Purification As A Tool For Enhancing Process Control - Validated
BI OPRO C E S S TECHNICALBuilding Process Control intoChromatographic Purificationof Viruses, Part 2Purification As a Tool for Enhancing Process ControlDenise Gavin and Pete GagnonPurification represents a nexusin the manufacture ofbiopharmaceutical products: apoint at which allmanufacturing components and theirindividual variations converge. Thischallenges process developers toconfigure the components in waysthat either cancel or minimize thepotentially negative impacts of theirrespective variations. This is fully asimportant as achieving a specifiedlevel of purity because this is where itis established that a process willreproducibly yield high-qualityproduct. One hallmark ofchromatography methods is theirability to support this aspect ofprocess development.The more fundamental role ofpurification is to remove contaminants.Numerous chromatography methodshave been reported for viruspurification, including affinity (1–4),size exclusion (4–8), ion exchange (6–12),PRODUCT FOCUS: ALL VIRAL PRODUCTSORTHOGONAL PROCESS DESIGNPROCESS FOCUS: DOWNSTREAMPROCESSINGWHO SHOULD READ: PROCESSDEVELOPMENT AND MANUFACTURINGKEYWORDS: PROCESS OPTIMIZATION,CHROMATOGRAPHY, VALIDATION,QUALIFICATION, VACCINES, GENE THERAPIESLEVEL: INTERMEDIATE28BioProcess InternationalD ECEMBER 2006hydrophobic interaction (7, 8), andhydroxyapatite chromatography (12).Many studies comment that evensingle-step chromatography proceduresachieve better purity than multistepdensity-gradient–based methods.This two-part article focuses onchromatographic purification ofviruses for human therapeuticapplications. In Part 1 (BioProcessInternational 4(10) 2006: 22–30) wediscussed qualification of rawmaterials. Now in Part 2 we discussopportunities to enhance processcontrol in purification processdevelopment, highlighting ways tomaximize process control inchromatographic purification ofviruses. Our suggestions are based onapproaches that have been shown tohave practical value in themanufacture of recombinant proteintherapeutics and development ofemerging viral products. Please referto pertinent regulatory documents formore information (13–20).Orthogonal process design is thefoundation of well-controlledpurification procedures (21). The ideais that combining the steps with thegreatest complementarity shouldprovide the best overall purification.The strongest embodiment of theconcept is usually achieved whenrespective steps are based on distinctseparation mechanisms. For example, aArtist’s conception of a virusRAFAL ZDEB (WWW.ISTOCKPHOTO.COM)two-step process that contains onefractionation step based on product sizeand another on product charge wouldbe considered orthogonal; similarly, aprocess with one step based on productcharge and another on hydrophobicitywould also be orthogonal.An important feature of orthogonalprocess design is that the purificationcapability of any one step ismeasurable only within the context ofits potential partner(s) (22). This isillustrated in Figures 1 and 2. InFigure 1, each step is capable ofachieving 90% purification from rawproduct, but a major contaminantcoelutes with the product in bothsteps. In Figure 2, the first step is thesame as in Figure 1. The second stepachieves only 60% purification fromraw sample, but when combined with
Figure 1: A two-dimensional plot of resultsfrom two different chromatographicmethods. In spite of good fractionation byboth methods, a common contaminant(black) coelutes with the viral product (blue).The plot shows that this combination ofmethods will not yield pure product. DNA isindicated in red. See text for discussion.12step 1, the result is 100% puritybecause no major contaminants coelutebetween the two steps. This revealsthe inherent fallacy in judgingindividual purification methods basedsolely on their purification factor.Context is paramount.It is impossible to predict whatcombination of separation methods willwork best for a given virus purificationprocess, and how many steps will berequired to achieve the degree ofpurification required to support aparticular application. Developmentbegins with screening potentialcandidates under various conditions,then evaluating the respective resultsfor the highest degree ofcomplementarity. It then proceeds toidentify the smallest subset of methodsthat fulfills the application’s needs.Purification procedures for proteinbased therapeutics from cell culturecommonly use three chromatographicsteps but may use more depending onsource material and application.Figures 2 and 3 illustrate howmaximizing complementarity amongsteps reduces the impact of variationand thereby increases process control.In Figure 3, the two steps provide thesame purity as in Figure 2, but theircomplementarity is greater. None ofthe contaminants eluting near theproduct in the individual steps cooccur with the product in thecombined process. This implies thatthe result will be more insulated fromFigure 2: A two-dimensional plot of resultsfrom two different chromatographicmethods. Method 1 is the same as in Figure 1.Method 2 is a different method, which byitself produces a relatively poor fractionationbut yields pure product in combination withmethod 1. This is indicated by the lack ofcontaminants overlapping the product. DNAis indicated in red. See text for discussion.Figure 3: A two-dimensional plot of resultsfrom two different chromatographic methods.Method 1 is the same as in Figures 1 and 2.Method 2 is a different method than theprevious. This combination of methodsachieves the same purity as in Figure 2, but thelarger open area around the product indicatesthat this combination should be more robust.DNA is indicated in red. See text for discussion.1122Table 1: Relative retention of DNA andendotoxin by different roxyapatite StronglyVariable,bound strongly boundmaterial or process variations. Theimplication needs to be proven, butthe probabilities are more favorablethan for a process that is alreadyoperating close to its tolerance limitsunder the best of circumstances.The other side of thecomplementarity coin is redundancy.Redundancy has a special meaning inchromatography: It refers not torepetition of the same chemicalseparation mechanism, but to thecompound ability of complementarymechanisms to reduce levels of a specificcontaminant or class of contaminants.This has particular value for processcontrol because it relates tocontaminants that must be reduced toextremely low levels (e.g. DNA,endotoxin, and contaminating virus)(21). From the perspective of DNAremoval, all methods in Table 1 areredundant, even though they achieveredundancy through differentmechanisms. This is also reflected inthe distribution of DNA in Figures 1–3.LINEAR GRADIENTS, STEP GRADIENTSThe majority of chromatographybased industrial purification processesuse step gradients. Most developmentand industrial chromatographysystems can easily accommodate lineargradients, but such gradients tend touse larger volumes of buffer. Processwater also has proven to be a majorexpense (23). Linear gradients mayrequire collecting a larger number offractions. This complicates plumbingat process scale and makes it necessaryto perform more assays to determinewhich fractions to pool going into thenext step.Linear gradients have importantadvantages despite these issues,especially in terms of process control(22), and by providing real-timeprocess monitoring. The evolvingelution profile itself provides acontinuous real-time index of processstatus and generally allowsdetermination at a glance — whetheror not a process is operating withinspecification. The finished elutionprofile provides hard-copydocumentation that the process hasbeen conducted within establishedspecifications. Neither benefit isobtained with step gradients, whichD ECEMBER 2006BioProcess International29
produce a single peak per step withoutrespect to the number of componentseluting within that step.The most important advantage oflinear gradients is that they providebetter process control. In the presentcontext, this refers to their ability toabsorb process variation, which in turntranslates into better process consistency.Most process variables either weaken orstrengthen chromatographic retention(24). The effect of such variables on alinear gradient is to shift the entireprofile laterally but conserve the elutionrelationships of individual peaks (Figure4). Figure 5 contrasts the effects of thesame variation with a correspondingstep-gradient elution of the samehypothetical sample. The leadingcontaminant elutes partially within theproduct peak, and the product elutespartially within the trailing contaminantpeak. Product purity and recovery areboth compromised.The ability of linear gradients toendow better process control can beespecially valuable at early stages ofprocess development, when sources ofprocess variation are not yet fullycharacterized. By the time a process isready for licensure, sources of variationshould be fully characterized andminimized. In parallel, step-gradientintervals should have been defined toensure the ability of the purificationprocess to reproducibly achieve thenecessary fractionation.Figure 4: The effect of external processvariation on linear gradients. The bluecomponent represents the viral product. Thegray components represent contaminants.Profile A illustrates a gradient under idealconditions. Profile B illustrates the differencewhen external variation is introduced.Variation like this might derive from processbuffers, chromatography media, temperature,or other variables. As shown, the entire profileis shifted to the right but the separation isconserved, illustrating the ability of lineargradients to enhance process control. See textfor discussion.ABFigure 5: The effect of external processvariation on step gradients. The bluecomponent represents the viral product. Thegray components represent contaminants.Profile A illustrates a gradient under idealconditions. Profile B illustrates the differencewhen external variation is introduced. Productpurity is compromised by partial elution ofthe leading contaminant in product peak.Recovery is compromised by loss of productin the trailing contaminant peak. See text fordiscussion.ABMEDIA USE (AND REUSE)The dominant material costs inbioprocessing are for chromatographymedia. It is therefore not surprising thatmany manufacturers seek to improveprocess economy by using a single lot ofmedia for multiple process cycles (25).Some chromatography media have beenvalidated to retain function for morethan 1,000 manufacturing cycles,reducing the net cost per cycle tovirtually nothing (26). This provides apowerful economic incentive for reuse.On the other hand, the single use of achromatography column or other formathas the potential to alter its function,making reuse a key process control issue(16, 23, 26–29).The first step is development ofcleaning, sanitization, and storageprocedures that remove all30BioProcess InternationalD ECEMBER 2006contaminants and keep the media cleanwhile restoring original function. Thenext is to demonstrate that nocontaminant carryover occurs from onevirus product lot to the next. Thatapplies especially to microbialcontaminants and endotoxins. Inpractice, personnel, process water, andthe manufacturing environment are themost common sources of bioburden,but examples have been cited in whichsanitizing reagents contained resistant,contaminating microbes (30). Lot-to-lotcarryover of viral product is also apotential concern because it threatenslot integrity — and because productcarryover also implies carryover ofcontaminants. Carryover can bemeasured after conducting a runwithout sample after a normal run (26).The second major consideration inreuse is to demonstrate conservation ofcapacity and fractionationperformance. Performance testing mayinclude the same parameters used toevaluate incoming lots of the samemedia (see Part 1). Data from scaledown manufacturing simulationsprovide an additional dimension ofcharacterization (26, 29). An increasein backpressure may indicate anaccumulation of impurities,compression, or chemical breakdownof column media. Other tests mayinclude comparison of elution profiles,comparison of product yield andpurity, and clearance of specificimpurities. Used chromatographicmedia are not expected to retain 100%of their original function, but at theend of their designated lifetimes theyare expected to completely fulfillspecifications for the processes inwhich they are used.Reuse or Single-Use: Althoughreuse is driven by process economy,the expense of developing proceduresfor cleaning, sanitization, and storage— and the expense of developing theassays to validate their effectiveness,and the expense of materials and laborto conduct these procedures in amanufacturing setting — has createdan interest in single-use products,especially in virus purification. Somechromatography media, such as ionexchange filters, are marketedspecifically for this application, butstrictly speaking, any chromatographymedium can be designated for singleuse. The choice represents a balancebetween capability and cost.Fresh media can be used forpreparation of early clinical lots, evenif media are intended for multiple usein a final manufacturing process.Fresh media may be needed for use inearly clinical trials, given thatcleaning, sanitization, and storageprocedures may not yet be validated.The purification process used for
preparation of phase 3 clinicalmaterial should follow the intendedmanufacturing process, includingmedia restoration. In addition,comparability studies may benecessary if clinical data are to be usedfrom viral products produced underdifferent conditions (20). If aparticular chromatography material isgoing to be used as a disposable, itshould be designated accordinglybefore this point.EXTERNAL PROCESS VARIATIONInadvertent microbial or endotoxincontamination can have a majorimpact on product safety. Cleanlinessof the processing environment istherefore an important control issue.Chromatography can improve processcontrols by minimizing the potentialimpact of nonideal processingenvironments (30). Even the simplestchromatography systems can beconfigured to protect a product fromexternal exposure before, during, andafter separation, and such systems alsocan be sanitized to prevent internalexposure.The skills and awareness of processoperators are an important factor inkeeping product free of microbialcontamination. Skilled operators canachieve high levels of hygiene even inmarginal environments. Operatorinfluence can be minimized at laterdevelopment stages by exploiting theautomation capabilities of currentchromatography skids, but welltrained operators will still helpminimize process aberrations betweenprocess steps.Temperature also can have a directeffect on chromatography mechanisms,especially those that have stronghydrophobic components such ashydrophobic-interactionchromatography and some affinitymechanisms (31). Temperaturedifferences among processingenvironments can cause significantshifts in selectivity, and suchdifferences can affect product quality.It is also important to consider thatprocess variations due to temperaturecan be very difficult to trace becausethe evidence is lost as soon as thetemperature changes. The best solution32BioProcess InternationalD ECEMBER 2006SOURCES OF PROCESS VARIATIONFor chromatographic methods, processvariations can come from Sample compositionProduct concentrationConcentration of key contaminants Buffer compositionpHConductivity Process temperature Flow rate Lot variations in media Variations across scale inchromatography instrumentation Process variationsdue to temperaturecan be very difficultto trace because theevidence is LOST assoon as thetemperaturechanges.is to conduct all stages of processdevelopment as closely as possible tothe temperature of the manufacturingenvironment in which the finalpurification process will be conducted.Chromatographic equipmentvariations at different process scales canalso contribute significantly to processvariation. Mixing occurs betweenbuffer inlet valves upstream of thepumps, through the pumps themselves,and through bubble traps leading to acolumn. That converts a programmedstep in buffer composition to a gradienttransition. The volume of the transitionis characteristic for a givenchromatograph, but the magnitude ofthe effect varies with the volume of thecolumn (24). With a large ratio ofcolumn volume to transition volume,aberrations in buffer composition fromthe programmed values will be small.If the ratio is small, aberrations will belarge. Those aberrations can affectcolumn equilibration volume, theeffectiveness of washes, and gradientprecision. Transition volume and itseffects are easy to characterize andaccommodate, but it is important toaddress the issue proactively to ensureconsistency of process control acrossscales.CHARACTERIZING ANDACCOMMODATING VARIATIONVariability occurs in all purificationprocesses despite best efforts both toqualify manufacturing components andimplement process controls thatameliorate their effects. This is not aproblem so long as variation is wellcharacterized, and each process isdocumented to reproducibly yield highquality product within its range. Theprevailing approach to characterizingvariability and assessing its impactinvolves design of experiments (DOE)with subsequent statistical analysis tocharacterize individual contributions ofeach variable (23, 32, 33). This approachis commonly used for optimizingseparation conditions, but it serves justas effectively for defining processfailure thresholds. DOE representssignificant effort, but factorial designsenable dramatic reductions in theexperimental work load. The “Sourcesof Process Variation” box identifiesfactors that may be included in DOEstudies.GOOD COMMUNICATION IS ESSENTIALChromatography has proven its abilityto support good process control andgenerate high-quality proteintherapeutics, and it could do the samein the field of virus purification. Theprinciples for developing wellcontrolled chromatographicprocedures should apply equally toviruses, but viruses embody a differentrange of characteristics. Those can beexpected to influence both the choiceof purification tools and theconditions under which they areapplied, with the result that each viruspurification procedure will be unique.Establishing good communicationswith regulatory authorities early in thedevelopment process will help ensurethat such procedures conform withcurrent regulations.REFERENCES1 Aurichio A, et al. Isolation of HighlyInfectious and Pure Adeno-Associated Virus
Type 2 with a Single Step Gravity FlowColumn. Hum. Gene Ther. 12(1) 2001: 71–76.2 Aurichio A, et al. A Single StepAffinity Column for Purification of Serotype-5Based Adeno-Associated Virus. Hum. Mol.Ther. 4(4) 2001: 372–374.3 Slepushkin V, et al. Large ScalePurification of a Lentiviral Vector By SizeExclusion Chromatography or Mustang Q IonExchange Capsule. Bioprocessing J. September–October 2003: 89–95.4 Segura M, et al. A Novel Strategy forRetrovirus Gene Therapy Using HeparinAffinity Chromatography. Biotechnol. Bioeng.90(4) 2005: 391–404.5 Transfiguracion J, et al. Size ExclusionChromatography of High Titer VesicularStomatitis Virus G Glycoprotein-PseudotypedRetrovectors for Cell and Gene TherapyApplications. Hum. Gene Ther. 14(12) 2003:1139–1153.6 Boratynski J, et al. Preparation ofEndotoxin Free Bacteriophages. Cell. Mol. Biol.Lett. 9(2) 2004: 253–259.7 Vellekamp G. Empty Capsids inColumn Purified Recombinant AdenovirusPreparations. Hum. Gene Ther. 12(15) 2001:1923–1936.8 Huyghe B, et al. Purification of a Type5 Recombinant Adenovirus Encoding Humanp53 By Column Chromatography. Hum. Gene.Ther. 6(11) 1995: 1403–1416.9 Kaludov N, Handelman B, Chiorni J.Scalable Purification of Adeno-AssociatedVirus Type 2, 4, And 5 Using Ion ExchangeChromatography. Hum. Gene. Ther. 13(10)2002: 1235–1243.10 Kramberger P, et al. Concentration ofPlant Viruses Using MonolithicChromatography Supports. J. Virol. Methods120(1) 2004: 51–57.11 Spech R, et al. Densonucleosus VirusPurification By Ion Exchange Membranes.Biotechnol. Bioeng. 88(4) 2004: 463–473.12 O’Riordan C, et al. ScaleableChromatographic Purification Process forRecombinant Adeno-Associated Viruses. J.Gene. Med. 2(6) 2000: 444–454.13 US Food and Drug Administration,Center for Biologics Evaluation and Research.Guidance for FDA Review Staff and Sponsors:Content and Review of Chemistry,Manufacturing, and Control (CMC) Informationfor Human Gene Therapy Investigational NewDrug Applications (INDs); Draft Guidance,2004: www.fda.gov/cber/gdlns/gtindcmc.htm.14 US Food and Drug Administration,Center for Biologics Evaluation and Research.Guidance for Industry: INDs — Approaches toComplying with CGMP During Phase 1; DraftGuidance, 2006: www.fda.gov/cber/gdlns/indcgmp.htm.34BioProcess InternationalD ECEMBER 200615 International Conference onHarmonisation (ICH). Guidance Q5D:Quality of Biotechnological/BiologicalProducts: Derivation and Characterization ofCell Substrates Used for Production ofBiotechnological/Biological Products. Fed.Regist. 63(182) 1998: 50244–50249; www.fda.gov/cber/gdlns/qualbiot.pdf.16 International Conference onHarmonisation (ICH) Guidance Q5A: ViralSafety Evaluation of Biotechnology ProductsDerived from Cell lines of Human or AnimalOrigin. Fed. Regist. 63(185) 1998: 51074–51084; www.fda.gov/cber/gdlns/virsafe.pdf.17 US Food and Drug Administration,Center for Drugs and Biologics and Center forDevices and Radiological Health. FDAGuideline on General Principles of ProcessValidation, 1987; www.fda.gov/cber/gdlns/validation0587.pdf18 International Conference onHarmonisation (ICH). Guidance for IndustryQ7A: Good Manufacturing Practice Guidance forActive Pharmaceutical Ingredients, August 2001;www.fda.gov/cber/gdlns/ichactive.pdf.19 International Conference onHarmonisation (ICH). Guidance for IndustryQ9: Quality Risk Management, June 2006;www.fda.gov/cber/gdlns/ichq9risk.pdf.20 US Food and Drug Administration,Center for Biologics Evaluation and Research.Guidance for Industry: Comparability Protocols —Protein Drug Products and Biological Products —Chemistry, Manufacturing, and ControlsInformation, 2003; www.fda.gov/cber/gdlns/protcmc.htm .21 Gagnon P. The Secrets of OrthogonalProcess Development. Validated Biosystems,2006: www.validated.com/revalbio/pdffiles/orthopd.pdf.22 Gagnon P. Linear and Step GradientElution, Data Versus Dogma. ValidatedBiosystems 1(3) 1996: 1–6; 3 Sofer G, Hagel L. Handbook of ProcessChromatography: A Guide to Optimization, Scaleup and Validation. Academic Press: New York,NY, 1997.24 Gagnon P. Avoiding InstrumentAssociated Aberrations in Purification ScaleUp and Scale-Down. BioPharm 10(3), 1997:42–45.25 Rathore AS, et al. Costing Issues inProduction of Biopharmaceuticals. BioPharmIntl., 2004; icleDetail.jsp?id 86832.26 Rathore A, Sofer G. Life Span Studiesfor Chromatography and Filtration Media.Process Validation in Manufacturing ofBiopharmaceuticals: Guidelines, Current Practices,and Industrial Case Studies. Rathore A, Sofer G,Eds. Taylor and Francis: Boca Raton, 2005.27 US Food and Drug Administration,Center for Biologics Evaluation and Research.Compliance Program Guide, Chapter 41: LicensedTherapeutic Products — Inspection of TissueEstablishments, March 2003; www.fda.gov/Cber/cpg/7341002Atis.htm.28 Cherny B. CBER’s Expectations onDetermining Resin Lifespan. Presented at theFDA/PDA Process Validation meeting:Washington, DC, 2000.29 Campbell J. Validation of a FiltrationStep. Process Validation in Manufacturing ofBiopharmaceuticals: Guidelines, Current Practices,and Industrial Case Studies. Rathore A, Sofer G,Eds. Taylor and Francis: Boca Raton, 200530 Nims R, et al. Adventitious Agents:Concerns and Testing for Biopharmaceuticals.Process Validation in Manufacturing ofBiopharmaceuticals: Guidelines, Current Practices,and Industrial Case Studies. Rathore A, Sofer G,Eds. Taylor and Francis: Boca Raton, 2005.31 Gagnon P. Purification Tools forMonoclonal Antibodies. Validated Biosystems:Tucson, AZ, 1996.32 Seely J. Process Characterization. ProcessValidation in Manufacturing ofBiopharmaceuticals: Guidelines, Current Practices,and Industrial Case Studies. Rathore A, Sofer G,Eds. Taylor and Francis: Boca Raton, 2005.33 Seely R, Haury J. Applications ofFailure Modes and Effects Analysis toBiotechnology Manufacturing Processes.Process Validation in Manufacturing ofBiopharmaceuticals: Guidelines, Current Practices,and Industrial Case Studies. Rathore A, Sofer G,Eds. Taylor and Francis: Boca Raton, 2005. Denise Gavin is a biologist at the Office ofCellular, Tissues, and Gene Therapy atFDA/CBER, 1401 Rockville Pike, Rockville,MD 20852; corresponding author PeteGagnon is chief scientific officer atValidated Biosystems, Inc., 240 AvenidaVista Montana, Suite 7F, San Clemente, CA92672; 1-949-276-7477, fax 1-949-606-1904,pete@validated.com.The opinions expressed in this article havenot been formally disseminated by the Foodand Drug Administration and should not beconstrued to represent any agencydetermination or policy.
individual purification methods based solely on their purification factor. Context is paramount. It is impossible to predict what combination of separation methods will work best for a given virus purification process, and how many steps will be required to achieve the degree of purification required to support a particular application. Development
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