125 WHO Drug Information Vol. 29, No. 2, 2015 Contents Regulatory collaboration 127 The African Vaccine Regulatory Forum (AVAREF): A platform for collaboration in a public health emergency WHO prequalification 133 Update on prequalification of diagnostics and medicines Norms and standards 138 Biotherapeutics and biosimilars Safety news 142 Restrictions Bromhexine; Codeine for cough and cold; 142 Safety warnings Sitagliptin; SGLT2 inhibitor diabetes medicines; Hepatitis C drugs and amiodarone; Asunaprevir and daclatasvir; Fingolimod; Pomalidomide; High-dose ibuprofen and dexibuprofen; ADHD medicines; Varenicline; Rebamipide146 Known risks Ferumoxytol; Triamcinolone acetonide; Cyclophosphamide; Panitumumab; Pazopanib; Zoledronic acid; Duloxetine148 Unchanged recommendations Rotavirus vaccine; Natalizumab; Olanzapine150 Data integrity concerns GVK Biosciences; Hospira S.P.A; Zhejiang Hisun Pharma, Polydrug Laboratories151 Falsified product alert Falsified meningitis vaccines circulating in West Africa Regulatory news 152 Assessment Final FDA guidance on opioids with abuse- deterrent properties; EMA scientific advice on clinical trials leads to faster approvals; Generics information-sharing pilot extended; TGA reviews its guidance on evaluation of biosimilars; Updated risk management plan format in Australia 153 Transparency WHO calls for disclosure of clinical trial results; Australia adopts new regulator performance framework 154 Databases Health Canada launches searchable inspection database; WHO launches open access to its global medicines safety database; EMA to record adverse events from literature in EudraVigilance 155 Approved Cholic acid; Eluxadoline; Empaglifozin & metformin; Evolocumab; Isavuconazonium sulfate; Atazanavir & cobicistat; Anthrax immunoglobulin (human); Dinutuximab; Filgrastim-sndz; Tasimelteon157 Extensions of indications Moxifloxacin; Sirolimus158 Generic Glatiramer acetate 158 Early access PembrolizumabPublications and events 159 Global health WHO publishes 2015 World Health Statistics ; Sixty-eighth World Health Assembly closes 160 Access to medical products WHO updates essential medicines lists; Access to new medicines in Europe; Ketamine not to be placed under international control 161 Medicines quality Falsified antimalarials less common than previously thought 161 Ebola Focus on vaccination and malaria in Ebola- affected countries; First Ebola vaccine efficacy trial launched in Guinea; WHO proposes emergency use assessment procedures; WHO lists Ebola diagnostic tests for emergency use in West Africa 162 Hepatitis WHO publishes first hepatitis B treatment guidelines; Patent landscapes of hepatitis C medicines; Hepatitis C diagnostics needed 163 Dementia Advancing research and care Continued WHO Drug Information
70
Embed
WHO Drug Information · 166 Draft note for guidance on organic impurities in active pharmaceutical ingredients and finishedpharmaceutical products ... WHO Drug Information Vol. 29
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
125
WHO Drug Information Vol. 29, No. 2, 2015
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;
; Pomalidomide:risksofcardiacfailure,interstitiallungdiseaseandhepatotoxicity;High-doseibuprofenanddexibuprofen:cardiovascularrisks;ADHDmedicines :riskofsuicidalthoughtsincertainpatients; Varenicline: potential alcohol interaction and other
effects; Rebamipide:adverseeffectsontheeye;
146 Known risksFerumoxytol:strengthenedwarnings; Triamcinolone acetonide:
154 DatabasesHealthCanadalaunchessearchableinspectiondatabase;WHOlaunchesopenaccesstoitsglobalmedicinessafetydatabase;EMAtorecordadverseeventsfromliterature in EudraVigilance
161 EbolaFocusonvaccinationandmalariainEbola-affectedcountries; FirstEbolavaccineefficacytriallaunchedinGuinea; WHO proposesemergencyuseassessmentprocedures;WHOlistsEboladiagnostictestsforemergencyuseinWestAfrica
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
The African Vaccine Regulatory Forum (AVAREF)AVAREFisaregionalregulatorynetworkfoundedbyWHOin2006,atatimewhenthefocusonclinicaltrialsofvaccinesbegantoshiftfromdevelopedcountriestodevelopingcountries,includingthoseinsub-SaharanAfrica.Thenetworkbringstogethernationalregulatoryauthorities(NRAs)andethicscommitteesofthecountriesintheWHOAfricanRegion.Itcurrentlyhas23members1.AVAREFaimstosupportNRAsin
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
productsthatcouldhelptopreventortreatEbola are particularly challenging: The designofclinicaltrialsisbecomingmoredifficultduetoveryspecificfeaturesofthedisease,andthecapacityconstraintsaregreaterthaneverinaffectedcountries.Inresponsetothissituation,the
Clinical trial and product approvalsTheAVAREFmeetingopeneddiscussionsonhowregulatoryauthorizationsofclinicaltrialsandapprovalsofproductsforemergencyusecanbeaddressedinthecurrentEbolaoutbreakwithoutcompromisingthesafetyofpopulations.ThesediscussionswerebasedonavailableregulatoryexperienceandexpertiseoftheU.S.FDA,HealthCanadaandEMA.MostAfricancountrieslackspecificregulatorypathwaysandmechanismsandcouldthereforeadoptoradaptsomeofthemechanismsusedinothercountries.ThesessionalsohighlightedtheneedforaglobalregulatorymechanismtobeputintoplaceforproductdevelopmentinemergenciessuchastheEbolaoutbreakandtheearlierpandemicinfluenza.Themeetingparticipantsreached
AVAREFplatform.Todate,ethicalandregulatoryapprovalhasbeensecuredwithin90daysfromthecompletionofthejointreview.WHOplayedaconveningandsupportiveroleinthejointreviewsessionsby:• facilitating agreement on the format for theclinicaltrialapplications;
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.
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
Integration of workstreamsTheyear2014sawthemergeroftheindependentprequalificationstreamsfordiagnostics,medicaldevices,medicinesandvaccinesandthecreationofthePrequalificationTeam.Thisgeneratedgreatersynergy,butalsodemandedconsiderabletimeandeffort
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
Source: Global Fund Price and Quality Reporting (PQR)database.GlobalFund-financedprocurementrepresentsasignificantportionofinternationally-fundedprocurement.
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.
Medicines of the futureRecognizingthatbiotherapeuticsprovidenewtreatmentoptionstosavelivesandrestorehealth,the67th World Health Assemblyadoptedaresolutiononaccesstobiotherapeutics(1),callingforeffectiveregulationandequitableaccess.Thisisatimelycall,consideringthespeedat
139
WHODrugInformationVol.29,No.2,2015 Norms and standards
Biosimilars are not genericsAlthoughthemarketaspectsappearsimilar,thereareimportantdifferencesbetweengenericsandbiosimilars.Whilegenericsareexactcopiesofthechemicalstructuresoftheirreferenceproducts,biosimilarsarehighlycomplexmoleculesproducedinlivingsystemswithinherentvariability.Bydefinitiontheywillnotbeidentical to their biotherapeutic reference products.Thishasimplicationsforregulatoryassessment.Forgenerics,regulatorysafetyand
WHO guidanceWHOprovidedguidanceonbiosimilarsin2009(3). Theguidancetextisa“livingdocument”tobedevelopedfurtherinlinewithadvancesinscientificknowledgeandexperience.WHAResolution67.21callsforan
updateoftheWHOguidancetext,takingintoaccountthetechnologicaladvancesforthecharacterizationofbiotherapeuticsandconsideringnationalregulatoryneedsandcapacities.The2014InternationalConference of Drug Regulatory Authorities(ICDRA)adoptedanumberofrecommendationsonbiotherapeutics
Norms and standards WHODrugInformationVol.29,No.2,2015
140
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
Naming of biosimilarsNamingofbiotherapeuticsandbiosimilarshasimportantimplicationsforarangeofstakeholdersincludingregulators,thepharmaceuticalindustry,healthsystems,healthprofessionalsandpatients.Differentnamingsystemsforbiosimilars
regulatoryauthoritiestheWHOINNProgrammehasproposedaBiologicalQualifierscheme(7),whichiscurrentlyunderdiscussion.Recognizingthevalueofregulatoryconvergenceasatooltoincreaseglobalaccesstosafe,effective,qualitybiosimilars,participantstothe16th ICDRA recommended that a clearterminologyshouldbedefinedfornamingtheseproducts,enablingaclearidentificationoftheevaluationpathway(4).Systemsincountriesaremeanwhile
valuefromastakeholders’perspective.WHOenvisagesacomprehensivereviewof the current concept of biological standardsandtheiruse,startingwithstandardsforbiotherapeuticproducts,includingbiosimilars,in2015.However,thescopeofworkandrequiredresourcestocoverthecontinuouslygrowingexpectationsexceedthecurrentcapacityoftheOrganization’sSecretariat.DiscussionswillcontinueatWHOtoplanthisworkandtoidentifyanewfundingstrategy. æ
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
N e w Z e a l a n d –Medsafehaswarnedabouttheabove-mentionedrisksandhasrecommendedtorestricttheuseofcodeine-containingproductsforcoughandcoldsymptomstoadultsandchildren12yearsofageandover.(2)
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.
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
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
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
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,
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
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
C a n a d a –AHealthCanadasafetyreviewfoundthatoralibuprofentakenatdosesof2 400mgperdayormoreincreasestheriskofheartattackandstroketolevelssimilartothoseseenwithCOX-2inhibitorsanddiclofenac.Prescriptionoralibuprofenproductsin
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®)
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
► 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
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
Panitumumab: Stevens-Johnson syndromeJ a p a n –FollowingreportsofadverseeventssuggestiveofStevens–Johnsonsyndromeinpatientstreatedwithpanitumumab(Vectibix®)inJapanandelsewhere,approvedproductinformationinJapanhasbeenrevisedtoincludethisrisk.(1)EMA-approvedproductinformationfor
Pazopanib: retinal detachmentJ a p a n –Followingreportsofretinaldetachmentinpatientstreatedwiththeantineoplasticagentpazopanib(Votrient®)inJapanandelsewhere,thePMDAhasrecommended to add information about thisadverseeventtoproductinformationapprovedinJapan.Ifpossiblesignssuchaseyefloaters,photopsia,visualfielddefectorreducedvisualacuityareobserved,ophthalmologicexaminationshouldbeperformedandappropriatemeasurestaken.(1)EMA-approvedproductinformationfor
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
J a p a n –ThePMDAhaswarnedaboutneurolepticmalignantsyndromehavingoccurredinpatientstreatedwithduloxetine(Cymbalta®)inJapan,andhasrecommendedtoupdatetheproductinformation.In2006theFDAhadwarnedabout
Rotavirus vaccine: benefits outweigh risksG e n e v a –TheGlobalAdvisoryCommitteeonVaccineSafetyhasissuedastatementtoaffirmthatthesafetyprofileofcurrentrotavirusvaccinesisacceptable,withthebenefitsofvaccinationgreatlyexceedingrisks.Thisfollowsreportedcasesof
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
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
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.
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,
Falsified meningitis vaccines circulating in West AfricaWHOhaspublishedamedicalproductalertrelatingtotheconfirmedcirculationoffalsifiedversionsofmeningitisvaccinesinNiger.FollowingareportsubmittedtotheWHOSurveillanceandmonitoringsystemforsubstandardandfalsifiedmedicalproductsbythefocalpointwithintheNigerRegulatoryAuthority,increasedvigilanceisrequestedforthefollowinglots/batchesofvaccinesandsolvents.
►WHOMedicalProductAlertsNo.2/2015,22May2015 and 3/2015,27May2015.(Withphotographs.)WHOrecognisestheseriousnessofthecurrentmeningitisoutbreakinWestAfricaandtheadditionaldemandformeningitisvaccines.Furtherinformationconcerningthisoutbreakisavailableat www.who.int/mediacentre/news/situation-assessments/meningitis-niger/en/. æ
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
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
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.
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
WHO calls for disclosure of clinical trial resultsG e n e v a –WHOhasissuedapublicstatementcallingforthedisclosureofresultsfromclinicaltrialsformedicalproducts,whatevertheresult,tohelpallactorstosetprioritiesforresearchanddevelopmentaswellaspublichealthinterventions.Thecallfordisclosureincludesolderunreportedclinicaltrials,theresultsofwhichmaystillhaveanimportantbearingonscientificresearchtoday.WHOalsoreaffirmstheneedfor
Australia adopts new regulator performance frameworkA u s t r a l i a –TheAustralianGovernmenthasdevelopedaregulatorperformanceframeworkcomprisingsixoutcomes-basedkeyperformanceindicators(KPIs).TheKPIsaresupportedbyaseriesofqualitativeandquantitativeoutputsandevidence,asdevelopedinconsultationwiththeTGAIndustryConsultativeCommitteeandtheAustralianTherapeuticGoodsAdvisoryCouncil,toassesstheTGA’sachievementsinthedifferentareasofgoodregulatoryperformance.
Health Canada launches searchable inspection databaseC a n a d a –HealthCanadahaslauncheditsDrugandHealthProductInspectionsDatabase,asearchablewebtoolprovidinginformationonforeignanddomesticinspectionsofpharmaceuticalmanufacturingsitesconductedbyHealthCanadaandabroadsince2012.Thispubliclyavailabledatabasebringstogetherkeydataaboutdrugestablishmentsandinspectionresults,includingdetailedinspectionsreportcards.Thenewtoolisamilestoneunder
WHO launches open access to its global medicines safety databaseWHOhaslaunchedanopenaccessplatformtoitsdatabaseofsuspectedadversereactionreportsmaintainedbytheUppsalaMonitoringCentreinSweden.Theplatform,namedVigiAccess,isanewwebapplicationthatwillallowanyonetoaccessinformationonreportedcasesofadverseeventsrelatedtoover150000medicinesandvaccines,withmorethan
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
Dinutuximab: to prolong survival in children with high-risk neuroblastomaProduct name: Unituxin®Dosage form:InjectionClass:Antineoplasticagent,monoclonalantibody;ATC code:L01XC16
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.
Safety information: Pembrolizumab may be associatedwithsideeffectsresultingfromexcessiveactivityoftheimmunesystem.Mostwillresolvefollowingappropriatetreatmentoronstoppingpembrolizumab.
WHO publishes 2015 World Health Statistics G e n e v a –WHOhaspublishedits2015World Health Statistics,assessingprogressmadeinMemberStatestowardshealth-relatedgoals.2015isthefinalyearfortheUnited
reportshowsthataccessisstilllimited,especiallywheredrugsarenotavailableinthepublicsectorandwherepriceshaveincreasedasaresultofincreasesincountries’wealth.[AccordingtoWorld Bank data,73%oftheworld’spoortodayliveinmiddle-incomecountries–Ed.]Countrieswilldecideonnewglobal
Sixty-eighth World Health Assembly closesG e n e v a –TheSixty-EighthWorldHealthAssembly,heldon18–26May2015inGeneva,adoptedanumberoflandmarkresolutionsanddecisions,includinganhistoricresolutiononairpollution,thefirstglobalplanofactiononantimicrobialresistance,anewglobalmalariastrategyanddecisionsontheInternationalHealthRegulations.Indecisionsstemmingfromthe2014
Publications and events WHODrugInformationVol.29,No.2,2015
160
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
Ketamine not to be placed under international controlV i e n n a –Duringits58thSessionheldon9–17March2015inVienna,theUnitedNationsCommissiononNarcoticDrugs(CND)deferredactionontheschedulingofketamineasaninternationallycontrolledsubstance.Ketamineisawidelyusedanaesthetic
WHODrugInformationVol.29,No.2,2015 Publications and events
Medicines quality
Falsified antimalarials less common than previously thought Twostudiesofantimalarialdrugqualityconducted in Cambodia and Tanzania foundnoevidenceoffalsifiedmedicinesineithercountry.Previousreportshadsuggestedthatuptoonethirdofantimalarialscouldbefalsified.However,substandarddrugswerefoundin31%ofsamplesinCambodiaandin12%ofsamplesinTanzania.Theresultshighlighttheneedtostrengthenregulatorysystems,enablingthemtocarryouteffectiveroutinesurveillance.InTanzania,onefourthof1737samples
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
aspatientshavebeenunableorafraidtoseektreatmentduringtheEbolaoutbreak.ToreducethenumberoffebrilepeoplewithmalariapresentingatEbolaevaluationfacilities,WHOrecommendedmassdrugadministrationofanti-malarialmedicinestoalleligiblepeopleinareasheavilyaffectedbyEbola.Anestimated3millionpeoplehavebeenreachedinSierra Leone and Liberia from October 2014toJanuary2015throughdoor-to-doordistribution.Thefocusonvaccinationsandmalaria
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.
WHO proposes emergency use assessment proceduresG e n e v a –WHOhasproposedasetofEmergencyUseAssessmentandListing(EUAL)proceduresforinvitrodiagnosticproducts,medicinesandvaccinesintendedtoaddressapublichealthemergencycausedbyadisease.Itapplieswhenthecommunitymaybewillingtotoleratelesscertaintyaboutthesafetyandefficacyofaproduct(oritssafetyandperformanceinthecaseofadiagnostic),giventhehighmorbidityand/ormortalityofthediseaseandtheshortfallofoptionstodiagnose,preventand/ortreatit.AnEUALisgrantedonadefined
WHO lists Ebola diagnostic tests for emergency use in West AfricaG e n e v a –WHOhaslistedfourdiagnostictestsasbeingeligibleforUNprocurementinEbolaaffectedcountries,aftersuccessfulassessmentthroughtheEUALprocedure.AstheEbolaoutbreakiswindingdown,sensitive,effectivediagnostictestsareimportanttoidentify
comprisesthreekeycomponents:(1)areviewoftechnicaldocumentationrelatingtosafetyandperformance;(2)areviewof documentation about the manufacture oftheproductandthemanufacturer’squalitymanagementsystem(QMS);and(3)anindependentlaboratoryevaluationcoordinated by WHO to determine the product’sperformanceandoperationalcharacteristics.
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
Patent landscapes of hepatitis C medicinesG e n e v a –WHOhasanalyzedthepatentsituationfornewhepatitistreatmentstoprovideclarityonwhetherornotthemedicinesarepatent-protectedinindividualcountries.Updatedinformationhasbeenpublishedforsofosbuvirinabout20countries,aswellasonledipasviranddaclatasvir,thelatterwithacompletedatasetfortheprimarypatent.HepatitisCVirusinfectionisachronic
Hepatitis C diagnostics neededAn article in The Lancet Global Health emphasizestheimportanceandeconomicimpactofreliablediagnosticsinthefightagainsthepatitisC.Thisdiseaseisseverelyunderdiagnosed,especiallyin
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
L o n d o n –OnthefirstdayoftheWHOconferencetheMHRApublishedtheconclusionsofaworkshopheldwithrepresentativesoftenregulatoryauthoritiesinNovember2014.Theparticipantsidentifiedsixareastoworktowardsaddressingthescientificgapsintheunderstandingofdementia,enablingregulatorstocontributetostrategiestobringinnovativetherapiestothemarket.(2)
WHO prequalification programme proposes new financing modelG e n e v a –TheWHOprequalificationprogrammeforin-vitrodiagnostics,medicaldevices,medicinesandvaccineshascalledforcommentsonitsnewfinancingmodelforitsservicesandsupporttonormativeandregulatoryfunctions,whichareincreasinglyconsideredtobeaglobalpublichealthgood.Inthelasttwodecades,prequalification
tothefeescurrentlychargedforinitialassessmentandmajorvariations,anannualfinancialcontributionfrommanufacturersisproposedtobeintroduced.Themodelaimstogenerateatleast50%ofthefundsrequiredtooperatetheprequalificationprogramme,whichiscurrently funded entirely by international donorsthroughshort-termgrants.Thenewmodelwasdesignedfollowing
WHO officials meet with CFDA Vice MinisterOnMarch27,2015,theViceMinisteroftheChinaFoodandDrugAdministration(CFDA),metwithaWHOdelegationtoexchangeopinionsonvariousmedicines-relatedtopicsincludingdrugprequalification,generalassessmentofdrugregulatorysystems,thereformofdrugevaluationandapprovalsystems,andpoliomyelitisvaccines.ThemaindirectorsofCFDA’sDepartmentofDrugandCosmeticsSupervisionandrelevantdirectorsofDepartmentofInternationalCooperationattendedthemeeting.
WHODrugInformationVol.29,No.2,2015 Publications and events
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.
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.
guidance.1Compliancewithpreviousmonographshastobeevaluatedusingthereplaced text Related substances in finished pharmaceutical product monographs2 or onacase-by-casebasis.
2. Defining the purity of APIs and FPPs Tocontrolrelevantorganicimpuritiesspecificmonographsusuallycontainadiscriminative,stability-indicatingtestentitled“Relatedsubstances”.Thistestmaybesupplementedbyaspecifictestwhereagivenimpurityisnotadequatelycontrolledbytherelatedsubstancestestorwherethereareparticularreasons(forexample,safetyreasons)forrequiringspecificcontrol.
2 OncethisnewnoteforguidanceisadoptedbytheExpertCommitteeonSpecificationsforPharmaceuticalSubstances,thereplacedtextcanbefoundinThe International Pharmacopoeia under “Omittedtexts”.
4. Compliance with the requirementsWhereamonographhasnorelatedsubstancestest(orequivalent)orwheretheexistingtestdoesnotcomplywiththerequirementsoftheapplicableregulatorystandardstheuserofamonographmustneverthelessensurethatthereissuitablecontroloforganicimpurities.
Identifyimpurityusingfurthermeans,forexample,referencesubstancesofexcipientsandpotentialimpuritiesnotreferredto in the monograph or hyphenated analytical techniques,e.g.LC-MS.
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.
1.2 Terminology Chemical reference substance Thetermchemicalreferencesubstance,asusedinthistext,referstoanauthenticated,uniformmaterialthatisintendedforuseinspecifiedchemicalandphysicaltests,inwhichitspropertiesarecomparedwiththoseoftheproductunderexaminationandwhichpossessesadegreeofpurityadequateforitsintendeduse.
Primary chemical reference substance Adesignatedprimarychemicalreferencesubstanceisonethatiswidelyacknowledgedtohavetheappropriatequalitieswithinaspecifiedcontextandwhoseassignedcontent
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.
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.
ICRSareestablishedandreleasedundertheauthorityoftheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.TheCommitteeadoptsnewICRSandnewlotsasbeingsuitableforuseasdescribedinThe International Pharmacopoeia orinotherWHOqualityassurancedocuments.
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.
1.6 Rational use of ICRSSpecificationsandtestproceduresofThe International Pharmacopoeia are intended tobeapplicableinallWHOMemberStateswishingtoimplementthem.Procuringreferencesubstancesmay,however,bedifficultincertainareasoftheworldduetodelaysintheirdeliveryandthecostofpurchase.The International Pharmacopoeia thereforeendeavourstoreducethenumberofreferencesubstancesrequiredto
1.8 Ordering informationSinceApril2010theEuropeanDirectoratefortheQualityofMedicines&HealthCare(EDQM),CouncilofEurope,isresponsiblefortheestablishment,preparation,storageanddistributionofICRSforThe International Pharmacopoeia.AlistofcurrentlyavailableICRScanbefoundonitswebsite(seehttp://www.edqm.eu).
2. International Infrared Reference SpectraInternationalinfraredreferencespectraareprovidedforuseinidentificationtestsasdescribedinmonographsofThe International Pharmacopoeia or other WHO quality assurancedocumentsadoptedbytheWHOExpertCommitteeonSpecificationsforPharmaceuticalPreparations.
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.
Injectsolution50µLofsolution(3).Theassayisnotvalidunlesstheresolutionfactorbetweenthetwoprincipalpeaksduetolevonorgestrel(retentiontimeabout12minutes)andthepeakduetoethinylestradiol(witharelativeretentionofaboutx)isatleastx.x.[Note from the Secretariat. The missing figures will be added at a later stage.]
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.
A. Carryouttheexaminationasdescribedunder1.7Spectrophotometryintheinfraredregion.TheinfraredabsorptionspectrumisconcordantwiththespectrumobtainedfromestradiolcypionateRSorwiththereferencespectrumofestradiolcypionate.
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.
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.]
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 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
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 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