Disposable technology in manufacturing of … 25-26.04. 2017 CONFIDENTIAL Page 1 Adriana...

CONFIDENTIALFinesse CellWorld 2017, 25-26.04. 2017

AdrianaKiędzierska-MencfeldProductionDirector Gdańsk

PolpharmaBiologics

Disposabletechnologyinmanufacturingofbiosimilarmonoclonalantibodies


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 3

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


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


PolpharmaBiologicsBiosimilars manufacturer

Utrecht

Gdańsk

Duchnice


PolpharmaBiologicsBusinessmodel

Treepillarsofouractivitiesinbiotechnology

MANUFACTURINGDEMAND

Developmentand

Productionof

OWNBIOSIMILARS

LICENSING

CDMOAnd

Fill&Finish


Agenda








Howsingleusetechnologycanfitinbiosmilarsmanufacturing?

time

cost

quality - biosimilarity

safety

flexibilityBiosmilars

vsSUSandSS

1

2

3

4

5

SUS SS


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


Singleuse Mammalian ManufacturingplatformU

PSTR

EAM

PR

OC

ESS


DOWNSTREAM PROCESS

Singleuse Mammalian Manufacturingplatform

BUFFERSUPPLY


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


Agenda








Supply chain

Customersupport

Qualitycontrolstrategy

Costofequipment

Whichsupplierforprocesstochoose?

Minandmaxscaleavailability

Deliverytime

Costofconsumables

Whattotakeinconsideration?



Rawmaterialssource andcontrol strategy

Controlstrategy forproduct

Validation package

Supplychain

Extractables packageQuality

1

2

3

4

5



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


Agenda


2) Disposableorstainlesssteel– projectstartdecision.

3) Whichsupplierforprocesstochoose– decisiondrivers.



6) Laboratoryscaleandproductionscale– howtoalign.


Howtokeepqualityandsimilarityofproductusingdisposabletechnology?

Understanding ofmolecule

(chargévariants,aggregation etc.)

Controlstrategy forproduct

Understanding andcompleteness ofdevelopmentdata

Goodcommunication

Understanding ofchemistry ofraw materialsandtheirpotential influenceonproduct

Qualityand

similarity

1

2

3

4

5


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


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


Agenda








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


§ Thedecisionregardingwhethertousesingle-useorstainlesssteeltechnology

isa significantoneinabiomanufacturing production

§ Thereisnouniversaltechnologyplatformforeachproductandeachproject,

decisionshouldbetakenbasedon project status, knowledgeandqualityrisk

assessment

ManagementviewonprocesscostsinProductionscale


Agenda


2) Disposableorstainlesssteel– projectstartdecision.






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


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


PolpharmaBiologicsGdanskMammalianProduction

GMPProduction inGdansk:• Manufacturingbasedonmammalian celllines

• FlexiblesetupbasedonSingleUseSystem-bothinUpstreamandDownstream,

• 1000Lbioreactorwithcapacitytoexpandto2x1000L,

• Bulkproductionupto50KgperYear

Stateoftheartfacilitycompliant

withEUandUSGMP

GMPlicence since October 2016


Summary

Itiscrucialtoimplementcost-effectiveplatform,butthemostimportantconsiderationistoimplementstrategywhichdeliversafeandhighquality

product

Tobecost-competitiveinbiosimilars production,youneedtothinkaboutitandevaluateitalreadyinearlyphasesofprocessdevelopmentand

establishmentofproduction


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