CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 1
AdrianaKiędzierska-MencfeldProductionDirector Gdańsk
PolpharmaBiologics
Disposabletechnologyinmanufacturingofbiosimilarmonoclonalantibodies
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 2
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision
3) Whichsupplierforprocesstochoose– decisiondrivers
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 33
Staraya Kupavna
Starogard Gdański
Sieradz
API - Starogard Gdański
• GMP/FDA approved• 1 dedicated and 5
multipurpose plants• Pilot plant• 40 dedicated reactors• 165 multipurpose reactors
Staraya Kupavna
• Russian Federation GMP approved
• 3.1 bln tablets, 150 m capsules, 400 ton of ointments, gels, creams
FDF - Starogard Gdański
• GMP approved• 6 billion units of solid forms
& 190 m of liquid forms
FDF - Sieradz
• GMP approved• Solids• Semisolids• Oral liquids• Capacity of 800 m tablets
and 26 m bottles with liquids• 600 m soft gelatine
capsules
FDF, API - Warsaw
• FDF and API production • GMP certificate• Liquid forms : ampules,
drops, syrups,
Duchnice FDF - Shymkent
• 1 billion tablets, capsules, granules
• 250 million ampoules• 24 million vials of antibiotics• 20 million bottles of liquids• 5 million Tubes, ointments,
gels
Anti-infectives FDF at Duchnice
• FDF production building • GMP certificate• Capacity of 20 m vials,
60 m tablets• Headcount of 90
Warsaw
21
FDF - Nowa Dęba
• FDF production • GMP certificate• Gels, tabletts, capsules
Nowa Dęba
Pruszków
• Fitopharmaceuticalsproduction
Pruszków
Biotech - Gdańsk• R&D• QC and QA• GMP Production– 1000L
Gdańsk
Polpharma GroupFootprint
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 4
DevelopmentofPolpharmagroup
StrategicalliancewithBSP(advanced
oncologycentreinItaly,EMA
approvalgrantedin2008)
BiotechnologyR&D
centre inGdańsk
established
JVwithneuraxpharm
groupinBiotechnology
AcquisitionofBioceros NV -
celllinedevelopmentplatform
Acquisition of Akrikhinin Russia
Acquisition of Farmaprojects -
a product development
platform
Acquisition of anti-infectivesbusiness unit from Bioton
Acquisition of controlling stake
in Santo (Kazahstan)
Acquisition of Polfa Warszawa
S.A.
Privatisationof Polpharma
Fifteenyearsofdynamicgeographicandproductexpansionfromgenericstobiosimilars
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 5
PolpharmaBiologicsBiosimilars manufacturer
Utrecht
Gdańsk
Duchnice
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PolpharmaBiologicsBusinessmodel
Treepillarsofouractivitiesinbiotechnology
MANUFACTURINGDEMAND
Developmentand
Productionof
OWNBIOSIMILARS
LICENSING
CDMOAnd
Fill&Finish
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 7
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision
3) Whichsupplierforprocesstochoose– decisiondrivers
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 8
Howsingleusetechnologycanfitinbiosmilarsmanufacturing?
time
cost
quality - biosimilarity
safety
flexibilityBiosmilars
vsSUSandSS
1
2
3
4
5
SUS SS
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 9
GdanskstatuswhendecisionwastakenMammalian production
Nodefined pipeline
Noprocess developed
Noexperience with stainless steel
Limitedspace – location inoffice building (rental)SUSorSS
1
2
3
4
5
Limitedutilities– location inthecentre ofthecity
SUS SS
TIMELIMITED– SUS
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 10
Singleuse Mammalian ManufacturingplatformU
PSTR
EAM
PR
OC
ESS
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 11
DOWNSTREAM PROCESS
Singleuse Mammalian Manufacturingplatform
BUFFERSUPPLY
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Manufacturingstrategy
Decision drivers§ Limited space designated for production
§ Limited utilities
§ Time pressure for finalization of investment
§ High probability of products changeover§ Clinical trials supply
§ Own biosmilars under development
§ Potential CMO business
Challenges§ Existing development platform not fully SU§ Not fully developed proces
§ Limited experience with SUS
Finaldecision– singleuseplatformforbiosmilars mAbmanufacturing
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 13
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision
3) Whichsupplierforprocesstochoose– decisiondrivers
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 14
Supply chain
Customersupport
Qualitycontrolstrategy
Costofequipment
Whichsupplierforprocesstochoose?
Minandmaxscaleavailability
Deliverytime
Costofconsumables
Whattotakeinconsideration?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 15
Whichsupplierforprocesstochoose?
Rawmaterialssource andcontrol strategy
Controlstrategy forproduct
Validation package
Supplychain
Extractables packageQuality
1
2
3
4
5
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 16
Whichsupplierforprocesstochoose?
Smallsupplier:§ Flexibility
§ Morefocusoneachcustomer
§ Shorterdeliverytime
§ Higherriskofbusiness
discountinuation
Bigsupplier:§ Lessflexibility
§ Limittedfocusonsmallcustomers
§ Longer deliverytime
§ LowerriskofbusinessdiscountinuationSmallor big supplier
Onesupplier:§ Lessworkduringsupplier
qualification
§ Compatibilityofconnections
§ Easiertonegotiatecontractconditions
§ Consistent extractablesandvalidationpackage
§ Highdependencyononesupplier
Moresuppliers:§ Moreworkduringsupplier
qualification
§ Riskofincompatibilityofconnections;add.costofmanifolds
§ Morediffuculttonegotiatecontractconditions
§ RiskofInconsistencyofextractablesandvalidationpackage
§ Nodependencyononesupplier
Oneor more suppliers
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 17
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision.
3) Whichsupplierforprocesstochoose– decisiondrivers.
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign.
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 18
Howtokeepqualityandsimilarityofproductusingdisposabletechnology?
Understanding ofmolecule
(chargévariants,aggregation etc.)
Controlstrategy forproduct
Understanding andcompleteness ofdevelopmentdata
Goodcommunication
Understanding ofchemistry ofraw materialsandtheirpotential influenceonproduct
Qualityand
similarity
1
2
3
4
5
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 19
AnalyticalmethodsusedinDevelopmentandQC
Physicochemical methods forDrug Substance andDrug Producttesting:
• Fullglycananalysis,• Identity• AminoAcidsAnalysis• Impurities,• Titer,• ChargeVariants
Andmanymore…
• UPLCmethods(LC-UV,LC-SEC,LC-IEX
• MassSpectrometry(LC-ESI-MS)• UV/VISmethod• IEF/2DEF• CapillaryGelEF
Biological methods forDrug Substance andDrug Producttesting:• Cellbasedmethods,• SPR,• ELISA,• FACS,• RT-PCR
• Targetbindingassaysbothinvitro(ELISA,SPR) andinvivo(CellBased)
• AssaysexplainingMoA• Fc receptorbindingassays,
Andmanymore…
MicrobiologicalQuality Control:§ FacilityandEnvironmentalControl§ Clean mediatesting – gases,PWandWFI,clean steam§ Intermediates,Drug substance anddrug product testing§ Rawmaterialstesting
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 20
Considerationandconcernsregardingoverallsafetyarestillthehighestimportance!
§ Proper control strategy should be implemented to monitor the product quality during
the whole process.
§ IPC control for intermediates and release tests for drug substance (DS) and drug
product (DP) should demonstrate/establish identity, strength/potency, quality, and
purity of a product.
Safety
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 21
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision
3) Whichsupplierforprocesstochoose– decisiondrivers
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 22
ManagementviewonprocesscostsinProductionscale
Expectations:cheap,good andfast?
§ Thelowest possible andeven lower§ Possible further cost reduction§ Resistance forinnovative or new technologies
SSor SUS?SSforcheap forhighvolume products;productswithknown demand;oneproduct line
SUSforexpensive products,notknown demand or changing forecasts;multiproductline;CMObusiness;flexibility required
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§ Thedecisionregardingwhethertousesingle-useorstainlesssteeltechnology
isa significantoneinabiomanufacturing production
§ Thereisnouniversaltechnologyplatformforeachproductandeachproject,
decisionshouldbetakenbasedon project status, knowledgeandqualityrisk
assessment
ManagementviewonprocesscostsinProductionscale
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 24
Agenda
1) Polpharma– company overview
2) Disposableorstainlesssteel– projectstartdecision.
3) Whichsupplierforprocesstochoose– decisiondrivers
4) Howtokeepqualityandsimilarityofproductusingdisposabletechnology
5) Managementviewonprocesscostsinproduction scale
6) Laboratoryscaleandproductionscale– howtoalign?
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 25
Laboratoryscaleandproductionscale– howtoalign?
§ Scale-up is an important and potentially time-consuming step in the developmentof industrial processes
§ Implementation of single use technologies is possible from development scale tomanufacturing scale
§ Incorporation of single use materials early in development allows for reducedtimelines and resources during Tech Transfer
§ Scalable single use platform is needed to smoothly transfer the process fromlaboratory to production scale
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Two-stepscaleupapproachusingSUS
§ Developemnt batches atlaboratory scale to establishthe process to be transfered
DevelopmentrunsLaboratoryscale
TechnicalBatchesMediumor/andfullproductionscale
EngineeringBatchesFullproductionscale
§ Experimental batches forexecution of the process atmedium or/and full scale totest equipment, train theStaff, verify the impact ofscale, test single use materials
§ Full-scale batches of the finalprocess to demonstrate processperformance
ThenGMPproduction infinal scale withQuality Control
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PolpharmaBiologicsGdanskMammalianProduction
GMPProduction inGdansk:• Manufacturingbasedonmammalian celllines
• FlexiblesetupbasedonSingleUseSystem-bothinUpstreamandDownstream,
• 1000Lbioreactorwithcapacitytoexpandto2x1000L,
• Bulkproductionupto50KgperYear
Stateoftheartfacilitycompliant
withEUandUSGMP
GMPlicence since October 2016
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Summary
Itiscrucialtoimplementcost-effectiveplatform,butthemostimportantconsiderationistoimplementstrategywhichdeliversafeandhighquality
product
Tobecost-competitiveinbiosimilars production,youneedtothinkaboutitandevaluateitalreadyinearlyphasesofprocessdevelopmentand
establishmentofproduction
CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017 Page 29
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