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DCVMN-MedigenworkshoponGlobalRegistra:onandSupplyShortagesfrom6thto10thMarch2017,Taipei

Leo Wang Director Asia Business Development 泰坦公司中国,北京代表 Tel: 86-010-5920-4209 Cell: 86-138-101-64918 Fax: 86-010-5920-4222 email:Leow@temptimecorp.com ; www.temptimecorp.com 北京市朝阳区建国路79号 中心写字楼2座9楼 951 100025; 9F, Tower 2, China Central Place, No.79 Jianguo Road, Chaoyang District, Beijing China, 100025 莫里斯平原,新 西州,美国’116 American Rd Morris Plains, NJ 07950

2016

SharingExperiencesofHEATmarker®VaccineVialMonitor

forWHOPQ

2007UNICEF/WHOJointPolicyStatementUrgingMemberStates,DonorAgenciesandNGOstoIncludeVVMsAsMinimumRequirementforPurchaseofVaccine

2012WHOIncludesVVMsAsCri:calCharacteris:cforVaccine

Prequalifica:on

UNICEF/WHOPoliciesonCri:calityofHEATmarkers(VVMs)

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Vaccine vial monitor (VVM)

All vaccines Proof of feasibility and intent to apply a VVM to the proposed vaccine, as defined below. The vaccine presented for prequalification presents data confirming that it has a thermostability profile that will enable it to be matched to a current WHO-approved VVM type (VVM2, VVM7, VVM14 orVVM30) or a future VVM type approved by WHO(WHO/V&B/99.187, WHO/IVB/07.048). Signed declaration, as part of the cover letter submitted along with the file for prequalification confirming that the manufacturer will apply a VVM to the vaccine, and has the technical capacity to do so if requested by the purchasing specifications.

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MonitorCumula:veHeatwithHEATmarkerVVM

Ac'veSquare

ReferenceCircle

•  TheAc'veSquareisthecolorchangingreac'vepor'on•  Itislightatthestartandprogressivelyandirreversibly

darkens•  Thecolorchangeisfasterathighertemperatures•  EndpointisreachedwhenthecoloroftheAc'veSquare

areaisequaltotheReferenceCircle

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TheHEATmarkerTTIIsEasyToRead

ü

û

TheAc'veSquareislighterthantheReferenceCircle.

Iftheexiprydateisnotpassed,USEthevaccine.

TheAc'veSquarematchesorisdarkerthantheReferenceCircle.

DONOTUSEthevaccine.

ü

û

USE USE DONOTUSE

DONOTUSE

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HEATmarkerVVMCategories

_____30days@37°C_____14days@37°C_____7days@37°C_____2days@37°C

TheVVM(VaccineVialMonitor)istheTTIusedbyWHO/UNICEFintheglobalimmuniza'onprogram.Temp'mehasmorethan17differentcategoriesofTTIsavailablefromdaysatrefrigeratedtemperaturetoyearsatroomtemperature.

HEATmarker VVM for Use on Vaccines

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Pharmaceu:calProduct

Indica:on Customer Temp:meProduct

ValueDelivered

Children’sImmuniza'onCampaignsforarangeofcontagiousdiseases:•  BCG•  Diphtheria•  Tetanus•  Pertussis•  DTP•  HepB•  HiB•  MeningococcalAandC•  Measles•  Mumps,Pneumococcal•  OPV•  Rotavirus•  Rubella•  TetanusToxoid•  YellowFever

OtherCampaigns:•  HPV•  IPV•  Rabies•  Typhoid

GSK,SanofiPasteur,Merck,Crucell,Pfizer,Novar's,SerumIns'tuteofIndia,Biofarma,JapanBCG,BB-NCIPD,BharatBiotech,StatensSerumIns'tute,BiologicalE,BharatSerumsandVaccines,Hagine,plusothers

VVM2,VVM7,VVM14,VVM30

•  Preventsimmuniza'onwithheatdamagedvaccines

•  Expandsreachofimmuniza'onprogramstoremotepopula'ons

•  Increasesimmuniza'onprogramsefficiency

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StepstoVVMImplementa:on

1.  VaccineManufacturerSubmitsDossiertoWHOforPrequalifica'onwhichIncludesVaccineStabilityData

2.  WHOIden'fiestheApprovedCategoryofVVMbasedontheStabilityDataoftheVaccine

3.  VaccineManufacturerValidatestheVVMReac'vity&Performance

4.  Determina'onofVVMType(DotorFullLabel)andPlacementontheVial(ArtworkApprovalNecessaryforFullLabels)

5.  SOPsatManufacturerforVVMReceipt,StorageandUse

6.  Installa'onandValida'onofVVMApplica'onEquipment

●  GOAL− AcceleratedstabilitydatamustbegeneratedthatallowsthechoiceofthehigheststabilityVVMcategorypossible.

● RATIONALE− Atelevatedtemperatures,thehighestcategoryVVMwhichreachesitsendpointbeforethevaccinestoredatthesametemperaturebecomessub-potentshouldbechosen.ThisensuresthattheproductissHllsuitabletousewhileminimizeswastagethroughprematurediscardofvaccinethatissHllpotent.

AcceleratedStabilityStudiesforWHOPrequalifica:on

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Thetemperaturesensi'vityofvaccinecharacteris'cs,par'cularlypotency,hasamajorimpactonthesuccessofglobalimmuniza'onprogrammes.WHOhasacknowledgedtheimportanceofclearlydefiningthestabilitycharacteris'csofavaccine.

Chapter10.Labelingstates:“IfVaccineVialMonitors(VVM)aretobeused,adequatestabilitydatashouldbegeneratedtosupportselec'onofappropriateVVMforavaccineinques'on.FurtherdetailsontheuseofVVMfordifferenttypesofproductsareavailableelsewhere.”2

1hnp://www.who.int/biologicals/publica'ons/trs/areas/vaccines/stability/Microsoo%20Word%20-%20BS%202049.Stability.final.09_Nov_06.pdf

2WHOTemperatureSensiHvityofVaccines(WHO/IVB/06.10)hnp://whqlibdoc.who.int/hq/2006/WHO_IVB_06.10_eng.pdf

WHOGuidelinesonStabilityEvalua:onofVaccines1

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● ThebasisforchoosingaVVMcategoryforagivenvaccineistheAcceleratedDegrada'onTest(ADT).

● Inthistestsamplesaresubjectedtoarangeofelevatedtemperaturesatwhichsignificantandreadilydetectabledegrada'onisinducedinarela'velyshort'me.Therateatwhichdegrada'onoccursismeasuredandanalyzedinaccordancewiththeArrheniusequa'on.

● Vaccinesshouldbetestedtofailureattheseacceleratedtemperatures.

● VaccinesdonotneedtofollowtheArrheniusequa'onexactlytohaveasuitableVVMapplied.

3hnp://whqlibdoc.who.int/hq/2006/WHO_IVB_06.10_eng.pdf

WHOTemperatureSensi:vityofVaccines3

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●  Chapter7inthisGuidelineprovidesspecificrequirementsforinclusionintheproductdossiersubmissionregardingstability.

●  Chapter7.2addressesacceleratedstabilitytes'ngofthefinalproducttodefinetheVVMcategorytobeusedwiththespecificvaccine:

“TablesofacceleratedstabilitydataarerequiredtodefinetheVVMcategorytobeusedwiththespecificvaccine(stabilityat2differenttemperaturesarerequiredandtheseareusually2-8°Cand37°Cor45°C),HoweverrealHmedataestablishestheexpirydaHng.Conclusionsonstabilityandtheclaimedshelflifeofthevaccine(s)shouldbepresented.”

•  Manufacturersarestronglyencouragedtoinclude25°Casoneoftheacceleratedtesttemperatures.

4hnp://whqlibdoc.who.int/hq/2006/WHO_IVB_06.16_eng.pdf

GuidelineForthePrepara:onoftheProductSummaryFileforVaccinePrequalifica:on4

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Category (Vaccines) No. of days to end point at +37°C

No. of days to end point at +25°C

Time to end point at +5°C

VVM 30: High Stability 30 193 > 4 yearsVVM 14: Medium Stability 14 90 > 3 years

VVM 7: Moderate Stability 7 45 > 2 years

VVM 2: Least Stable 2 N/A* 225 days

VVMReac:onRates

● ThefourcategoriesofVVMareVVM2,VVM7,VVM14andVVM30.

● Thenumberfollowing“VVM”correspondstotheupperlimitindaysat37°Cforatleast95%ofVVMstoreachtheendpoint.

● ThisTableliststheupperlimitindaysat25°Cfor95%ofeachVVMcategorytoreachtheendpoint,exceptforVVM2.

● Thecri'caltemperaturesforVVM2are37°Cand5°C.VVM2isonlyusedforOralPolioVaccineandisnotincludedinfurtherdiscussion.

5  hnp://www.who.int/immuniza'on_standards/vaccine_quality/who_pqs_e06_in05_rev_july2011.pdf

WHO PQS Performance Specification – Vaccine Vial Monitor (WHO/PQS/E06/IN05)5

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● Thesetest'mesarecoincidentwiththeupperlimit'mesintheVVMPerformanceSpecifica'on.

● Thesetest'messhouldbeconsideredastheminimumrequirement.

● Addi'onaltes'ngisencouraged.● Testsshouldbecon'nuedun'lproductfailure,ifpossible.

− Forexample,donotstopthetestaoer7daysat37°C,con'nuetes'ngat14daysand30days.

− Donotstopthetestifasingleassayisbelowtheproductspecifica'on.

● Somevaccineformula'onsareverystabletowardsheatexposure.Manufacturersshouldconsiderextendingtestsat37°Cto45and60daysorlongerasappropriate.Similarlyextendedtestperiodsat25°Cshouldalsobeconsidered.

MinimumTestTimesat25°Cand37°CTest Temperature

(°C)Test Times

(days)

37 7, 14 and 30

25 45, 90 and 193

Minimum Stability Data to Support Choice of VVM Category (except OPV)

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ProductAStabilityDataandVVMCategories

051015202530353740

1

10

100

1000

10000

100000

DegreesC

DAYS

VVM30 VVM14 VVM7 VVM2

CHOOSEVVM7

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•  VVMisacri'calcharacteris'cforWHOprequalifica'on

•  SufficientstabilitydataneedstobeincludedintheProductSummaryFiletosupportthechoiceofthelongestVVMcategoryavailable

•  Accelerateddegrada'onstudiesmustbecarriedoutforsufficientdura'ontoreachendofproductlifeattheacceleratedtemperature

•  StabilitydataandVVMcategoryrequestsubminedtoWHOinProductSummaryFile

•  WHOapprovestheVVMcategoryforapar'cularvaccine

•  No'fica'onofVVMcategoryisprovidedtomanufacturerandTemp'me

Summary–VaccineStabilityandVVMCategory

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VVMsarenormallyshippedinanLD3containerwiththeVVMspackagedonawoodenpallet,

Thereceivinginspec:onprocessbeginsonthedaytheHEATmarkerVVM’saredelivered.

Alterna:vely,VVMsaresentininsulatedshipperscontainingVVMspackagedwithdryice.

ReceiptandInboundInspec:on

SOPsforIQAmustbedeveloped

• Physicalcondi'onandVVMcolor

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•  VVMsshouldbestoredatorbelow-24°Ctominimizeanymeasurablechangeinini:alstar:ngop:caldensity.–  Careshouldbetakenwhenselec'ngastorageareawithinthefreezer.–  TheVVMsshouldbekeptawayfromthedoorsoastominimizetemperature

varia'onsthatcanbeashighasseveraldegreesCelsiusandcauseprematurecolordevelopment.

–  Temperaturesduringfrozenstorageshouldbemaintainedandrecorded.

FrozenStorage

StorageVolume

• 10,000VVMsperroll

• 20rolls/carton(200,000VVMs)

• Cartonsize:23x25x41cm

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•  VVMsarereleasedbylot•  ACer'ficateofAnalysisisincludedeachlot•  Eachreceivedlotshouldbesampledandtestedaccordingtotheestablished

procedureshouldbesampledandtestedat37°CandcolorofVVMmeasuredwithdensitometer

ControlofVVMEndPointat37°C

SOPsforsampling,controltestandreleasemustbedeveloped

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•  VVMscanbeappliedmanuallyorbyautoma:clabelapplica:on–  ChengduIns'tuteofBiologicalProductsapplied10millionVVMsmanually

duringtwoyears–  StudiesbyChengdushowednodifferenceinadhesionbetweenmanualor

automa'capplica'on

•  NoVVMrequiredtemperature/humiditycontrolofenvironmentduringlabelapplica:onbyanymanufacturer–  VVMsarenormallyappliedduringfinallabelingprocess–  Somemanufacturershavevalidatedcoldstorageinfinallabelingarea

Applica:onofVVMtoVial

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Loca:onofVVMonVaccine5

Theloca'onoftheVVMonthevialdependsuponwhetherthevaccinemustbediscardedattheendoftheimmuniza'onsessioninwhichitisopened,orwhetheranyremainingcontentsinanopenedvialcanberetainedforuseinsubsequentsessions.Thefollowingcasesapply:

•Formul:-dosevialscontainingavaccinethatcanbeusedinsubsequentsessions:

Regardlessofthevaccinepresenta'on(liquid,freeze-driedortwovialcombina'onsofliquidandfreeze-dried),theVVMmustbepermanentlyanachedtothelabelofthevaccinevialandmustremainreadilyobservablebefore,during,andaoeruse,un'ltheen'recontentsofthevialhavebeenused.

•Forvaccinesthatmustbediscardedattheendofthesessionorwithin6hours,whichevercomesfirst:TheVVMmustbeanachedtothevaccinevialorampouleandmustremainreadilyobservableun'lthevialorampouleisopened,butnotobservableaoeropening.Inordertoachievethisrequirement,theVVMmustbelocatedontheflip-offtopofavialorontheneckofanampoule.

Onaproductbyproductbasis,WHOwilladviseboththevaccineandtheVVMmanufacturerwheretheVVMistobelocated.

Loca'ngtheVVMonthebonomofavialorampouleisneveracceptable–itmustalwaysbeinavisibleloca'on.

5  hnp://www.who.int/immuniza'on_standards/vaccine_quality/who_pqs_e06_in05_rev_july2011.pdf

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Automa@cApplica@onofVVMs

JapanBCG

SerumIns'tuteofIndia

Kartoglu-WHO

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ExamplesofFullLabelVVMandVVMDot

VVMDot

FullLabelVVM-VVMPrintedasPartofVialLabel

10mm

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VVMsareSuppliedonRolls10,000VVMs/roll

FullLabelVVM

VVMDot

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VVMsareAppliedDuringFinalLabeling

● PreferredtoapplyVVMinlineduringfinallabelingopera'on

● PossibletoapplyVVMasasecondaryprocess

● Ambienttemperatureandligh'ng(avoidexcessivelightexposure)

● SomemanufacturershavelocalcoldstorageofVVMinlabelingarea

PLAYKartoglu-WHO

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•  VVMs Dots are normally applied to the cap of the vial

YouTube Link to Serum Institute of India Video

http://www.youtube.com/watch?v=ytpS1SB_qGY

•  VVM Dot rectangles are applied to the neck of ampoules

VVMDotApplica:ontoCapofVialorNeckofAmpoule

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● VVM applied with existing equipment● Speeds over 400/minute in routine operation

Applica:onofFullLabelVVMtoVial

PLAY

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VVMApplica:ononPrintedLabel

ThevaccinemanufacturercandecidetoapplytheVVMdotontothe

commonlabel(printedlocally)athisfacilitybeforetheviallabeling.

Pre-printedLabel

VVMDot

PrintedLabelwith

VVM

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VVMApplica:ononPrintedLabel

1)VVMdotisappliedtopre-printedcommonlabelwithnoVVM

2)CommonlabelwithVVMisappliedtovaccinevial

CrucellCrucell

2StepProcess

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Automa:cLabelApplica:onEquipmentSuppliers

SeveralcompaniesthatarefamiliarwithVVMapplica:onare:

• Accraply(Barry-WehmillerGroup)• Bausch&Strobel• Herma(Labelworx)• Neri• MaharshiUdyogand• PharmaPack

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LessonLearned

AdhesionofVVMtocapstronglydependentoncapcomposi:onandtexture• FieldcomplaintofpooradhesionofVVMtocap–VVMslioingorcomingoff

• Raisedleneringonplas'ccapandmanefinishshouldbeavoided• Bestsurfaceisflatandglossy(shiny)

• 2ndfieldcomplaintwithdifferentmanufacturer• Capchangedandnotestofadhesionperformedpriortouse

• Noreportedproblemswithmetalcaps.Nootheradhesionproblemsreported.

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Conclusions

• SuccessfulGMPimplementa'onofVVMatlargeandsmallvaccinemanufacturersaroundtheworld

• independentofsizeofmanufacturer• VVMimplementa'onbylocalmanufacturersforlocaldistribu'oninIndiaandIndonesia

• SOPs(includingtraining)mustbeputinplaceforreceipt(IQA),storageandapplica'onofVVM

• AdhesionofVVMtocapmustbeverified

• Applica'onofVVMtovialscanbeaccomplishedatroomtemperaturebyhandorbyautoma'cequipment

•  Thanks!

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