystems,Inc., forthewordprocessingassistanceshe
gave to this edition.
Scotch Plains, NewJersey Henry C. Vogel
Bridgeport, New Jersey CelesteL. Todaro
September, 1996
Preface to the
First Edition
This bookisintendedtoassistthedevelopment, designand produc
tion engineer who is engaged in the fermentation industry. Particular
emphasisisgiventothose unitoperationsmostfrequently encounteredinthe
commercialproductionofchemicals and pharmaceuticalsviafermentation,
separation, and purification.
Sometheory isincludedtoprovidethenecessaryinsightintotheunit
operation but is not emphasized. Rather, the emphasis is placed on the
practicalaspectsofdevelopment,designandoperation-howonegoesabout
collecting design data, what are the scale-up parameters, how to select the
right piece of equipment, where operating problems arise and how to
troubleshoot.
Thetextiswritten from apracticalandoperatingviewpoint, andall
ofthe contributing authors have been chosen because oftheir industrial
backgroundandorientation. Sincethehandbook concerns fermentationand
oftentheengineers involvedinfermentation are notversed inmicrobiology,
itwasthoughtadvisabletointroducethissubjectatthebeginningofthebook.
Similarly,sincemuch offermentation deals withtheproductionofantibiot
ics,itwasdeemedadvisabletoincludesomechaptersspecificallyorientedto
the productionofsterile products.
The engineering using this handbook may wish that other unit
operationsordifferentpiecesofequipmenthadbeenincludedotherthanthose
viii
Prefacetothe First Edition ix
selected. Theselectionwas basedontheindividualcontributorsandmyown
experience, over many years ofwork in the field, with unit operations and
pieces ofequipment that have been the backbone and workhorses ofthe
industry.
The editor wished to express his thanks to Mr. Stanley Grossel of
Hoffmann-LaRocheand Mr. JohnCarneyofDavy McKee Corporationfor
reviewingandeditingthedraftcopies. HealsothanksMiss MaryWatsonof
DavyMcKee Corporationfor typing assistance,and Mr. Michael Garzeof
Davy McKee Corporationfor hishelpinproducingmanyofthegraphsand
illustrations. Dr. SolBarer,theauthorofthemicrobiologychapteracknowl
edges the valuable input to the Celanese Biotechnology Department, and
especiallythanks Miss MariaGuerraforherpatienceintyping and retyping
the manuscript.
Berkeley Heights, New Jersey Henry C. Vogel
June 1983
Contributors
Michael J. Akers Edwin O. Geiger
Eli Lilly and Company PfizerInc.
Indianapolis, IN Groton, CT
Giovanni Bellini Stephen M. Glasgow
3V Cogeim S.P.A. Union Carbide Chemical and
Dalmine, Italy Plastics Co., Inc.
South Charleston, WV
Ramesh R. Bhave
U.S. Filter Corporation Elliott Goldberg
Warrendale, PA Consultant
FortLee, NJ
FrederickJ. Dechow
BiocrystPharmaceuticals Inc. Yujiro Harada
Birmingham, AL K. F. Engineering Co., Ltd.
Tokyo, Japan
Barry Fox
Niro Inc. Willem Kampen
Columbia, MD Louisiana State University
Agriculture Center
Howard L. Freese Baton Rouge, LA
A1lvac
Monroe, NC
x
Contributors xi
MarkKeyashian Shinsaku Takayama
CENTEON Tokai University
Kankakee, IL Numazu, Shizuoka Pref., Japan
John P. King Celeste L. Todaro
Foxboro Company Heinkel Filtering Systems, Inc.
Rahway, NJ Bridgeport,NJ
MaungK. Min David B. Todd
Gemini ManagementConsultants Todd Engineering
New York, NY Princeton, NJ
James Y.Oldshue Henry C. Vogel
Mixing Equipment Co., Inc. Consultant
Rochester, NY Scotch Plains, NJ
Laura Pellegrini MarkR. Walden
Politecnicodi Milano EliLilly Company
Milano, Italy Indianapolis, IN
Russell T. Roane
Bechtel Engineering
San Francisco, CA
Kuniaki Sakato
Kyowa Hakko Kogyo Co., Ltd.
Tokyo, Japan
Seiji Sato
KyowaMedex Co., Ltd.
Sunto-gun, Shizuoka Pref., Japan
Allan C. Soderberg
Fort Collins, CO
Curtis S. Strother
Eli Lilly Company
Indianapolis, IN
1
Fermentation Pilot Plant
Yujiro Harada, Kuniaki Sakata, Seiji Sato
andShinsaku Takayama
PROLOGUE(by YujiroHarada)
The rapiddevelopmentofbiotechnologyhas impacteddiverse sectors
oftheeconomy overthelastseveral years. The industriesmostaffected are
the agricultural, fine chemical, food processing, marine, and pharmaceuti
cal. Inorderforcurrentbiotechnologyresearchtocontinuerevolutionizing
industries, newprocesses must bedeveloped to transformcurrentresearch
intoviablemarketproducts. Specifically,attentionmust bedirected toward
the industrialprocessesofcultivationofcells, tissues,and microorganisms.
Althoughseveral suchprocessesalreadyexist(e.g., r-DNAandcellfusion),
more are needed and it isnot even obvious which ofthe existingprocesses
is best.
To develop the most cost efficient process, scale-up data must be
collected by repeating experiments at thebench and pilot scale level. These
datamustbeextensive. Unfortunately,thecollectionisfarmoredifficultthan
it would be in the chemical and petrochemical industries. The nature of
working withlivingmaterialmakescontaminationcommonplaceand repro
ducibility ofdata difficult to achieve. Such problems quickly distort the
relevant scale-up factors.
In this chapter,three research scientistsfrom Kyowa Kogyo Co. Ltd.
have addressed the problems of experimentation and pilot scale-up for
1
2 Fermentation andBiochemicalEngineeringHandbook
microorganisms, mammalian cells, plantcells, and tissue. It is our sincere
hope that the reader will find this chapter helpful in determining the best
conditionsforcultivationandthecollectionofscale-updata. Hopefully,this
knowledgewill,inturn, facilitatethetransformationofworthwhileresearch
programs into commercially viable processes.
1.0 MICROBIAL FERMENTATION(by KuniakiSakato)
Chemical engineers are still faced with problems regarding scale-up
and microbial contamination in the fermentation by aerobic submerged
cultures. Despitemanyadvancesinbiochemicalengineeringtoaddressthese
problems,theproblemsneverthelesspersist. Recently, manyadvanceshave
beenmadeintheareaofrecombinantDNA, whichthemselveshave spunoff
newand lucrativefields intheproductionofplantand animal pharmaceuti
cals. Acarefulstudy ofthis technology isthereforenecessary, not onlyfor
the implementationofefficient fermentation processes, but also for compli
ance with official regulatorybodies.
There are several major topics to consider in scaling up laboratory
processestothe industrial level. Ingeneral, scale-up isaccomplishedfor a
discrete system through laboratory and pilot scale operations. The steps
involvedcanbebrokendownintoseventopicsthatrequiresomeelaboration:
1. Strain improvements
2. Optimizationofmediumcompositionandculturalcondi
tions such as pH and temperature
3. Oxygen supply required by cells to achieve the proper
metabolic activities
4. Selection ofan operative modefor cultureprocess
5. Measurementofrheological properties ofcultural broth
6. Modelling and formulation ofprocess control strategies
7. Manufacturingsensors, bioreactors,andotherperipheral
equipment
Items 1and2shouldbedeterminedinthelaboratoryusingshakeflasks
or smalljarfermenters. Items 3-7are usuallydetermined inthepilot plant.
The importanceofthe pilot plantis,however, not limitedto steps 3-7. The
pilot plant also provides the cultured broths needed for downstream
FermentationPilotPlant 3
processing and can generate information to determine the optimal cost
structureinmanufacturingandenergyconsumptionaswellasthetestingof
various raw materials inthe medium.
1.1 Fermentation Pilot Plant
Microorganisms such as bacteria, yeast, fungi, or actinomycete have
manufacturedamino acids, nucleic acids, enzymes, organic acids, alcohols
and physiologically active substances on an industrial scale. The "New
Biotechnology"ismakingitincreasingly possible to use recombinantDNA
techniquestoproduce manykindsofphysiologically active substancessuch
as interferons, insulin,and salmongrowth hormonewhichnowonlyexist in
small amounts inplants and animals.
This sectionwilldiscuss thegeneral problemsthatarise inpilot plant,
fermentation and scale-up. The sectionwill focus onthree maintopics: (i)
bioreactors and culture techniques, (ii) the application of computer and
sensingtechnologies to fermentation, and (iii) the scale-up itself.
1.2 Bioreactors and Culture Techniques for Microbial Processes
Currentbioreactorsaregroupedintoeitherculturevesselsandreactors
usingbiocatalysts(e.g.,immobilizedenzymes/microorganisms)orplantand
animal tissues. The latter is sometimes used to meanthe bioreactor.
Table 1shows a number ofaerobic fermentation systems which are
schematically classified into (i) internal mechanical agitation reactors, (ii)
external circulation reactors, and (iii) bubble column and air-lift loop
reactors. This classification is based on both agitation and aeration as it
relatestooxygensupply. Inthistable, reactor1isoftenusedattheindustrial
leveland reactors (a)2, (b)2, (c)2,and (c)3, can befittedwith draughttubes
to improve both mixing and oxygen supply efficiencies.
Culture techniques can be classified into batch, fed-batch, and con
tinuousoperation(Table2). Inbatchprocesses,allthenutrientsrequiredfor
cell growth and product formation are present in the medium prior to
cultivation. Oxygenissuppliedbyaeration. Thecessationofgrowthreflects
the exhaustion of the limiting substrate in the medium. For fed-batch
processes, the usual fed-batch and the repeated fed-batch operations are
listed inTable 2.
Afed-batch operationisthatoperationinwhichoneormorenutrients
are addedcontinuouslyor intermittentlytothe initialmediumafterthestart
ofcultivation or fromthehalfway point through the batch process. Details
4 Fermentation andBiochemicalEngineeringHandbook
offed-batchoperationare summarizedinTable3. Inthetable thefed-batch
operationisdividedintotwobasicmodels,onewithoutfeedback control and
the other with feedback control. Fed-batchprocesseshave been utilized to
avoid substrateinhibition, glucoseeffect, and cataboliterepression, as well
as for auxotrophic mutants.
Table 1. ClassificationofAerobic Fermentation Systems
(a) Internal mechanicalagitation reactors
1. Turbine-stirring installation
2. Stirredvesselwithdrafttube
3. Stirredvesselwith suctiontube
(b) External circulationreactors
1. Waterjet aerator
2. Forcedwaterjet aerator
3. Recyclingaeratorwithfritteddisc
(c) Bubblecolumnandair-loopreactors
1. Bubblecolumnwithfritteddisc
2. Bubblecolumnwithadrafttubeforgyrationflow
3. Airlift reactor
4. Pressurecyclereactor
5. Sieveplatecascadesystem
Table2. ClassificationofFermentationProcesses
1. Batchprocess
2. Fed-batchprocess(semi-batchprocess)
3. Repeatedfed-batchprocess(cyclicfed-batchprocess)
4. Repeatedfed-batchprocess(semi-eontinuousprocessorcyclic
batchprocess)
5. Continuousprocess