Bioprocess membrane technology

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JournalofMembraneScience297(2007)

16–50

Review

Bioprocessmembranetechnology

RobertvanReis∗,AndrewZydney

Genentech,Inc.,1DNAWay,SouthSanFrancisco,CA94080,UnitedStates

Received5October2006;receivedinrevisedform23January2007;accepted13February2007Availableonline1March2007

Abstract

Membraneprocessesplayacriticalroleinthepurificationofbiotechnologyproducts.Earlymembranesystemswereadoptedfromtechnologyoriginallydevelopedforotherindustrialapplications.Duringthelast2decades,newmembranesandmoduleshavebeendevelopedspecificallytomeettherequirementsofthebiotechnologyindustry.Thisincludesapplicationsofmembranesforsterilefiltration,clarification,initialharvest,virusremoval,proteinconcentration,bufferexchange,andproteinpurification.Thismanuscriptprovidesanoverviewofrecentdevelopmentsinmembranetechnology,focusingonthespecialcharacteristicsofthemembranesystemsthatarenowusedforthecommercialproductionandpurificationofrecombinantproteinproducts.Futuredevelopmentsinmembranetechnologyarealsodiscussedthatmaybeabletomeetthegrowingneedsforhigherproductivity,lowercostofproduction,andincreaseddevelopmentspeedinthebiotechnologyindustry.©2007ElsevierB.V.Allrightsreserved.

Keywords:Biotechnology;RecombinantDNA;Protein;Microfiltration;Ultrafiltration

Contents

1.Introduction—membraneapplicationsoverview.............................................................................181.1.Definitionsofmembraneprocesses..................................................................................181.2.Keymembranephenomena.........................................................................................192.Overviewofbioprocessing................................................................................................202.1.Propertiesofbiomolecules..........................................................................................202.2.Feedstockcharacteristics............................................................................................202.3.Overviewofprocessingapplications.................................................................................202.4.Requirementsforthebiotechnologyindustry..........................................................................213.Sterilefiltration..........................................................................................................213.1.Principles.........................................................................................................213.1.1.Classicalfoulingmodels....................................................................................213.1.2.Poreblockage—cakefiltrationmodel........................................................................223.1.3.VmaxandPmaxanalysis......................................................................................223.2.Membranes........................................................................................................233.2.1.Isotropicmembranes.......................................................................................233.2.2.Anisotropicmembranes.....................................................................................233.2.3.Compositemembranes.....................................................................................243.2.4.Multi-layermembranes.....................................................................................243.3.Modules..........................................................................................................243.3.1.Code7cartridges..........................................................................................243.3.2.Othercartridgetypes.......................................................................................243.3.3.Pleatingtechnology........................................................................................24

∗Correspondingauthor.Tel.:+16502251522;fax:+16502254049.E-mailaddress:rvr@gene.com(R.vanReis).

0376-7388/$–seefrontmatter©2007ElsevierB.V.Allrightsreserved.doi:10.1016/j.memsci.2007.02.045R.vanReis,A.Zydney/JournalofMembraneScience297(2007)16–5017

3.4.Equipment........................................................................................................243.4.1.Stainlesssteelhousings.....................................................................................243.4.2.Capsules..................................................................................................253.5.Processes..........................................................................................................254.Tangentialflowmicro-filtration............................................................................................264.1.Principles.........................................................................................................264.1.1.Shear-induceddiffusion.....................................................................................264.1.2.Inertiallift.................................................................................................264.1.3.Criticalfluxanalysis........................................................................................264.2.Membranes........................................................................................................274.2.1.Hollowfiber...............................................................................................274.2.2.Flatsheet..................................................................................................274.3.Modules..........................................................................................................274.3.1.Nonsteam-in-place(SIP)...................................................................................274.3.2.Steam-in-place.............................................................................................284.4.Processes..........................................................................................................284.4.1.Mediumexchangeandperfusion.............................................................................284.4.2.Harvest...................................................................................................285.Depthfiltration...........................................................................................................285.1.Principles.........................................................................................................285.2.Filtermedia.......................................................................................................295.3.Equipment........................................................................................................295.4.Processes..........................................................................................................306.Virusfiltration...........................................................................................................306.1.Principles.........................................................................................................306.1.1.Virusretention.............................................................................................306.1.2.Foulingphenomena........................................................................................306.2.Membranes........................................................................................................306.2.1.Flatsheet..................................................................................................306.2.2.Hollowfiber...............................................................................................316.3.Modules..........................................................................................................316.3.1.Tangentialflowmodules....................................................................................316.3.2.NormalflowVFmodules...................................................................................316.4.Equipment........................................................................................................316.5.Processes..........................................................................................................316.5.1.Proteincapacitystudies.....................................................................................316.5.2.Virusfiltrationvalidationstudies.............................................................................316.5.3.Industrialscaleprocesses...................................................................................327.Membranechromatography...............................................................................................327.1.Principles.........................................................................................................327.1.1.General...................................................................................................327.1.2.Convectionanddiffusion...................................................................................327.1.3.Exclusionphenomena......................................................................................327.2.Membranes........................................................................................................327.3.Modules..........................................................................................................327.3.1.Stackedsheet..............................................................................................327.3.2.Pleated....................................................................................................327.4.Equipment........................................................................................................337.5.Processes..........................................................................................................337.5.1.Flowthroughapplications...................................................................................337.5.2.Bindandeluteapplications..................................................................................338.Ultrafiltration............................................................................................................348.1.Principles.........................................................................................................348.1.1.Permeability...............................................................................................348.1.2.Sizeexclusion.............................................................................................348.1.3.Electrostaticexclusion......................................................................................348.1.4.Masstransfer..............................................................................................348.2.Membranes........................................................................................................368.2.1.Flatsheet..................................................................................................368.2.2.Hollowfiber...............................................................................................368.3.Modules..........................................................................................................368.3.1.Linearscalecassettes.......................................................................................36