New Bioprocessing Strategies: Development and Manufacturing of Recombinant Antibodies and Proteins

473 Pages·2018·9.06 MB·English

by  Bob Kiss

Advances in Biochemical Engineering/Biotechnology 165
Series Editor: T. Scheper
Bob Kiss · Uwe Gottschalk 
Michael Pohlscheidt Editors
New Bioprocessing
Strategies:
Development and
Manufacturing of
Recombinant
Antibodies and
Proteins
165
Advances in Biochemical
Engineering/Biotechnology
Serieseditor
T.Scheper,Hannover,Germany
EditorialBoard
S.Belkin,Jerusalem,Israel
T.Bley,Dresden,Germany
J.Bohlmann,Vancouver,Canada
M.B.Gu,Seoul,Korea(Republicof)
W.-S.Hu,Minneapolis,Minnesota,USA
B.Mattiasson,Lund,Sweden
J.Nielsen,Gothenburg,Sweden
H.Seitz,Potsdam,Germany
R.Ulber,Kaiserslautern,Germany
A.-P.Zeng,Hamburg,Germany
J.-J.Zhong,Shanghai,Minhang,China
W.Zhou,Shanghai,China
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asAdv.Biochem.Engin./Biotechnol.andcitedasajournal.
Moreinformationaboutthisseriesathttp://www.springer.com/series/10
Bob Kiss • Uwe Gottschalk • Michael Pohlscheidt
Editors
New Bioprocessing
Strategies: Development
and Manufacturing
of Recombinant Antibodies
and Proteins
With contributions by
(cid:1) (cid:1) (cid:1) (cid:1)
E. Abraham B. B. Ahmadian C. Bell J. Bender
(cid:1) (cid:1) (cid:1) (cid:1)
B. Boedeker S. Buziol A. Goldstein U. Gottschalk
(cid:1) (cid:1) (cid:1) (cid:1)
C. Hakemeyer D. Hatton S. Herzer K. Holderness
(cid:1) (cid:1) (cid:1) (cid:1) (cid:1)
M. Jenzsch A. Joseph B. Kelley F. Kepert R. Kiss
(cid:1) (cid:1) (cid:1) (cid:1)
R. Kshirsagar M. Laird Y. Levinson E. Mahajan
(cid:1) (cid:1) (cid:1) (cid:1) (cid:1)
H.-C. Mahler R. Mathaes E. McAfee N. Oien R. Patil
(cid:1) (cid:1) (cid:1) (cid:1)
M. Pohlscheidt S. Rameez T. Ryll M. Shiratori
(cid:1) (cid:1) (cid:1) (cid:1)
A. A. Shukla N. Singh X. Swanson R. Takeya
(cid:1) (cid:1) (cid:1) (cid:1)
B. Thorne N. Titchener-Hooker R. Turner F. Vitelli
(cid:1) (cid:1) (cid:1)
J. Walther H. Wegele L. S. Wolfe J. Zhu
Editors
BobKiss UweGottschalk
SutroBiopharmaInc. Lonza
SanFrancisco,CA,USA Basel,Switzerland
MichaelPohlscheidt
SolothurnManufacturingFacility
BiogenInternationalGmbH
Luterbach,Switzerland
ISSN0724-6145 ISSN1616-8542 (electronic)
AdvancesinBiochemicalEngineering/Biotechnology
ISBN978-3-319-97108-7 ISBN978-3-319-97110-0 (eBook)
https://doi.org/10.1007/978-3-319-97110-0
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Contents
AnIntroductionto„RecentTrendsintheBiotechnologyIndustry:
DevelopmentandManufacturingofRecombinantAntibodiesand
Proteins“. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
MichaelPohlscheidt,RobertKiss,andUweGottschalk
NewMammalianExpressionSystems. . . . . . . . . . . . . . . . . . . . . . . . . . 9
JieZhuandDianeHatton
InnovationinCellBanking,Expansion,andProductionCulture. . . . . . 51
RashmiKshirsagarandThomasRyll
RiskMitigationinPreventingAdventitiousAgentContamination
ofMammalianCellCultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
MasaruShiratoriandRobertKiss
ManufacturingofProteinsandAntibodies:ChapterDownstream
ProcessingTechnologies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
RichardTurner,AdrianJoseph,NigelTitchener-Hooker,andJeanBender
DownstreamProcessingTechnologies/Capturing
andFinalPurification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
NripenSinghandSibylleHerzer
FullyDisposableManufacturingConceptsforClinicalandCommercial
ManufacturingandBallroomConcepts. . . . . . . . . . . . . . . . . . . . . . . . . 179
BertholdBoedeker,AdamGoldstein,andEktaMahajan
TrendsinProcessAnalyticalTechnology:PresentState
inBioprocessing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
MarcoJenzsch,ChristianBell,StefanBuziol,FelixKepert,HaraldWegele,
andChristianHakemeyer
NextGenerationBiopharmaceuticals:ProductDevelopment. . . . . . . . . 253
RomanMathaesandHanns-ChristianMahler
v
vi Contents
ContinuousManufacturingofRecombinantTherapeuticProteins:
UpstreamandDownstreamTechnologies. . . . . . . . . . . . . . . . . .. . . . . . 277
RohanPatilandJasonWalther
PlatformsforManufacturingAllogeneic,AutologousandiPSC
CellTherapyProducts:AnIndustryPerspective. . . . . . . . . . . . . . . . . . 323
EytanAbraham,BehnamBaghbaderaniAhmadian,KathrynHolderness,
YonatanLevinson,andErikaMcAfee
GeneTherapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
BarbThorne,RyanTakeya,FrancescaVitelli,andXinSwanson
High-ThroughputProcessDevelopmentforBiopharmaceuticals. . . . . . 401
AbhinavA.Shukla,ShahidRameez,LeslieS.Wolfe,andNathanOien
ADifferentPerspective:HowMuchInnovationIsReallyNeeded
forMonoclonalAntibodyProductionUsingMammalianCell
Technology?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
BrianKelley,RobertKiss,andMichaelLaird
Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
AdvBiochemEngBiotechnol(2018)165:1–8
DOI:10.1007/10_2017_39
©SpringerInternationalPublishingAG2018
Publishedonline:5May2017
„
An Introduction to Recent Trends
in the Biotechnology Industry: Development
and Manufacturing of Recombinant
“
Antibodies and Proteins
MichaelPohlscheidt,RobertKiss,andUweGottschalk
Abstract Theproductionofthefirsttherapeuticproteinsintheearly1980sheralded
thelaunchofthebiopharmaceuticalsindustry.Thenumberofapprovedproductshas
grownyearonyearoverthepastthreedecadestonowrepresentasignificantshareof
the entire pharmaceuticals market. More than 200 therapeutic proteins have been
approved, approximately a quarter of which are represented by monoclonal anti-
bodiesandtheirderivatives.In2016,thelistofthetop15best-sellingdrugsincluded
morethaneightbiologicsandin2020thetrendwillcontinue,withmorethan50%of
the top 20 best-selling drugs predicted to be biologics. From 1986 to 2014 several
first-in-class, advance-in-class, and breakthrough designated therapeutic options
were approved, with advanced therapies such as immuno-oncology and cell-based
therapiesbeingapprovedforseveralindications.
Keywords Antibodyformatsandevolution,Biotechnology,Cellculture,PAT,
Processingtechnologies,QbD
Contents
1 IntroductiontothisSpecialIssue.............................................................. 2
2 ProductEvolutionofRecombinantAntibodies............................................... 3
3 ProcessandTechnologyImprovements....................................................... 4
4 TheNextDecade:VisibleTrendsforNewHolisticProcessingStrategies.................. 6
5 TheStructureofthisSpecialIssue............................................................ 6
References.......................................................................................... 7
M.Pohlscheidt(*),R.Kiss,andU.Gottschalk
BiogenInternationalGmbH,InternationalManufacturing,Zug,Switzerland
e-mail:[email protected]
2 M.Pohlscheidtetal.
1 Introduction to this Special Issue
Theproductionofthefirsttherapeuticproteinsintheearly1980sheraldedthelaunch
of the biopharmaceuticals industry. The number of approved products has grown
yearonyearoverthepastthreedecadestonowrepresentasignificantshareofthe
entire pharmaceuticals market. More than 200 therapeutic proteins have been
approved, approximately a quarter of which are represented by monoclonal anti-
bodies andtheirderivatives[1–6].In2016,thelistofthetop15best-sellingdrugs
included more than eight biologics and in 2020 the trend will continue, with more
than 50% of the top 20 best-selling drugs predicted to be biologics. From 1986 to
2014severalfirst-in-class,advance-in-class,andbreakthroughdesignatedtherapeu-
ticoptionswereapproved,withadvancedtherapies suchasimmuno-oncologyand
cell-basedtherapiesbeingapprovedforseveralindications[1–6].
The first biopharmaceuticals were produced in bacteria, but these relatively
simplecellsareonlysuitablefortheproductionofsmallproteinsthatdonotrequire
complex post-translational modifications [7, 8]. Mammalian cells are required for
theexpression ofproteins that containmultipledisulfidebonds, glycans, andother
modifications,becausetheycontainthenecessarycellularmachinerytoachievethe
correct modifications efficiently [9, 10]. Since the first mammalian cell fermenters
were deployed by the industry, continuous process developments (including the
optimization of cell lines, cultivation equipment, media, and downstream
processing) have resulted in product titers increasing from less than 0.1 g/L to
more than 10 g/L in fed-batch processes [11–13]. Yet this rise in productivity has
only served to keep pace with increasing market demand as the number of new
products continues to grow [5, 6]. The current state of the art in mammalian cell
platformsinvolvesmanufacturingscalesofupto25m3inbatch,repeatedbatch,or
fed-batch modes, followed by a sequence of filtration, chromatography, and con-
centrationstepsthatdeliverproductbatchsizesof50–100kg[11,12].Therapeutic
proteins are diverse in terms of size, charge, and solubility, so an equally diverse
panelofpurificationtechnologiesisrequired.However,monoclonalantibodieshave
agenericstructurethatcanbepurifiedusingaplatformapproach,typicallyinvolving
clarificationbymultistepfiltrationorcentrifugation,followedbyProteinAcapture
chromatography and orthogonal downstream chromatography steps to separate the
product from host cell proteins and product-related impurities [13]. More recently,
large-scale fed-batch processes have been replaced by perfusion-based processes
that require smaller bioreactors (up to 1,000 L, compared with 25,000 L for
fed-batch processes) and that last for up to 200 days compared with the typical
5–18daysinfed-batchprocesses[14–21].Similarly,thebatch-basedpurificationof
therapeuticproteinscanbeacceleratedbyswitchingtocontinuousprocessing,asis
commoninfoodproductionandotherindustries[22,23].
AnIntroductionto„RecentTrendsintheBiotechnologyIndustry... 3
2 Product Evolution of Recombinant Antibodies
Advancesinproductiontechnologyhavebeenmatchedbyinnovationsinthedesign
of therapeutic proteins to increase their efficacy and reduce off-target effects.
Nowhere is this more apparent than in the development of monoclonal antibodies
andtheirderivatives,whichbenefitfromarangeofenhancedmolecularapproaches.
The original hybridoma technology described by Kohler and Milstein is rapidly
beingsupplantedbymoleculartechniquessuchasphagedisplaythatallowthedirect
selection of heavy and light chains and their transfer to mammalian cells for
expression [24]. Hybridomas produce murine antibodies, and various strategies
have been developed to humanize them in order to avoid triggering immune
responses against the murine components, including the creation of chimeric anti-
bodies with murine antigen-binding regions grafted onto a human antibody frame-
work,throughtotheproductionoffullyhumanantibodiesisolateddirectlybyphage
display or produced in transgenic mice carrying human immunoglobulin genes.
Indeed,ofthe19‘fullyhuman’therapeuticantibodiescurrentlyapproved,13were
isolated from transgenic mice [25]. Other innovations include the exploitation of
antibody fragments for their favorable characteristics (such as the small size and
absence of effector functions in minimal constructs like the single chain fragment
variable),glyco-engineeredvariantsforimprovedefficacy[26],andtheintroduction
of novel scaffolds based on antibody technology (e.g., bi-specific antibodies)
[27]. Initially, antibody-drug conjugates were monoclonal antibodies labeled with
radioisotopes, but now these conjugates include a range of products in which
antibodies are conjugated to various effector molecules such as anticancer drugs
[28],aswellasprotein-onlyversions(fusionproteinsknownasimmunotoxins),in
which antibodies are directly fused at the genetic level to peptides, protein toxins,
andeffectorenzymesthatinduceapoptosisintargetcells[29].Inprinciple,existing
technologiesandcombinationsofexistingunitoperationsaresuitableforproducing
thesenewmolecularformats.Thereforenospecificchapterinthisbookisdedicated
tothesenewformats.
Fortoday’sandtomorrow’snewmolecularformats,themajorchallengesforthe
pharmaceutical industry include maintaining research and development (R&D)
successratestoensurethattherapeuticoptionsremainaccessibleforpatientsaround
theworld.Althoughthebiologicsmarketcontinuestogrow,patentexpiryisamajor
threat to developers and manufacturers, particularly given the high R&D costs
associated with bringing these products to market. In the small-molecule drugs
market,theimpactofpatentexpiryhasbeenfelt,withseveralmanufacturerslosing
80–90%ofsalestoso-calledgenericsinthefirstyearoffpatent.Asimilarlandscape
islikelytoemergeinthebiopharmaceuticalsindustrywithinthenextfewyears,with
manybest-sellingdrugscomingoffpatentandmanyantibodiesnotfarbehind.The
global biosimilarsmarket wasworthUS$1.3billionin2013andcould reach US$
35 billion by 2020 [30]. The European Medicines Agency has approved so-called
biosimilars or bio-betters of several products. Some examples include a version of
®
humangrowthhormone(Omnitrope )inEuropein2006,followedmorerecentlyby