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Contents

Regulatory collaboration127 The African Vaccine Regulatory Forum

(AVAREF): A platform for collaboration in a public health emergency

WHO prequalification 133 Updateonprequalificationofdiagnosticsand

medicines

Norms and standards138 Biotherapeuticsandbiosimilars

Safety news142 Restrictions

Bromhexine:nottobeusedinchildrenundersixinNewZealand; Codeine for cough and cold:nottobeusedinchildrenunder12;

142 Safety warningsSitagliptin: thrombocytopenia;SGLT2inhibitordiabetesmedicines:ketoacidosis;HepatitisCdrugsandamiodarone :

symptomaticbradycardia;Asunapreviranddaclatasvir : erythema multiforme ; Fingolimod:progressivemultifocalleukoencephalopathy

; Pomalidomide:risksofcardiacfailure,interstitiallungdiseaseandhepatotoxicity;High-doseibuprofenanddexibuprofen:cardiovascularrisks;ADHDmedicines :riskofsuicidalthoughtsincertainpatients; Varenicline: potential alcohol interaction and other

effects; Rebamipide:adverseeffectsontheeye;

146 Known risksFerumoxytol:strengthenedwarnings; Triamcinolone acetonide:

tendon rupture;Cyclophosphamide :rhabdomyolysis; Panitumumab:Stevens-Johnson

syndrome; Pazopanib: retinal detachment; Zoledronicacid :furthermeasurestominimizeriskofosteonecrosisofthejaw; Duloxetine:neurolepticmalignantsyndrome;

148 Unchanged recommendationsRotavirusvaccine :benefitsoutweighrisks;Natalizumab :nodefinitelinkwithmelanoma; Olanzapine:inconclusivefindingsaftertwodeathsin2013;

150 Data integrity concernsGVKBiosciences :EMAconfirmssuspensionofproductsoverflawedstudies;HospiraS.P.A:HealthCanadarestrictimports; ZhejiangHisunPharma,PolydrugLaboratories:HealthCanadarecommendsvoluntaryquarantine;

151 Falsified product alertFalsifiedmeningitisvaccinescirculatinginWestAfrica

Regulatory news152 Assessment

FinalFDAguidanceonopioidswithabuse-deterrentproperties; EMAscientificadviceonclinicaltrialsleadstofasterapprovals;Genericsinformation-sharingpilot extended; TGAreviewsitsguidanceonevaluationofbiosimilars;UpdatedriskmanagementplanformatinAustralia

153 Transparency WHOcallsfordisclosureofclinicaltrialresults;Australiaadoptsnewregulatorperformanceframework

154 DatabasesHealthCanadalaunchessearchableinspectiondatabase;WHOlaunchesopenaccesstoitsglobalmedicinessafetydatabase;EMAtorecordadverseeventsfromliterature in EudraVigilance

155 ApprovedCholic acid:forrarebileacidsynthesisdisorders; Eluxadoline:forirritableboweldisease; Empaglifozin & metformin:fordiabetes; Evolocumab :tolowercholesterol; Isavuconazoniumsulfate:forcertaininvasivefungalinfections; Atazanavir&cobicistat:fortreatmentofHIV-1infection; Anthrax immunoglobulin (human); Dinutuximab:toprolongsurvivalinchildrenwithhigh-riskneuroblastoma;

Filgrastim-sndz :,firstbiosimilarintheU.S.; Tasimelteon :toregulatesleeppatternsinblindadults;

157 Extensions of indicationsMoxifloxacin : for treatment of plague; Sirolimus :forveryrarelungdisease;

158 Generic Glatiramer acetate :

158 Early accessPembrolizumab:

Publications and events159 Global health

WHOpublishes2015WorldHealthStatistics;Sixty-eighthWorldHealthAssemblycloses

160 Access to medical productsWHOupdatesessentialmedicineslists;AccesstonewmedicinesinEurope; Ketamine not to be placed under international control

161 Medicines qualityFalsifiedantimalarialslesscommonthanpreviouslythought

161 EbolaFocusonvaccinationandmalariainEbola-affectedcountries; FirstEbolavaccineefficacytriallaunchedinGuinea; WHO proposesemergencyuseassessmentprocedures;WHOlistsEboladiagnostictestsforemergencyuseinWestAfrica

162 Hepatitis WHOpublishesfirsthepatitisBtreatmentguidelines;PatentlandscapesofhepatitisCmedicines;HepatitisCdiagnosticsneeded

163 DementiaAdvancingresearchandcare

Continued

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164 WHO mattersWHOprequalificationprogrammeproposesnewfinancingmodel;WHOofficialsmeetwithCFDAViceMinister

165 Upcoming events3rdInternationalPPRIConferenceonmedicinespricingandreimbursement; 2015WHO-UNICEF-UNFPAmeetingwithmanufacturers

Consultation documents166 The International Pharmacopoeia166 Draftnoteforguidanceonorganicimpurities

inactivepharmaceuticalingredientsandfinishedpharmaceuticalproducts

172 Draftrevisionofthechapteronreferencesubstancesandreferencespectra

179 Levonorgestrel187 Estradiolcypionate

ATC/DDD classification191 ATC/DDDclassification(temporary)193 ATC/DDDclassification(final)

International Nonproprietary Names (INN)195 ProposedINN:List113

Continued

Abbreviations and web sites

CHMP CommitteeforMedicinalProductsforHumanUse(EMA)EMA EuropeanMedicinesAgency(www.ema.europa.eu)EU European UnionFDA U.S.FoodandDrugAdministration(www.fda.gov)HealthCanadaFederaldepartmentresponsibleforhealthproductregulationinCanada(www.hc-sc.gc.ca)MHLW MinistryofHealth,LabourandWelfare,JapanMHRA MedicinesandHealthcareProductsRegulatoryAgency,UnitedKingdom

(www.mhra.gov.uk)Medsafe NewZealandMedicinesandMedicalDevicesSafetyAuthority(www.medsafe.govt.nz)PRAC PharmacovigilanceRiskAssessmentCommittee(EMA)PMDA PharmaceuticalsandMedicalDevicesAgency,Japan(www.pmda.go.jp/english/index.htm)Swissmedic SwissAgencyforTherapeuticProducts(www.swissmedic.ch)TGA TherapeuticGoodsAdministration,Australia(www.tga.gov.au)U.S. UnitedStatesofAmerica

Note:Theonlineversionofthisissue(availableatwww.who.int/medicines/publications/druginformation)hasdirectclickablehyperlinkstothedocumentsandwebpagesreferenced.

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Regulatory collaborationThe African Vaccine Regulatory Forum (AVAREF):

A platform for collaboration in a public health emergency

The Ebola virus disease outbreak in West Africa has been followed by a global multi-stakeholder response, led by WHO, to make medical products available to treat and prevent the disease. The swift pace of product development has challenged regulatory systems globally, and especially those of resource-constrained sub-Saharan African countries.

To address the challenge of authorizing clinical trials of Ebola candidate vaccines with limited available data, the WHO African Vaccine Regulatory Forum (AVAREF) was used as a collaboration platform enabling regulators, ethics committees and sponsors to reach consensus on key ethical and regulatory questions. Given AVAREF’s crucial role in speeding up product development through coordinated regulatory efforts to combat Ebola it is essential that necessary resources are allocated to further strengthen its capacity.

Challenges of product development during public health emergencies Medicalproductsarecomplex,andhighlevelsofscientificexpertiseareneededtoascertaintheirquality,safetyandefficacy.Traditionally,productdevelopmentandapprovalstakeyears,withcarefullyplanned,robustandsystematicallyexecuted,largeclinicaltrialsservingasbasisforsafetyandefficacydatatoinformregulatorydecision-making.Whiledevelopedcountrieshave

adequateregulatorysystemsandcapacityinplacetoassessandauthorizeclinicaltrialsinordertoensuretheirscientificintegrity,mostAfricanregulatoryauthoritieshavesevereresourceconstraintsandthereforelackthecapacitytoadequatelyreviewand

authorizeclinicaltrialsandtoensurethesafetyoftrialsubjectsduringtheclinicaldevelopmentofproducts(1).Publichealthemergenciesimpose

onAfricanregulatorstheadditionalpressureofhavingtoaccelerateaccesstoneededproductsforthepublicgoodbyapprovingclinicaltrialapplicationsandproductswithinmuchshortertimelinesthanusual.Thefundamentalquestionregulatorshavetograpplewithis:Howtoauthorizeapromisingproductwithverylimitedevidenceofsafetyandefficacyininstanceswherelargeclinicaltrialsarenotpossible? Thisisthescenariocreatedbythe

largest-everoutbreakofEbolaVirusdisease,whichstartedinGuinea,LiberiaandSierraLeonewithafewcasesinother

ThisarticlewascontributedbyDrBartholomewAkanmori(WHORegionalOfficeforAfrica,ImmunizationandVaccinesDevelopment),withinputfromDrAhmedBellah,DrMikeWardandProfessorLembitRägo(WHO,EssentialMedicinesandHealthProducts).

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WestAfricancountries,EuropeandNorthAmerica (2).Aspartoftheglobalresponsetothis

publichealthemergency,WHOconvenedseveralconsultationsondifferentaspectsofproductdevelopmentwithaviewtoacceleratedevelopmentandaccesstopromisingproductsincludingvaccines.Oneoftheoutcomesoftheseconsultationswasthedecisiontouseexistingregulatorynetworksasplatformstosupportacceleratedproductdevelopmentandapprovals.

The African Vaccine Regulatory Forum (AVAREF)AVAREFisaregionalregulatorynetworkfoundedbyWHOin2006,atatimewhenthefocusonclinicaltrialsofvaccinesbegantoshiftfromdevelopedcountriestodevelopingcountries,includingthoseinsub-SaharanAfrica.Thenetworkbringstogethernationalregulatoryauthorities(NRAs)andethicscommitteesofthecountriesintheWHOAfricanRegion.Itcurrentlyhas23members1.AVAREFaimstosupportNRAsin

regulatorydecision-making.Itprovidesinformationtocountriesonvaccinecandidatesandtimelinesforclinicaltrials,andpromotescommunicationandcollaborationbetweenAfricanNRAsandethicscommittees.ItalsoprovidesopportunitiestobringintheexpertiseandadviceofregulatorsfromEuropeandNorthAmerica–includingHealthCanada,theEuropeanMedicinesAgency(EMA)andtheUnitedStates’FoodandDrugAdministration(FDA)’s1 Botswana,Burundi,Cameroun,CentralAfricanRepublic,Ethiopia,EquatorialGuinea,Gabon,Gambia,Ghana,Guinea,Kenya,Malawi,Mali,Mozambique,Nigeria,Rwanda,Senegal,SierraLeone,SouthAfrica,UnitedRepublicofTanzania,Uganda,ZambiaandZimbabwe

CenterforBiologicsEvaluationandResearch(CBER)–forthebenefitoftheirAfricancounterparts.AtthesametimeAVAREFpromotesconvergencetowardsharmonizationofregulatorypracticesandprocessestoensuretimelyregulatoryevaluationsandapprovalsofclinicaltrialapplicationsandproducts.KeyamongAVAREF’sachievements

hasbeenfirstlytheestablishmentofinnovativeregulatorypathwaysforclinicaltrials,secondlythedevelopmentanduseofcommonguidelinesforsubmissionofclinicaltrialapplications,andthirdlytheuseofjointreviewsofmulticountryclinicaltrialapplicationsandjointgoodclinicalpractice(GCP)inspections.Thesestrategicformsofcollaborationcansignificantlyimprovetimelinesforproductdevelopment(3, 4).JointreviewsandGCPinspections

haveplayedakeyroleinensuringtimelyregulatoryauthorizationandapprovalsofMenAfriVac®,themeningococcalAconjugatevaccinewhoserolloutinthemeningitisbeltofAfricahaseliminatedepidemicmeningitisduetoGroupANeisseria meningitidisasapublichealthproblem (5).AjointreviewapproachwasalsousedtocoordinateandexpeditethereviewofthemulticountryPhaseIIIclinical trial for the lead malaria candidate vaccine,RTS,S/AS01,whichisabouttoconcludeinsevenAfricancountries.

WHO’s use of the AVAREF platform in responding to the Ebola emergency The Ebola outbreak created a global urgency and a need for accelerated developmentofvaccinesandtreatments.Inthewakeoftheoutbreak,promptauthorizationofclinicaltrialapplicationsandoverallregulatoryoversightof

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productsthatcouldhelptopreventortreatEbola are particularly challenging: The designofclinicaltrialsisbecomingmoredifficultduetoveryspecificfeaturesofthedisease,andthecapacityconstraintsaregreaterthaneverinaffectedcountries.Inresponsetothissituation,the

annualmeetingofAVAREF,heldinPretoria,SouthAfricaon3–7November2014,devotedtwodaystodiscussionsaddressingthekeyregulatoryquestionsaroundtheEbolaoutbreak.Participantsdiscussedwaystoputintoplacemechanismsforthereviewandauthorizationofclinicaltrialswhileplanningfortheapprovalofproductsforemergencyuse.Themeetingenabledregulatorsand

manufacturerstoachieveprogressinthreeprincipalareas:firstly,pre-submissiondiscussionswithsponsorsandmanufacturers,secondlythegeneralprinciplesandmechanismsfortheauthorizationofclinicaltrialsandproducts,andthirdlytheorganizationofjointreviewstofacilitatetimelyapprovalsofclinicaltrials.

Pre-submission discussions Pre-submissionmeetingswithregulatorsinAfricacanbeverychallengingformanufacturers,especiallywhentheyaredealingwithseveralcountrieswithdifferentrequirements.TheAVAREFmeetingprovidedauniqueopportunityforsponsorsandmanufacturerstopresentanddiscussthecharacteristicsoftheirproducts,preclinicaldataavailablefromnon-humanprimatestudiesandfromfirstin-humanstudieswhereavailable.Allknownandpotentialtargetcountriesforclinicaltrialswererepresentedinoneplacefordiscussionsontheproductsandthedesignsandtimelinesofclinical

trials.Inaddition,theAfricanregulatorsaswellasethicscommitteemembersandregulatorsfromEurope,theU.S.andCanada–wheresomefirsttrialsforsomeoftheproductsinhumanshavebeenapproved–wereabletomakesuggestionstosponsorsaboutclinicaltrialdesignsanddatatosubmitforapprovaloftrialapplications.

Clinical trial and product approvalsTheAVAREFmeetingopeneddiscussionsonhowregulatoryauthorizationsofclinicaltrialsandapprovalsofproductsforemergencyusecanbeaddressedinthecurrentEbolaoutbreakwithoutcompromisingthesafetyofpopulations.ThesediscussionswerebasedonavailableregulatoryexperienceandexpertiseoftheU.S.FDA,HealthCanadaandEMA.MostAfricancountrieslackspecificregulatorypathwaysandmechanismsandcouldthereforeadoptoradaptsomeofthemechanismsusedinothercountries.ThesessionalsohighlightedtheneedforaglobalregulatorymechanismtobeputintoplaceforproductdevelopmentinemergenciessuchastheEbolaoutbreakandtheearlierpandemicinfluenza.Themeetingparticipantsreached

consensusaroundtheuseofAVAREFasacollaborativeplatform,andthevalueofjointreviewsasausefulmeansofensuringthatclinicaltrialapplicationsforproductsagainstEbolaarereviewedadequatelyandthatshortertimelinesconsistentwithacceleratedproductdevelopmentandmanufacturertimelinesaremet.

Joint reviewsWHOconvenedthreejointreviewsofclinicaltrialapplicationsutilizingthe

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AVAREFplatform.Todate,ethicalandregulatoryapprovalhasbeensecuredwithin90daysfromthecompletionofthejointreview.WHOplayedaconveningandsupportiveroleinthejointreviewsessionsby:• facilitating agreement on the format for theclinicaltrialapplications;

• ensuringtheparticipationofsupportingagencies(theregulatoryauthoritiesofGhana,theUnitedStates,Europe,theUnitedKingdom,CanadaandSwitzerland);

• liaisingwithsponsorsregardinginformation-sharingamongsupportingagenciesaboutproductsunderreview;

• settingupanelectronicplatformtomanagethereviewprocessandtomakenecessarydocumentsavailabletoregulatorsandethicscommitteemembers;and

• facilitatingthefinalizationofasummaryreportstatingagreed-uponactionsandtimelinesfollowingthereview.

RecommendationsThemeetingrecommendationswerecirculatedamongallstakeholders,NRAs,ethicscommittees,manufacturers,sponsorsandpartners.TheagreedrecommendationsarepresentedinAnnex 1.

Support and fundingThe ninth annual plenary meeting of AVAREFwasorganizedwithsupportfromtheBill&MelindaGatesFoundationand the Programme for Appropriate TechnologiesinHealth/MalariaVaccinesInitiative(PATH/MVI).Inaddition,theCenterforBiologicsEvaluationandResearchoftheU.S.FDA(CBERFDA),

theHealthProductsandFoodBranchofHealth Canada and the EMA contributed throughtheparticipationoftheirexperts.ThejointreviewsweresupportedbyWHO.

ConclusionToensurethathealthproductsaresafe,effectiveandofgoodquality,regulatoryoversightofproductdevelopmentincountriesshouldbeconsistentwithICHandotherrelevantinternationalguidelines.Regulatoryagenciesofdevelopingcountrieswhichlackthefullcapacitytomeettheserequirementsshouldbesupportedtobuildorstrengthentheircapacitiesinlinewithinternationalregulatorystandards.WHOfullyrecognizesthisandisactivelysupportingMemberStatestostrengthentheirregulatorysystemsthroughregularassessments,capacity-buildinginavarietyofwaysandbypromotingregionalharmonizationefforts.AVAREFisaWHO-supportedplatform

thathasproventobeinstrumentalinprovidingregulatorysupporttoaccelerateproductdevelopmentduringpublichealthemergencies,asexemplifiedwithproductsindevelopmentagainstEbola.Goingforward,theseachievementswillalsosupporttheworkofAfricanregulatorsonvaccinesfordiseasessuchasHIV,tuberculosisandmalaria,whichareaffectingmanymillionsofpeopleintheAfricanregion.Lastly,AVAREFmayserveasanimportantregionalplatformlinkedwithinternationalnetworkssuchastheDevelopingCountriesVaccineRegulatoryNetwork(DCVRN)topromotetheincreasingnumberofmulti-regionalorglobaltrials.

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References1 KisserA,HeiningerU,MoorthyVS,

AkanmoriBD,LeroyO.Addressingtheneedsandgapsinsafetyassessmentofvaccinesduringclinicaltrialsinresourcelimitedcountries.Vaccine2011;29:4173-4.

2 OleribeOO,SalakoBL,KaMM,AkpaluA,McConnochieM,FosterM,Taylor-RobinsonSD.EbolavirusdiseaseepidemicinWestAfrica:lessonslearnedandissuesarisingfromWestAfricancountries. Clin Med.2015Feb;15(1):54-7.doi:10.7861/clinmedicine.15-1-54.

3 MaïgaD,AkanmoriBD,ChocarroL.RegulatoryoversightofclinicaltrialsinAfrica:progressoverthepast5years.Vaccine2009,27(52):7249-52.

4 MaïgaD,AkanmoriBD,ChocarroL.Jointreviewsandinspections:strategicformsofcollaborationforstrengtheningtheregulatoryoversightofvaccineclinicaltrialsinAfrica.Vaccine2009,28(2):571-5.

5 MeningitisVaccineProject.Eliminatingepidemicmeningitisasapublichealthprobleminsub-SaharanAfrica[website].www.meningvax.org.

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Annex 1: 9th AVAREF meeting recommendationsSponsors/

manufacturers:Regulatory authorities

(RAs):WHO:

Ebola1.Toimmediatelyreleasetheplannedtimelinesforsubmissionofclinicaltrialapplicationsindicatingspecifictrialsites.

2.Toholdpre-submissionmeetingswitheachparticipatingNRAsandEC,andtoattend

3.Manufacturerstoattendthejointreviewsessionswiththeirappropriatestaff;

4.Manufacturerstofileclinicaltrialapplicationsthrough the focal personsidentifiedbyHeadsofNRAs

5.TousetheAVAREFclinicaltrialsformat(African Common Clinical Trial Document) forthesubmissionsof clinical trial applications.

6.Toincludeintheirsubmissionsallpertinentdatathatisavailableatthetimeofsubmission

7.TorespondswiftlytoanyqueryfromNRAsor EC/IRB

National RAs and ethics committees (ECs) /

institu tional review boards (IRBs):

1.Toprioritizeassessmentofclinicaltrialapplicationsinparallel(regulatory/ethics)tominimizedelaysandtoapplyfast-trackprocedures

2.Toimmediatelyreleaseallnational/regionalprovisionsgoverningtheareaofclinicaltrialsandhighlightaspectsfavourabletofasttrackprocedures

3.Toaccepttoreviewallclinicaltrialssubmittedbymanufacturers/sponsors

Supporting RAs (EMA, USFDA, Health

Canada):1.IncollaborationwithWHO,doeverythingintheirpowertosharedatarelevanttoclinicaltrialswiththeNRAsofparticipatingcountries

2.ToprovideexpertisetosupportNRAsinthejointreviewswhenrequested

1.TorequestHeadsofRAsto:a.Identifyandnamedseniorregulatorsstaffastheagencyentryfocalpointsfor Ebola

b.Designatenamedreviewer(s)toparticipateinajointreviewprocesswiththemandatetotakeregulatory/ethicsdecisions(reviewersareempoweredtotakedecisionsduringthejointreviewmeeting).

2.Tofacilitateajointreviewsessionoftheclinicaltrialapplicationswithatargetdateof15December2014

3.ToinvolvetheNRAsoftheEbola-affectedcountriesinthejointreviewprocess

4.Toprovideexpertiseanddevelopbriefingmaterialsforethicscommittees

5.Todevelopadditionalbriefingmaterialsonthevaccines,andnovelclinicaltrialdesigns,toassistthenational/regionalreviews

6.Toproactivelyplaytheneededbrokerroleinfacilitatingtheinteractionbetweenmanufacturersandcountries

7.ToengagewithheadsofInstitutionsandresearchinstitutionsandprovidenecessarysupporttocountriestodevelopproceduresforacceleratedreviewofEbolarelatedresearch.

8.Toensurethatethicscommitteeshavethenecessarysupporttofollowupapprovedtrialsandresearchstudiesthroughsitemonitoringandhavingmechanismstorapidlyreviewamendmentsetc.

Tuberculosis, HIV/AIDS and malaria vaccines

1.Tograduallystrengthenregional harmonization of technicalprocessesandprocedures

2.Toemphasizeutilizationofjointprocessimplementation

3.ToestablishmechanismsforstrengtheningTransparencyonprocesses/proceduresand on country/regional performance (including adaptingindicatorsforresearchethicssystems)

4.TointeractactivelywiththeAfricanMedicinesRegistrationHarmonizationInitiative(AMRH)

1.TosupportandstrengthencollaborativemechanismsamongNRAsandethicscommitteesincludingcapacitybuildingthroughregulartrainings

2.Toencouragemultiplicationofjointimplementationofregulatoryactivitiesincludingjointreviewsandjointinspections

3.TohostandmanagetheAVAREFvirtualcommunityplatformdevelopedbyHealthCanada,thesecretariattoimplementthetransitionbyendJanuary2015

4.WHOtoprovidespecificguidelinesforevaluationofclinicaltrialapplicationsforvaccinesagainstTBandHIV,buildcapacitytoefficientlyaddressotheranticipatedproductsinthepipeline

æ

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WHO prequalification Updateonprequalificationofdiagnosticsandmedicines

In addressing shortcomings in manufacture, regulation and supply that exist across multiple diseases and product types, WHO prequalification is probably the single, most effective source of hands-on regulatory capacity building. And by serving as a single entry point to donor funding for manufacturers who are willing to offer quality products, it greatly facilitates international procurement and distribution.

In 2014, the prequalification programme both consolidated its processes for the different product categories and continued to broaden its achievements. This article provides an overview of those achievements.

Norms and standardsEstablishedonthebasisofthenormsandstandardsadoptedbytheWHOExpertCommitteeforSpecificationsonPharmaceuticalPreparations,thePrequalificationTeamhasbecomeanimportantsourceoffeedbacktothestandard-settingprocessformedicines.In2014itcontributedtoawiderangeofpharmaceuticalqualityguidelinesandproposedaconceptpaperfornewguidanceongooddatamanagement.ThePrequalificationTeamalsoprovided

significantinputintodiscussionstoaligninternationalqualityassurancerequirementsfordiagnosticproductsbasedonstringentregulatoryprinciplesandemergingglobalconsensus.Itfurtherissueddraftguidanceonpost-marketsurveillanceofinvitrodiagnostics(IVDs)for comment (1).

Integration of workstreamsTheyear2014sawthemergeroftheindependentprequalificationstreamsfordiagnostics,medicaldevices,medicinesandvaccinesandthecreationofthePrequalificationTeam.Thisgeneratedgreatersynergy,butalsodemandedconsiderabletimeandeffort

forreorganizationandestablishmentofaqualitymanagementsystem.Fordiagnostics,significantresourceswerededicatedtostreamliningprocesses,inparticulartoimprovecommunicationandenhancetransparency.

FundingIntheabsenceofWHObudgetaryallocations,prequalificationiscurrentlylargelyfundedbyjusttwodonors:UNITAIDandtheBill&MelindaGatesFoundation.Userfeeswereintroducedfor

prequalificationofmedicinesin2014,feeshadalreadybeenintroducedpreviouslyfordiagnosticsandvaccines.Areviewof2014applicationsshowedthatthenumberofsubmissionsformedicinesdidnotappeartohavebeenaffectednegativelybytheintroductionofuserfees.Afinancingmodelaimedatcreating

asustainablesourceoffundingwasdevelopedandmadeavailableforcomment(seealsopage164).

ResultsAnoverviewof2014resultsfordiagnosticsandmedicinesispresentedonthenextpages.

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WHOprequalificationinnumbers: 2014 results for diagnostics and medicines

A participatory approach

Rotational posts: Future partners in Member States

3 Rotationalassessorsformedicinescompleteda3-monthfellowship(2)From:Botswana,D.R.Congo,Uganda

2 Rotationalinspectorscompleteda4-monthfellowshipinthePrequalificationTeam–a“first”From:China,Uganda

12 Formerrotationalstafffromeightcountrieswereinvolvedincollaborativeregistration(→page 136)

Eligible products

Invitations for Expression of Interest (EoI) for prequalification of medicines: Adapting to changing needs

6 UpdatedEoIsissuedin2014(3) i.e.for:HIV-relatedproducts 2Antimalarials 1Reproductivehealthproducts 1Activepharmaceuticalingredients(APIs) 2

32 HIV-relatedformulationsaddedincluding12medicinestotreathepatitisBandC

7 Antimalarialsforchildrenre-specifiedaccording to input from the WHO malaria programme

3 Reproductivehealthproductsadded:• Levonorgestrelintrauterinesystemforfiveyearscontinuoususe

• Misoprostol25mcgtablet• Magnesiumsulfateinjection

8 APIsadded:dolutegravir,clofazimine,linezolid,ribavirin,rifabutin,simeprevir,sofosbuvir,valgancyclovirTwoAPIsremoved:didanosine,ofloxacin

Assessment

Diagnostics: Building streamlined procedures

54 TechnologiesunderassessmentasatDecember2014(38throughthefullprocedure,16throughtheabbreviatedprocedure):HIV-related: 31HepatitisC-related: 11HepatitisB-related: 5Malaria-related: 7

24 Inspectionsperformedin2014withregulatorystaffparticipation

20 Submissionsunderscreening(asatDecember2014)

Medicines: A tried and tested approach

81 Dossiersforfinishedproductsunderassessment(asatDecember2014)

6 Jointassessmentsessions(“Copenhagensessions”)heldin2014Participationfromregulatoryauthorities,includingstaffinvolvedincollaborativeregistration

94 Inspectionsconductedin2014withparticipationofregulatorystaff:Offinishedproductsites: 39OfAPIsites: 32Ofcontractresearchorganizations: 11Ofqualitycontrol(QC)laboratories: 12

105 Invitationstosubmitanapplicationforrequalificationsenttomanufacturers,leadingto:73submissionsbeingassessed29productswithdrawnbymanufacturers1productcancelledbyWHO.(2invitationswereawaitingaresponse.)

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WHOprequalificationinnumbers:2014resultsfordiagnosticsandmedicines (continued)

Lists of products and services

Prequalified medicines: More choices for procurement

416 MedicineslistedonWHOwebsite(4)(asat31March2015)

53 Medicinesprequalifiedin2014“Firsts:”• Dexamethasoneinjection• Genericcapreomycininjection• Azithromycin250mgtablets,• Dolutegravirtablets• Mifepristonetablets• Sulfadoxine/pyrimethamine +

amodiaquine • Genericmorphinetablets• FirstproductsmanufacturedinEgypt• FirstfourNigerianmanufacturerscomplywithWHO-GMP

“Firsts”,2015: Buprenorphine,oxytocine

Prequalified APIs: More choices for manufacturers

78 APIslistedonWHOwebsite(5)(asat12March2015)

22 APIsprequalifiedin2014“Firsts”:• Efavirenz• Levofloxacin• Pyronaridine • Zinc

Prequalified quality control laboratories: Trusted partners in QC testing

38 LaboratorieslistedonWHOwebsite(6) (asat22January2015)WHOAfricanRegion: 8WHORegionoftheAmericas: 7WHOSouth-EastAsiaRegion: 4WHOEuropeanRegion: 13WHOEasternMediterraneanRegion:2WHOWesternPacificRegion: 4

7 Laboratoriesprequalifiedin2014

Prequalified IVDs: Safe, well-performing diagnostics to guide prevention and treatment decisions

38 IVDslistedonWHOwebsite(7)(asat31March2015)

9 IVDsprequalifiedin2014HIVassays 6Malariarapiddiagnostictests 2HepatitisB(HbsAg)assay 1

3 “Firsts”:• An IVD manufactured in India • An IVD manufactured in China• Firstproductprequalifiedunderthenewstreamlinedprocess(aCD4technology;assessmenttime:81days)

51Clearing the backlog:Non-progressingapplicationsclosedorwithdrawnin2014

Bridging the gaps

Expert Review Panel (ERP): Risk assessment for needed products that are not yet available as stringently assessed versions

Diagnostics:PilotandRound1(8)0 Technologiesfoundacceptableinpilot

(of2point-of-careHIVearlyinfantdiagnosistechnologiesassessed)

5 Technologiesfoundacceptablefortime-limitedprocurementinRound1 (of12acceptedforreview)Foranyinternationalprocurement: 2Onacase-by-casebasis: 3

Medicines(9):Rounds11and1212 Productsfoundacceptablefortime-

limited procurement includingnewerARVs,paediatricanti-malarials,2ndlinetuberculosisproducts(of64productsacceptedforreview)

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Training and advocacy

Events for manufacturers and regulators: Building capacity and awareness

>350 ParticipantsattendedthejointUNICEF/UNFPA/WHOmeetingformanufacturersandsuppliers(10) –recordparticipation

Diagnostics,2014:19 IVDmanufacturersincentivizedto

submitapplications6 IVDmanufacturersreachedinone-

on-onemeetingsontheirresearchanddevelopmentactivities

1 Trainingsessionheldondiagnosticsdossierscreeningandassessment

Medicines,2014:33 Eventsorganizedorco-organized27 Technicalassistancemissions

Manufacturerssupported: 20Countriesofmanufacture: 5 (China,India,Kenya,Nigeria,Pakistan)

1 TechnicalassistanceprojectforNigerianmanufacturers(11)

6 NationalQClaboratoriessupportedwithtechnicalassistance

Use of prequalified products in WHO Member States

Pharmaco vigilance: Monitoring medicines safety

10 Countriesparticipatedininter-regionalactivesurveillancetrainingworkshop

3 Gapassessmentsfortuberculosis-relatedproductscompleted(DRCongo,Swaziland,Zanzibar)

5 Nationalcohorteventmonitoring(CEM)databasessetup

Use of prequalified products in WHO Member States (continued)

Collaborative registration of medicines: Putting countries in the driving seat

23 Participatingcountries19African,4EasternEuropean

62 Marketingauthorizationsapproved,listedonWHOwebsite(12) +55submissionsunderreview(asat6May2015)

36 Marketingauthorizationsapprovedin2014

93 days

Median time from information-sharingtoregistration(2014)

International procurement: Rewarding investments in quality

US$ 399

million

GlobalFund-financedprequalifiedmedicines deliveredin2014Bycategory, millionUS$ (PQonly*)Antiretrovirals: 301 (43%)Antimalarials: 67 (100%)Anti-tuberculosisproducts 1stline: 11 (100%)2ndline: 19 (82%)

*PQ-only=notapprovedbyastringentregulatoryauthority

US$ 55.6

million

GlobalFund-financedprequalifiedIVDsdeliveredin2014Bycategory millionUS$:HIVRDT&EIA: 30.5MalariaRDT: 12.5HIVCD4technologies: 7.1HIVvirologicaltechnologies: 5.6

Source: Global Fund Price and Quality Reporting (PQR)database.GlobalFund-financedprocurementrepresentsasignificantportionofinternationally-fundedprocurement.

WHOprequalificationinnumbers:2014resultsformedicinesanddiagnostics (continued)

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ConclusionsDrivenbythestringentqualityrequirementsofdonors,WHOprequalificationoffersmanufacturersameansofaccessingmarketsforproductsthatmeetinternationalqualitynormsandstandards.In2014,prequalificationofmedicines

succeededinmakingefficientuseofitstriedandtested“generic”approachtoassessthequalityofawiderangeofchemicalmedicines,buildingonthesafetyandefficacyassessmentofinnovatorproductscarriedoutbystringentregulatoryauthorities.ThroughitshighlyparticipatoryandcollaborativeactivitiesWHOleveragedthesewell-establishedprocessestoincreasethecapacityofmanufacturersandregulatorstoimplementstringentqualitystandardsforpharmaceuticalproducts.Qualityassuranceofdiagnostic

technologiespresentsmorecomplexchallenges.Thisproductcategoryisdiverseandrapidlyevolving,yetinmanypartsoftheworld,regulatorymechanismsforassessingdiagnosticsareverylimited.WHOprequalificationisplayingakeyroleininternationaleffortstounderstandthemarketsandregulatorylandscapesofneededdiagnostictechnologiesforprioritydiseases,andtodefinestringentstandardsfortheirassessmentandpost-marketsurveillanceinthosecountrieswheretheyareneededmost. æ

References1 WHO.Guidanceforpost-market

surveillanceofinvitrodiagnostics.Draft.Version5,19January2015.Postedat:http://www.who.int/diagnostics_laboratory/postmarket/en/

2 WHOPrequalificationofMedicinesProgrammerotationalfellowships. WHO DrugInformation2012;26(3):248-54.

3 WHOPrequalification.InvitationsforExpressionsofInterest(EOIs)[webpage].

4 WHOListofprequalifiedmedicinalproducts[webpage].

5 PrequalificationofActivePharmaceuticalIngredients-ListofPrequalifiedAPIs [webpage].

6 WHOListofPrequalifiedQualityControlLaboratories.

7 WHOlistofprequalifiedinvitrodiagnosticproducts.

8 TheGlobalFundtoFightAIDS,TuberculosisandMalaria.ProcurementandSupplyManagement.Information for Suppliers[webpage].

9 WHOPrequalificationofmedicinesprogramme.ExpertReviewPanel.Briefingpaper,27April2012.

10 Prequalification:Meetings.JointWHO-UNICEF-UNFPAMeetingwithManufacturersandSuppliersofDiagnosticProducts,FinishedPharmaceuticalProducts,ActivePharmaceuticalIngredientsandVaccines.

11 Buildingquality-assuredmanufacturingcapacityinNigeria.WHODrugInformation;2014;28(4):425-30.

12 WHOPrequalification:Collaborativeregistration[webpage].

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Norms and standardsBiotherapeuticsandbiosimilars

Advances in biotechnology have enabled scientists to produce biological medicinal products that provide new treatment options for a wide range of diseases, including life-threatening ones. However, these complex medicines are expensive to develop and produce, and their high cost potentially affects equitable access to them.

Biosimilars – products that are very similar to already approved biotherapeutic products – could make this new generation of medicines available more widely at a more affordable cost to health systems. This article describes some recent developments in global efforts to create regulatory pathways and naming systems for biotherapeutics, including biosimilars.

Biotherapeutic productsNewtechnologieshavemadeitpossibletoproducelargequantitiesofmedicinesthatarederivedfromlivingsystems.Biotherapeuticmedicinescannowbeproducedinlargequantitiesinbacteria,yeast,transformedcelllinesofmammalianorigin(includinghumanorigin),insectandplantcells,aswellastransgenicanimalsandplants.Inmostcasesthisisdonebyusinggeneticallymodifiedcells,whichareengineeredtoproducethedesiredproteins.Somebiotherapeuticsareproteins

thatarenaturallypresentinthehumanbody,suchasgrowthhormones,insulin,erythropoietins,enzymesorantibodies.Othersarebiologicallyactiveproteinsthatdonotexistinnatureandareproducedbytechniquessuchasrecombinantdeoxyribonucleicacid(rDNA)technology.Examplesincludechimeric,humanizedorfullyhumanmonoclonalantibodies,antibody-relatedproteinsorfusionproteins.Thesesubstancescantreatawiderangeofdiseases,includingvariousformsofcancer,heartattacks,stroke,

diabetes,rheumatoidarthritis,multiplesclerosis,hepatitisC,chronicrenalfailure,anaemia,lowwhitebloodcellcounts,inflammatoryboweldiseaseandothers.Biotherapeuticsaremorecomplexthan

chemicalmedicinesandarethereforemorechallengingandmoreexpensivetodevelopandproduce.Oftentheyareinitiallyapprovedforanindicationwhiletheyarebeingstudiedfurther,andthelicenceissubsequentlymodifiedtoapproveadditionalusesasnewclinicaldatabecomeavailable.Biotherapeuticsalsopresentspecialsafetychallengesbecausetheyareimmunogenic,meaningthattheyarerecognizedasforeignproteinsinthebodyandcantriggerunwantedimmunereactions.

Medicines of the futureRecognizingthatbiotherapeuticsprovidenewtreatmentoptionstosavelivesandrestorehealth,the67th World Health Assemblyadoptedaresolutiononaccesstobiotherapeutics(1),callingforeffectiveregulationandequitableaccess.Thisisatimelycall,consideringthespeedat

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whichthemarketsfornewgenerationofmedicinesareevolving.Accordingtoa recent report (2)biologicmedicinesaccountedfor27%ofpharmaceuticalsalesinEuropeattheendof2013,withayear-on-yeargrowthalmostthreetimesthatofthepharmaceuticalsalesvalueasawhole,andwithpatentsformanytop-sellingbiologicalsexpiringorduetoexpireby2020.

BiosimilarsTheexpiryofpatentsand/ordataprotectionforthefirstmajorgroupoforiginator’sbiotherapeuticshasusheredinaneraofproductsthataredesignedtobe“similar”toalicensedoriginatorproduct.Theseproductsrelyfortheirlicensingpartlyonexistinginformationregardingsafetyandefficacyobtainedwiththeoriginatorproducts.Biosimilars–alsocalled“similarbiotherapeuticproducts”,“follow-onbiologicalproducts”or“subsequententrybiologics”indifferentregulatorysystems–canbringdownthecostofmedicinesbyincreasingcompetitionandcanthusincreasepatientaccess.Asimilardevelopmentwasseeninrecentdecadeswithgenericversionsofchemicalmedicines.

Biosimilars are not genericsAlthoughthemarketaspectsappearsimilar,thereareimportantdifferencesbetweengenericsandbiosimilars.Whilegenericsareexactcopiesofthechemicalstructuresoftheirreferenceproducts,biosimilarsarehighlycomplexmoleculesproducedinlivingsystemswithinherentvariability.Bydefinitiontheywillnotbeidentical to their biotherapeutic reference products.Thishasimplicationsforregulatoryassessment.Forgenerics,regulatorysafetyand

efficacyassessmentreliesonarelatively

simplepremise:Ifagenericisshowntobebioequivalent(distributedinthebodyatthesamerateasthereferenceproduct)thenitcanbeassumedtobeequallysafeandeffectiveasthereferenceproduct,anditwillbeinterchangeablewiththelatter,meaningthatitcanbesubstitutedorswitchedwithoutconsultingtheprescriber.Forbiosimilars–whicharenotidentical

tothebiotherapeuticreferenceproduct–the‘generic’approachbydemonstrationofbioequivalenceisnotsufficienttoensureadequatedevelopment,regulatoryassessmentandlicensing.Moresophisticatedscientificapproachesarerequiredtocompareabiosimilarwithitsreferenceproductbasedonbothnon-clinicalandclinicaldata.Tailor-madestudiesareneededforeachbiosimilartodefinethedegreeofdifferencefromitsreferenceproduct,andtodeterminewhetheritisinterchangeablewiththereferenceproductandwhetheritsefficacy,safety,immunogenicityandinterchangeabilitycanbeassumed(“extrapolated”)foradifferentindicationorinadifferentpopulationthanthatstudied.

Regulation of biosimilars

WHO guidanceWHOprovidedguidanceonbiosimilarsin2009(3). Theguidancetextisa“livingdocument”tobedevelopedfurtherinlinewithadvancesinscientificknowledgeandexperience.WHAResolution67.21callsforan

updateoftheWHOguidancetext,takingintoaccountthetechnologicaladvancesforthecharacterizationofbiotherapeuticsandconsideringnationalregulatoryneedsandcapacities.The2014InternationalConference of Drug Regulatory Authorities(ICDRA)adoptedanumberofrecommendationsonbiotherapeutics

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andbiosimilars(4),identifyingsomeareastodevelopfurtherintheWHOguidance.Theseinclude:extrapolationofindication,specialconsiderationsforevaluationofmonoclonalantibodies,acceptancecriteriaandevaluationofreferencebiotherapeuticproductsincludingtherelianceonreferenceagencies,andthedesign,conductandinterpretationofstudiestoevaluatecomparability.Atits65th meeting the WHO Expert

Committee on Biological Standardization decided to initiate an update of the WHO biosimilarsguidanceandtoimplementrecommendationsfromthe16th ICDRA meetingonbiotherapeuticsincludingbiosimilars(5).

National requirementsWhileWHOprovidesnormsandstandards,nationalregulatoryoversightiswhatensuresthequality,safetyandefficacyofbiotherapeuticproducts.Countriesneedefficientpathwaystoapproveclinicaltrialsandbiotherapeuticproducts.Onceproductsareonthemarket,effectivepharmacovigilancesystemsareneededtotrackadverseevents,includingunwantedimmunereactions.Nationalregulationsonbiosimilars

haveevolvedinthelastdecade.TheEuropeanMedicinesAgency(EMA)publisheditsfirstregulationsforbiosimilarsin2005,andon1stJune2015therewere19biosimilarslistedontheEMAwebsite1.BiosimilarsregulationsbasedonEMAand/orWHOguidelineshavebeenintroducedinanumberofcountries,withsomeadaptationstosuitthenationalcontext,forexampletolowerthebarriersofclinicaltrialrequirementsortoacceptreferenceproductsthatarenotlicenceddomestically.

1 www.ema.europa.eu–Findmedicine–HumanMedicine–(browsebytype):Biosimilars

IntheUnitedStatesapathwayforapprovalofbiosimilarswasputintoplaceafterthesigningoftheBiologicsPriceCompetitionandInnovationActon23March2010byPresidentBarackObama.TheFDA’sbiosimilarsregulationguidelinecameintoforcein2014,andinMarch2015thefirstbiosimilarwasapprovedunderthenewguidance(6).InSeptember2014theFDApublishedthefirsteditionofits“PurpleBook”,asetoflistsoflicensedbiologicalproducts.Goingforward,WHOguidelines

willprovideavaluablereferenceforestablishingnewnationalregulatoryrequirementsorupdatingexistingones,andforpromotingconvergenceatthegloballeveltoenableregulatorycooperation.

Naming of biosimilarsNamingofbiotherapeuticsandbiosimilarshasimportantimplicationsforarangeofstakeholdersincludingregulators,thepharmaceuticalindustry,healthsystems,healthprofessionalsandpatients.Differentnamingsystemsforbiosimilars

arecurrentlyinuseincountries.SomeregulatoryauthoritieshavebeenusingtheInternationalNonproprietaryName(INN),whileothershaveaddedaqualifierwhichinsomecasesincorporatesthecompanyname.Tocomplicatemattersfurther,aproductmaybeviewedasabiosimilartoagivenreferenceproductinsomejurisdictionsbutnotothers.Variousargumentshavebeenvoiced

forandagainstgivingdistinctnamestobiosimilars.Thoseinfavourarguethateachbiosimilardiffersfromitsreferenceproductandfromotherbiosimilars,andthatdistinctnameswillmakeiteasiertoknowwhichproductapatientisreceiving,toensurecorrectuseandtotrackadverseevents.Thoseagainstreasonthatby

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definitionbiosimilarsarehighlysimilartothereferenceproductwithnoclinicallymeaningfuldifferences,andthatacommonnameisthereforesufficientandwillhelptolimitmarketingcosts,makingproductsmoreaffordableforhealthsystems.Followingrequestsfromseveraldrug

regulatoryauthoritiestheWHOINNProgrammehasproposedaBiologicalQualifierscheme(7),whichiscurrentlyunderdiscussion.Recognizingthevalueofregulatoryconvergenceasatooltoincreaseglobalaccesstosafe,effective,qualitybiosimilars,participantstothe16th ICDRA recommended that a clearterminologyshouldbedefinedfornamingtheseproducts,enablingaclearidentificationoftheevaluationpathway(4).Systemsincountriesaremeanwhile

evolving.Aplaceholdernon-proprietarynamewasassignedtothefirstbiosimilarapprovedintheUnitedStatesthroughthenewabbreviatedregulatorypathwayforbiosimilars(6),andinAustraliaaninterimsystemfornamingofbiosimilarshasbeenproposedgiventhattheWHOproposalhassupersededthepreviouspositiononwhichthenationalnamingpolicywasbased(8).

ConclusionEnsuringregulationofbiotherapeuticproductsinWHOMemberStatesalonggloballyconsistentprinciplesisanurgentmatterwithsignificantpublichealthimpact.Informationandeducationofallstakeholderswillalsobecrucial,asdoctors’andpatients’perceptionsofbiosimilarmedicines,localpricingandreimbursementregulationsandprocurementpoliciesandtermswillallinfluenceequitableaccesstobiotherapeutics.ImplementationofWHOstandardsfor

biologicalsisrecognizedashavingagreat

valuefromastakeholders’perspective.WHOenvisagesacomprehensivereviewof the current concept of biological standardsandtheiruse,startingwithstandardsforbiotherapeuticproducts,includingbiosimilars,in2015.However,thescopeofworkandrequiredresourcestocoverthecontinuouslygrowingexpectationsexceedthecurrentcapacityoftheOrganization’sSecretariat.DiscussionswillcontinueatWHOtoplanthisworkandtoidentifyanewfundingstrategy. æ

References1 ResolutionWHA67.21.Accessto

biotherapeuticproductsincludingsimilarbiotherapeuticproductsandensuringtheirquality,safetyandefficacy.In:Sixty-seventhWorldHealthAssembly,Geneva,19–24May2014.Resolutionsanddecisions,annexes.

2 IMSInstituteforHealthcareInformatics.AssessingbiosimilaruptakeandcompetitioninEuropeanmarkets.October2014.

3 Guidelinesonevaluationofsimilarbiotherapeuticproducts(SBPs).In:WHO Expert Committee on Biological Standardization.Sixtiethreport.Geneva:WorldHealthOrganization;2013:Annex2(WHOTechnicalReportSeries,No.977),

4 16thInternationalConferenceofDrugRegulatoryAuthorities(ICDRA).WHODrugInformation.2014;28(3):297-306.

5 WHO Expert Committee on Biological Standardization.Mainoutcomesofthemeetingheldfrom13–17October2014.

6 U.S.FoodandDrugAdministration.FDA approvesfirstbiosimilarproductZarxio.[Newsrelease].6March2015.(Seealsopage 157.)

7 WHO Programme on International NonproprietaryNames(INN).Biological Qualifier.AnINNProposal.INNWorkingDoc.14.342.ReviseddraftJuly2014.

8 TherapeuticGoodsAdministration.Evaluationofbiosimilars.[Webpage].20April2015.(Seealsopage153.)

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Safety news

Restrictions

Bromhexine: not to be used in children under six in New ZealandN e w Z e a l a n d –Followinginternationalreportsofrarebutseriousallergicreactions(includinganaphylaxisandsevereskinreactions)associatedwiththeuseofbromhexine,theregulatoryauthorityofNewZealand,Medsafe,hasrecommended that bromhexine-containing medicinestotreatcoughandcoldsymptomsshouldonlybeusedinadultsandchildrensixyearsofageandoverasthereisnotenoughevidencetosupporttheiruseinyoungeragegroups.InFebruary2015,theEMAhadwarned

abouttheserisksandhadrecommendedthattheyshouldbeincludedinproductinformation of bromhexine and ambroxol (theactivemetaboliteofbromhexine).

►MedsafeSafetyinformation,29April2015.

Codeine for cough and cold: not to be used in children under 12; E u r o p e a n U n i o n –TheEuropeanMedicinesAgency(EMA)hasconcludeditsreviewofcodeine-containingcoughandcoldmedicinesinchildrenandhasrecommendedfurtherrestrictionstominimizetheriskofmorphine-inducedsideeffects,suchasbreathingproblems,thatoccurduetotheconversionofcodeineintomorphineinthebody.Codeineshouldneverbeusedin

childrenbelow12years.Itsusetorelievecoughandcoldisnotrecommended

inchildrenandadolescentsbetween12and18yearswhohaveproblemswithbreathing.Allliquidcodeinemedicinesshouldbeavailableinchild-resistantcontainerstoavoidaccidentalingestion.In2013theEMAhadreviewedtherisks

andbenefitsofusingcodeineforpainreliefinchildren,andhadrecommendedsimilarrestrictions.(1)

N e w Z e a l a n d –Medsafehaswarnedabouttheabove-mentionedrisksandhasrecommendedtorestricttheuseofcodeine-containingproductsforcoughandcoldsymptomstoadultsandchildren12yearsofageandover.(2)

► (1) EMAPressrelease,24April2015.(2) MedsafeSafetyinformation,29April2015.

Safety warnings

Sitagliptin: thrombocytopeniaJ a p a n –ThePharmaceuticalsandMedicalDevicesAgency(PMDA)haswarnedaboutcasesofthrombocytopeniareportedinpatientstreatedwiththeanti-diabeticmedicinesitagliptinhydrate(Glactiv®,Januvia®)inJapan,andhasrecommended to update the product informationforthesemedicines.Patientsshouldbemonitored,andincaseofabnormalitiesthedrugshouldbediscontinuedandappropriatemeasuresshouldbetaken.

► PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.

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SGLT2 inhibitor diabetes medicines: ketoacidosisU n i t e d S t a t e s o f A m e r i c a –TheU.S.FoodandDrugAdministration(FDA)haswarnedthatseriouscasesofketoacidosishavebeenreportedintheUnitedStatesinpatientstreatedwiththesodium-glucosecotransporter-2(SGLT2)inhibitorscanagliflozin,dapagliflozin,andempagliflozin.Thesemedicinesareapprovedtotreattype-2diabetesandareavailableassingle-ingredientproductsandincombinationwithotherdiabetesmedicinessuchasmetformin.TheFDAisinvestigatingwhetherchangesareneededintheprescribinginformationfortheseproducts.PatientstakingSGLT2inhibitorswho

havesymptomsofketoacidosis(difficultybreathing,nausea,vomiting,abdominalpain,confusion,unusualfatigueorsleepiness)shouldbeevaluated.Ifketoacidosisisconfirmed,healthprofessionalsshoulddiscontinuetheSGLT2inhibitorsandtakeappropriatemeasurestocorrecttheacidosisandmonitorbloodsugarlevels.

►FDASafetyannouncement,5May2015.

Hepatitis C drugs and amiodarone: symptomatic bradycardiaU n i t e d S t a t e s o f A m e r i c a –FollowingreportsofsymptomaticbradycardiainpatientstakinghepatitisCmedicinesandtheantiarrhythmicdrugamiodarone,theFDAhaswarnedthatseriousslowingoftheheartratecanoccurwhenamiodaroneistakentogetherwitheitherledipasvir/sofosbuvir(Harvoni®)orwithsofosbuvir(Sovaldi®)andanotherdirectactingantiviral,suchastheinvestigationaldrugdaclatasvirorsimeprevir(Olysio®).Wherealternativetreatmentoptionsare

unavailable,theFDArecommendsheartratemonitoringinaninpatienthospitalsettingforthefirst48hours,followedbydaily monitoring by a doctor or the patient duringatleastthefirsttwoweeksoftreatment.Warningshavebeenaddedtothe

productinformationandpatientleafletforledipasvir/sofosbuvirandforsimeprevir.TheFDAwillcontinuetomonitortheriskandinvestigatethereasonfortheadverseevents.(1)

C a n a d a –HealthCanadahaswarnedthatpostmarketingcasesofsymptomaticbradycardia,includingtwocasesthatoccurredinCanada,havebeenreportedinpatientstakingamiodaronewiththeabove-mentionedhepatitisCproducts.Co-administrationofamiodaronewithHarvoni™orSovaldi®incombinationwithanotherdirect-actingantiviralisnotrecommended.Theregulatoryauthorityisworkingwith

the manufacturer to update the product monographsforHarvoni™andSovaldi®toreflectthisnewinformation.(2)

E u r o p e a n U n i o n –AnEMAreviewconductedasaresultofasafetysignalhasconfirmedariskofseverebradycardiaorheartblockwhensofosbuvirwithledipasvir(Harvoni®)oracombinationofsofosbuvir(Sovaldi®)anddaclatasvir(Daklinza®)areusedinpatientswhoarealsotakingamiodarone.TomanagethisrisktheEMA

recommendsthatinpatientstakingthesehepatitisCmedicinesamiodaroneshouldonlybeusedifotherantiarrhythmicscannotbegiven,andonlywithclosemonitoring.Duetothelonghalf-lifeofamiodaronemonitoringisalsoneededinpatientsstartingsuchhepatitisC

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treatmentswithinafewmonthsofstoppingamiodarone.(3)

► (1)FDASafetyAnnouncement,24March2015.(2) HealthCanadaAdvisory,2April2015.(3) EMAPressrelease,24April2015.

Asunaprevir and daclatasvir: erythema multiforme J a p a n –ThePMDAhaswarnedthatcasesoferythemamultiformehavebeenreportedinpatientstreatedconcomitantlywithdaclatasvir(Daklinza®)andasunaprevir(Sunvepra®)inJapan.ThetwoproductsareapprovedinJapanforimprovementofviraemiainpatientswithserogroup1(genotypeI)chronichepatitisCorcompensatedcirrhosistypeC.Productinformationforbothproductswillbeupdatedtoincludethisinformation.

► PMDA Summaryofinvestigationresults and Revisionsofprecautions,23April2015.

Fingolimod: progressive multifocal leukoencephalopathyU n i t e d K i n g d o m –Themarketingauthorizationholder,inagreementwiththeEMAandMedicinesandHealthcareProductsRegulatoryAgency(MHRA),haswarnedhealthprofessionalstobevigilantfortheriskofprogressivemultifocalleukoencephalopathy(PML)inpatientstreatedwithfingolimod.ThemedicineshouldbepermanentlydiscontinuedifPMLisconfirmed.Thisfollowsthefirstreportedcase,

inFebruary2015,ofPMLinamultiplesclerosispatienttakingfingolimod(Gilenya®)withoutprevioustreatmentwithnatalizumaborotherimmunosuppressivemedicines.PMLwassuspectedonaroutinebrainMRIscanandconfirmedbypositiveJCvirusDNAincerebrospinal

fluidusingquantitativePCR.FingolimodwasstoppedimmediatelyuponconfirmationofPML,andnosignsorsymptomsofPMLhadappearedatthetimeofcommunication.PMLisarareandseriousbraindisease

causedbyreactivationoftheJCvirusinpatientswithaweakenedimmunesystem.TheriskofPMLwithfingolimodisbeingevaluatedfurther.

►DrugSafetyUpdatevolume8issue10May2015:4.Lettertohealthprofessionals,29April2015.

Pomalidomide: risks of cardiac failure, interstitial lung disease and hepatotoxicityU n i t e d K i n g d o m –TheMHRAhasissuednewmonitoringinstructionsforpomalidomide(Imnovid®),usedtotreatrelapsedandrefractorymultiplemyeloma.ThisfollowsanEMAreviewwhichidentifiedcardiacfailureandinterstitiallungdiseaseascommonsideeffectsofthismedicine(affectinguptoonein10patients),whileseriousliverdamagewasfound to be uncommon (affecting up to onein100patients).Cardiacfailureoccurredmostlyin

patientswithcardiacdiseaseorcardiacriskfactors.Pomalidomideshouldbeusedwithcautioninthesepatients,andtheyshouldbemonitoredforsignsandsymptomsofheartfailure.Interstitiallungdiseasetypicallystarted

withinsixmonthsofstartingtreatment,buttookaslongas18monthstoappearinsomecases.Healthprofessionalsshouldcarefullyassesspatientswithanyneworworseningrespiratorysymptomsandstoppomalidomideduringassessment.Ifinterstitiallungdiseaseisconfirmed,itshouldbetreatedappropriatelyandpomalidomideshouldonlyberesumed

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afterathoroughevaluationofthebenefitsandrisks.Serioushepatotoxicitymanifested

mainlyasacutehepatitis.Regularliverfunctionmonitoringisrecommendedduringthefirstsixmonthsoftreatment,whenthisriskappearstobehighest.Insufficientdataareavailabletosupportspecificguidanceonmonitoringfrequency.

►MHRADrugsafetyupdate,20May2015.

High-dose ibuprofen and dexibuprofen: cardiovascular risksE u r o p e a n U n i o n –TheEMA’sPharmacovigilanceRiskAssessmentCommittee(PRAC)hascompletedareviewconfirmingasmallincreaseintheriskofcardiovascularproblems,suchasheartattacksandstrokes,inpatientstakinghighdosesofibuprofen(2 400mgormoreperday).Noincreaseincardiovascularriskisseenwithibuprofenatdosesupto1 200mgperday.ThePRACrecommendstoavoiddoses

of2 400mgofibuprofenperdayorhigherinpatientswithseriousunderlyingheartorcirculatoryconditionsandinthosewhohavepreviouslyhadaheartattackorstroke,andtoassessapatient’scardiovascularriskfactorsbeforeinitiatinglong-termtreatmentwithibuprofen,particularlyathighdoses.Datafromlaboratorystudiesfurther

indicatethatibuprofenreducestheanti-clottingeffectsofaspirin.Inclinicalpractice,occasionaluseofibuprofenshouldnotbeaproblem;howeveritslong-termusemayaffectthebenefitsoflow-doseaspirininpreventingheartattacksandstrokes.Theabovefindingsand

recommendationsalsoapplytodexibuprofen,with1 200mgormoreperdaybeingconsideredahighdose.

Updatedinformationwillbeincludedinproductinformationforbothmedicines.(1)

C a n a d a –AHealthCanadasafetyreviewfoundthatoralibuprofentakenatdosesof2 400mgperdayormoreincreasestheriskofheartattackandstroketolevelssimilartothoseseenwithCOX-2inhibitorsanddiclofenac.Prescriptionoralibuprofenproductsin

Canadahaveamaximumrecommendeddailydoseof2 400mgandareauthorizedtorelievethepainandinflammationofrheumatoidarthritisandosteoarthritis.Theprescribinginformationwillbeupdatedtowarnthatdosesof2 400mgperdayshouldnotbeusedinpatientswhohaveahistoryofheartdiseaseandstroke,orwhohavecardiovascularriskfactorssuchassmoking,diabetes,highbloodpressure,highbloodcholesterolorastrongfamilyhistoryofcardiovasculardisease.Thereviewfoundnoevidenceofan

increasedcardiovascularriskwithover-the-counteribuprofenproductsiftheyareusedasdirected,i.e.atamaximumdailydoseof1 200mgfornomorethansevendays. (2)

► (1) EMAPressrelease,13April2015.

(2) HealthCanadaInformationupdate,23April2015.

ADHD medicines: risk of suicidal thoughts in certain patientsC a n a d a –Followingreportsofsuicide-relatedeventsinpatientstreatedwithAttentionDeficitHyperactivityDisorder(ADHD)medicines,HealthCanadahasrevisedtheprescribinginformationformethylphenidate,amphetaminesandguanfacin-containingADHDproductsavailableontheCanadianmarket.Forthe ADHD drug atomoxetin (Strattera®)

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theriskwasalreadyknownandcommunicatedin2005.HealthCanadaconsidersthatalthough

thesemedicinesmaycontributetosuicidalthoughtsincertainpatients,thebenefitsoftreatmentcontinuetooutweightherisks.Healthprofessionalsshouldtakepsychiatricdisordersintoaccountwhenprescribingthesemedicinesandshouldmonitoreachpatient’spsychologicalstateduringtreatment.

►HealthCanadaInformationupdate,30March2015.

Varenicline: potential alcohol interaction and other effectsU n i t e d S t a t e s o f A m e r i c a –TheFDAiswarningthatthesmokingcessationmedicinevarenicline(Chantix®)canchangethewayinwhichpeoplereacttoalcohol.Inaddition,rareaccountsofseizuresinpatientstreatedwithvareniclinehavebeenreported.TheFDAhasapprovedchangestotheproductinformationtowarnabouttheserisks.Untilpatientsknowhowvareniclineaffectstheirabilitytotoleratealcohol,theyshoulddecreasetheamountofalcoholtheydrink.Patientstakingvareniclinewhohaveaseizureshouldstopthemedicineandseekmedicalattentionimmediately.Studieshavebeenundertaken

toinvestigatetheriskofseriousneuropsychiatricsideeffectsofvarenicline.TheFDAwillupdatethepublicwhentheoutcomesbecomeavailable.

►FDADrugsafetycommunication,9March2015.

Rebamipide: adverse effects on the eye ;

J a p a n –ThePMDAhasreportedthatlacrimalductobstructionand

dacryocystitishavebeenobservedinJapaninpatientstreatedwithrebamipide(Mucosta®),anophthalmicsolutionusedtotreatdryeyes.Productinformationwillbeupdatedtorecommendpatientmonitoring,withdiscontinuationofthemedicineandappropriatemeasuresincaseofanyabnormalities.

► PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.

Known risks

Ferumoxytol: strengthened warningsU n i t e d S t a t e s o f A m e r i c a –TheFDAhasstrengthenedanexistingwarningthatserious,potentiallyfatalallergicreactionscanoccurwiththeintravenousiron replacement product ferumoxytol (Feraheme®).TheproductnowcarriesaBoxedWarningabouttheseseriousrisks,andiscontraindicatedinpatientswithahistoryofhypersensitivitytoanyintravenousironproduct.Inotherpatientsitshouldonlybeusedifthebenefitsoutweightherisks,andshouldbeadministeredbyinfusionoveratleast15minuteswithappropriatedilution.(1)InJuly2014anEMAreviewof

ferumoxytolhadcometosimilarconclusions.(2)

► (1) FDADrugsafetycommunication,30March2015.

(2) EMANews,11July2014.

Triamcinolone acetonide: tendon ruptureJ a p a n –ThePMDAhasreportedthatcasesoftendonrupturehaveobservedinpatientstreatedwithinjectabletriamcinolone acetonide (Kenacort-A®) in

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Japan.ProductinformationinJapanwillbeupdatedtoreflectthisrisk.(1)Theseobservationsconfirmtherisk

reflectedinapprovedproductinformationin Europe (2),whichcarryawarningthatrepeatedinjectionofthismedicineintoinflamedtendonsshouldbeavoidedasithasbeenshowntocausetendonrupture.

► (1) PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.(2) Example: www.medicines.org.uk/emc/medicine/6392

Cyclophosphamide: rhabdomyolysis J a p a n –Followingreportsofrhabdomyolysisinpatientstreatedwiththeantineoplasticagentcyclophosphamidehydrate(Endoxan®)inJapan,thePMDAhasrecommendedtoupdatetheproductinformationfororalandinjectableproducts.Signsofrhabdomyolysisincludemyalgia,feelingsofweakness,increasedcreatinekinase(creatinephosphokinase),increasedbloodmyoglobin,andincreasedurinemyoglobin.Ifrhabdomyolysisoccurs,themedicineshouldbestoppedandappropriatemeasurestaken.(1)Approvedproductinformationfor

cyclophosphamideintheUnitedKingdom(2)includesrhabdomyolysisasaveryrareadverseevent.

► (1) PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.

(2) Example: www.medicines.org.uk/emc/medicine/29592

Panitumumab: Stevens-Johnson syndromeJ a p a n –FollowingreportsofadverseeventssuggestiveofStevens–Johnsonsyndromeinpatientstreatedwithpanitumumab(Vectibix®)inJapanandelsewhere,approvedproductinformationinJapanhasbeenrevisedtoincludethisrisk.(1)EMA-approvedproductinformationfor

panitumumab (2) listsStevens-Johnsonsyndromeandtoxicepidermalnecrolysisrareadverseevents,occurringinoneof1001-10000patientstreated.

► (1) PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.(2) EMA.Vectibix : EPAR - Product Information.Lastupdated2March2015.

Pazopanib: retinal detachmentJ a p a n –Followingreportsofretinaldetachmentinpatientstreatedwiththeantineoplasticagentpazopanib(Votrient®)inJapanandelsewhere,thePMDAhasrecommended to add information about thisadverseeventtoproductinformationapprovedinJapan.Ifpossiblesignssuchaseyefloaters,photopsia,visualfielddefectorreducedvisualacuityareobserved,ophthalmologicexaminationshouldbeperformedandappropriatemeasurestaken.(1)EMA-approvedproductinformationfor

pazopanib (2) includesthisadverseeffectasuncommon,occurringinoneof101-1000patientstreated.

► (1) PMDA Summaryofinvestigationresults and Revisionsofprecautions,24March2015.(2) EMA.Votrient : EPAR - Product Information.Lastupdated9February2015.

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Zoledronic acid: further measures to minimize risk of osteonecrosis of the jawE u r o p e a n U n i o n –TheEMAhascompletedaperiodicreviewofzoledronicacid(Aclasta®),oneofthebisphosphonatemedicineswithaknownriskofosteonecrosisofthejaw.Althoughtheriskisverylow,theEMAhasrecommendedtoupdatetheproductinformation and to introduce a patient remindercardtominimizethisrisk.Patientsshouldhighlightanydental

problemstotheirdoctorbeforestartingtreatment,ensuregooddentalhygieneduringtreatment,informtheirdentistthattheyarebeingtreatedwithzoledronicacid,andcontactthedoctoranddentistifanyproblemswiththemouthorteethoccurduringtreatment.Theriskalsoexistswithothermedicines

usedforosteoporosisandotherconditionsthataffectthebones,suchasotherbisphosphonatesanddenosumab.Similarrevisionswillbeconsideredaspartofperiodicreviewsduring2015and2016.

►EMAPressrelease,27March2015.

Duloxetine: neuroleptic malignant syndrome ;

J a p a n –ThePMDAhaswarnedaboutneurolepticmalignantsyndromehavingoccurredinpatientstreatedwithduloxetine(Cymbalta®)inJapan,andhasrecommendedtoupdatetheproductinformation.In2006theFDAhadwarnedabout

theriskofapotentiallylife-threateningserotoninsyndromewithserotoninnoradrenalinereuptakeinhibitors(SNRIs)andselectiveserotoninreuptakeinhibitors

(SSRIs),particularlywithconcomitantuseofcertainothernervoussystemdrugs.

► (1) PMDA Summaryofinvestigationresults and Revisionsofprecautions,23April2015.

(2) FDAAlert[7/2006]:PotentiallyLife-ThreateningSerotoninSyndromewithCombinedUseofSSRIsorSNRIsandTriptanMedications.Webpagelastupdated14July2013.

Unchanged recommendations

Rotavirus vaccine: benefits outweigh risksG e n e v a –TheGlobalAdvisoryCommitteeonVaccineSafetyhasissuedastatementtoaffirmthatthesafetyprofileofcurrentrotavirusvaccinesisacceptable,withthebenefitsofvaccinationgreatlyexceedingrisks.Thisfollowsreportedcasesof

intussusceptioninmultiplecountriesforthetwomostwidelyusedvaccinestopreventrotavirusgastroenteritisinyounginfantsglobally.Thefindingsunderscoretheimportanceofclosemonitoringofinfantsandpromptmedicalcareaftervaccination.Ifrecognizedandtreatedearly,intussusceptiongenerallyhasagoodoutcomeandisrarelyfatal.Thebenefitsofrotavirusvaccination

areparticularlyimportantinresource-poorcountrieswhererotavirusdiseaseremainsanimportantcauseofmortalityamongyoungchildren.

►WHOEssentialmedicinesandhealthproducts.News,11May2015.

Natalizumab: no definite link with melanomaA u s t r a l i a –TheTherapeuticGoodsAdministration(TGA)hasconcludeditsreviewoftheimmunosuppressant

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medicinenatalizumab(Tysabri®),andhasfoundinsufficientevidenceofadefinitelinkbetweenthismedicineandmelanoma.Natalizumabisusedtotreatpatients

withrelapsing-remittingmultiplesclerosis.GiventhehighincidenceofmelanomainAustralia,theTGAwillcontinuetomonitorthisissue.Healthprofessionalsshouldensurethatanyneworchangedsuspiciousskinlesionsinpatientstreatedwithnatalizumabarepromptlydetectedandinvestigated.

►TGAMonitoringcommunication,21May2015.

Olanzapine: inconclusive findings after two deaths in 2013 ;

U n i t e d S t a t e s o f A m e r i c a –Followingthedeathsoftwopatientsin2013

afterinjectionofappropriatedosesofolanzapinepamoate(ZyprexaRelprevv®),theFDA’sstudytodeterminethecauseshasendedwithinconclusiveresults.Itispossiblethatthedeathswerecausedbyrapid but delayed entry of the drug into thebloodstreamfollowingintramuscularinjection,andthatthehighdruglevelsfoundinthetwopatients’bloodoccurredafterdeath.Onthebasisofalloftheinformation

reviewed,theFDAisnotrecommendinganychangestotheprescribingoruseofolanzapine.HealthcareprofessionalsareremindedtofollowtherequirementsoftheRiskEvaluationandMitigationStrategy(REMS)fortheproduct.

►FDASafetyannouncement,23March2015.

Safety reviews started

Medicine Use Concerns Reviewing authority reference

Natalizumab(Tysabri®)

Treatment of multiple sclerosis

Possibleneedtoreviseadviceonmanagingtheriskofprogressivemultifocalleukoencephalopathy

►EMANews,8May2015.

Inhaled corticosteroids

Treatment of chronicobstructivepulmonarydisease(COPD)

NeedtoevaluatetheknownriskofpneumoniawhenthesemedicinesareusedforCOPD

asabove

Crizotinib (Xalkori®)

Treatment of certain typesoflungcancer

Possibleriskofcardiacfailure

►PMDAriskcommunication,8May2015.

Technetium (99m Tc) injection(Clearbone®)

Scintigraphy Possibleriskofshockandanaphylaxis

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Data integrity concerns

GVK Biosciences: EMA confirms suspension of products over flawed studiesE u r o p e a n U n i o n –TheEMAhasconfirmeditsJanuary2015recommendationtosuspendanumberofmedicinesforwhichauthorizationintheEUwasprimarilybasedonclinicalstudiesconductedatGVKBiosciencesinHyderabad,India.Thisistheoutcomeofare-examinationrequestedbymarketingauthorizationholdersforsevenofthemedicinesconcerned.Around700pharmaceuticalformsand

strengthsofmedicinesstudiedattheHyderabadsiteremainrecommendedforsuspension,whileforaround300others,includingoneincludedinthere-examination,sufficientsupportingdatafromothersourceshadbeenprovided.AnupdatedlistofmedicinesrecommendedforsuspensionisavailableontheEMAwebsite.Someofthesemayremainonthemarketincountrieswheretheyareofcriticalimportancetomeetpatients’needs;asdecidedbythenationalauthoritiesoftherespectiveEUMemberState.Formedicinesthatareconsideredcritical,companiesaregiven12monthstosubmitadditionaldata.

►EMAPressrelease,22May2015.

Hospira S.P.A: Health Canada restrict importsC a n a d a –HealthCanadahasrestrictedtheimportationofmedicinesfromHospiraS.P.A.inLiscate,Italy,duetodataintegrityconcernsraisedbyatrustedregulatorypartner about the reliability of the laboratorydatageneratedatthissite.

TheCanadianimportlicencesformedicinesfromthisfacilityarebeingamended to require independent third-partytestingagainsttheapprovedCanadianspecificationspriortoreleaseofanymedicallynecessaryproducts.ProductsthatarenotonthemedicallynecessarylistwillnotbeimportedorreleasedtotheCanadianmarketuntilHealthCanadaissatisfiedthatthedataintegrityissueshavebeenaddressed.Alistofaffectedproductsisavailableontheauthority’swebsite,andupdateswillbeprovidedthroughtheonlineInspectionTracker.

►HealthCanadaAdvisoryinformationupdate,12June2015(withsubsequentupdates).

Zhejiang Hisun Pharma, Polydrug Laboratories: Health Canada recommends voluntary quarantine;

C a n a d a –HealthCanadahasrequestedthatCanadianimportersvoluntarilyquarantinedrugproductswithactivepharmaceuticalingredients(APIs)manufacturedortestedbyZhejiangHisunPharmaCompanyLtd.,inZhejiang,China (1)aswellasthosemanufacturedortestedbyPolydrugLaboratories,inAmbarnath,Maharashtra,India(2),duetodataintegrityconcerns.Norisktohealthhasbeenidentified,

andHealthCanadaisnotrequestingarecallofanyproducts.TheauthorityisprovidingupdatesonthesituationthroughitsInspectionTracker.

► (1)HealthCanadaAdvisoryinformation,16June2015.(2) HealthCanadaAdvisoryinformation,24June2015.

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Falsified product alert

Falsified meningitis vaccines circulating in West AfricaWHOhaspublishedamedicalproductalertrelatingtotheconfirmedcirculationoffalsifiedversionsofmeningitisvaccinesinNiger.FollowingareportsubmittedtotheWHOSurveillanceandmonitoringsystemforsubstandardandfalsifiedmedicalproductsbythefocalpointwithintheNigerRegulatoryAuthority,increasedvigilanceisrequestedforthefollowinglots/batchesofvaccinesandsolvents.

• Product: Mencevax ACW Batch number: AMENA020AA; manufacturing date: 12-2014,expirydate:11-2017 Thebatchnumberisgenuinebutthemanufacturingandexpirydatesarefalse.Thegenuineversionofthisbatchexpiredin2011.Theproductcontains50dosespervial.

• Product: Mencevax ACWY Batch number: AMEHA020AA; manufacturing date: 12-2013,expirydate:11-2016 Thebatchnumber,manufacturingdateandexpirydateforthisproductarefalse.Thisfalsifiedproductcontains50dosespervial.

• Product: Diluent for Mencevax Batch number: A003B128AA;manufacturingdate:02-2013,expirydate:01-2019 Thebatchnumber,manufacturingdateandexpirydateforthisdiluentarefalse.Thisfalsifiedproductcontains50dosesofdiluent.

• Product: Menomune ACY-W135;batchnumber:UH301AA;expirydate:29APR17 Thebatchnumberisgenuinebuttheexpirydateisfalse.Thegenuineversionofthisbatchofvaccineexpiredin2014.Thisfalsifiedproductcontains10dosespervial.

• Product: Menomune ACYW-135;batchnumber:UH301AA;expirydate:28FEB16 Thebatchnumberisgenuinebuttheexpirydateisfalse.Thegenuineversionofthisbatchofvaccineexpiredin2014.Thisfalsifiedproductcontains10dosespervial.

• Product: Menomune ACYW-135;batchnumber:UH299AA;expirydate:28FEB16 Thebatchnumberisgenuinebuttheexpirydatefalse.Thegenuineversionofthisbatchofvaccineexpiredin2014.Thisfalsifiedproductcontains10dosespervial.

• Product: Diluant for Menomune;batchnumber:UH262AA;expirydate:25OCT16 Thebatchnumberisgenuinebuttheexpirydatefalse.Thegenuineversionofthisbatchofdiluantexpireson25OCT15.Thisfalsifiedproductcontainssufficientsolventtoreconstitute10dosesofvaccine.

• Product: Diluant for Menomune;batchnumber:D0953-1;expirydate:20-2017 ThisisnotagenuinebatchnumberforadiluentforMenomuneVaccine.Thisfalsifiedproductcontainssufficientsolventtoreconstitute10dosesofvaccine.

Noseriousadversereactionslinkedtothesebatchesoffalsifiedvaccineshavebeenreportedatthisstage.GenuineMencevaxismanufacturedbyGlaxoSmithKline(GSK),andgenuineMenomuneismanufacturedbySanofiPasteur.Thesefalsifiedproductshavenotyetbeensubjecttolaboratoryanalysis.ThealertwasissuedonthebasisofinconsistenciesinthepackagingmaterialandconfirmationfromGSKandfromSanofiPasteurthatthebatchnumbers,manufacturingdatesandexpirydatesareinconsistentwiththegenuineproduct.WHOadvisesincreasedvigilancewithinthesupplychainsofcountrieslikelytobeaffectedbythesefalsifiedproducts.Itisnecessarytoensurethatvaccinesareobtainedfromauthenticandreliablesources.MinistryofPublicHealth/NationalmedicinesregulatoryauthoritiesareaskedtoimmediatelynotifyWHOviarapidalert@who.intiftheabove-mentionedbatchesarediscoveredintheircountries.

►WHOMedicalProductAlertsNo.2/2015,22May2015 and 3/2015,27May2015.(Withphotographs.)WHOrecognisestheseriousnessofthecurrentmeningitisoutbreakinWestAfricaandtheadditionaldemandformeningitisvaccines.Furtherinformationconcerningthisoutbreakisavailableat www.who.int/mediacentre/news/situation-assessments/meningitis-niger/en/. æ

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Regulatory news

Assessment

Final FDA guidance on opioids with abuse-deterrent propertiesU n i t e d S t a t e s o f A m e r i c a –TheFDAhasissueditsfinalguidancetoassistindustryindevelopingopioiddrugproductswithpotentiallyabuse-deterrentproperties.ThedocumentexplainstheFDA’scurrentthinkingaboutthestudiesthatshouldbeconductedtodemonstratethatagivenformulationhasabuse-deterrentproperties.Itmakesrecommendationsabouthowsuchstudiesshouldbeperformedandevaluated,anddiscusseswhatlabellingclaimsmaybeapprovedbasedonthestudyresults.Thisguidancedoesnotaddressgeneric

opioidproducts.TheFDAisworkingondraftguidanceinthisarea.

►FDANewsrelease,1April2015.

EMA scientific advice on clinical trials leads to faster approvalsE u r o p e a n U n i o n –AnEMAanalysisof marketing authorization application outcomesbetween2008and2012hasfoundthatcompaniesthatchangedtheirclinicaldevelopmentplansinaccordancewithEMArecommendationsweremore likely to be granted a marketing authorization.EMA,throughitsScientificAdvice

WorkingParty(SAWP),providesscientificadvicetoapplicantsindesigningclinicaltrialsthatarescientificallysoundandgenerate adequate data for regulatory benefit-riskassessment.Theanalysis

foundthattwooutofthreeclinicaltrialdesignssubmittedwereinadequate,andthatthesuccessrateofapplicationswithinadequatetrialswashalfashigh(41%)thanthatofapplicationswithadequatetrialdesigns(84%)orthosechangedaccordingtoSAWPrecommendations(86%).Thescientificadvicethusleadstostrongerapplicationsfromindustry,andprotectspatientsfromparticipatinginclinicaltrialsthatareunlikelytoleadtotheapprovalofnewmedicines.

►EMANews,17April2015.

Generics information-sharing pilot extendedE u r o p e a n U n i o n –TheEMAhasinformedapplicantsthatthedeadlineforparticipationintheinformation-sharingpilotprojectforgenericshasbeenextended.Companiesareencouragedtosubmitexpressionsofinterest.TheEuropeanMedicinesAgency

(EMA)launchedthisprojectinJanuary2015forcentrallyapprovedproductsaspart of the International Generic Drug RegulatorsPilot(IGDRP)programme.ThepilotallowsEMAtoshareitsassessmentsofapplicationsforgenericmedicinesinrealtimewithcollaboratingregulatoryagenciesinordertofacilitatethetimelyauthorizationandavailabilityofsafe,effectiveandhighqualitygenericmedicinesworldwide.

►EMANews,21April2015.SwissmedicNews,4May2015.More information about IGDRP: The InternationalGenericDrugRegulatorsPilot.WHODrugInformation28(1);2014:3-10.

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TGA reviews its guidance on evaluation of biosimilarsA u s t r a l i a –TheTherapeuticsGoodsAdministration(TGA)isreviewingitsguidanceonevaluationofbiosimilarsinlightofagloballyevolvingunderstandingofbiotherapeutics.Inparticular,aninterimsystemfornamingofbiosimilarshasbeenproposed,giventhattheWHOdraftpolicyBiological Qualifier - An INN Proposal,publishedinJuly2014,hassupersededthepreviouspositiononwhichtheTGApolicywasbased.TheinterimsystemwillusetheAustralianbiologicalnamewithoutaspecificbiosimilaridentifiersuffix.ForexampleabiosimilartothereferenceproductNeupogenfilgrastimwouldbenamed‘Tradename’filgrastim.

►TGANews,20April2015.

Updated risk management plan format in Australia A u s t r a l i a –TheTGAhaspublisheditsupdatedguidelineonsubmissionofriskmanagementplans(RMPs)bycompanies,includingatemplateforanAustralian-specificAnnextoRMPs.AnRMPoutlineshowsafetyconcerns

willbeidentifiedandmitigatedonceapharmaceuticalproductisonthemarkettohelpensurethatthebenefit-riskbalanceremainsfavourable.SubmissionofRMPshasbeenrequiredinAustraliasince2009forallnewchemicalentities,aswellasforalreadyregisteredproductswhenthereisamajorchangeinthewayinwhichtheproductisusedorifanewsafetyconcernisidentified.

►TGANews,4May2015.

Transparency

WHO calls for disclosure of clinical trial resultsG e n e v a –WHOhasissuedapublicstatementcallingforthedisclosureofresultsfromclinicaltrialsformedicalproducts,whatevertheresult,tohelpallactorstosetprioritiesforresearchanddevelopmentaswellaspublichealthinterventions.Thecallfordisclosureincludesolderunreportedclinicaltrials,theresultsofwhichmaystillhaveanimportantbearingonscientificresearchtoday.WHOalsoreaffirmstheneedfor

allclinicaltrialstoberegisteredonaWHOprimaryclinicaltrialregistrysothattheycanbeaccessiblethroughtheInternationalClinicalTrialsRegistryplatform.Thisplatformwasestablishedinresponsetoa2005callbyWHO.Itregularlyimportstrialrecordsfrommajornationalandregionalclinicaltrialregistries.

►WHONoteforthemedia,14April2015.

Australia adopts new regulator performance frameworkA u s t r a l i a –TheAustralianGovernmenthasdevelopedaregulatorperformanceframeworkcomprisingsixoutcomes-basedkeyperformanceindicators(KPIs).TheKPIsaresupportedbyaseriesofqualitativeandquantitativeoutputsandevidence,asdevelopedinconsultationwiththeTGAIndustryConsultativeCommitteeandtheAustralianTherapeuticGoodsAdvisoryCouncil,toassesstheTGA’sachievementsinthedifferentareasofgoodregulatoryperformance.

►TGAkeyperformanceindicatorsandmeasures:RegulatorPerformanceFramework.Version1.0,May2015.[webpage].10June2015.

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Databases

Health Canada launches searchable inspection databaseC a n a d a –HealthCanadahaslauncheditsDrugandHealthProductInspectionsDatabase,asearchablewebtoolprovidinginformationonforeignanddomesticinspectionsofpharmaceuticalmanufacturingsitesconductedbyHealthCanadaandabroadsince2012.Thispubliclyavailabledatabasebringstogetherkeydataaboutdrugestablishmentsandinspectionresults,includingdetailedinspectionsreportcards.Thenewtoolisamilestoneunder

HealthCanada’sRegulatoryTransparencyandOpennessFramework.AnotherusefultoolunderthisframeworkisHealthCanada’sInspectionTracker, whichprovidesasnapshotofemergingissuesidentifiedthroughtheinspectionprogrammeandtheactionsthattheauthorityistaking.

►HealthCanadaNewsrelease,13April2015.

WHO launches open access to its global medicines safety databaseWHOhaslaunchedanopenaccessplatformtoitsdatabaseofsuspectedadversereactionreportsmaintainedbytheUppsalaMonitoringCentreinSweden.Theplatform,namedVigiAccess,isanewwebapplicationthatwillallowanyonetoaccessinformationonreportedcasesofadverseeventsrelatedtoover150000medicinesandvaccines,withmorethan

tenmillioncasesreportedfromover120countries.Byprovidingopenaccesstothis

database,WHOaimstoimprovepatientsafety,increasetransparencyandencouragethereportingofadverseeffectsfrommedicinalproducts.Theplatformcanbeaccessedatwww.vigiaccess.org.

►WHOEssentialmedicinesandhealthproducts.Mediaadvisory,17April2015.

EMA to record adverse events from literature in EudraVigilanceE u r o p e a n U n i o n –AnewserviceofferedbyEMAisexpectedtoimprovesafetymonitoringofmedicinesandsimplifypharmacovigilanceactivitiesforcompanies.InaccordancewiththeEuropeanUnion’s(EU)pharmacovigilancelegislation,theAgencywillscreenmedicalliteraturefor400activesubstancegroupsandwillenteridentifiedreportsofsuspectedadversereactionsintothetheEUadversedrugreactioncollectionandmanagementsystem,EudraVigilance.AlistofthesubstancesandscientificjournalscoveredisavailableontheEMAwebsite.Theservicewillstarton1July2015andwillbefullyrolledoutinSeptember2015.Thisinitiativewillbenefitover4000

companiesthatwillnolongerneedtoentersuspectedadversereactionsintoEudraVigilancefortheactivesubstancesandliteraturecovered.

►EMANews,12May2015.

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Approved

Cholic acid: for rare bile acid synthesis disordersProduct name: Cholbam®Dosage form:CapsulesClass: Bile acid preparation

ATC code:A05AA03Approval:FDA(rarepaediatricdiseasepriorityreview)

Use:Treatmentofpatientswithbileacidsynthesisdisordersduetosingleenzymedefects,andpatientswithperoxisomaldisorders(includingZellwegerspectrumdisorders)

Benefits:Firstapprovedtreatmentoptionforpatientslackingcholicacidduetorare,geneticmetabolicdisorders.Inchildren,iftheseconditionsarenottreatedtheywillimpairgrowthandcanleadtolife-threateningliverinjury. ►FDANewsrelease,17March2015.

Eluxadoline: for irritable bowel diseaseProduct name: Viberzi®Dosage form:TabletsClass:Mu-opioidreceptoragonistApproval: FDAUse:Treatmentofirritableboweldiseasewithdiarrhoeainadults

Benefits: Additional treatment option for irritableboweldiseasewithdiarrhoea

Safety information:EluxadolinecancausespasminthesphincterofOddi,whichcanresultinpancreatitis.Eluxadolineshouldnotbeusedinpatientswithahistoryofbileductobstruction,pancreatitis,severeliverimpairment,orsevereconstipation,norinpatientswhodrinkmorethanthreealcoholicbeveragesperday.

Note:TheFDAhasalsoapprovedanextensionofindicationsforrifaximin (Xifaxan®)toincludetreatmentofirritableboweldiseaseinadults.Rifaximin,anantibioticderivedfromrifampicin,waspreviouslyapprovedastreatmentfor

travellers’diarrhoeacausedbyE. coli and forreductionoftheriskinadultpatientsofrecurringoverthepaticencephalopathy. ►FDANewsrelease,27May2015.

Empaglifozin & metformin : for diabetesProduct name:Synjardy®Dosage form:Film-coatedtabletsClass:Fixed-dosecombinationoforalbloodglucoseloweringagents ATC code:A10BD20

Approval: EMAUse:Treatmentofadultswithtype2diabetesmellitusasanadjuncttodietandexerciseinpatientsinadequatelycontrolledonothertreatments.

Benefits:Clinicallyrelevantimprovementinglycaemiccontrolcomparedwithmetforminonitsown. ►EMASummaryofopinion,26March2015.

Evolocumab: to lower cholesterolProduct name: Repatha®Dosage form:Solutionforinjectioninapre-filledsyringeorinapre-filledpen

Class:Lipid-loweringagent,monoclonalantibody,PCSK9protein-blocker(first-in-classtreatment) ATC code:C10AX13

Approval: EMAUse:Treatmentofhypercholesterolaemiaormixeddyslipidaemiainadults,andtreatmentofhomozygousfamilialhypercholesterolaemiainadultsandadolescents.Theeffectofevolocumaboncardiovascularmorbidityandmortalityhasnotyetbeendetermined.

Benefits:ReducesserumLDL-cholesterollevelsin.patientswhoareunabletocontroltheircholesterolwithstatins.

Safety information:Theuseofevolocumabmayleadtoverylowcholesterollevelswheresafetyhasnotyetbeenestablished. ►EMAPressrelease,22May2015.

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Approved

Isavuconazonium sulfate: for certain invasive fungal infectionsProduct name:Cresemba®Dosage form:Availableinoralandintravenousformulations

Class: Azole antifungal agentApproval:FDA(QualifiedInfectiousDiseaseProductdesignation)

Use:Treatmentofinvasiveaspergillosisandinvasivemucormycosis.

Benefits:Treatmentoptionfortworarebutseriousfungalinfections.

Safety information:Seriouspotentialsideeffectsincludeliverproblems,infusionreactionsandsevereallergicandskinreactions. ►FDANewsrelease,6March2015.

Atazanavir & cobicistat: for treatment of HIV-1 infectionProduct name:Evotaz®Dosage form:Fixed-dosecombinationtabletsClass:Antiretroviral

ATC code:J05AR15Approval: EMAUse:TreatmentofHIV-1infectioninadultswithoutknownmutationsassociatedwithresistancetoatazanavir

Benefits:sustainablevirologicalsuppressionifgivenincombinationwithotherantiretrovirals. ►EMASummaryofopinion,21May2015.

Anthrax immunoglobulin (human)Product name:Anthrasil®Dosage form:Solutionforintravenousinjection

Class:SpecificimmunoglobulinApproval: FDAUse:Treatmentofpatientswithinhalationalanthraxincombinationwithappropriateantibacterialdrugs

Benefits:Theresultsofstudiesinresearchanimalsprovidedsufficientevidencethattheproductisreasonablylikelytobenefithumanswithinhalationalanthrax.

Note:Inhalationalanthraxisararediseasethatcanoccurafterexposuretoinfectedanimalsorcontaminatedanimalproducts,orasaresultofanintentionalreleaseofanthraxspores.TheproducthasbeenpurchasedfortheU.S.StrategicNationalStockpile.ItsapprovalmakesitavailableinanemergencywithoutaprioremergencyuseauthorizationfromtheFDA. ►FDANewsrelease,25March2015.

Dinutuximab: to prolong survival in children with high-risk neuroblastomaProduct name: Unituxin®Dosage form:InjectionClass:Antineoplasticagent,monoclonalantibody;ATC code:L01XC16

Approval:FDA(priorityreviewandorphanproductdesignation);EMA(orphandesignation)

Use:Incombinationwithotherdrugs,first-linetherapyforpaediatricpatientswithhigh-riskneuroblastoma,atypeofcancerthatmostoftenoccursinyoungchildren.

Benefits:Firstspecificapprovedtreatmenttoprolongsurvivalinchildrenwithhigh-riskneuroblastoma

Safety information:Dinutuximabirritatesnervecells,causingseverepainthatrequirestreatmentwithintravenousnarcotics.Despiteprophylaxis,twothirdsofchildrenexperiencepainandabout40%experienceseverepain.Themedicinecanalsocausenervedamageandlife-threateninginfusionreactions,andhassomeotherserioussideeffects. ►FDANewsrelease,10March2015.EMAPressrelease,22May2015.

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Approved

Filgrastim-sndz:, first biosimilar in the U.S.Placeholder nonproprietary name*:Filgrastim-sndz

Product name:Zarxio®Dosage form:SolutionforinjectionorinfusionClass:Immunostimulant,colonystimulatingfactor;ATC code:L03AA02

Reference product:Filgrastim(Neupogen®)Approval: FDA Use:Toreducetheeffectsofneutropeniainpatientswithcancerreceivingvarioustypesofchemotherapyorundergoingbonemarrowtransplantationandinpatientswithseverechronicneutropenia;tomobilizebloodprogenitorcellsintothe peripheral blood for collection and autologoustherapy.

Benefits: Reduction of neutropeniaNote:ThisisthefirstbiosimilarproductapprovedintheU.S.throughtheBiologicsPriceCompetitionandInnovationActof2009(BPCIAct),whichcreatedanabbreviatedregulatorypathwayforbiosimilars.BiosimilarfilgrastimproductshavebeenmarketedinvariouscountriesoutsidetheU.S.

*Acomprehensivenamingpolicyforbiosimilarandotherbiologicalproductsremainstobeadopted.TheFDAintendstoissuedraftguidanceinthenearfutureonhowcurrentandfuturebiologicalproductsmarketedintheU.S.shouldbenamed.

►FDANewsrelease,6March2015.

Tasimelteon : to regulate sleep patterns in blind adults;

Product name: Hetlioz®Dosage form:HardcapsulesClass:Psycholeptic,melatoninreceptoragonist;ATC code:N05CH03

Approval:EMA(orphandesignation)Use:Treatmentofnon-24-hoursleep-wakedisorderintotallyblindadults.

Benefits:Abilitytoentrainthemasterbodyclockinpeoplewhodonotperceivelight,andwhosesleep-wakepatternisnotsynchronizedwiththe24-hourclock. ►EMAPressrelease,24April2015.

Extensions of indications

Moxifloxacin: for treatment of plagueProduct name:(Avelox®)Dosage form:TabletsClass:Antibacterial,fluoroquinolone;

ATC code:J01MA14Approval: FDANewly approved use: Treatment of pneumonic plagueandsepticemicplague;preventionofplagueinadultpatients

Note:Theapprovalwasgrantedbasedonananimalstudy,asitwouldnothavebeenfeasibleorethicaltoconducttrialsinhumans. ►FDANewsRelease,8May2015

Sirolimus: for very rare lung disease ;

Product name: Rapamune®Dosage forms:Tablet,oralsolutionClass:Selectiveimmunosuppressant;

ATC code:L04AA10Approval:FDA(breakthroughtherapy,priorityreview;orphanproductdesignation)

Newly approved use: Treatment of lymphangioleiomyomatosis(LAM),arare,progressivelungdiseasethatprimarilyaffectswomenofchildbearingage.

Safety information:Serioussideeffectsincludinghypersensitivityandswelling(edema)havebeenobservedinrenaltransplantpatients.

Note:ThisisthefirstmedicineapprovedintheU.S.totreatLAM. ►FDANewsrelease,28May2015.

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Approved

Generic

Glatiramer acetate : AcomplexactiveingredientReference product: Copaxone®Dosage form:InjectionClass:Immunostimulant;ATC code:L03AX13Approval: FDAUse:Treatmentofrelapsingformsofmultiplesclerosis

Note:Thereferenceproductisacopolymermixturewithinherentbatch-to-batchvariability.Forthisapproval,FDAscientiststhereforeestablishedascientificapproachfordemonstratingthattheactiveingredientofthegenericisthesameasthatofthereferenceproduct. ►FDANewsrelease,16April2015.

Early access

Pembrolizumab: EarlyaccessintheUnitedKingdomProduct name: Keytruda® Dosage form:Powderforconcentrateforsolutionforinfusion

Class:antineoplastic;monoclonalPD-1antibody.ATCcode(temporary):L01XC18

Approval:EMA(previouslyapprovedintheU.S.inSeptember2014)

Use:Treatmentofunresectableormetastaticmelanoma

Benefits:Canslowtheprogressionofcancerinaconditionwhereothertreatmentscurrentlyhavepoorresults.

Safety information: Pembrolizumab may be associatedwithsideeffectsresultingfromexcessiveactivityoftheimmunesystem.Mostwillresolvefollowingappropriatetreatmentoronstoppingpembrolizumab.

Note:PembrolizumabisthefirstmedicinetobeapprovedintheUnitedKingdomundertheMHRA’sEarlyAccesstoMedicinesScheme(EAMS),aheadofreceivingapositiverecommendationfromEMA.TheEAMSwasintroducedin2014toprovideearlyaccesstonewmedicinesintheUnitedKingdomforpatientsthathaveahighunmetclinicalneed.ThescientificopinionsissuedunderthisSchemedescribetherisksandbenefitsofthemedicineandthecontextforitsuse,supportingtheprescriberandthepatienttomakeadecisiononwhethertousethemedicinebeforeitslicenceisapproved. ►MHRAAnnouncement,11March2015.EMAPressrelease,22May2015. æ

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Publications and events

Global health

WHO publishes 2015 World Health Statistics G e n e v a –WHOhaspublishedits2015World Health Statistics,assessingprogressmadeinMemberStatestowardshealth-relatedgoals.2015isthefinalyearfortheUnited

Nations’MillenniumDevelopmentGoals(MDGs),whichweresetbygovernmentsintheyear2000.Bytheendofthisyear,ifcurrenttrendscontinue,theworldwillhavemetglobaltargetsforturningaroundtheepidemicsofHIV,malariaandtuberculosis,andwillhavemadesubstantialprogressinreducingmaternalandchilddeaths.Howeverwidegapspersistbetweenandwithincountries.Withregardtoessentialmedicinesthe

reportshowsthataccessisstilllimited,especiallywheredrugsarenotavailableinthepublicsectorandwherepriceshaveincreasedasaresultofincreasesincountries’wealth.[AccordingtoWorld Bank data,73%oftheworld’spoortodayliveinmiddle-incomecountries–Ed.]Countrieswilldecideonnewglobal

goalsfor2030attheUNGeneralAssemblyinSeptember.Additionalemergingchallengestotackleinthepost-2015agendaincludethegrowingimpactofnoncommunicablediseasesandthechangingsocialandenvironmentaldeterminantsthataffecthealth.

►WHONews,13May2015.

Sixty-eighth World Health Assembly closesG e n e v a –TheSixty-EighthWorldHealthAssembly,heldon18–26May2015inGeneva,adoptedanumberoflandmarkresolutionsanddecisions,includinganhistoricresolutiononairpollution,thefirstglobalplanofactiononantimicrobialresistance,anewglobalmalariastrategyanddecisionsontheInternationalHealthRegulations.Indecisionsstemmingfromthe2014

Ebolaoutbreak,theAssemblygavethego-aheadforstructuralreformsintendedtoenableWHOtorespondeffectivelytofutureemergencies.AUS$100-millioncontingencyfundwillbesetupforin-fieldoperations.DelegatesappreciatedOrganization’skeycoordinationroleinsupportingdevelopmentofEbolavaccines,diagnosticsandmedicines(seealsopages161–162).TheyfurtherrequestedWHOtocontinuehelpingcountriestostrengthennationalhealthsystems.Inotherdecisionsrelatedtomedical

productstheAssemblyagreedtoimproveaccesstosustainablesuppliesofaffordablevaccines,topreparethephasedwithdrawaloforalpoliovaccines,tostrengthenemergencyandessentialsurgicalcareincludingaccesstosafeanaestheticssuchasketamine(seealsopage 160),andtopostponethereviewoftheMemberStatemechanismtocombatsubstandard,spurious,falselylabelled,falsifiedandcounterfeitmedicalproductsuntil2017.

►WHOMediacentre.Sixty-eighthWorldHealthAssembly[webpage].

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Access to medical products

WHO updates essential medicines listsG e n e v a –WHOhaspublishedthe2015editionsofitsModel List of Essential Medicines anditsModel List of Essential Medicines in Children.Amongthemedicinesthathavebeenaddedarefivenewdirect-actingoralantiviralstotreathepatitisC,16anti-cancermedicinesandfiveanti-tuberculosismedicines,fourofwhich–includingbedaquilineanddelamanide–targetmulti-drugresistanttuberculosis.Theessentialmedicineslistsare

updatedeverytwoyearsbyaWHOExpertCommittee,basedonevaluationsoftheefficacy,safetyandcost-effectivenessoftheproposedmedicines.AsgovernmentsandinstitutionsaroundtheworldareincreasinglyusingtheWHOlisttoguidethedevelopmentoftheirownessentialmedicineslists,thechangescouldhaveenormouspublichealthimpactglobally.Thisyear,theCommitteeunderscoredthe urgent need to take action to promote equitableaccesstoseveralnewhighlyeffectivemedicines,someofwhicharecurrentlytoocostlyevenforhigh-incomecountries.

►WHONewsrelease,8May2015.

Access to new medicines in EuropeC o p e n h a g e n –TheWHORegionalOfficeforEuropehasreleasedareportonaccesstonewmedicinesinEurope.Thestudyfeaturesfindingsfrom27countriesandexploresdifferentapproachesthathealthauthoritiesinEuropeancountriesareusingtodealwithhighspendingonnewmedicines.Asthenumberofnewmedicines

introducedinEuroperises,governments

neednovelpolicyapproachestoevaluatethecost–effectivenessofnewdrugsandmakeinformedpublichealthchoices.Thereportoutlinespossiblepolicydirectionsandchoicesthatmayhelpgovernmentstoreducehighpriceswhenintroducingnewdrugs.Thefindingssuggestthatcooperationandtransparencyarethebesttoolstoensureequitablepricingandaccess.

►WHORegionalOfficeforEurope.Pressrelease,26March2015.

AccesstonewmedicinesinEurope:technicalreviewofpolicyinitiativesandopportunitiesforcollaborationandresearch.Copenhagen,WHORegionalOfficeforEurope,2015.

Ketamine not to be placed under international controlV i e n n a –Duringits58thSessionheldon9–17March2015inVienna,theUnitedNationsCommissiononNarcoticDrugs(CND)deferredactionontheschedulingofketamineasaninternationallycontrolledsubstance.Ketamineisawidelyusedanaesthetic

includedintheWHOessentialmedicineslist.TheGovernmentofChinapostponeditsproposaltoincludeketamineinaScheduleunderthe1971ConventiononPsychotropicSubstancesandsuggestedthatmoreinformationshouldbegathered.WHOandanumberofgovernmentswelcomedChina’sdecision,seeingthatinternationalcontrolswouldlimitaccesstoaneededmedicineespeciallyinthedevelopingworld,andthatcountriescanimposenationalcontrolstominimizeabuseandtrafficking.

► Livereportingfromthe58thSessionoftheCommissiononNarcoticDrugsanditsSpecialSegmentonthe2016UNGASS.13March2015.

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Medicines quality

Falsified antimalarials less common than previously thought Twostudiesofantimalarialdrugqualityconducted in Cambodia and Tanzania foundnoevidenceoffalsifiedmedicinesineithercountry.Previousreportshadsuggestedthatuptoonethirdofantimalarialscouldbefalsified.However,substandarddrugswerefoundin31%ofsamplesinCambodiaandin12%ofsamplesinTanzania.Theresultshighlighttheneedtostrengthenregulatorysystems,enablingthemtocarryouteffectiveroutinesurveillance.InTanzania,onefourthof1737samples

analyzedwereWHO-prequalified,andthesewerelesslikelytobeofpoorqualitythanthosenotprequalified.Thesearethefirstpublishedresults

fromtheACTConsortium’sdrugqualityprogramme,whichanalyzedover10000samplesfrommalaria-endemiccountriesoverfiveyears.ThestudieswerefundedbytheBill&MelindaGatesFoundation;theCambodiastudyalsoreceivedsupportfrom the UK Department for International Development.ResultsfromNigeria,EquatorialGuinea,GhanaandRwandawillbepublishedinthenextfewmonths.

► London School of Hygiene and Tropical Medicine,News.20April2015.

Ebola

Focus on vaccination and malaria in Ebola-affected countriesG e n e v a –WHOhascalledforintensificationofroutineimmunizationservicesinallareasofEbola-affectedcountries,andformassmeaslesvaccinationcampaignsinareasthatarefreeofEbolatransmission.TheEbola

outbreak,whichhasinfectedsome24000peopleandkilledaround10000ofthem,hasalsoreducedvaccinationcoverageinGuinea,LiberiaandSierraLeoneashealthfacilitiesandstaffhavefocusedonhaltingtheoutbreak.Themalariaburdenhasalsoincreased

aspatientshavebeenunableorafraidtoseektreatmentduringtheEbolaoutbreak.ToreducethenumberoffebrilepeoplewithmalariapresentingatEbolaevaluationfacilities,WHOrecommendedmassdrugadministrationofanti-malarialmedicinestoalleligiblepeopleinareasheavilyaffectedbyEbola.Anestimated3millionpeoplehavebeenreachedinSierra Leone and Liberia from October 2014toJanuary2015throughdoor-to-doordistribution.Thefocusonvaccinationsandmalaria

ispartofWHO’seffortstosupportcountriesinearlyrecoveryontheirwaytorebuildingtheirhealthsystems.

►WHONews,20March2015.

First Ebola vaccine efficacy trial launched in GuineaC o n a k r y –TheGuineanGovernmentwiththeWorldHealthOrganization(WHO)hasinitiatedthefirstefficacytrialofanEbolavaccine.RingvaccinationtestsofVSV-EBOV,aleadEbolavaccinedevelopedbythePublicHealthAgencyofCanada,aretobeconductedinoneoftheareasinGuineawheremostEbolacasesoccurred.Theconceptofthetrialisbasedonvaccinatingthe“rings”–thegroupofcontactsofanewlydiagnosedEbola“indexcase”–eitherimmediatelyafterconfirmeddiagnosisoftheindexcase,orthreeweekslater.Thisstrategyallowsallknowncontactstobevaccinatedwithinashortperiodoftimeandconstitutesanalternativetotheuseofaplacebo.

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TheGuineaEbolavaccinetrialisacoordinatedeffortamongnumerousinternationalpartners.Atotalofaround10000peoplein190ringsareplannedtobevaccinated.ResultscouldbeavailableasearlyasJuly2015.

►WHONews,20March2015.

WHO proposes emergency use assessment proceduresG e n e v a –WHOhasproposedasetofEmergencyUseAssessmentandListing(EUAL)proceduresforinvitrodiagnosticproducts,medicinesandvaccinesintendedtoaddressapublichealthemergencycausedbyadisease.Itapplieswhenthecommunitymaybewillingtotoleratelesscertaintyaboutthesafetyandefficacyofaproduct(oritssafetyandperformanceinthecaseofadiagnostic),giventhehighmorbidityand/ormortalityofthediseaseandtheshortfallofoptionstodiagnose,preventand/ortreatit.AnEUALisgrantedonadefined

minimumlevelofinformation,makingaproductavailableforatime-limitedperiodinanemergencywhilefurtherdataarebeinggatheredandevaluated.ItisimportanttonotethattheproceduresarenotthesameasWHOprequalificationandshouldnotbethoughtofassuch.

►WHOEssentialMedicinesandHealthProducts.News,10March2015.

WHO lists Ebola diagnostic tests for emergency use in West AfricaG e n e v a –WHOhaslistedfourdiagnostictestsasbeingeligibleforUNprocurementinEbolaaffectedcountries,aftersuccessfulassessmentthroughtheEUALprocedure.AstheEbolaoutbreakiswindingdown,sensitive,effectivediagnostictestsareimportanttoidentify

anyremaininginfectionsandkeepthemfromspreading.TheEUALevaluationfordiagnostics

comprisesthreekeycomponents:(1)areviewoftechnicaldocumentationrelatingtosafetyandperformance;(2)areviewof documentation about the manufacture oftheproductandthemanufacturer’squalitymanagementsystem(QMS);and(3)anindependentlaboratoryevaluationcoordinated by WHO to determine the product’sperformanceandoperationalcharacteristics.

►WHOEssentialMedicinesandHealthProducts.News,8May2015.WHOInvitrodiagnosticsandlaboratorytechnology.EmergencyUseAssessmentandListing(EUAL)ProcedureforEbolaVirusDisease(IVDs)[webpage].

Hepatitis

WHO publishes first hepatitis B treatment guidelinesG e n e v a –WHOhasissueditsfirst-everguidance for the treatment of chronic hepatitisB.Thisdiseasehasahugehealthimpactasitcanleadtocirrhosisandlivercancer,andthemedicinesthatcanpreventthedevelopmentoftheseconditionsarecurrentlyoutofreachformanypatients.

The WHO guidelines for the prevention, care and treatment of persons living with chronic hepatitis B infectioncoverthefullspectrumofcare,withafocusonsettingswithlimitedresources,andtakingintoaccountspecialpopulationssuchaspeopleco-infectedwithHIV,childrenandadolescents,andpregnantwomen.Keyrecommendationsincludetheuse

ofsimpleteststoassessthestageofliverdisease,prioritizingtreatmentforthosewithcirrhosis,theuseoftenofovirorentecavirtotreatchronichepatitisB,and

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regularmonitoringtoassesstreatmentoutcomesanddetectlivercanceratanearlystage.TopreventnewhepatitisBinfections.WHOrecommendstovaccinateallchildrenwithafirstdosegivenatbirth.WHO’srecentlylaunchedpolicyoninjectionsafety,callingfortheworldwideuseof“smart”syringestopreventthere-useofsyringesorneedles,willalsohelppreventnewhepatitisBinfections.In2014WHOpublisheditsfirst

guidelinesontreatinghepatitisC. ►WHONewsrelease,12March2015.

Patent landscapes of hepatitis C medicinesG e n e v a –WHOhasanalyzedthepatentsituationfornewhepatitistreatmentstoprovideclarityonwhetherornotthemedicinesarepatent-protectedinindividualcountries.Updatedinformationhasbeenpublishedforsofosbuvirinabout20countries,aswellasonledipasviranddaclatasvir,thelatterwithacompletedatasetfortheprimarypatent.HepatitisCVirusinfectionisachronic

diseasethatoftenleadstosevereliverdiseaseandkillsbetween350000and500000peopleannually.TheWorldHealthAssembly,initsResolutionWHA67.6,requestsWHOtoassistMemberStatesinensuringequitableaccesstoquality,effective,affordableandsafehepatitistreatments.

►WHOEssentialmedicinesandhealthproducts.News,24March2015.

Hepatitis C diagnostics neededAn article in The Lancet Global Health emphasizestheimportanceandeconomicimpactofreliablediagnosticsinthefightagainsthepatitisC.Thisdiseaseisseverelyunderdiagnosed,especiallyin

limited-resourcesettings.Theauthorsadvocateforaconcertedefforttodevelopandfundappropriatediagnostictests,whichwillmaximizetheeffectoftreatmentprogrammesandtherebyreducetheoverallcosttohealthsystems.

►DenkingerCM,KesselM.DiagnosticsforhepatitisC:anurgentneedforaction.TheLancetGlobalHealth2015;3(4),e195,April2015.DOI:http://dx.doi.org/10.1016/S2214-109X(15)70092-6.

Note: HepatitisCdiagnosticsareamongthepriorityproductsassessedbytheWHOprequalificationteaminviewofprocurementbyinternationalorganizations.Attheendof2014fourproductswereunderfullassessment,sevenwereunderabbreviatedassessmentinrecognitionofstringentregulatoryapproval,andfor17productscompletionofdossierswasongoing.FormoreinformationonWHOprequalificationofinvitrodiagnosticsseeWHO Drug Information 28(3);2014:312-316,andthearticlestartingonpage 133 ofthisissue.

Dementia

Advancing research and care G e n e v a –AttheFirstMinisterialConferenceonGlobalActionAgainstDementia,hostedbyWHOon16–17March2015,theGovernmentof the United Kingdom announced that overUS$100millionwillbeinvestedinapioneeringnewglobalDementiaDiscoveryFund.Majorpharmaceuticalcompanieshavecommittedinprincipletoinvestinginpromisingresearcheffortsfor dementia that could bring about a breakthroughintreatment.Anestimated47millionpeople

arelivingwithdementiaworldwide.Thisnumberisexpectedtotripleby2050,withenormouspersonal,socialandeconomicconsequencesthatcouldaffectlow-andmiddle-income

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countriesdisproportionately.Theconferenceparticipants–whichincludedrepresentativesof80WHOMemberStates,80philantropicfoundations,45on-governmentalorganizationandfourUnitedNationsagencies–adoptedacallforactionondementiaatthegloballevel.(1)

L o n d o n –OnthefirstdayoftheWHOconferencetheMHRApublishedtheconclusionsofaworkshopheldwithrepresentativesoftenregulatoryauthoritiesinNovember2014.Theparticipantsidentifiedsixareastoworktowardsaddressingthescientificgapsintheunderstandingofdementia,enablingregulatorstocontributetostrategiestobringinnovativetherapiestothemarket.(2)

► (1) WHONewsrelease,17March2015.(2) MHRANews,16March2015.

WHO matters

WHO prequalification programme proposes new financing modelG e n e v a –TheWHOprequalificationprogrammeforin-vitrodiagnostics,medicaldevices,medicinesandvaccineshascalledforcommentsonitsnewfinancingmodelforitsservicesandsupporttonormativeandregulatoryfunctions,whichareincreasinglyconsideredtobeaglobalpublichealthgood.Inthelasttwodecades,prequalification

hashelpedtogreatlyincreaseaccesstoaffordable,quality-assuredmedicaltechnologiesinlow-andmiddle-incomecountries.Itsstandardsandprocessesarenowbeingleveragedincollaborativeproceduresandregionalregulatorynetworks,enablingregulatorstospeed

upproductassessmentsincountries,organizejointreviewsanddevelopandintroducestandardregulatorydossierformats.Whilenomajorchangeswillbemade

tothefeescurrentlychargedforinitialassessmentandmajorvariations,anannualfinancialcontributionfrommanufacturersisproposedtobeintroduced.Themodelaimstogenerateatleast50%ofthefundsrequiredtooperatetheprequalificationprogramme,whichiscurrently funded entirely by international donorsthroughshort-termgrants.Thenewmodelwasdesignedfollowing

discussionswithrepresentativesofprequalificationstakeholdersandareviewofarangeofalternativeoptions.WHOthensoughtadditionalinput―viaquestionnaire―inordertoassesswhetheranyoftheparametersofthemodelrequiredadjustment.Theinputreceivedisnowunderreview.

► WHOEssentialmedicinesandhealthproducts.CallforpubliccommentsonthenewfinancingmodelforWHOPrequalificationandsupportingregulatoryfunctions[webpage].

WHO officials meet with CFDA Vice MinisterOnMarch27,2015,theViceMinisteroftheChinaFoodandDrugAdministration(CFDA),metwithaWHOdelegationtoexchangeopinionsonvariousmedicines-relatedtopicsincludingdrugprequalification,generalassessmentofdrugregulatorysystems,thereformofdrugevaluationandapprovalsystems,andpoliomyelitisvaccines.ThemaindirectorsofCFDA’sDepartmentofDrugandCosmeticsSupervisionandrelevantdirectorsofDepartmentofInternationalCooperationattendedthemeeting.

►CFDAPressrelease,31March2015.

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Upcoming events

3rd International PPRI Conference on medicines pricing and

reimbursementThe3rd Pharmaceutical Pricing and ReimbursementInformation(PPRI)conferencewillbeheldon12-13 October 2015inVienna,Austria.Registrationwillcloseon30September.TheeventwillbeorganizedbytheWHO

Collaborating Centre on Pharmaceutical PricingandReimbursementPolicies.Titled“ChallengesBeyondtheFinancialCrisis”itwilltakeacriticallookatrecentdevelopments,policyreformsandinitiativestakentomaintainaccesstomedicinesinacontextoffinancialcrisis.

Visittheconferencewebsiteat http://whocc.goeg.at/Conference2015formoreinformation.

2015 WHO-UNICEF-UNFPA meeting with manufacturers

The2015jointWHO-UNICEF-UNFPAmeetingwithpharmaceuticalanddiagnosticsmanufacturersandsupplierswillbeheldinCopenhagenduringtheweekof 23-27 November.

Moreinformationwillbepublishedonthethreeorganizations’websitesclosertotheevent.

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Consultation documents

ToreceivedraftmonographsbyemailpleasecontactMrsWendyBonny(bonnyw@who.int),specifyingthatyouwishtobeaddedtotheelectronicmailinglist.

The International Pharmacopoeia

Draftnoteforguidanceonorganicimpuritiesinactivepharmaceuticalingredientsandfinishedpharmaceutical

products

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.606, May 2015).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int.

[Note from the Secretariat. Considering current practices in use for The International Pharmacopoeia and available guidance on how to establish limits for impurities, the following note for guidance on organic impurities in active pharmaceutical substances and finished pharmaceutical products was drafted. It is intended to replace the text on Relatedsubstancesinfinishedpharmaceuticalproductmonographs in the folder Notes for guidance, Supplementary Information section with the following chapter.]

1. ScopeImpuritiesarecriticalqualityattributesofactivepharmaceuticalingredients(APIs)andfinishedpharmaceuticalproducts(FPPs),whichpotentiallyaffecttheirsafetyandefficacy.Therefore,allapplicablemonographsinThe International Pharmacopoeia(Ph.Int.)shallcontainrequirementsforthecontrolofimpurities.

ImpuritiesinAPIsandFPPsmayincludestartingmaterials,by-products,intermediates,degradationproducts,reagents,ligands,catalystsandorganicsolvents.Theycanbeclassifiedaseitherorganicorinorganic.

ThisnoteforguidancecoversrequirementsforcontrollingorganicprocessimpuritiesanddegradationproductsinAPIsandFPPs,andprovidesguidanceonhowtoassesscompliancewithPh.Int.requirements.

Severalstatementsinthisdocumentreferinparticulartothefuture,i.e.theyareapplicabletomonographsincludedinthePh.Int.afterthepublicationofthisnoteof

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guidance.1Compliancewithpreviousmonographshastobeevaluatedusingthereplaced text Related substances in finished pharmaceutical product monographs2 or onacase-by-casebasis.

Excludedfromthisnoteforguidancearebiological/biotechnologicalproducts,peptides,oligonucleotides,radiopharmaceuticals,herbalproductsandcrudeproductsofanimalandplantorigin.Thesetypesofsubstancesrequirespecificconsiderations.

Furtherexcludedarethefollowingsubstances:• extraneouscontaminantsthatshouldnotoccurinAPIsandFPPsandaremore

appropriatelyaddressedasgoodmanufacturingpractices(GMP)issues;• enantiomericimpurities;• crystallographicmodifications(“polymorphicforms”);• residualsolventsresultingfromAPIorFPPmanufacture;• impuritiesthatarisefromprintinginks,container-closuresystemsorexcipients(not

excluded,however,arereactionproductsbetweenexcipientsandAPIs);• organicimpuritiesthatareleachedfromcontainer-closuresystems.

2. Defining the purity of APIs and FPPs Tocontrolrelevantorganicimpuritiesspecificmonographsusuallycontainadiscriminative,stability-indicatingtestentitled“Relatedsubstances”.Thistestmaybesupplementedbyaspecifictestwhereagivenimpurityisnotadequatelycontrolledbytherelatedsubstancestestorwherethereareparticularreasons(forexample,safetyreasons)forrequiringspecificcontrol.

MonographsonAPIsshallincludespecificationsforprocess-relatedimpuritiesthatresultfromthemanufacturingprocessanddegradationproductsobservedduringmanufactureandstabilitystudies,whilemonographsonFPPsshallincludetestsandlimitsfordegradationproducts.Ifappropriate,testsforimpuritiesindosageformsmayalsolimitimpuritiesarisingduringthesynthesisofAPIs.Thisapproachprovides,inconjunctionwiththemonographontheAPI,themeansforanindependentcontrollaboratory(e.g.asmallregulatorylaboratory)withoutaccesstomanufacturer’sdata,toestablishwhetherornotanAPIofpharmacopoeialqualityhasbeenusedtomanufacturetheFPPunderexamination.3

Instructionforcontrolofimpuritiesmayalsobeincludedinthemanufacturesectionofamonograph,forexample,wheretheonlyanalyticalmethodappropriateforthecontrolofagivenimpurityistobeperformedbythemanufacturersincethemethodistootechnicallycomplexforgeneraluse.Theproductionprocess(includingthepurificationsteps)needstobevalidatedtogivesufficientcontrolsothattheproduct,iftested,wouldcomplywiththespecifiedlimitsusingasuitableanalyticalmethod.

1 SincethepublicationoftheFourthSupplementoftheFourthEdition,theyearofpublication(togetherwithatwodigitnumber)isaddedbelowthetitleofeachtext(monograph,generalchapterortextforthesupplementaryinformation).

2 OncethisnewnoteforguidanceisadoptedbytheExpertCommitteeonSpecificationsforPharmaceuticalSubstances,thereplacedtextcanbefoundinThe International Pharmacopoeia under “Omittedtexts”.

3 ItisrecognizedthatlimitsfordegradationimpuritiesgiveninFPPmonographsmayneedtobehigherthanthelimitsforthesameimpuritiesthatappearinthemonographforthecorrespondingAPI.

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Underthesectionon“impurities”inthemonographsforpharmaceuticalsubstancesanddosageforms,substancesarelisted(transparencylist)thatareknowntobelimitedbythedescribedtestmethod(s).IndosageformmonographsreferencemayalsobemadetothelistinthemonographofthecorrespondingAPI.Wheneverpossibletheimpuritiesareidentifiedasdegradantsand/orsynthesisimpurities.

Testsforrelatedsubstancesareintendedtoprovideappropriatelimitationofknownpotentialoractualimpuritiesratherthantoprotectagainstallpossibleimpurities.Thetestsarenotnecessarilydesignedtodetectanyadventitiouscontaminantsoradulteration.Materialorproductsfoundtocontainanimpuritynotdetectablebymeansoftheprescribedtestsisnotofpharmaceuticalqualityifthenatureoramountoftheimpurityfoundisincompatiblewithgoodpharmaceuticalpractices(GPP)orapplicableregulatorystandards.

3. Setting acceptance criteria for organic impuritiesLimitsinthePh.Int.areusuallysetbasedon:

• theevaluationofinformation,providedbymanufacturers,concerningthenatureofimpurities,thereasonfortheirpresence,theconcentrationsthatmaybeencounteredinmaterialpreparedunderconditionsofgoodpharmaceuticalmanufacturingpracticesandthemannerinwhichtheAPIorFPPmaychangeduringstorageandwhensubjectedtostressconditions(e.g.light,heat,moisture,acid,baseoroxygen),togetherwithanindicationofthetoxicityofanyimpurityinrelationtothatofthesubstanceitself;

• justifiedlimitsacceptedbyregulatoryauthoritiesorbytheWHOPrequalificationTeamafterafullconsiderationofthetoxicitystudiesandclinicaltrialscarriedoutbeforegrantingamarketingauthorizationorbeforeinclusionoftheproductintheWHOlistofprequalifiedmedicinalproductsortheWHOlistofprequalifiedAPIs.Thelimitsmaybeamendedintheeventthatnewsafetydatabecomeavailablefollowingregulatoryevaluation;

• limitspublishedbyotherpharmacopoeiasapplyinggoodpharmacopoeialpractices(GPhP);4

• principlespublishedincurrentregulatoryguidancedocuments,suchasthosepublishedbytheInternationalConferenceonHarmonisationofTechnicalRequirementsforRegistrationofPharmaceuticalsforHumanUse(ICH).

Commentsreceivedduringthepublicconsultationofthedraftmonographsareevaluatedandtakenintoconsiderationifrelevant.

Acceptancecriteriaforimpuritiesfocusinparticularonsafetyconsiderations.Theyshouldnotbesolelybasedonprocesscapabilities.Thehistoricalsafetyrecord,therouteofadministration,thetypeofdosageform,themaximumdailydose,thedurationoftreatment,theneedforandtheavailabilityofthemedicinecanalsobetakenintoconsiderationwhensettinglimitsforimpurities.

Highlytoxic(e.g.genotoxic)impuritiesordegradationproductsareaddressedusingapplicableguidance.

4 Atthetimethisnoteforguidancewasdraftedthedraftproposalforgoodpharmacopoeialpractices(GPhP)(QAS/13.526/Rev.5)wassentoutforpublicconsultation(seehttp://www.who.int/medicines/areas/quality_safety/quality_assurance/GPhP-Rev5-QAS13-526.pdf?ua=1).Thestatementmadethusreferstothefuture,i.e.toatimewhengoodpharmacopoeialpracticeshavebeenimplementedandputintopracticebypharmacopoeias.

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4. Compliance with the requirementsWhereamonographhasnorelatedsubstancestest(orequivalent)orwheretheexistingtestdoesnotcomplywiththerequirementsoftheapplicableregulatorystandardstheuserofamonographmustneverthelessensurethatthereissuitablecontroloforganicimpurities.

WhereapharmaceuticalsubstancemaycontainimpuritiesotherthanthosementionedintheImpuritiessection(forexample,becauseitwasmanufacturedusinganewmethodofsynthesis)itisnecessarytoverifythattheseimpuritiesaredetectablebythemethod(s)describedinthemonograph;otherwiseanewmethodshouldbedevelopedandarevisionofthemonographshouldberequested.

Whereapeakoraspotcannotbeassignedunambiguouslytoalistedimpurityusingthemeansdescribedinthemonograph(retentiontimes,relativeretentions,Rfvaluesorcomparisontoreferencesubstancesmentionedinthemonograph)theuserhastoapplyadditionalmeasuresinordertoidentifytheimpuritiesconclusively.Thesemeansmayinclude,forexample,theanalysisofreferencesubstancesofexcipients,potentialimpuritiesnotreferredtointhemonographortheuseofadditionalanalyticaltechniques,e.g.so-calledhyphenatedanalyticaltechniques,e.g.GC-orLC-massspectroscopicmethods.

WhereanimpurityotherthanthoselistedundertheImpuritiessectionisfoundinanAPIorinadosageformitistheresponsibilityoftheuserofamonographtocheckwhetherithastobeidentified/qualified,dependingonitscontent,natureandsafety,onthemaximumdailydoseoftheAPIandrelevantidentification/qualificationthresholdsfortheimpurity,etc.,inaccordancewiththeapplicableregulatorystandardsandsoundscientificprinciplestocontrolimpurities.

Thegeneralacceptancecriterionforimpurities(“anyotherimpurity”,“otherimpurity”,“anyimpurity”)equivalenttoanominalcontentgreaterthantheapplicableidentificationthresholdisvalidonlyforthoseimpuritiesidentifiedinthetransparencylist,exceptthosethathavetheirownspecificacceptancecriterioninthemonograph.Itisthustheresponsibilityoftheusertodeterminethevalidityoftheacceptancecriteria(i.e.toqualifythelimit)forimpuritiesnotmentionedintheImpuritysection.

See Figure 1forguidanceonhowtoassesscompliancewiththeacceptancecriteriaofthetestsforrelatedsubstancesinthePh.Int.

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Glossarydegradation product. Animpurityresultingfromachemicalchangeintheactivepharmaceuticalingredient(API)broughtaboutduringmanufactureand/orstorageoftheAPIorthedosageformbytheeffectof,forexample,light,oxygen,temperature,pH,waterorbyreactionwithanexcipientand/ortheimmediatecontainerclosuresystem.

extraneous contaminant. Animpurityarisingfromanysourceextraneoustothemanufacturingprocess.

identification threshold. Alimitabove(>)whichanimpurityshouldbeidentified,basedontheapplicableregulatorystandards.

identified impurity. Animpurityforwhichastructuralcharacterizationhasbeenachieved.

Figure 1. Decision tree for assessing compliance with the acceptance criteria of the test for related substances in the International Pharmacopoeia

Unidentifiedimpurityabovethe applicable identificationthreshold?

Performtestforrelatedsubstances.Recordsignalsandassurethattheydonotoriginatefromthesolvent,excipients

orreagents.

Assignimpuritiestosignalsusingtheanalyticalmeansdescribedinthemonograph(retentiontime,relative

retention,Rfvalues,referencesubstancesmentionedinthemonograph).

Evaluateimpuritybasedontheapplicableregulatorystandardsand/orusingscientificrationale.

SampledoesnotcomplywithPh.Int.requirements.

SamplecomplieswithPh.Int.requirements.

Identifyimpurityusingfurthermeans,forexample,referencesubstancesofexcipientsandpotentialimpuritiesnotreferredto in the monograph or hyphenated analytical techniques,e.g.LC-MS.

No

Yes

YesNo

Yes

NoYes

Allimpuritiesidentified?

Impurity listedunder

Impurity section?

No

Impurities>specificorgenerallimitandlistedunder Impurity

section?

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impurity (pharmaceutical substance). Anycomponentofapharmaceuticalsubstancethatisnotthechemicalentitydefinedasthepharmaceuticalsubstance.

impurity (dosage form). Anycomponentofthedosageformthatisnotthepharmaceuticalsubstanceoranexcipientinthedosageform.

intermediate. Amaterialproducedduringstepsofthesynthesisofanactivepharmaceuticalingredientthatundergoesfurtherchemicaltransformationbeforeitbecomesanactivepharmaceuticalingredient.

ligand. Anagentwithastrongaffinitytoametalion.

polymorphic forms. Differentcrystallineformsoftheactivepharmaceuticalingredient.Thesecanincludesolvationorhydrationproducts(alsoknownaspseudo-polymorphs)andamorphousforms.

qualification threshold. Alimitabove(>)whichanimpurityshouldbequalified.

specified impurity. Animpuritythatisindividuallylistedandlimitedwithaspecificacceptancecriterioninthemonograph.Aspecificimpuritycanbeeitheridentifiedorunidentified.

starting material. Amaterialusedinthesynthesisofanactivepharmaceuticalingredient(API)thatisincorporatedasanelementintothestructureofanintermediateand/oroftheAPI.Startingmaterialsarenormallycommerciallyavailableandofdefinedchemicalandphysicalpropertiesandstructure.

unidentified impurity. Animpurityforwhichastructuralcharacterizationhasnotbeenachievedandthatisdefinedsolelybyqualitativeanalyticalproperties(e.g.chromatographicretentiontime).

unspecified impurity. Animpuritythatislimitedbyageneralacceptancecriterion,butnotindividuallylistedwithitsownspecificacceptancecriterion(e.g.relativeretentiontime).

***

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Draftrevisionofthechapteronreferencesubstancesandreferencespectra

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.607, May 2015).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int.

[Note from the Secretariat. Following up on a recommendation of the forty-ninth meeting of the Expert Committee on Specifications for Pharmaceutical Preparations to use in The International Pharmacopoeia, where appropriate, ultraviolet (UV) absorptivity values for assays and other quantification purposes with a view to limit reference to International Chemical Reference Substances (ICRS), it is proposed to revise the chapter on reference substances and reference spectra. Additional changes are proposed to reflect recent discussions within the ICRS Board.

[Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.]

1. International Chemical Reference Substances

1.1 Introduction InternationalChemicalReferenceSubstances(ICRS)areprimarychemicalreferencesubstancesforuseinphysicalandchemicaltestsandassaysdescribedinThe International Pharmacopoeia or in other World Health Organization (WHO) quality assurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.ICRSareusedtoidentify,determinethepurityorassayofpharmaceuticalsubstancesandpreparationsortoverifytheperformanceoftestmethods.

ThischapterdescribesprinciplestobeappliedduringtheestablishmentanduseofICRS,whichguaranteethatthereferencesubstancesaresuitablefortheirintendedpurpose.

ThischapterisnotapplicabletoWHOInternationalBiologicalReferencePreparations.

1.2 Terminology Chemical reference substance Thetermchemicalreferencesubstance,asusedinthistext,referstoanauthenticated,uniformmaterialthatisintendedforuseinspecifiedchemicalandphysicaltests,inwhichitspropertiesarecomparedwiththoseoftheproductunderexaminationandwhichpossessesadegreeofpurityadequateforitsintendeduse.

Primary chemical reference substance Adesignatedprimarychemicalreferencesubstanceisonethatiswidelyacknowledgedtohavetheappropriatequalitieswithinaspecifiedcontextandwhoseassignedcontent

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whenusedasanassaystandardisacceptedwithoutrequiringcomparisonwithanotherchemicalsubstance.

Secondary chemical reference substance Asecondarychemicalreferencesubstanceisasubstancewhosecharacteristicsareassignedand/orcalibratedbycomparisonwithaprimarychemicalreferencesubstance.

1.3 Purpose of ICRS ThepurposeofestablishingICRSistoprovideusersofThe International Pharmacopoeia orotherWHOqualityassurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationswithauthenticatedsubstancesforreference.Manyanalyticaltestsandassaysarebasedoncomparisonofphysicalorchemicalattributesofasamplewiththoseofthereferencesubstance.ICRSserveassuchreferencesubstancesandthusenabletheanalysttoachieveaccurateandtraceableresults.FurthermoreICRSmaybeusedtoassesssystemsuitabilityduringanalysesandtocalibrateanalyticalinstruments.

ICRSmayalsobeemployedtoestablishsecondaryreferencesubstancesforroutineanalysisaccordingtotheWHOGeneral guidelines for the establishment, maintenance and distribution of chemical reference substances.1Incasesofdoubtfulresultsordispute,however,thetestsperformedusingICRSaretheonlyauthoritativeones.

1.4 Production of ICRS AlloperationsrelatedtotheestablishmentanddistributionofICRSshouldbecarriedoutaccordingtotherelevantguidelines.Amongthese,theWHOGeneral guidelines for the establishment, maintenance and distribution of chemical reference substances1 and InternationalOrganizationforStandardization(ISO)Guide34–General requirements for the competence of reference material producers (includingrelatedguides)takeprecedence.

Manufacture

WHOencouragespharmaceuticalmanufacturerstodonatesuitablecandidatematerialsandthustocontributetotheavailabilityofICRS.

CandidatematerialfortheestablishmentofICRSmaybesynthesizedandpurifiedforthispurposeormaybeselectedfromthepharmaceuticalproductionprovidedthatthepurityandhomogeneityaresuitable.Insomecases,forexample,inordertoimprovethestabilityofthereferencesubstanceitmaybeusefultoprocessthereferencesubstance(e.g.byfreezedrying)ortoselectanalternativesalt(orsaltvsbase),solvateorhydrate.Thecontentassignedtothestandardtakesintoaccountwhichsubstanceisselected.

CompliancewiththerelevanttestsofthecorrespondingmonographaspublishedinThe International Pharmacopoeia isrequiredwhereapplicable.

Referencesubstancesaredispensedintosuitablecontainersunderappropriatefillingandclosureconditions,toensuretheintegrityofthereferencematerial.Thecontainersemployedarepreferablysingle-useinordertominimizetheriskofdecomposition,contaminationandmoistureuptake.Wheremultiple-usecontainersareemployed

1 WHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.Forty-firstreport.Geneva,WorldHealthOrganization.WHOTechnicalReportSeries,No.943,2007,Annex3.

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appropriateuseandhandlingcontrolsshouldbeimplementedbytheusertoassuretheirsuitability.

Analytical characterization

Thecandidatematerialshouldbetestedwithsuitableanalyticaltechniquesaimingtocharacterizeallrelevantqualityattributes.Theidentityisconfirmedandthepurityisdetermined,usuallybasedonresultsobtainedwiththevalidatedmethodsoftherespectivemonographs.However,theuseoffurtheranalyticaltechniquesmaybeappropriateinordertofullycharacterizethecandidatematerial.Absolutemethods(forexample,volumetrictitrations,differentialscanningcalorimetry)shouldbeemployedtocomplementandverifytheresultsofrelativemethodswherethepropertiesofasamplearecomparedwiththoseofareferencesubstance(forexample,chromatographicmethods).Theextentoftestingandthenumberoflaboratoriesinvolvedincharacterizingthematerialdependsontheintendeduseofthereferencesubstancetobeestablished.Ifrequired,assaystandardsarecharacterizedininterlaboratorytrialstoincreasetheaccuracyoftheassignedvalue.

Athoroughpurityinvestigationofthecandidatematerialisperformedtoverifytheidentityofallrelevantcomponents(i.e.maincomponent,organicandinorganicimpurities,waterandresidualsolvents)andtoquantifythem.Thecumulativepercentageofallcomponentsshouldyield100%(massbalanceapproach).

Thepurityofacandidatematerialiscalculatedonthe“asis”basis,sothattheanalystcanusethesubstancewithoutpretreatment,forexample,drying.

Providedthatallcomponentsthemselvesareexpressedasapercentageoftheweightofsampletakenthe“asis”contentcanbecalculatedasfollows:

Purity = 100 – organic impurities [%] – inorganic impurities [%] – water [%] – residual solvents [%]

Formula 1. FormulatocalculatethepurityofICRSonan“asis”basis.

Whenchromatographicmethodsareusedtotestforrelatedsubstancesimpurityconcentrationsareoftendeterminedinrelationtotheprincipalcompound.The“asis”contentoforganicimpurities,tobesubstitutedinformula1,canbecalculatedasfollows:

Organic impurities = chromatographic result x (100 [%] – water [%] – residual solvents [%] – inorganic impurities [%]) / 100

Formula 2. Formulatocalculatethepercentageoforganicimpurities,determinedbyachromatographicmethod,onan“asis”basis.

ThecontentassignedtoaquantitativeICRSdependsonthepurityofthecandidatematerialandisspecifictothemethodforwhichthesubstancewillserveasareference.IfthereferencesubstanceisintendedtobeusedwithamethodthathasthesameselectivityasthemethodusedtodetermineitspuritythecalculatedpuritywillbeassignedasthecontentoftheICRS.However,iftheintendedmethodislessdiscriminativeitmaybenecessarytoaddtothepuritythecontentofimpuritiesthatcannotbediscriminatedfromtheresponseoftheparentcompound.Thefollowingexampleillustratesthis:

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A candidate material is analysed with different analytical methods to identify and quantify all relevant components. The results reveal that, besides the labelled substance, the following components are present: 2.0% water (analysed by Karl Fischer titration, calculated on an “as is” basis); 1.0% enantiomer of the labelled substance (analysed by chiral high-performance liquid chromatography (HPLC), calculated in relation to the sum of the peak areas of both enantiomers); and two organic impurities, each 0.75% (analysed by an achiral HPLC method, calculated in relation to the sum of the peak area of all peaks, ignoring solvent and injection peaks). The purity of the standard is calculated to 95.55% (purity = 100% – (2.5% x 0.98) – 2%). The candidate material is intended to be used as a reference in an assay test, which stipulates the use of the same HPLC method as already applied to determine the organic impurities in the characterization of the candidate material. A content of 96.53% is assigned to the reference substance (assigned content = 100% – (1.5% x 0.98) – 2%). The concentration of the enantiomer is not taken into consideration as the method, for which the reference substance is intended, is not selective for the enantiomer.

Labelling

Thelabellingshouldprovideallthenecessaryinformationtousethereferencesubstanceasintended,i.e.thenameofthereferencesubstance,thebatchnumber,storageconditions,etc.Ifintendedforquantificationtheassignedcontentorpotency(formicrobiologicalassays)isalsogiven.Theaccompanyingleafletisconsideredtobepartofthelabelling.

Release and adoption

ICRSareestablishedandreleasedundertheauthorityoftheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.TheCommitteeadoptsnewICRSandnewlotsasbeingsuitableforuseasdescribedinThe International Pharmacopoeia orinotherWHOqualityassurancedocuments.

Stability monitoring and distribution

AttheWHOcustodiancentreforICRStheestablishedreferencesubstancesarestoredanddistributedunderconditionssuitabletoensuretheirstability.

Thefitness-for-purposeofICRSismonitoredbyregularre-examinations.Theirfrequencyandextentisbasedon:

• thestabilityoftheICRS;• thecontainerandclosuresystems;• thestorageconditions;• thehygroscopicity;• thephysicalform;• theintendeduse.Theanalyticalmethodsemployedtoverifythestabilityarechosenamongthoseusedduringtheestablishmentofthereferencestandard.Themaximumpermitteddeviationfromtheassignedvalueshouldbepredefinedand,ifexceeded,thebatchshouldbere-establishedorreplaced.

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1.5 Use and storage of ICRS by the user ThelettersRSafterthenameofasubstanceinatestorassaydescribedinThe International Pharmacopoeia orinotherWHOqualityassurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationsindicatetheuseoftherespectiveICRS.

ICRSaresuitablefortheanalyticalpurposedescribedinThe International Pharmacopoeia orotherWHOqualityassurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.Theanalyticalspecificationsandtestmethodsinthesedocumentsarebeingrevisedtostayabreastofadvancesinanalyticalscienceandregulatory.AlongwiththesechangestheintendeduseofalreadyestablishedICRSoftenneedstobeadjusted,forexample,becauseanICRSpreviouslyusedforidentificationonlyshallnewlyalsobeemployedinquantitativetests.InformationontheactuallyestablishedintendedusesofanICRScanbefoundintheleafletenclosedwiththesubstancewhendistributedoraccessibleviatheICRSonlinedatabase(seehttp://www.edqm.eu).Theinformationfoundinthecurrentleafletsisapplicabletoallstandardsoftherespectivebatchnumber.

Ifusedforotherpurposestheresponsibilityofassessingthesuitabilityrestswiththeuserortheauthoritythatprescribesorauthorizesthisuse.IfreferencesubstancesotherthanICRSareusedforpurposesdescribedinThe International Pharmacopoeia orinotherWHOqualityassurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationsthesuitabilityofthesesubstanceshastobedemonstratedbytheuser.

Theuserhastoapplyanassignedcontentinassaydeterminationsorwhenitisindicatedinthemethoddescription.

ICRSaresuppliedinadequatequantitiesforimmediateuseafteropeningofthecontainer.Usersshouldpurchaseonlysufficientunitsforshort-termuse.

ItisgenerallyrecommendedthattheuserstoresICRSprotectedfromlightandmoistureandpreferablyatatemperatureofabout5±3°C.Whenspecialstorageconditionsarerequiredthisisstatedonthelabelorintheaccompanyingleaflet.

Ifanunopenedcontainerisstoredundertherecommendedconditionsitremainssuitableforuseaslongastherespectivebatchisvalid.InformationoncurrentbatchnumbersisprovidedonthewebsiteoftheWHOcustodiancentreforICRS(seeunderOrderinginformation).

Referencestandardsthatarenormallystoredat5±3°Caredispatchedatambienttemperaturesinceshort-termexcursionsfromthestoragerecommendationsarenotconsideredtobedeleterioustothereferencesubstance.Referencesubstancesstoredat-20°Carepackedoniceordryiceanddispatchedbycourier.Referencesubstancesstoredat-80°Corstoredunderliquidnitrogenarepackedondryiceanddispatchedbycourier.

1.6 Rational use of ICRSSpecificationsandtestproceduresofThe International Pharmacopoeia are intended tobeapplicableinallWHOMemberStateswishingtoimplementthem.Procuringreferencesubstancesmay,however,bedifficultincertainareasoftheworldduetodelaysintheirdeliveryandthecostofpurchase.The International Pharmacopoeia thereforeendeavourstoreducethenumberofreferencesubstancesrequiredto

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performtheincludedtestsandassays.Forthispurposethefollowingstrategiesandpracticesmaybeappliedduringtheelaborationofmonographs:

• insitupreparationofimpuritiesforidentificationpurposes;• quantificationofimpuritiesbycomparingtheirresponseswiththeresponseoftheparentcompoundinadilutedsamplesolutionalongwiththeestablishmentofcorrectionfactorstocompensatefordifferencesintheresponsesoftheimpurityandtheparentcompound;

• provisionofInternationalInfraredReferenceSpectra(IIRS)foruseinidentificationtests;

• provisionofassaymethodsnotrequiringreferencesubstances,liketitrationsandUVspectrophotometryusingabsorptivityvalues.Thesemethodsshallbeprovidedasalternativesinparticulartochromatographicassaysinmonographsforpharmaceuticalsubstances.

Thesestrategies,however,shallonlybeappliedwhen,duringtheelaborationofthemethods,evidencecouldbeobtainedthattheintendedmeasuresdonotcompromisethequalityoftheanalyticalresultsandareequallysatisfyingtoconclusivelydemonstrateconformancetotheapplicablestandards.

1.7 Analytical data provided in the leaflet of the ICRSTheleafletsoftheICRSmayprovideanalyticalinformation,including,butnotlimitedto:

• theIRspectrumofthesubstance(togetherwithadescriptionofthesamplepreparation);

• additionalanalyticalinformationatthetimeofestablishment;• theassignedcontent.Thesection“Additionalanalyticalinformationatthetimeofestablishment”providesdataaboutthepurityofthereferencesubstanceandthemethodsusedtodetermineit.Theinformationwasvalidatthetimeoftheestablishmentofthestandardandwillnotbemonitoredoradjusted.Theinformationmayhelptheusertounderstandthecalculationofthecontentthathasbeenassignedtoastandardforquantification.ItmayfurtherbeofvaluetoassessrisksoruncertaintiesassociatedwithanunintendeduseofanICRS.Thisinformation,however,isnotgiventoauthorizesuchanunintendeduse.Aslaiddownundersection1.5,ICRSareadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparationsfortheirintendedusesonly;theresponsibilityforanunintendeduseofanICRSrestswiththeuserortheauthoritythatprescribesorauthorizesthisuse.

1.8 Ordering informationSinceApril2010theEuropeanDirectoratefortheQualityofMedicines&HealthCare(EDQM),CouncilofEurope,isresponsiblefortheestablishment,preparation,storageanddistributionofICRSforThe International Pharmacopoeia.AlistofcurrentlyavailableICRScanbefoundonitswebsite(seehttp://www.edqm.eu).

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OrdersforICRSshouldbesentto:

EuropeanDirectoratefortheQualityofMedicines&HealthCare 7alléeKastner CS30026 F-67081Strasbourg,France Fax:+33(0)388412771-totheattentionofEDQMSalesSection Email:orders@edqm.eu

ThecurrentpriceforICRSperpackage,aswellasthecostforthedeliveryisavailableontheabove-mentionedwebsite.

2. International Infrared Reference SpectraInternationalinfraredreferencespectraareprovidedforuseinidentificationtestsasdescribedinmonographsofThe International Pharmacopoeia or other WHO quality assurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.

Thereferencespectraareproducedfromauthenticatedmaterialusinganappropriatesamplepreparationtechnique.TheyarerecordedwithaFouriertransforminfraredspectrophotometer(FTIR).Instructionsforthepreparationofspectraaregivenin1.7Spectrophotometryintheinfraredregion;Identificationbyreferencespectrum.

Aspectrumofthetestsubstanceisconsideredtobeconcordantwithareferencespectrumifthetransmissionminima(absorptionmaxima)oftheprincipalbandsinthetestspectrumcorrespondinposition,relativeintensitiesandshapetothoseinthereferencespectrum.

***

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LevonorgestrelumLevonorgestrel

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.614, May 2015).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int.

[Note from the Secretariat. It is proposed to revise the monograph on Levonorgestrel.Comments are particularly sought on whether the monograph should include a limit test for dextronorgestrel.][Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.]

Molecular formula. C21H28O2

Relative molecular mass.312.5

Graphic formula

Chemical name.(-)-13-Ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one; CASReg.No.797-63-7.

Description.Awhiteoralmostwhite,crystallinepowder.

Solubility. Practicallyinsolubleinwater;sparinglysolubleindichloromethaneR,slightlysolubleinethanol(~750g/L)TSandetherR.

Category. Contraceptive.

Storage. Levonorgestrelshouldbekeptinawell-closedcontainer,protectedfromlight.

RequirementsDefinition.Levonorgestrelcontainsnotlessthan98.0%andnotmorethan102.0%ofC21H28O2,calculatedwithreferencetothedriedsubstance.

Identity tests• EithertestsAandCortestsBandCmaybeapplied.

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A.Carryouttheexaminationasdescribedunder1.7Spectrophotometryintheinfraredregion.TheinfraredabsorptionspectrumisconcordantwiththespectrumobtainedfromlevonorgestrelRSorwiththereferencespectrumoflevonorgestrel.

B.Carryouttheexaminationasdescribedunder1.14.4High-performanceliquidchromatographyusingtheconditionsdescribedunder“Relatedsubstances”,MethodA.Preparethefollowingsolutions.Forsolution(1)dissolve10mgofthetestsubstancein7mLofacetonitrileRusingsonicationanddiluteto10mLwithwaterR.Dilute1volumeto100volumeswithasolventmixtureconsistingof30volumesofwaterRand70volumesofacetonitrileR.Forsolution(2)useasolutioncontaining0.01mglevonorgestrelRSpermLofthesamesolventmixture.Inject50µLofsolution(1)and(2).Theretentiontimeoftheprincipalpeakinthechromatogramobtainedfromsolution(1)issimilartotheprincipalpeakinthechromatogramobtainedfromsolution(2).

C.Determinethespecificopticalrotation(1.4)usinga10mgpermLsolutionofthetestsubstanceindichloromethaneR.Calculatewithreferencetotheanhydroussubstance;thespecificopticalrotationisbetween-35°to-30°.

Sulfated ash (2.3).Notmorethan1.0mg/g,determinedon1.0g.

Loss on drying.Drytoconstantweightat105°C;itlosesnotmorethan5.0mg/g.

Related substances. • PerformtestAandB.

A.Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography usingastainlesssteelcolumn(25cm×4.6mm)packedwithbase-deactivatedparticlesofsilicagel,thesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctylsilylgelgroups(5µm).Thematerialcontainsembeddedpolargroups.1

Usethefollowingconditionsforgradientelution:

MobilephaseA:Mix400volumesofacetonitrileRwith600volumesofwaterR.

MobilephaseB:UseacetonitrileR.

Time (min)

MobilephaseA (%v/v)

MobilephaseB (%v/v)

Comments

0–50 100to20 0to80 Linear gradient

50–51 20to100 80to0 Returntoinitialcomposition

51–65 100 0 Re-equilibration

Operatewithaflowof0.7mL/min.Asadetectoruseanultravioletspectrophotometersetatawavelengthof215nmand,forimpurityO,at200nm.Maintainthecolumnat30°C.

Prepareasasolventsolutionamixtureof30volumesofwaterRand70volumesofacetonitrileR.

Preparethefollowingsolutions.Forsolution(1)dissolveabout10mgofthetestsubstancein7mLofacetonitrileRusingsonicationanddiluteto10mLwithwaterR.

1 ASymmetryShieldRP8columnwasfoundsuitable.

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Forsolution(2)dilute1volumeofsolution(1)to1000volumeswiththesolventsolution.Forsolution(3)dissolve5.0mgofnorethisteroneRSin35mLofacetonitrileRanddiluteto50.0mLwithwaterR.Dilute1.0mLofthissolutionto100mLwithsolution(2).

Injectsolution50µLofsolution(3).Theassayisnotvalidunlesstheresolutionfactorbetweenthetwoprincipalpeaksduetolevonorgestrel(retentiontimeabout20minutes)andthepeakduetonorethisterone(impurityU)(witharelativeretentionofabout0.8)isatleast3.0.

Injectalternately50µLeachofsolutions(1)and(2).Thechromatogramobtainedwithsolution(1)mayshowthefollowingimpuritiesatthefollowingrelativeretentionwithreferencetolevonorgestrel(retentiontimeabout20minutes):impurityH:about0.5;impurityU:about0.8;impurityK:about0.85;impurityA:about0.91;impurityM:about0.95;impurityO:about1.16;impurityB:about1.26;impurityS:about1.9.Usealsothechromatogramobtainedwithsolution(3)toidentifyimpurityU.

Inthechromatogramobtainedwithsolution(1):

• theareaofanypeakcorrespondingtoimpurityA,whenmultipliedbyacorrectionfactorof0.4,isnotgreaterthan3timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.3%);

• theareaofanypeakcorrespondingtoeitherimpurityBorKisnotgreaterthan3timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.3%);

• theareaofanypeakcorrespondingtoimpurityM,whenmultipliedbyacorrectionfactorof3.1,isnotgreaterthan2timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.2%);

• theareaofanypeakcorrespondingtoimpurityO(recordedat200nm),whenmultipliedbyacorrectionfactorof2.6,isnotgreaterthan3timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.3%);

• theareaofanypeakcorrespondingtoeitherimpuritySorUisnotgreaterthan2timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.2%);

• theareaofanypeakcorrespondingtoimpurityHisnotgreaterthan1.5timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.15%);

• theareaofanyotherpeak,otherthantheprincipalpeakduetolevonorgestrel,isnotgreaterthantheareaoftheprincipalpeakobtainedwithsolution(2)(0.10%);

• thesumofthecorrectedareasofanypeakcorrespondingtoimpurityAandMandtheareasofallotherpeaks,otherthantheprincipalpeakoranypeakcorrespondingtoimpurityO,isnotgreaterthan10timestheareaoftheprincipalpeakobtainedwiththesolution(2)(1.0%).Disregardanypeakwithanarealessthan0.05timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.05%).

B.Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography usingastainlesssteelcolumn(15cm×4.6mm)packedwithbase-deactivatedparticlesofsilicagel,thesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctadecylsilylgelgroups(3µm).2

Usethefollowingconditionsforgradientelution:

MobilephaseA:Mix400volumesofacetonitrileRwith600volumesofwaterR.

MobilephaseB:Mix100volumesofwaterRwith900volumesofacetonitrileR.

2 APackODS-AQ(YMC)columnwasfoundsuitable.

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Time (min)

MobilephaseA (%v/v)

MobilephaseB (%v/v)

Comments

0–1 92 8 Isocratic

1–3 92to82 8to18 Linear gradient

3–6 82 18 Isocratic

6–16 82to60 18to40 Linear gradient

16–21 60to0 40to100 Linear gradient

21–32 0 100 Isocratic

32–33 0to92 100to8 Returntoinitialcomposition

33–50 92 8 Re-equilibration

Operatewithaflowof1.0mLperminute.Asadetectoruseanultravioletspectrophotometersetatawavelengthof200nm.

Prepareasasolventsolutionamixtureof30volumesofwaterRand70volumesofacetonitrileR.

Preparethefollowingsolutions.Forsolution(1)dissolve10.0mgofthetestsubstancein7mLofacetonitrileRusingsonicationanddiluteto10.0mLwithwaterR.Forsolution(2)dissolve5.0mgofethinylestradiolRSin35mLofacetonitrileRusingsonicationanddiluteto50.0mLwithwaterR.Dilute3.0mLofthesolutionto100.0mLwiththesolventmixture.Forsolution(3)dilute1.0mLofsolution(1)to100.0mLwithsolution(2).

Injectsolution50µLofsolution(3).Theassayisnotvalidunlesstheresolutionfactorbetweenthetwoprincipalpeaksduetolevonorgestrel(retentiontimeabout12minutes)andthepeakduetoethinylestradiol(witharelativeretentionofaboutx)isatleastx.x.[Note from the Secretariat. The missing figures will be added at a later stage.]

Injectalternately50µLeachofsolutions(1)and(2).Thechromatogramobtainedwithsolution(1)mayshowthefollowingimpuritiesatthefollowingrelativeretentionwithreferencetolevonorgestrel(retentiontimeabout12minutes):impurityW:about0.9;impurityV:about1.9.

Inthechromatogramobtainedwithsolution(1):

• theareaofanypeakcorrespondingtoimpurityWisnotgreaterthantheareaoftheprincipalpeakobtainedwithsolution(2)(0.3%);

• theareaofanypeakcorrespondingtoimpurityVisnotgreaterthan0.5timestheareaoftheprincipalpeakobtainedwithsolution(2)(0.15%).

Assay. Dissolve0.200gin45mLoftetrahydrofuranR.Add10mLofsilvernitrate(100g/L)TS.After1minutetitratewithsodiumhydroxide(0.1mol/L)VS,determiningtheend-pointpotentiometrically.Carryoutablanktitration.1mLofsodiumhydroxide(0.1mol/L)VS,isequivalentto31.25mgofC21H28O2.

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Impurities

A.13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,8(14)-dien-20-yn-3-one,

B.13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-5(10)-en-20-yn-3-one,

C.13-ethyl-3-ethynyl-18,19-dinor-17α-pregna-3,5-dien-20-yn-17-ol,

D.13-ethyl-18,19-dinor-17α-pregn-4-en-20-yn-17-ol(3-deoxolevonorgestrel),

G.13-ethyl-6α,17-dihydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one(6α-hydroxylevonorgestrel),

H.13-ethyl-6β,17-dihydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one(6β-hydroxylevonorgestrel),

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I.13-ethyl-10,17-dihydroxy-18,19-dinor-17α-pregn-4-en-20-yn-3-one(10-hydroxylevonorgestrel),

J.13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-4-en-20-yne-3,6-dione(6-oxolevonorgestrel),

K.13-ethyl-17β-hydroxygon-4-en-3-one(18-methylnandrolone),

L.13-ethylgon-4-ene-3,17-dione(levodione),

M.13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-4,6-dien-20-yn-3-one(Δ6-levonorgestrel),

N.13-ethylgon-5(10)-ene-3,17-dione(Δ5(10)-levodione),

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O.13-ethyl-17-hydroxy-5α-methoxy-18,19-dinor-17α-pregn-20-yn-3-one(4,5-dihydro-5α-methoxylevonorgestrel),

P.13-ethyl-17-hydroxy-18,19-dinor-17α-pregn-5-en-20-yn-3-one(Δ5-levonorgestrel),

Q.13-ethyl-3-methoxygona-2,5(10)-dien-17β-ol,

R.13-ethyl-3-methoxygona-2,5(10)-dien-17-one,

S.13-ethyl-3-methoxy-18,19-dinor-17α-pregna-3,5-dien-20-yn-17-ol,

T.13-ethyl-3-methoxy-18,19-dinor-17α-pregna-2,5(10)-dien-20-yn-17-ol,

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U.17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one(norethisterone),

V.13-ethyl-3-methoxy-18,19-dinor-17α-pregna-1,3,5(10)-trien-20-yn-17-ol,

W.13-ethyl-17-hydroxy-18,19-dinor-17α-pregna-5,7,9-trien-20-yn-3-one.

***

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Estradioli cypionasEstradiolcypionate

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.618, May 2015).

The working document with line numbers is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: schmidth@who.int.

Molecular formula. C26H36O3

Relative molecular mass.396.56

Graphic formula

Chemical name.Estra–1,3,5(10)–triene–3,17–diol,(17β)–,17–cyclopentanepropanoate;estradiol17–cyclopentanepropionate;CASReg.No.313–06–4.

Description.Awhitetoalmostwhite,crystallinepowder.

Solubility.Solubleinalcohol,acetoneanddioxane;sparinglysolubleinvegetableoils;insolubleinwater.

Category.Contraceptive.

Storage.Estradiolcypionateshouldbekeptintightlyclosedcontainers,protectedfromlight.

RequirementsDefinition.Estradiolcypionatecontainsnotlessthan97.0%andnotmorethan102.0%(“Assay”,MethodA)ornotlessthan98.0%andnotmorethan102.0%(“Assay”,MethodB)ofC26H36O3,calculatedwithreferencetothedriedsubstance.

Identity tests• EithertestAaloneortestsBandCmaybeapplied.

A. Carryouttheexaminationasdescribedunder1.7Spectrophotometryintheinfraredregion.TheinfraredabsorptionspectrumisconcordantwiththespectrumobtainedfromestradiolcypionateRSorwiththereferencespectrumofestradiolcypionate.

B.Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography usingtheconditionsgivenunder“Assay”,MethodA.Theretentiontimeoftheprincipalpeakinthechromatogramobtainedwithsolution(1)correspondstotheretentiontimeofthepeakduetoestradiolinthechromatogramobtainedwithsolution(2).

C.Meltingrange,149°C–153°C.

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Specific optical rotation (1.4).Usea20mg/mLsolutionindioxaneR; =+39°to+44°.

Loss on drying.Dryat105°Cfor4hours;itlosesnotmorethan10mg/g.

Sulfated ash (2.3).Notmorethan1.0mg/g.

Heavy metals.Use1.0gforthepreparationofthetestsolutionasdescribedunder2.2.3Limittestforheavymetals,Procedure3;determinetheheavymetalscontentaccordingtoMethodA;notmorethan10μg/g.

Related substances.Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography,usingtheconditionsgivenbelowunder“Assay”,MethodA.

PreparethefollowingsolutionsinacetonitrileR.Forsolution(1)transfer50mgofthetestsubstancetoa50mLvolumetricflaskanddilutetovolume.Forsolution(2)dilute1.0mLofsolution(1)to100.0mL.Forsolution(3)useasolutioncontaining0.5mgofestradiolcypionateRSand0.5mgofestradiolcypionateimpurityBRSpermL.

Inject25μLofsolution(3).ThetestisnotvalidunlesstheresolutionbetweenthepeakduetoimpurityB(witharelativeretentionofabout0.91)andthepeakduetoestradiolcypionate(retentiontimeabout15minutes)isatleast1.5.

Injectalternately25μLeachofsolution(1)and(2).

Inthechromatogramobtainedwithsolution(1)thefollowingimpurities,ifpresent,areelutedatthefollowingrelativeretentionwithreferencetoestradiolcypionate:impurityAabout0.17;impurityEabout0.76;impurityBabout0.91;impurityCabout1.44;andimpurityDabout2.22.

Inthechromatogramobtainedwithsolution(1):

• theareaofanypeakcorrespondingtoimpurityA,impurityCorimpurityDisnotgreaterthan0.15timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.15%);

• theareaofanypeakcorrespondingtoimpurityB,whenmultipliedbyacorrectionfactorof0.4,isnotgreaterthan0.2timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.2%);

• theareaofanypeakcorrespondingtoimpurityEisnotgreaterthan0.15timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.15%);

• theareaofanyotherpeak,otherthantheprincipalpeak,isnotgreaterthan0.1timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.10%);

• thesumoftheareaofanypeakcorrespondingtoimpurityA,C,D,E,thecorrectedareaofanypeakcorrespondingtoimpurityBandtheareasofallotherpeaks,otherthantheprincipalpeak,isnotgreaterthantheareaoftheprincipalpeakobtainedwithsolution(2)(1.0%).Disregardanypeakwithanarealessthan0.05timestheareaoftheprincipalpeakinthechromatogramobtainedwithsolution(2)(0.05%).

Assay• EithertestAortestBmaybeapplied.

A. Carryoutthetestasdescribedunder1.14.4High-performanceliquidchromatography,usingastainlesssteelcolumn(25cmx4.6mm)packedwithbase-deactivated

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particlesofsilicagel,thesurfaceofwhichhasbeenmodifiedwithchemically-bondedoctadecylsilylgroups(5µm).1

Usethefollowingconditionsforgradientelution:MobilephaseA:WaterRMobilephaseB:AcetonitrileR

Time(min)

MobilephaseA(%v/v)

MobilephaseB(%v/v)

Comments

0–25 20 80 Isocratic25–30 20to0 80to100 Linear gradient30–40 0 100 Isocratic40–41 0to20 100to80 Returntoinitialcomposition41–50 20 80 Re-equilibration

Operatewithaflowrateof1.2mLperminute.Asadetectoruseanultravioletspectrophotometersetatawavelengthof280nm.

PreparethefollowingsolutionsinacetonitrileR.Forsolution(1)use1.0mgsolutionofthetestsubstancepermL.Forsolution(2)use1.0mgofestradiolcypionateRSpermL.Forsolution(3)useasolutioncontaining0.5mgofestradiolcypionateRSand0.5mgofestradiolcypionateimpurityBRSpermL.

Inject25μLofsolution(3).ThetestisnotvalidunlesstheresolutionbetweenthepeakduetoimpurityB(witharelativeretentionofabout0.91)andthepeakduetoestradiolcypionate(retentiontimeabout15minutes)isatleast1.5.

Injectalternately25μLeachofsolution(1)and(2).Measuretheareasofthepeakscorrespondingtoestradiolcypionateobtainedinthechromatograms,andcalculatethepercentagecontentofestradiolcypionate(C26H36O3),usingthedeclaredcontentofC26H36O3inestradiolcypionateRS.

B. Dissolveabout0.05g,accuratelyweighed,insufficientmethanolRtoproduce100mL;dilute2.0mLofthissolutionto100mLwiththesamesolvent.Measuretheabsorbance(1.6)ofa1cmlayerofthedilutedsolutionatthemaximumatabout280nmandcalculatethepercentagecontentofestradiolcypionate(C26H36O3)usingtheabsorptivityvalueofestradiolcypionate.

[Note from the Secretariat. It is intended to determine the absorptivity value of estradiol cypionate during the establishment of estradiol cypionate RS. The value will then be included in the test description.]

1 AnAgilentZORBAXSB-C18columnhasbeenfoundsuitable.

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Impurities

A. Estradiol

B. 3–Hydroxyestra–1,3,5(10),9(11)-tetraene-17β–ylcyclopentanepropanoate

C. 3–Hydroxy–4-methylestra–1,3,5(10)-trien–17β–ylcyclopentanepropanoate;4-Methylestradiolcypionate

D. Estra–1,3,5(10)-trien–3,17β–diyldi(cyclopentanepropanoate);Estradioldicypionate

E. Estra–1,3,5(10)–triene–3,17–diol,(17β)–,17-cyclopentaneacetate

***

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ATC/DDD classification

TheAnatomicalTherapeuticChemical(ATC)classificationsystemandtheDefinedDailyDose(DDD)asameasuringunitaretoolsforexchangingandcomparingdataondruguseatinternational,nationalorlocallevels.TheATC/DDDsystemhasbecomethegoldstandardforinternationaldrugutilizationresearch.ItismaintainedbytheWHOCollaboratingCentreforDrugStatisticsMethodologyinOslo,Norway. Visitwww.whocc.no/formoreinformation.

ATC/DDDclassification(temporary)

The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in March 2015.Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology (whocc@fhi.no) before 1 September 2015. If no objections are received before this date, the new ATC codes and DDDs will be considered final and will be included in the January 2016 version of the ATC/DDD Index.

New ATC 5th level codes:ATC level name/INN ATC codeanthrax immunoglobulin J06BB19armodafinil N06BA13atorvastatin,amlodipineandperindopril C10BX11begelomab L04AA35brexpiprazole N05AX16brodalumab L04AC12cediranib L01XE32ceftazidime,combinations J01DD52conjugatedestrogensandbazedoxifene G03CC07drisapersen M09AX04droxidopa C01CA27dulaglutide A10BX14emtricitabine,tenofoviralafenamideandrilpivirine J05AR19ibuprofen R02AX02idarucizumab V03AB37ivacaftorandlumacaftor R07AX30ixazomib L01XX50lesinurad M04AB05necitumumab L01XC22palbociclib L01XE33

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New ATC 5th level codes, continued:ATC level name/INN ATC codepantoprazole,amoxicillin,clarithromycinandmetronidazole A02BD11perindoprilandbisoprolol C09BX02ramucirumab L01XC21reslizumab R03DX08salmeterolandbudesonide R03AK12saxagliptinanddapagliflozin A10BD21selexipag B01AC27sodiumbenzoate A16AX11tivozanib L01XE34valsartanandlercanidipine C09DB08valsartanandsacubitril C09DX04zoledronicacid,calciumandcolecalciferol,sequential M05BB08

Change of ATC codes:ATC level name/INN PreviousATCcode New ATC codecalcium acetate1) A12AA12 V03AE07ferric citrate B03AB06 V03AE08

1) Previous ATC level name: calcium acetate anhydrous

New DDDs:ATC level name/INN DDD unit Adm.R* ATC codealogliptin 25 mg O A10BH04armodafinil 0.15 g O N06BA13artesunate 0.28 g P P01BE03clenbuterol 40 mcg O R03CC13colistin 3 MU Inhal.powder J01XB01dasabuvir 0.5 g O J05AX16dulaglutide 0.16 mg P A10BX14eliglustat 0.168 g O A16AX10empagliflozin 17.5 mg O A10BX12teduglutide 5 mg P A16AX08tofacitinib 10 mg O L04AA29umeclidinium bromide 55 mcg2) Inhal.powder R03BB07

* Administration Route: O=oral; P=parenteral2) Refers to umeclidinium, delivered dose

Change of DDDs:ATC level name/INN PreviousDDD New temporary DDD ATC code

DDD unit Adm.R* DDD unit Adm.R*apixaban 5 mg O 10 mg O B01AF02dabigatran etexilate 0.22 g O 0.3 g O B01AE07humanmenopausalgonadotrophin 30 U P 75 U P G03GA02

rivaroxaban 10 mg O 20 mg O B01AF01* Administration Route: O=oral; P=parenteral æ

Temporary

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ATC/DDDclassification(final)

The following ATC codes, DDDs and alterations were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in October 2014. These are considered as final and will be included in the January 2016 version of the ATC/DDD Index.

New ATC 5th level codes:ATC level name/INN ATC codeasfotasealfa A16AB13ataluren M09AX03atazanavirandcobicistat J05AR15belinostat L01XX49benzyl alcohol P03AX06blinatumomab L01XC19brivaracetam N03AX23bupropion and naltrexone A08AA62ceftolozane and enzyme inhibitor J01DI54dasabuvir J05AX16dasabuvir,ombitasvir,paritaprevirandritonavir J05AX66drospirenone G03AC10efinaconazole D01AC19emtricitabineandtenofoviralafenamide J05AR17emtricitabine,tenofoviralafenamide,elvitegravirandcobicistat J05AR18insulindegludecandliraglutide A10AE56isavuconazole J02AC05lamivudineandraltegravir J05AR16lenvatinib L01XE29luliconazole D01AC18nemonoxacin J01MB08nintedanib L01XE31nivolumab L01XC17obeticholic acid A05AA04octenidine R02AA21olodaterol and tiotropium bromide R03AL06ombitasvir,paritaprevirandritonavir J05AX67papillomavirus(humantypes6,11,16,18,31,33,45,52,58) J07BM03pembrolizumab L01XC18pitolisant N07XX11rosuvastatinandvalsartan C10BX10sebelipasealfa A16AB14sirolimus S01XA23smallpox,liveattenuated J07BX01sofosbuvirandledipasvir J05AX65sonidegib L01XX48tasimelteon N05CH03

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New DDDs: ATC level name/INN DDD unit Adm. R.* ATC codeabarelix 3.6 mg P L02BX01albiglutide 5.7 mg P A10BX13aripiprazole 13.3 mg P depot N05AX12azilsartanmedoxomil 40 mg O C09CA09canagliflozin 0.2 g O A10BX11cobicistat 0.15 g O V03AX03daclatasvir 60 mg O J05AX14dexmethylphenidate 15 mg O N06BA11lomitapide 40 mg O C10AX12loxapine 9.1 mg1) Inhal.powder N05AH01misoprostol 0.2 mg V2) G02AD06olodaterol 5 mcg Inhal.sol R03AC19peginterferonbeta-1a 8.9 mcg P L03AB13riociguat 4.5 mg O C02KX05siltuximab 37 mg P L04AC11simeprevir 0.15 g O J05AE14sucroferricoxyhydroxide 1.5 g O V03AE05vedolizumab 5.4 mg P L04AA33

* Route of administration (Adm.R): O=oral; P=parenteral; V=vaginal; Inhal=inhalation1) delivered dose2) vaginal insert, refers to the content of one vaginal insert æ

Final