Chlorhexidine for Umbilical Cord Care

C A S E S T U DY

Chlorhexidine for

Umbilical Cord Care

February 2012 Revised version, July 2012

Prepared for the United Nations

Commission on Commodities for

Women’s and Children’s Health

ii

Authors

JoelSegrè1,PatriciaCoffey2,MutsumiMetzler2,ShirleyVilladiego2,Neal

Brandes3,SteveHodgins4,LukeMullany5,SaulMorris6.

1ConsultanttotheBill&MelindaGatesFoundation;2PATH;3UnitedStatesAgencyforInternational

Development;4MaternalandChildIntegratedProgram;5TheJohnsHopkinsUniversityBloomberg

SchoolofPublicHealth;6theBill&MelindaGatesFoundation.

Acknowledgments

Theauthorswouldliketothankthefollowingindividualsfortheircontributions:AbraGreene,

JanetSaulsbury,JillSherman‐Konkle,andGretchenShively.

PATH’scontributiontothiscasestudywasmadepossiblebythegeneroussupportoftheAmericanpeoplethroughtheUnitedStatesAgencyforInternationalDevelopment(USAID)underthetermsof

theHealthTechCooperativeAgreement#AID‐OAA‐A‐11‐00051.ThecontentsprovidedbyPATH

aretheresponsibilityofPATHanddonotnecessarilyreflecttheviewsofUSAIDortheUS

Government.

Cover photograph credits

Photograph1:AmotherinNepallieswithherbaby.©2008Suaahara/JHUCCP;courtesyofPhotoshare.

Photograph2:AbabyinDjoliba,Mali.©2000HannahKoenker;courtesyofPhotoshare.

Photograph3:AnewbornchildsleepsnexttohismotherattheTinhGiaDistrictHealthCenterinVietnam.©2004PhilippeBlanc;courtesyofPhotoshare.

C A S E S T U D Y C h l o r h e x i d in e f o r U m b i l i c a l C o r d C a r e

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Acronyms

ASHA Accreditedsocialhealthactivist

CDK Cleandeliverykit

CHX Chlorhexidine

EMA EuropeanMedicinesAgency

EMLc Pediatricessentialmedicineslistormodellistofessentialmedicinesforchildren

FCHV FemaleCommunityHealthVolunteer

HDPE High‐densitypolyethylene

ICH InternationalConferenceonHarmonizationofTechnicalRequirementsfor

RegistrationofPharmaceuticalsforHumanUse

RCT Randomizedcontrolledtrial

RH Relativehumidity

TBA Traditionalbirthattendant

USFDA UnitedStatesFoodandDrugAdministration

WHO WorldHealthOrganization

WTP Willingnesstopay


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TableofContents

ExecutiveSummary..............................................................................................................................................v1.EfficacyandEffectivenessofChlorhexidine............................................................................................11.1.Historicaluseoftheproductandsafetyrecord............................................................................................11.2.Completedstudiesforumbilicalcordcare......................................................................................................21.3Additionalstudiesunderwayonumbilicalcordcare..................................................................................3

2.GlobalPolicyandRegulation........................................................................................................................42.1WHOguidelinesforumbilicalcordcare............................................................................................................42.2.TheWorldHealthOrganizationModelListofEssentialMedicinesforChildren............................4

3.NationalRegulatoryPolicy............................................................................................................................63.1.SouthAsiancountries:Nepal,India,Bangladesh..........................................................................................73.2.Africancountries:Zambia,Tanzania,others..................................................................................................7

4.FinancingChlorhexidine................................................................................................................................74.1Costandcost‐effectivenessdata...........................................................................................................................74.2CurrentuseinNepal..................................................................................................................................................84.3Potentialforpublicprocurement.........................................................................................................................84.4Potentialforprivatepurchase...............................................................................................................................8

5.User‐CenteredProductDesign:WhatWomenWant............................................................................95.1Formulationconsiderations....................................................................................................................................95.2Packagingconsiderations......................................................................................................................................105.3Bundlingwithcleandeliverykits.......................................................................................................................12

6.Manufacturing.................................................................................................................................................126.1Theglobalchlorhexidineindustry.....................................................................................................................126.2Thefinishedproductmanufacturer’sbusinesscase..................................................................................136.3Localversuscentralizedmanufacturingoffinishedproducts...............................................................136.4Formulationdetails..................................................................................................................................................146.5Packagingdetails.......................................................................................................................................................15

7.SupplyChainManagement.........................................................................................................................157.1Shippingconsiderations.........................................................................................................................................157.2Shelflife.........................................................................................................................................................................16

8.CultivatingDemandfromCaregivers.....................................................................................................179.CultivatingDemandfromConsumers....................................................................................................1810.MonitoringandEvaluation......................................................................................................................1811.Recommendations......................................................................................................................................19


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ExecutiveSummary

Globally,neonatalinfectionsareestimatedtoaccountforover1millionnewborndeathsannually(overathirdofthetotalburden).Inmanyregions,infectionistheleadingcauseofneonatal

mortality,andinhigh‐mortalityregionsinfectionsareresponsibleforaroundhalfofallnewborn

deaths.Manyoftheseinfectionscomefromcontaminationoftheumbilicalcordstump.

Chlorhexidinedigluconateisawidelyused,low‐costantisepticeffectiveagainstmajoragentsof

neonatalinfection.Sinceitsintroductioninthe1950s,ithasbeenusedregularlyasasurgicalanddetailantisepticandcarefullystudiedforsafetyandefficacy.Recentcommunity‐levelrandomized

controlledtrialsinNepal,Pakistan,andBangladeshhaveshownthatapplyinga4%chlorhexidine

product(7.1%chlorhexidinedigluconate)totheumbilicalcordsaveslives(thePakistanandBangladeshfindingswerepublishedinTheLancetonFebruary8,2012).Acrossthethreecountries,

datafromover54,000newbornsshowedanaggregate23%reductioninneonatalmortality(not

includingdeathsinthefirstfewhoursoflife)anda68%reductioninsevereinfectionsforthechlorhexidineinterventiongroups.Thesearesomeofthelargesteffectsizesseeninanyneonatal

intervention.

Thereareliterallydozensofmanufacturerscurrentlymakingchlorhexidine‐basedproductsaround

theworld,atconcentrationsfrom<1%to20%.Chlorhexidinedigluconate—usedtomakeavarietyofchlorhexidinefinishedproducts—isreadilyavailableoneveryinhabitedcontinentatlowcost.

Thefinishedproductforcareoftheumbilicalcordstump(4%freechlorhexidine,or7.1%

chlorhexidinedigluconate)cancostlessthanUS$0.01inrawmaterialsperbaby.Ithasalongshelflife,requiresnocoldchain,andisextremelyeasytoapplywithminimaltrainingandnoequipment.

Thesefactorsmakeitsuitableforhospital,healthcenter,andhomecarealike.Fewother

interventionshavedemonstratedsuchpotentialforrapidlyreducingnewbornmortalityacrossso

manysettingsforsuchalowcost.

Whiletherehavebeeneffortstoimproveumbilicalcordhygienebyadvocating“drycordcare,”

theseeffortshavenotalwayshadtheintendedeffectinallsettings.Millionsofmothersaroundthe

worldcontinuetohaveastrongdesiretoapplysomethingtotheumbilicalcordstumpoftheirnewborns.Intheabsenceofaspecificallyrecommendedproduct,theyresorttoavarietyof

traditionalandnon‐traditionalsubstancesincludingedibleoils,ash,dirt,andfeces.Where

consumerresearchhasbeenconducted,mothershaveshownastronglatentdemandforapurpose‐madeantisepticlikechlorhexidineandalsohavedemonstratedtheabilitytousechlorhexidine

correctly.

Nepalisthefirstcountrytohaveregisteredachlorhexidineproductspecificallyforumbilicalcord

stumpcare.Additionally,Nepalhasincludedchlorhexidineintheir2011nationallistofessentialmedicines.Oneofthelargestpharmaceuticalproducersinthecountrymanufacturesitfornewborn

careprograms.ThegovernmentofNepalhasplanstoallocatefundsinthecomingyearfor

procuringtheproductforbroaderuse.


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Severalactionsarerequiredtotakeadvantageofthisopportunity,beyondNepal,andtoaddress

oneoftheleadingcausesofneonatalmortality:

Add4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcaretotheWHO

modellistofessentialmedicinesforchildren.

CorrectthecommonmisconceptionthatWHOadvocatesdrycordcareonly.TheWHOumbilical

cordcareguidelinesrecommendthatantimicrobialsbeused“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmful

traditionalsubstance).”TheseexceptionsarerarelycitedindiscussionsofWHO’sdrycordcare

recommendationbutmayapplytomorethanhalfofallbirthsaroundtheworld.

Fasttrackregistrationof4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcarewithnationalregulatoryauthoritiesandencourageadditionalmanufacturerstoproduce

thedrugwithguaranteedminimumvolumes.

Trainbirthattendantstocorrectlyapplychlorhexidinetotheumbilicalcord,aspartofnewborn

caretrainingprograms.

Allocateresourcestointegratechlorhexidineforumbilicalcordcareintoessentialnewborncareprogramsinordertogeneratesustainabledemandandattractivemanufacturingvolumes

fortheproduct.

Throughtheseactions,wearemuchmorelikelytoseeincreaseduseofthisoverlooked

intervention,therebycontributingtohundredsofthousandsofnewbornslivessavedannually.


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1.EfficacyandEffectivenessofChlorhexidine

1.1.Historicaluseoftheproductandsafetyrecord

Chlorhexidine(digluconateorgluconate)1isabroad‐spectrumantiseptic,effectiveagainstmajoragentsofneonatalsepsis.Sinceitsdevelopmentin1950,chlorhexidine(CHX)hasbeenwidelyused

inarangeofapplicationsincludinghandwashes,preoperativebodyshower,woundcare,

cosmetics,oralhygiene,generaldisinfection,andveterinarycare.Commonformulationscanbewater‐based,alcohol‐based,gels,orpowdersandarecommonlyappliedtoadult,infant,and

neonatalskin.

Consideringtheextentofitsuseasatopicalantisepticonhumans,reportedsideeffectsarerare,

buthaveincludeddelayedreactionssuchascontactdermatitisandphotosensitivity.Today,topical

solutionsatthelowerconcentrationof0.5%chlorhexidine(4%chlorhexidinedigluconatemixedwithothersubstancessuchasisopropylalcohol)arecommonlyusedforwoundcareandarewidely

availableoverthecounterintheUnitedStatesandinothercountriesundermultiplebrandedand

genericlabels.

Inthe1970sCHXbecamepopularforneonataluseintheUnitedStatesandelsewhereashexachlorophenewasdiscontinued.BathingofnewbornsinCHX‐basedsolutionsquicklybecame

routinepracticeinmanyclinicalsettingstoreducetheoccurrenceofstaphylococcaloutbreaksin

nurseries.2,3,4,5Additionally,theWorldHealthOrganization(WHO)hasrecognizedCHXasasuitable

antimicrobialforcordcarewherenecessaryandespeciallytodisplaceharmfulcordcarepractices.6

Inrecentyears,tensofthousandsofneonateshavereceivedarangeofCHX‐basedcleansing

interventions,includingfull‐bodyandumbilicalcordcleansing,withoutreportedadverseeffects.7

TherearenoreportsofadversehealthconsequencesasaresultofabsorptionofCHXinneonates,andthereisnodatatosuggestthatthelevelsofabsorptionreportedhaveanyclinicalimportance.

Transientcontactdermatitishasbeenreportedinpretermvery‐low‐birth‐weightinfantsafterlong‐

term(>7days)placementofchlorhexidine‐impregnateddressingsforcentralvenouscatheters,and

1NOTE:Itiscommonpracticetouse“chlorhexidinegluconate”and“chlorhexidinedigluconate”interchangeablywhenreferringtotheconcentratedchemicalantiseptic.“Chlorhexidinedigluconate:isusedthroughoutthisdocumentforprecisionandconsistency.2MullanyLC,DarmstadtGL,TielschJM.Safetyandimpactofchlorhexidineantisepsisinterventionsforimprovingneonatalhealthindevelopingcountries.PediatricInfectiousDiseaseJournal.2006;25:665–675.3MaloneyMH.Chlorhexidine:ahexachlorophanesubstituteinthenursery.NursingTimes.1975;71(37):21.4RosenbergA,AlatarySD,PetersonAF.Safetyandefficacyoftheantisepticchlorhexidinegluconate.Surgery,Gynecology,&Obstetrics.1976;143(5):789–792.5TukeW.Hibiscrubinthecontrolofstaphylococcalinfectioninneonates.NursingTimes.1975;71(37):20.6WorldHealthOrganization.CareoftheUmbilicalCord:AReviewoftheEvidence.Geneva:WHO/RHT/MSM;1999.Availableat:https://apps.who.int/rht/documents/MSM98‐4/MSM‐98‐4.htm.7MullanyLC,KhatrySK,SherchandJB,etal.Bacterialcolonizationofhospital‐borninfantsinNepalandimpactofchlorhexidineskincleansing:arandomizedcontrolledtrial.PediatricInfectiousDiseaseJournal.2008;27(6):505–511.


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thusthistypeofapplicationintheseinfantsshouldbemonitoredcarefully.Overall,CHXisvery

safe.8

1.2.Completedstudiesforumbilicalcordcare

In2004,aCochranereviewconcludedthattherewasinsufficientevidencetorecommendtopical

antisepticsforpreventionofumbilicalcordinfection(RR=0.53[0.25−1.13]).9Ofthe21studies

includedinthemostrecentversionofthereview,allbutonetookplaceindevelopedcountries(onewasinaBangkoktertiarycareteachinghospital).Insuchenvironments,onlysevenstudies

reportedcordinfection,andtheoverallrateofinfectionwaslow.CHXwasonlyusedinonestudy.

Nodeathswerereportedinanyofthestudies.ThiscombinationoffactorslimitstheextenttowhichthatCochranereviewcaninformdecision‐makingaboutoptimalcordcarepracticesinthe

developingworldcontextswhereneonatalinfectionishighest.

Inrecentyears,threelargecommunity‐basedrandomizedcontrolledtrials(RCT)evaluatingthe

effectivenessofCHXforumbilicalcordcareaspartofapackageofnewborninterventionshavebeenconductedinNepal,Pakistan,andBangladesh.Asimplifiedsummaryofeachstudyisprovided

inTable1below.

Table 1. Clinical trials evaluating the effectiveness of chlorhexidine for umbilical cord care.

Study Characteristic Nepal Bangladesh Pakistan

Overall NMR* (at time of study) 30/1000 36/1000 30/1000

Percent of Births at Home (at time of study) 92% 88% 80%

Total Sample Size 15,123 29,760 9,741

Primary Outcomes Neonatal mortalityOmphalitis

Neonatal mortality Omphalitis

Neonatal mortalityOmphalitis

Comparison Group Dry cord care Dry cord care Dry cord care

Frequency of Multiple Applications (day) 1,2,3,4,6,8,10 1,2,3,4,5,6,7 Daily for 14 days

Intervention Provider Project staff Project staff TBA† and caretaker

*Neonatal mortality rate. †Traditional birth attendant.

ThefulldetailsoftheNepalstudywerepublishedinTheLancetin200610whileresultsoftheother

twotrialswerepublishedonlineonFebruary8,2012.11,12Allthreestudiesshowedsubstantial

8MullanyLC,DarmstadtGL,TielschJM.Safetyandimpactofchlorhexidineantisepsisinterventionsforimprovingneonatalhealthindevelopingcountries.PediatricInfectiousDiseaseJournal.2006;25:665–675.9ZupanJ,GarnerP,OmariAA.Topicalumbilicalcordcareatbirth.CochraneDatabaseofSystematicReviews.2004;(3):CD001057.10MullanyLC,DarmstadtGL,KhatrySK,etal.TopicalapplicationsofchlorhexidinetotheumbilicalforpreventionofomphalitisandneonatalmortalityinsouthernNepal:acommunity‐based,cluster‐randomizedtrial.TheLancet.2006;367:910–918.11SoofiS,CousensS,ImdadA,BhuttoN,AliN,BhuttaZA.TopicalapplicationofchlorhexidinetoneonatalumbilicalcordsforpreventionofomphalitisandneonatalmortalityinaruraldistrictofPakistan:acommunity‐based,cluster‐randomisedtrial.TheLancet.PublishedonlineFebruary8,2012.


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reductionsinneonatalmortality(20%to38%)andevengreaterreductionsinomphalitis(24%to75%)intheCHXgroups.Severalgroupshaveconductedmeta‐analysesusingthedataasreported,

andtheunpublishedanalysessuggestreductioninmortalityofapproximately20%to23%.More

formalmeta‐analysesaredueforpublicationinthecomingmonths.

Additionally,Hodginsetal.publishedatrialshowingthenon‐inferiorityof4%CHXgelto4%CHXliquid.Thestudy,basedinKathmandu,recruited653neonatesinahospitalsettingandshowed

that24hoursafterapplication,liquidCHXoffereda64%reductionintheproportionofsamples

positiveforbacteria,whereasgelCHXofferedan86%reductionintheproportionofsamples

positiveforbacteria.13

Overall,thereiscurrentlysufficientevidencetorecommenda4%CHXproduct(7.1%CHX

digluconate)forumbilicalcordcleansingasastrategytoreduceneonatalmortalityinsettingswith

poorhygieneandhighneonatalmortality.

1.3Additionalstudiesunderwayonumbilicalcordcare

TwoadditionalRCTsareunderwaytodeterminetheeffectivenessofCHXinAfrica.Bothare

expectedtoreportresultsin2014.

Table 2. Clinical trials currently under way.

Pemba (Tanzania) Zambia

Institutional Lead The Johns Hopkins University Boston University

Trial Type Individually randomized, double‐blind, placebo‐controlled trial

Cluster randomized, unmasked comparison versus “dry” cord care

Sample Size 24,000 + additional 4,000 42,570 (90 clusters)

Product Type 10‐mL dropper bottle of liquid 4% CHX(7.1% CHX digluconate)

10‐mL dropper bottle of liquid 4% CHX(7.1% CHX digluconate)

Delivery Method Project staff demonstrate for mothers four times, mothers apply in other cases

Mothers

Intervention Duration 10 days, or three days after the stump separates, whichever is longer

Ten days, or three days after the stump separates, whichever is longer

Outcomes Primary: mortality. Sub‐study will examine impact on omphalitis as well as the etiology, sensitivity, and specificity of diagnosing omphalitis

Primary: mortality, Secondary: Incidence of omphalitis through 28 days

12ElArifeenS,MullanyLC,ShahR,etal.TheeffectofcordcleansingwithchlorhexidineonneonatalmortalityinruralBangladesh:acommunity‐based,cluster‐randomisedtrial.TheLancet.PublishedonlineFebruary8,2012.13HodginsS,ThapaK,KhanalL,etal.Chlorhexidinelotionvs.aqueousforpreventativeuseonumbilicalstump:arandomizednon‐inferioritytrial.PediatricInfectiousDiseaseJournal.2010;29(11):999–1003.


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2.GlobalPolicyandRegulation

2.1WHOguidelinesforumbilicalcordcare

ThereisacommonmisconceptionthattheWHOguidelinesadvocatefortheexclusiveuseofdrycordcare.Infact,inthe1999WHOdocumententitled“CareoftheUmbilicalCord:AReviewofthe

Evidence”WHOrecommendsthattopicalantimicrobialsbeusedonthestumpaftercuttinginhome

deliveries“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmfultraditionalsubstance).”14Additionally,WHOrecommends

thatininstitutionaldeliveries,antimicrobialsmaybeused“accordingtolocalsituation”and

specificallyidentifiesCHXasoneoffiverecommendedantimicrobialagents.

2.2.TheWorldHealthOrganizationModelListofEssentialMedicinesforChildren

The2011WHOModelListofEssentialMedicinesforChildren(EMLc)15includesCHXforumbilical

cordcareundersection15.DISINFECTANTSANDANTISEPTICS,subsection15.1Antiseptics.The

listingisasfollows:

Chlorhexidine

Solution:5%(digluconate);20%(digluconate)(needstobedilutedpriortouseforcord

care).

The17thExpertCommitteeontheSelectionandUseofEssentialMedicinesconvenedbyWHOin2009concludedthatdatafromacommunity‐based,cluster‐randomizedtrialinNepalshoweda

significantreductioninneonatalmortalityafteruseofa4%CHXsolution(7.1%CHXdigluconate)

forumbilicalcordcare.ThiswassufficienttoincludesuchaproductandindicationforuseintheWHOEMLc.Nevertheless,duetotheabsenceofacommerciallyavailable4%CHXproductatthat

time,thisrecommendationoftheexpertreviewcommitteeresultedinlisting20%CHX

(digluconate)withaninstructiontodiluteforumbilicalcordcareuse.Atthetimeofpublicationofthe2009WHOmodellist,PATHandtheUSAgencyforInternationalDevelopmentsubmittedajoint

lettertotheWHOexpertreviewcommitteestatingthattheindicationwasnotclearandsuggesting

thatitshouldberevisedtostipulateuseof4%CHXforumbilicalcordcare.WHOrespondedby

sayingthatsuchanissuewouldbetakenupduringthenextreviewoftheEMLcin2010–2011.

Clarityontheuseof4%CHXforumbilicalcordcareiscriticalbecausethereisaverycommon

confusionaroundtheconcentrationsoffreechlorhexidineversuschlorhexidinedigluconate.The

conversionbetweenthetwoislistedinTable3below.Itisworthnotingthatthecurrentlistingof5%CHXdigluconatewoulddeliverapproximately2.8%freeCHX,alevellowerthanwhatwasused

14WorldHealthOrganization.CareoftheUmbilicalCord:AReviewoftheEvidence.Geneva:WHO/RHT/MSM;1999.Availableat:https://apps.who.int/rht/documents/MSM98‐4/MSM‐98‐4.htm.AccessedFebruary10,2012.15WorldHealthOrganization.ModelListofEssentialMedicinesforChildren.3rdlist.Geneva:WHO;March2011.Availableat:http://whqlibdoc.who.int/hq/2011/a95054_eng.pdf.AccessedFebruary10,2012.


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intheRCTsforumbilicalcordcare.Ifoneisnotawareofthisdifference,onemaysee5%CHXontheEMLcandincorrectlythinkthatonedoesnothavetogothroughanyin‐countryregulatory

processbecausethe5%ishigherthanthe4%forumbilicalcordcare.

Table 3. Free chlorhexidine versus chlorhexidine digluconate.

Chlorhexidine Digluconate Free Chlorhexidine Notes

20% 11.3% Concentration listed on the EMLc

7.1% 4.0% Concentration used in the RCTs in five countries

5% 2.8% Concentration listed on the EMLc

Toavoidthisconfusion,theEMLcshouldstate:

Chlorhexidine

7.1%chlorhexidinedigluconatesolutionorgel,delivering4%chlorhexidineforumbilical

cordcare.

In2010,PATHsubmittedanamendmentwithadditionaldatatotheWHOexpertreviewcommittee

tosupporttheclarificationoftheindicationforuseofCHXforumbilicalcordcarebystipulatinguse

of4%CHXineithergeloraqueoussolution.TheexpertcommitteedecidedtomaintainthepreviouslistingforCHXuntilaproductofthestrengthandformulationusedinthetrialsis

commerciallyavailable(i.e.,availabilityoftheproductontheopenmarket,notjustfortrial

purposes).Specifically,TheUneditedReportof18thExpertCommitteeontheSelectionandUseof

EssentialMedicines(21to25March,2011)notedthat:

“Theproblemremainsthat,asin2009,acommerciallyavailablepreparationof7.1%chlorhexidinedigluconatesolutionorgel(delivering4%chlorhexidine)isnotyetavailable.

Whilethe20%requiresdilutionandmanipulationandisclearlynotoptimal,untilthereis

acommerciallyavailableproductofthestrengthandformulationusedinthetrials,thecurrentlistingcannotbeamended.However,theCommitteenotedthatanoptimized

4%chlorhexidineislistedasoneofthepriorityproductsfordevelopmentbyWHOonthe

PriorityMedicineslistformaternalandchildhealthandthereforeflaggeditasa‘missing’

essentialmedicine,giventheimpactonmortalitysuggestedinthetrials.”

Today,thereisonecompany,LomusPharmaceuticalsPvt.Ltd(Kathmandu,Nepal),producinga4%

CHXproductcommercially.Ithasbeeninuseinfourdistricts(andalargerprocurementis

currentlyunderway),butcouldbemadeavailableforsaleanywhereinthecountryandforexport.LomushasregisteredtheproductwiththeDepartmentofDrugsAdministrationinNepal.

Additionally,4%CHX(7.1%CHXdigluconate)isonNepal’snationalessentialmedicineslistfor

2011asasolutionorgelforumbilicalcordcare.Thisdatamayhelptoadd4%CHX(7.1%CHX

digluconate)totheWHOEMLc.


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3.NationalRegulatoryPolicy

CHXisincludedinsomenationalessentialmedicineslists,butNepalistheonlycountryknowntohaveaddedittotheirnationalessentialmedicineslistata4%concentrationforumbilicalcord

care.Inothercountriesitisnotatthecorrectconcentrationforumbilicalcordcare.Experiencein

BangladeshandNepaltodatedemonstratesthatCHXforumbilicalcordcarehasbeenclassifiedbycountryregulatoryagenciesasamedicine,andtheproductisrequiredtoberegisteredincountry

withtheappropriatedrugauthority.Over‐the‐counterdistributionoftheproductisindependentof

theneedtoregistertheproductasamedicine.

In2011,PATHreviewedvariousglobalregulatorypathwaysforCHXforumbilicalcordcare.

PathwaysinvestigatedincludedUnitedStatesFoodandDrugAdministration(USFDA),EuropeanMedicinesAgency(EMA),WHOprequalificationofmedicines,andacountry‐by‐countryapproach.

TheresultsofthisreviewsuggestthattheEMAprocedure(termedArticle58)mightappeartobe

promisingincertainrespects.Article58wasestablishedin2004tofacilitatedeveloping‐country

registrationofmedicinestopreventortreatdiseasesofmajorpublichealthinterest.

PerArticle58requirements,sincetheCHXproductisasimpleformulation,regulatoryassessment

ofthemanufactureandcontrolofthisdrugproductwouldbeconsideredtobestandard.Results

fromclinicaltrialsinSouthAsiaarealsoavailable;however,certainfactorsmakethisoptionless

thandesirable:

SignificantresourcesarerequiredtocompleteanArticle58applicationandmaintainthe

positivescientificopinionresultingfromsuccessfulsubmission.Itisquestionablewhethersuch

costcouldbejustifiedwhenusingpublicfunds.Also,itmightnotmakesensetomakesuchan

investmentofseveralhundredsofthousandsofdollarswhenrevenuesareexpectedtobelow.

Theholderofthepositiveopinionhassubstantialresponsibilities,includingpost‐opinion

submissionofresultsfromanyongoingandfutureclinicaltrialsandprovisionofadditional

informationontheproduct’sefficacyandsafety.Althoughanonprofitorganizationcanbeanopinionholder,itisquestionablewhetheranonprofitorganizationwouldbewillingtoassume

thosesubstantialresponsibilitiesonanongoingbasis.

Manufacturerswouldneedtoensuremanufactureoftheproductfromcertifiedsourcesof

activeingredientsifthemanufacturersweretopursueArticle58.Thismightincreasecostsand

thereforepricingoftheproduct.

RegistrationoftheCHXproductonacountry‐by‐countrybasiswouldstillneedtobe

undertaken.

Consideringtheabove,acountry‐by‐countryapproachwouldappeartobethebetterapproachto

taketosecureregistrationforaCHXproduct.AnexpertconsultationwithWHOshouldtakeplaceafterpublicationofrecentRCTresultsinBangladeshandPakistan.Favorablefindingsfromthis

consultation,alongwithanupdatedlistingontheEMLc,willlikelyfacilitateregulatoryreviewsat


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thecountryand/orregionallevel.ObtainingWHOprequalificationcouldbeexploredconcurrently

ifthisapproachisdeterminedtobereasonableconsideringtimeandresourcerequirements.

3.1.SouthAsiancountries:Nepal,India,Bangladesh

Country‐levelregulatoryprocessesvaryfromcountrytocountry.Acountry‐levelregistration

processshouldonlybeundertakenwheretheCHXproductinterventionwillberolledoutinthe

samecountry.Thisisthecase,forexample,inNepal,wheretheinterventionhasbeenrecentlyapprovedbytheMinistryofHealthandPopulationandtheproducthasobtainedregistrationin

country.InBangladesh,forexample,registrationwouldbeverystraightforwardtoobtainby

PopularPharmaceuticalLtd,themanufactureroftheproductusedinthemostrecentstudy.However,theywouldneedanincentivetodo(i.e.,assuranceofmarketdemand)thatcouldbe

demonstratedbyanenablingpolicyenvironmentandfirmsupportfortheinterventiononthepart

oftheMinistryofHealthandotherkeystakeholders.WhileIndiamayappeartobeagoodentrypointforproductregistrationintheregion,productregistrationissubjecttoapprovalbytheDrug

ControllerGeneralofIndia,andthedatarequirementsforapprovalareyettobedetermined.

3.2.Africancountries:Zambia,Tanzania,others

GiventhestatusofongoingRCTsinZambiaandTanzania,nationalregulatoryauthoritieswilllikely

bemostinterestedinproductregistrationaftertheRCTsarecompleted.IfRCTresultsarefavorable,andcorollaryministryofhealthpolicyandstakeholdersaresupportiveofthe

intervention,itispossiblethatthattheproductcouldberegisteredrelativelyeasily.Regulatory

approvalobtainedinonecountrymaybeappliedtoothercountriestherebyfacilitatingmarketclearanceinsub‐SaharanAfrica.Somecountriesintheregion,however,mayprefertohavemore

localizeddataabouttheinterventionbeforegivingmarketclearancefortheCHXproduct.

4.FinancingChlorhexidine

4.1Costandcost‐effectivenessdata

Assumingthateverybabyrequires3gofa4%CHXproduct(asisprovidedintheNepalprograms),

afinishedpharmaceuticalproductcostslessthan$0.005inrawmaterialsandanadditional$0.09‐

0.15inpackagingcosts.PreliminaryestimatesofcosteffectivenessfromacosteffectivenessstudyinSylhet,Bangladesh,suggestthatwhenumbilicalcordcleansingwitha4%CHXproductisadded

toaplatformofcommunity‐basedmaternalandnewbornhealthservices,themeanincremental

costperdisability‐adjustedlifeyear(DALY)avertedislessthanUS$10.00.16,17,18

16NOTE:Costswerederivedincrementallyontopofexistingplatformsofmaternalandnewbornhealthservices,fromaprogramperspectiveandincludedoperationalandsupportcostsaswellascostsassociatedwithproductdeliverythroughvillagehealthworkersandsupervisingcommunityhealthworkers.Costsmaybehigherorlowerinnon‐effectivenesstrialsettings,and/orwhereanexistingplatformandinfrastructureforcommunity‐basedmaternalandnewbornhealthdoesnotexist.


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4.2CurrentuseinNepal

CHXforumbilicalcordcareiscurrentlyusedinfourdistrictsofNepal(Parsa,Banke,Jumla,andBajhang).Todate,theprogramshavebeendonorfinanced,effectivelyworkingas“atscale”

demonstrations.Giventhestrongresultsinthesepilots,theGovernmentofNepalisintheprocess

ofcreatingabudgettoprocureCHXfromalocalmanufacturer(LomusPharmaceuticals)fordistributionprimarilyviaFemaleCommunityHealthVolunteers(FCHV).Donorfundingislikelyto

supportcontinuedprocurementfortheFCHVsuntilgovernmentfundingisavailable(expectedin

2013).TheLomusproductislistedwithamaximumretailpriceof18NepaliRupees(approximatelyUS$0.22)forasingleapplication,buttheactualtransferpricebetweenLomusand

theGovernmentofNepalisnotknownatthistime.Additionally,Lomushopestoselltheproduct

viaitstraditionalretailchannels.

4.3Potentialforpublicprocurement

ThelowcostofCHX—andparticularlythelowcostperlifesaved—makesitamongthe“bestbuys”inneonatalhealthandanexcellentcandidateforpublicprocurementincountrieswithhigh

mortalityduetoneonatalinfection.

4.4Potentialforprivatepurchase

Themajorityofhealthcareexpenditureinmuchofthedevelopingworldisprivateexpenditure,

andthecountrieswhereneonatesdiefrominfectionsarenoexception.Table4belowshows

privateexpenditureonhealthasapercentageoftotalexpenditureonhealthforselectedcountries.

17NOTE:ThisestimatefallsbetweenchildhoodimmunizationsforTB,DPT,polioandmeasles($8.00);andothercommonprogramslikeHIV/AIDSservicesvoluntarytestingandcounseling,ARVstopreventverticaltransmission,etc.($68);surgicalservicesandemergencycare($109);communitycasemanagementofchildhoodpneumonia($146);andmaternalandnewborncare,inclusiveofincreasedprimarycare,targetednewborncare,andimprovedemergencyandnewborncare($261).18MusgroveP,Fox‐RushbyJ.Cost‐effectivenessanalysisforprioritysetting.In:JamisonD,BremanJG,MeashamAR,etal.,eds.DiseaseControlPrioritiesinDevelopingCountries(2ndedition).Washington,DC:TheWorldBankandOxfordUniversityPress;2006.


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Table 4. Private expenditure on health as a percentage of total expenditure on health.

Country Annual Estimated Neonatal Deaths from Infection*†

% Private Expenditure‡

India 405,848 68%

Nigeria 150,459 63%

Pakistan 119,122 68%

DR Congo 109,091 46%

Ethiopia 66,159 48%

Bangladesh 45,722 69%

Tanzania 32,037 28%

Zambia 14,461 38%

Nepal 9,004 62%

*Source: Liu L, Johnson HL, Cousens S, et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012;379:2151–2161. †Partnership for Maternal, Newborn & Child Health. ‡Source: WHO; 2008.

Private‐sectorsalesareoftenanimportantcomplementtopublic‐sectorprovision.Asarelativelylow‐cost,easy‐to‐useproductwithalongshelflife,CHXmaybeparticularlywellsuitedtoprivate‐

sectorsales.Dataonwillingnesstopay(WTP)specificallyforCHXisscarce,butthedatainTable5

providessomeindicationforSouthAsia.

Table 5. Willingness to pay in South Asia.

Country WTP Range in US$ Type Source Year

Nepal $0.05–$0.06 TBAs’ stated WTP Tuladhar et al. 2007

Bangladesh $0.42–$0.70 Actual purchases Winch et al. 2009

Bangladesh $0.21–$0.85 Mothers’ stated WTP ICDDR,B 2010

India (urban) $0.50–$0.70 Mothers’ stated WTP Synovate 2011

India (rural) $0.30–$0.40 Mothers’ stated WTP Synovate 2011

TheseWTPfiguresare50%to200%greaterthantheprojectedwholesalecostofCHX,leaving

potentialretailmarginsforprivate‐sectordelivery.

5.User‐CenteredProductDesign:WhatWomenWant

Umbilicalcordcareisaculturallymediatedpracticewhereinconsumerpreferencesareakeydriverofwhatproductsareultimatelyadoptedanddiscarded.Inmanycommunities,thereisa

deepdesiretodressthecordwithsomething,butpracticesvarywidely.Thoughtfulcombinationof

formulationandpackagingmayincreasetheproduct’sadoptioninaspecificcommunity.

5.1Formulationconsiderations

BasedontheclinicaltrialsconductedinSouthAsiancountriesandasubsequenttesttoestablishnon‐inferiorityofthe4%CHXgel,theproductcanbeformulatedintoeitheraqueoussolution

(liquid)orgel.Table6illustratesseveraleffortstoassessuserpreferencesinregionsofinterest.


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Table 6. Efforts to understand user preferences.

Country Preference Notes

Bangladesh Gel

In 2010, PATH and ICDDR,B assessed the demand for the product among potential users (women who were currently pregnant or had a child over the last six months, and their husbands). The study indicated that when shown concept cards depicting a gel formulation and an aqueous solution 63% of the respondents (1,109 people) preferred gel formulation over aqueous solution. However, the price they were willing to pay did not differ significantly between the two formulation concepts.

Nepal Gel

The randomized non‐inferiority trial conducted in Nepal in 2009 included questions regarding user preference of dosage forms. Of the 30 subjects originally given gel (excluding those woman reporting a negative experience), 2 preferred aqueous. However, over half of those using aqueous indicated they would have preferred gel (17/30), believing that it would stay in place more easily and be longer lasting.

India Gel

In 2011, a consumer research group polled mothers, mothers‐in‐law, and caregivers in Uttar Pradesh for product preferences using an unlabeled tube of Lomus 4% gel and an unlabeled 70‐ml bottle of aqueous. The majority of respondents across all participant groups preferred the gel.

Tanzania Liquid

The Pemba study looked at consumer preferences for aqueous formulations in 10‐ml and 100‐ml bottles as well as tubes of gel formulations. 44.6% of mothers preferred the 10‐ml bottle, 33.9% preferred the tube of gel, and 21.5% preferred the 100‐ml bottle.

Zambia Liquid

The Zambia study looked at 10‐ml and 100‐ml liquid presentations as well as tubes that would contain a gel formulation. Unfortunately, the tubes did not contain CHX gel (a major limitation of the study) and were therefore not popular among respondents.

5.2Packagingconsiderations

Primarycontainerforliquid.BoththeNepalandBangladeshtrialsusedawhiteBostonround

bottleastheprimarycontainer(aBostonroundbottlecanbeseeninFigure1below)andacottonballastheapplicator.IntheoperationsresearchconductedinBangladesh,awhitehigh‐density

polyethylene(HDPE)bottlewithanozzlewasselectedasthematerialfortheprimarycontainerfor

the4%CHXaqueoussolutionbecause:1)HDPEisthemostcommonplasticmaterialforCHXdigluconate‐baseddrugs,2)thecolorwhiteprotectsCHXdigluconatefromsunlight,and3)the

nozzleminimizesoccasionsinwhichusersdirectlycontacttheumbilicalcord.Theresultsfromthe

followingtwostudiesledtoselectingthewhiteHDPEbottlewithanozzle:

PATHconductedaproductattributestudyin2008.Thisstudycomparedthesethreeoptions:1)whiteHDPEbottlewithanozzle,2)whiteBostonroundbottle,and3)amberglassbottle.

ResultsindicatedthatthewhiteHDPEbottlewithanozzlewastheoptionmostpreferredby

usersandserviceproviders(141outof165respondents[or85.5%]chosethisoption).

ThepretestingthattheProjahnmostudygroupconductedwithhealthcounselorsin2008indicatedthatthe4%CHXaqueoussolutionwasproperlyappliedtotheumbilicalcordwitha

nozzlebottleandconfirmedtheirdecisiontoselectanozzlebottleastheprimarycontainer.


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Primarycontainerforgel.InNepal,apreprintedaluminumtube(acommonprimarycontainerforsemi‐soliddrugproducts)wasselectedforthe4%CHXgelformulation.Whileothertypesof

primarycontainerscouldbeapplicablefor4%CHXgelincludingsachetsandplastictubes,

consumerresearchsuggestedthatmothersandcaregiversassociatedthistypeofpackagingwith

pharmaceuticalproductsandgoodhealth.

Secondarypackaging.TheoperationsresearchinBangladeshdidnotutilizeasecondarypackage.

TheinformationrequiredbythedrugauthorityinBangladeshwasprintedonalabeldesignedby

themanufacturer,whichwasattachedtotheprimarycontainer.PictorialinstructionsforuseweredevelopedthroughcollaborationamongProjahnmostudygroupmembers,PATH,andPopular

Pharmaceuticalsinordertosupplementtheinstructions‐for‐usetextprintedonthelabel.These

supplementalpictorialinstructionswerethenattachedtothecontainerwitharubberband.InNepal,thealuminumtubecontaining4%CHXgelwaspackagedinasmallpaperboxpreprinted

withlabelinginformation.

PleaseseeFigure1belowforpackagingexamplesandFigure2forexamplesofinstructionsforuse.

Figure 1. Liquid primary packaging as produced by a manufacturer in Bangladesh for study purposes only (left); primary and secondary packaging of gel product as produced by Lomus in Nepal (right).


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Figure 2. Pictorial instructions for use used in Nepal (left) and Bangladesh (right).

5.3Bundlingwithcleandeliverykits

SomehaveadvocatedthebundlingofaCHXproductwithcleandeliverykits(CDK)asawaytoincreaseavailabilityanduseoftheproduct.Todate,suchbundlinghasnotoccurred.InNepal,CHX

willnotbebundledwiththecleandeliverykitcurrentlybeingdistributedbyContraceptiveSales

Company.InBangladesh,physicallybundlinga4%CHXproductwithaCDK(puttingCHXandCDKintothesamepackage)willlikelyrequireadditionalregulatoryapprovalsinceCHXisa

pharmaceuticalproductandtheothercontentsoftheCDKarenot.Insteadofbundlingthetwo

products,nongovernmentalorganizationsthatdistributeCDKsmayusetheirowndepotholdersorcommunityworkerstopresenttheCHXandCDKconcurrentlyandexplainhowusingbothcouldbe

beneficial.

6.Manufacturing

6.1Theglobalchlorhexidineindustry

Chlorhexidinedigluconateisbroadlyavailablearoundtheworldbothinitsbulkdrugformof20%

chlorhexidinedigluconateandinmyriadfinishedproducts.InIndiaalonethereareover70brands

offinishedCHXproductsforsalefromover60differentcompanies.Theproducthasapplicationsasbothapreservativeandactiveingredientacrossabroadrangeofveterinary,dental,andother

healthcareapplications,assummarizedinTable7.

Table 7. Various uses for chlorhexidine.

Application Concentration of chlorhexidine digluconate

Veterinary 20%

Mouthwashes, toothpastes, oral rinses 0.12%–0.2%

Skin prep for surgery, procedural hand washing 0.5%–4%

Wound treatment 4%


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Thedrugmonographof20%chlorhexidinedigluconateislistedinUnitesStates,UnitesKingdom,European,andJapanesepharmacopeias.Therearealsomorethan50vendorsofbulk20%

chlorhexidinedigluconateconcentrate,severalofwhichhaveDrugMasterFileswithUSFDA.The

bulkproductistypicallysoldin200kgdrums,andtherearesufficientbufferstocksoneveryinhabitedcontinent.CommoditypricingforthisproductisoftenintherangeofUS$4.50per

kilogram.

Assumingthateverybabyrequires3gofa4%CHXproduct(asisprovidedintheNepalprograms),

thetotalrequirementof20%CHXdigluconatewouldbejustover1,000Lpermillionchildrentreated,orjustfivedrumsofactivepharmaceuticalingredientpermillionnewborns.Globalsupply

oftheactivepharmaceuticalingredient,therefore,isunlikelytobeaconcern.

6.2Thefinishedproductmanufacturer’sbusinesscase

CHXforumbilicalcordcareisalow‐volume,low‐marginproductwithfewbarrierstoentry.Ifthe

productisusedinallbirthsinagivenregion,annualsaleswouldcorrelatewithcrudebirthratesof30–50birthsperthousandinhighfertilityareas.Thisisarelativelylowsalesvolumewhen

comparedwithotherpharmaceuticalmanufacturingopportunitiesformorecommonlyusedover‐

the‐counterproducts.MarginsforCHXarelikelytobesimilarlylacklusterforaproductwhichisinthepublicdomain(notpatentable)andquitesimpletomake.Thecombinationofthesefactors

meansthatlargepharmaceuticalcompaniesareunlikelytotakeaninterestinindependent

manufactureanddistributionofCHXforumbilicalcordcare.Institutionalbuyersandlargevolumeordersaremorelikelytoattracttheattentionofpotentialmanufacturers,similartowhattookplace

withLomusPharmaceuticalsinNepal.

6.3Localversuscentralizedmanufacturingoffinishedproducts

ThereareseveralreasonstoconsiderlocalmanufacturingofaCHXproductforumbilicalcordcare.

Capitalcostsofmanufacturingarerelativelylow,andstandardequipmentfoundinmostpharmaceuticalcompanieswouldbeused.Themanufacturingprocessissimpleandrobustenough

tobeeasilyreplicated.Bulkchlorhexidinedigluconatecanbepurchasedin200‐kgdrumsoreven

20‐kgpails.SmallamountsofthebulkdrugyieldalargevolumeoffinishedCHXproductforumbilicalcordcare.Forexample,a20‐kgpailofchlorhexidinedigluconatecanserveabout20,000

newbornsatthedoseanddurationusedinNepal.Localmanufacturingcanalsosimplifylocal

regulationwhereindigenouspharmaceuticalcompaniesmaybebetterequippedthanforeignfirms

tonavigateanapprovalprocess.

Centralmanufacturingalsohassomebenefits.Asingle,centralmanufacturermaybemore

compelledbythebusinesscaseofmanufacturingaveryhigh‐volume,low‐costproduct.Andshould

therebeapooledprocurement,acentralizedmanufacturerwouldalsosimplifylogisticsandqualitycontrol.Theshelflifeat40°Cwith75%relativehumidity(RH)issufficienttowithstand

warehousingandshippinginmostclimates.


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Ultimately,thechoiceoflocalversuscentralmanufacturingshouldbemadeforbusinessreasons,dependingonwhattypeofmanufacturerisabletoofferthemostcompetitivepriceontheshortest

timeline.

6.4Formulationdetails

CHXforumbilicalcordcaremaybeformulatedasatopicalgelorliquid,whichhaveverysimilar

manufacturingprocesses,asdiagrammedbelowinFigure3—theonlydifferencebeingtheaddition

ofguargum(boxwithdottedlines)tothickentheproductintoagelifdesired.

Figure 3. Potential manufacturing processes.

SomemanufacturershavechosentoaddsmallamountsofbenzalkoniumchloridetoCHXproducts

asapreservative,butstabilitytestsconductedbyPATHhaveshownthatthismaynotbeacrucial

addition.Additionally,somemanufacturershaveaddedperfumeandcoloringasperconsumer

preferences.

Overall,theinputsforCHXmanufacturingareinexpensive.Onerepresentativeformulationforgel

isdetailedbelowinTable8.

Table 8. A representative formulation for chlorhexidine gel.

Formula Component Formulation Cost in US$ per 3 g Source

20% CHX gluconate/digluconate, BP* 7.10% $0.004795 Viporchemicals.com

50% benzalkonium chloride (optional) 0.10% $0.000000 Alibaba.com

Guar gum, NF† 1% $0.000060 Alibaba.com

Sodium hydroxide, NF pH to 6.0 $0.000009 Alibaba.com

Purified water, USP‡ Remainder $0.000001 (estimated water tariffs)

Total $0.004865

*British Pharmacopoeia. †National formulary. ‡United States Pharmacopeia.


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6.5Packagingdetails

PackagingisresponsibleformostofaCHXproduct’scost.Forliquidformulations,bottlesorsachetsmaybeused.DropperbottleshavebeenusedinalloftheRCTstodateandtypicallycost

aroundUS$0.15eachincludingfilling.Sachetsmaypackmoretightlyandshipmoreeasilyand

oftenhavepackingandfillingcostsintherangeofUS$0.01inIndia.

TheonlyCHXproductpackagedforretailsalesismadebyLomusPharmaceuticalsinKathmandu.Basedonuserfeedback,theirpackagingincludesatubeforthegel,afullcolorinstructional

packageinsert,andanouterbox(pleaserefertoFigures1and2above),totalingapproximately

US$0.09(Table9).

Table 9. Packaging costs example.

Packaging Component US$ per Unit Source

Preprinted collapsible aluminum tube $0.04 Perfect Tubes Pvt

Printed paperboard box $0.04 Lomus Pharmaceuticals

Printed color package insert <$0.01 Lomus Pharmaceuticals

Total $0.09

7.SupplyChainManagement

7.1Shippingconsiderations

Temperature,pHlevel,andexposuretosunlightadverselyaffectthestabilityofCHXdigluconate,

theactiveingredientof4%CHXforumbilicalcordcare.WhenCHXdigluconateiskeptundersuboptimalconditions,itdegradestop‐chloroanilineanditspurityiscompromised.Accordingto

theUSPharmacopeia,a20%aqueoussolutionofCHXdigluconateshouldmaintainitspHrange

between5.5and7.0.Italsostatesthat20%CHXdigluconateshouldbepreservedinatightcontaineratroomtemperatureandbeprotectedfromlight.Theserequirementsshouldalsobe

maintainedforshippingandstoring4%CHXforumbilicalcordcare.

Inaddition,selectinganappropriateprimarycontainerisimportantinordernotonlytomaintain

thequalityoftheproductbuttominimizeitsshippingcost.ThequalityoftheCHXdigluconatewouldbebestpreservedwithneutralglassorpolypropylene.Also,transparentprimarycontainers

shouldbeavoidedinordertoprotectCHXdigluconatefromlight.Acommonlyusedprimary

containerforcommerciallyavailableCHXdigluconate‐basedproductsisHDPEsinceitislighterthanglass(thusreducesshippingcost)anditmaintainsproductquality.Asanexample,Medichem

S.A.(Barcelona,Spain),oneofthe20%CHXdigluconatemanufacturerslistedintheDrugMaster

FilesubmittedtotheUSFDA,providesitsproductina200‐kgHDPEdrum.Inanycase,manufacturersshouldperformcompatibilitytestsaccordingtolocalregulationsinordertoconfirm

theappropriatenessoftheselectedprimarycontainers.


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7.2Shelflife

Adrugproduct’sshelflifeisthelengthoftimeduringwhichitisconsideredsuitableforsale,use,orconsumption.Shelflifeisaffectedbytemperature,humidity,andlight.Forthisreason,accordingto

InternationalConferenceonHarmonizationofTechnicalRequirementsforRegistrationof

PharmaceuticalsforHumanUse(ICH),eachcountryisclassifiedintooneoffourclimaticzoneswithdefinedstorageconditionsfordrugsubstancesandproducts(seetablebelow).Basedonthis

classification,inSouthAsia,BangladeshandIndiaarebothassignedtoZoneIV,whereasNepalis

assignedtoZoneII.InAfrica,TanzaniaisassignedtoZoneIVwhereasZambiaisassignedtoZoneII.

Table 10. Climatic zones for shelf life.

Climatic Zone Definition Storage Condition

I Temperate climate 21°C/45% RH

II Subtropical and Mediterranean climates 25°C/60% RH

III Hot, dry climate 30°C/35% RH

IV Hot, humid climate 30°C/70% RH

Source: ICH Q1F Guideline, “Stability Data Package for Registration in Climatic Zones III and IV.”

Manufacturersof4%CHXproductsmustperformstabilitytestsusingtheprimarycontainerthat

theyselectedfortheirproductsinordertoestablishtheirproductshelflifeunderthestorageconditionsassignedtothecountryinwhichtheproductswillbedistributedandused.Stabilitytests

canbeperformedusingacceleratedconditions(e.g.,ingeneral,40°C±2°C/75%RH±5%RHfor6

monthsforclimaticzonesIIIandIV).InadditiontothisICHguideline,manufacturersneedtocheckwiththeirlocaldrugregulatoryauthoritytoascertainwhetherthereareanyadditional

requirements.

In2009,PATHcommissionedacontractlaboratoryintheUnitedStatestoperformstabilitytestson

the4%CHXaqueoussolutionandgel.Testingwasconductedunderthefollowingprotocol:

Primarycontainer:4‐mLHDPEbottleandpolypropylenescrewclosure(materialscommonly

usedforcommercialCHX‐basedproducts).

Testingconditions:5°C,25°C/60%RHand40°C/75%RHtoestablish24‐monthstability.

Testedat:0,1,3,and6months.

Testedfor:appearance,pH,potency,andamountofp‐chloroanilinepresent(asubstancethatis

producedwhenCHXisdegraded).

Bothformulationspassedthestabilitytest,andtherewasnosignificantdifferenceinpotency,pH,

orpurity.Thepotencyofthegelformulationtendedtodecrease(althoughitremainedwithintheacceptablerange)probablybecausesufficienthomogeneitywasnotachievedduringlaboratory

testingwithoutaproperhomogenizer.Incommercialproduction,thisisunlikelytobeanissue.

Basedontheseresultsonthestabilityoftheproductinthis6‐monthacceleratedstudy,PATH

estimatesa24‐monthshelflifeatroomtemperatureacrossallclimaticzoneslistedabove.


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8.CultivatingDemandfromCaregivers

MostoftherecentworkonCHXforumbilicalcordcare(Nepal,Pakistan,Bangladesh,Zambia,andTanzania)hasfocusedoncommunity‐leveluseoftheproduct.Inthesecontexts,somecaregivers

mayhavefullmedicaltraining,butmostarecommunityhealthworkersorTBAs.Ineachcase,CHX

forumbilicalcordcarehasbeenwellreceivedwhenpresentedbyprogramstaff,withspecific

highlightsinTable11.

Table 11. Caregiver demand.

Location Caregiver Synthesis of comment or direct quotes

Pemba (Tanzania)

Unspecified “We are willing to use it. Mothers can apply if they are trained.” “Most mothers will be willing to use this medicine. They pray for such thing to be introduced in the community as they are very useful.”

Bangladesh TBA TBAs were the single largest source of CHX, even when the product was both given away through government community outreach workers and sold in pharmacies. The TBAs appeared to appreciate the product as a special service they could offer (and potentially resell) to their clientele.

India ASHA* As part of government training, ASHAs are instructed to advocate for dry cord care in Uttar Pradesh. However, they are often frustrated by mothers who insist on dressing the cord in one way or another despite their advice. As dry cord care is unable to displace traditional practices, ASHAs are excited to recommend CHX as a way to finally have something to offer mothers in their communities.

Nepal FCHV FCHWs have enthusiastically embraced the product in the four districts where it is currently used today and have been able to ensure correct usage of CHX in close to 70% of all births in their catchment areas. Training is incorporated into existing FCHV training programs on other maternal and neonatal health topics.

*ASHA: Accredited Social Health Activist.

AcriticalcomponentofcultivatingcaregiverdemandhasbeentrainingcaregiverstounderstandtheCHXproductandadministeritcorrectly.InNepal,FCHVsweretrainedusingdollsmodifiedto

haveumbilicalcordsmadefromballoonsaswellastheinstructionalaidepicturedbelow(Figure

4).Inafollow‐upstudy,FCHVstrainedusingthesetoolswereabletoensurecorrectadministration

ofCHXbyhouseholdcare‐giverstoroughly70%ofthenewbornsintheircatchmentareas.

Figure 4. Instructional aide and correct chlorhexidine application.


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9.CultivatingDemandfromConsumers

Discouragingmothersfromputtinganythingonthecordhasbeenapersistentchallengeincommunitiesaroundtheworld.QualitativestudiesinIndia,Nepal,Uganda,Ghana,andMalawi

showthatmothersareoftenhesitanttoleavethecorddryduetoconcernsthatthecordmighttake

longertoseparate,causethebabydiscomfort,orleavethebabyvulnerabletovariousmaladies.Infact,inUttarPradesh,India,despitegovernmentprogramstopromotedrycordcare,83%of

mothersapplysomesubstancetothecord.19FormativeworkinZambiaandPemba(Tanzania)also

showthatmothershaveastrongdesiretoputsomethingontheumbilicalcordstump.

Specificmotivationstodressthestumpvarybyregionandbyindividual,butthemostcommon

reasonsincludeadesiretomakethecordstumpseparatefasterandtopreventinfection.Theactualsubstancesappliedtothestumpvarywidely,sometimesevenbetweenindividualswithinthesame

community,butoftenfallintoafewmaincategories:

Edibleoilsandbuttersincludinggheeandsheabutter,andmustard,palm,peanut,andcoconut

oils(India,Nepal,Bangladesh,Ethiopia,Mozambique,Tanzania,Nigeria,Zambia,andothers

areas).

Medicinalproductsincludingpowders,alcohols,iodine,andantibiotics(India,Ghana,Guinea

Bissau,Malawi,Mozambique,Nigeria,Tanzania,Uganda,Zambia,andotherareas).

Wasteproductsincludinganimalfeces,ash,dust,sand,dirt(India,Nepal,Nigeria,Tanzania,

Zambia,Malawi,Uganda,andotherareas).

Wherestudied,thereappearstobeasignificantlatentdemandforpurpose‐builtumbilicalcordcareproductslikeCHXandoftenawillingnesstodisplaceexistingpracticewithaproduct

specificallypackagedforthispurpose.Mothersinmanycommunitiesaroundtheworldareeager

foraproducttouseincordcareandappearlikelytoadoptCHXoncetheyaremadeawareofits

existence.

10.MonitoringandEvaluation

ThereareseveraldifferentwaystomonitorandevaluatethetransformationofCHXforumbilical

cordcarefrombeinganoverlookedcommoditytostatusasawidelyusedintervention.Anumber

ofmetrics(Table12)maybeusefulinmonitoringthatprogressionandidentifyingwhere

additionalattentionmayberequired.

19VarmaDS,KhanME,HazraA.Increasingpostnatalcareofmothersandnewbornsincludingfollow‐upcordcareandthermalcareinruralUttarPradesh. JournalofFamilyWelfare.2010;56(specialissue):31–41.


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Table 12. Monitoring and evaluation metrics.

Supply Metrics Global monthly production volume of a 4% CHX product for neonatal use.

Geographic and demographic reach of manufacturers.

Quality of manufactured product.

Demand Metrics Number of countries recommending CHX for newborn care.

Volume of public tenders for CHX products.

% of public and private facilities with CHX in stock.

% of wholesale and retail pharmacies stocking CHX.

% of caregivers recommending the use of CHX.

% of consumers accepting CHX.

Correct‐Use Metrics

% of babies receiving CHX.

% of above within 2 hours of birth.

% of above where 3 g or more of product were used.

% of above where product was applied to the stump and surrounding areas.

% of mothers who report applying CHX and no other substance to the cord.

Impact Metrics Neonatal mortality rate.

Neonatal mortality from infection.

11.Recommendations

Severalsimpleactivitiescouldincreasetheuptakeandimpactofchlorhexidineforumbilicalcord

carearoundtheworld:

Add4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcaretotheWHO

modellistofessentialmedicinesforchildren.

CorrectthecommonmisconceptionthatWHOadvocatesdrycordcareonly.TheWHOumbilical

cordcareguidelinesrecommendthatantimicrobialsbeused“…asatemporarymeasure,accordingtoalocalsituation(e.g.,inneonataltetanus‐endemicareasortoreplaceaharmful

traditionalsubstance).”TheseexceptionsarerarelycitedindiscussionsofWHO’sdrycordcare

recommendationbutmayapplytoamorethanhalfofallbirthsaroundtheworld.

Fasttrackregistrationof4%chlorhexidine(7.1%chlorhexidinedigluconate)forumbilicalcordcarewithnationalregulatoryauthoritiesandencourageadditionalmanufacturerstoproduce

thedrugwithguaranteedminimumvolumes.

Trainbirthattendantstocorrectlyapplychlorhexidinetotheumbilicalcord,aspartofnewborn

caretrainingprograms.

Allocateresourcestointegratechlorhexidineforumbilicalcordcareintoessentialnewborncareprogramsinordertogeneratesustainabledemandandattractivemanufacturingvolumes

fortheproduct.

Throughtheseactions,wearemuchmorelikelytoseeincreaseduseofthisoverlooked

intervention,therebycontributingtohundredsofthousandsofnewbornlivessavedannually.

Chlorhexidine for Umbilical Cord Care

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