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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
asabove
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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([email protected]),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: [email protected].
[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: [email protected].
[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:[email protected]
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: [email protected].
[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: [email protected].
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 ([email protected]) 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
Continued/
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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
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