CPMP-Note for guideline on Harmonization of requirements for influenza vaccine欧盟-流感疫苗标准指南.pdf

The European Agency for the Evaluation of Medicinal ProductsHuman Medicines Evaluation Unit12 March 1997CPMP/BWP/214/96COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTSCOMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS(CPMP)(CPMP)NOTE FOR GUIDANCE ON HARMONISATION OF REQUIREMENTSNOTE FOR GUIDANCE ON HARMONISATION OF REQUIREMENTSFOR INFLUENZA VACCINESFOR INFLUENZA VACCINESDISCUSSION IN THE BIOTECHNOLOGY WORKING PARTYDISCUSSION IN THE BIOTECHNOLOGY WORKING PARTY(BWP)(BWP)TRANSMISSION TO THE CPMPTRANSMISSION TO THE CPMPTRANSMISSION TO INTERESTED PARTIESTRANSMISSION TO INTERESTED PARTIESDEADLINE FOR COMMENTSDEADLINE FOR COMMENTSRE-SUBMISSION TOTHE BWPRE-SUBMISSION TOTHE BWPRE-SUBMISSION TO THE CPMPRE-SUBMISSION TO THE CPMPAPPROVAL BY THE CPMPAPPROVAL BY THE CPMPDATE FOR COMING INTO OPERATIONDATE FOR COMING INTO OPERATIONMarch 1996July 1996July 1996January 1997March 1997March 1997March 1997April 19977 Westferry Circus,Canary Wharf,London E14 4HB,UKSwitchboard:(+44-171)418 8400 Fax:(+44-171)418 8551E_Mail:mailemea.eudra.org http:/www.eudra.org/emea.htmlHARMONISATION OF REQUIREMENTS FOR INFLUENZA VACCINESHARMONISATION OF REQUIREMENTS FOR INFLUENZA VACCINES(CPMP/BWP/214/96)(CPMP/BWP/214/96)A.A.YEARLY CHOICE OF INFLUENZA VIRUS STRAINS FOR VACCINESYEARLY CHOICE OF INFLUENZA VIRUS STRAINS FOR VACCINESWHO has three international influenza centres(at the National Institute for Medical Researchin Mill Hill UK;and at the Centers for Disease Control in Atlanta,USA and at CSL Ltd,Parkville,Australia),which are assisted by national laboratories,designated by WHO.Thenational laboratories isolate viruses and then refer them to an international centre for detailedantigenic analysis.Reports are regularly sent to WHO in Geneva.Once a year,in mid-February,a meeting of WHO experts takes place in Geneva,leading to arecommendation on the influenza A and B virus variants which should be used for theproduction of vaccine for the coming season,but there remains very broad flexibility withinthis recommendation.The WHO recommendations are aimed worldwide and therefore need tobe adapted to the epidemiological situation of the European Union(EU).The predominantinfluenza viruses are believed to be similar from one Member State of the EU to another,There is thus little scientific justification for different composition of vaccines throughout theEU.As from 1992,a meeting of EU experts will have to be convened each year after the WHOmeeting,as soon as practicallypossible,in order to take an EU wide decision regardinginfluenza virus strains for vaccine production for the next season,taking into consideration theepidemiology of influenza in the EU.B.B.LABELLINGLABELLINGThere should be clear information about influenza virus strains and season of use,since EUvaccines often contain virus strains which are related to,but not identical to thoserecommended by the WHO.This may cause confusion if some vaccine labels show the WHOstrains and others show the actual vaccine strains.Information on immediate package,outer packaging and package leaflet should comply withCouncil Directive 92/27/EEC and in addition the labelling and package leaflets should contain:Immediate packageOuter packaging-season of usee.g.1997/98 season-WHO/EU recommended strainse.g.A/Wuhan/359/95(H3N2)-like strain-season of use-WHO/EU recommended strainsfollowed byactual strains e.g.A/Wuhan/359/95(H3N2)-likestrain(A/Nanchang/933/95 RESVIR-9)-Statement that the vaccine complies with WHOrecommendation(northern hemisphere)and EUdecision for x seasonCPMP/BWP/214/961/18Package leafletThe actual vaccine strains(ie those approved at the annual meeting of EU experts)will also benamed in the dossier submitted for annual licensing and in the production and test protocols.C.C.POTENCY OF INFLUENZA VACCINEPOTENCY OF INFLUENZA VACCINEFor influenza vaccines to be acceptable throughout the EU,they should comply withtheEuropean Pharmacopoeia(EP)requirements and contain 15 g HA per strain and per dose.The lower 95%confidence limits of the potency assay should indicate a content of at least 12g HA per strain and per dose.D.D.1.1.CONTROL AUTHORITY BATCH RELEASE OF INFLUENZA VACCINECONTROL AUTHORITY BATCH RELEASE OF INFLUENZA VACCINEINTRODUCTIONINTRODUCTION1.11.1Directive 89/342/EEC relating to immunological products(consisting of vaccines,toxins or serums and allergens)provides in article 4.3.that,where a Member State considers itnecessary in the interests of public health,it may require that samples from each batch besubmitted for examination by a State laboratory or a designated laboratory for the followingmedicinal products:live vaccines;immunological medicinal products used in the primary immunisation of infants or othergroups at risk;immunological medicinal products used in public health immunisation programmes;newimmunological medicinal productsorimmunological medicinal productsmanufactured using new or altered kinds of technology or new for a particularmanufacturer,during a transitional period normally specified in the marketingauthorisation.Harmonisation of such examination by EU national authorities must be achieved to permiteffective batch release of vaccines within the EU.The objective of this batch examination is the verification that the product is in conformitywith the approved specifications.The testing has to be completed within 60 days of receiptof the samples.1.21.2Where a Member State has examined a batch of a product and declared it to beinconformity with the approved specifications,anotherMember State may not repeat thisexamination for the purpose of release.The objective of this document is the harmonisation of control tests carried out in theframework of batch examination in order to achieve mutual recognition.1.31.3Batch release should be carried out by a control authority with recognised competencein batch release of influenza vaccines.A vaccine batch released by one Member State must beacceptable to other Member States.Batch release depends upon mutual confidence andeffective exchange of information between the Member States.The batch release proceduresCPMP/BWP/214/962/18outlined below are phased to deal with vaccine submissions under normal circumstances(phase 1)and abnormal circumstances(phase 2).Phase 1 of batch release is necessary for allvaccine batches whereas phase 2 of batch release is introduced under the special circumstancesdescribed below.Test methods and results for phases 1 and 2 must comply with theEuropean Pharmacopoeia monograph on influenza vaccines.1.41.4Manufacturers are responsible for presenting release certificates delivered by thecompetent authorities when required.Records of batch release tests(phases 1 and 2)and the full documentation submitted by themanufacturer should be kept for at least 10 years by the control authority.They should beavailable to other EU control authorities upon request.2.2.2.12.1PHASE 1 OF BATCH RELEASE:PHASE 1 OF BATCH RELEASE:PROTOCOLPROTOCOL SUBMISSIONSUBMISSION ANDAND BATCHBATCHRELEASE TESTS(BASIC EP TESTS)RELEASE TESTS(BASIC EP TESTS)Protocol submissionProtocol submissionThe manufacturers detailed protocol of production and testscarried out according to theEuropean Pharmacopoeia monograph on influenza vaccines shall be approved by the controlauthority for each vaccine batch.The protocol should be based upon the WHO summaryprotocol for influenza vaccine(inactivated)(WHO Technical Report Series638,1979)anexample of which is illustrated in paragraph 5.Manufacturers should submit full details of testresults;it is insufficient to indicate only pass or fail.2.2.2.2.Basic EP testsBasic EP testsTests to be performed by the control authority in accordance with the EP monograph as abasis for batch release:2.2.12.2.1At least twenty doses of each vaccine batch(product supplied in final package)and 20ml of bulk vaccine shall be submitted to the control authority.For purified subunit vaccines,an additional 10 ml of monovalent vaccine shall be submitted for the first 5 lots of vaccineproduced from a new influenza strain;2.2.22.2.2Tests to be performed on each batch of vaccine prior to release:a)b)haemagglutinin antigen concentration/identity test using referencematerials suppliedcurrently by the National Institute for Biological Standards and Control,UK;endotoxin content;2.2.32.2.3Tests to be performed on each lot of blended bulk vaccine:a)none;2.2.42.2.4Tests to be performedon the first 5 lots of monovalent purified subunit vaccinefollowing the introduction of a new influenza strain:a)test for purity;CPMP/BWP/214/963/183.3.PHASEPHASE2 2OFOFBATCHBATCHRELEASE:RELEASE:PROTOCOLPROTOCOLSUBMISSIONSUBMISSIONANDANDADDITIONAL EP TESTSADDITIONAL EP TESTSAdditional tests from the EP monograph on influenza vaccines may be necessary for batchrelease in special circumstances:a change in the vaccine production process has been approved;a change in the site of manufacture has been approved;evidence of unexpected adverse clinical reactions or quality defects from previousbatches of a given vaccine;evidence of marked inconsistencies in the vaccine production process;a critical report from the inspector from the competent authority;changes in the manufacturers testing procedures;identification of unexpected variability of the manufacturers test results.Phase 2 batch release procedures:3.13.1The number of additional doses of each vaccine batch(product supplied in finalpackage)or the volume of trivalent or monovalent bulk vaccine to be submitted for testing tothe control authority will depend on the nature of the additional tests.3.23.2The nature of the additional batch release tests to be performed will depend on thecircumstances for introduction of phase 2 tests.3.33.3Information concerning failed batches may be required as part of phase 2 batch releaseprocedures.4.4.RELEASE CERTIFICATERELEASE CERTIFICATEA release certificate for each vaccine batch shall be presented to the manufacturer afterapproval when the results of testing are satisfactory.The release certificate must give detailsof:4.1.4.2.4.3.4.4.4.5.4.6.4.7.Name and address of manufacturerTrade name and proper name of productMarketing Authorisation Number(Country)Batch numberNumber of containersNumber of doses per containerType of containerCPMP/BWP/214/964/184.8.4.9.4.104.11Date of release and reference numberDate of expiryStatement of complianceName and function of signatory5.5.SUMMARY PROTOCOL FOR INACTIVATED INFLUENZA VACCINESSUMMARY PROTOCOL FOR INACTIVATED INFLUENZA VACCINESThe following summary protocol is an example of the type of information required for batchrelease.The data submitted should be in accordance with the current EP monograph oninfluenza vaccines.Name of product:.Marketing authorisation:.Name and address of manufacturer:.Batch number:.Filling lot number:.Date of manufacture:.Date of expiry:.Type of container:.Number of doses:.Dose volume:.Composition:.e.g.strain 1strain 2strain 315 g HA/0.5 ml15 g HA/0.5 ml15 g HA/0.5 mlCPMP/BWP/214/965/18Statement of quality:.e.g.I certify that lot number.of this product satisfies the requirements ofthe European monograph on influenza vaccines.Signature:.Name(typed):.CPMP/BWP/214/966/18PRODUCTION FLOW SHEETPrimary seedH3N2Lot no:.Primary seedHINILot no:.Primary seedBLot no:.Working seedH3N2Lot no:.Working seedHINILot no:.Working seedBLot no:.Monovalent bulkH3N2Lot no:.Monovalent bulkHINILot no:.Monovalent bulkBLot no:.Trivalent bulkLot no:.Final ProductFilling Lot no:.CPMP/BWP/214/967/18SEED VIRUSSEED VIRUS1.1.1.11.21.31.41.51.61.71.81.91.102.2.2.1Information on manufactureInformation on manufactureVirus strain:.Source and lot No of primary seed:.Date of receipt:.Passage history on receipt(dates,temperatures):.Comments:.Storage conditions:.Working seed lot No:.Passage history of seed lot(s)(dates,temperatures):.Added antibiotics:.Storage conditions of working seed lot(s):Tests on working seed virusTests on working seed virusSterilityMethod:.Date of test:.Volume tested:.Test results:.2.2Test for mycoplasmaMethod:.Date of test:.Volume tested:.Test results:.2.3Identity(a)HaemagglutininDate of test:.Test results:.CPMP/BWP/214/968/18e.g.HI titreAntiserumShang/11/87 Sich/2/87 Taiw/l/86 B/Yam/16/88AntigenA/Shang/11/87(H3N2)RefA/Sich/2/87(H3N2)RefA/Taiw/l/86(HINI)RefA/Shang/11/87Working seedlot no:.(b)NeuraminidaseDate of test:.Test results:.e.g.AntigenHI titre Antiserumanti-N2NAanti-NlNAanti-BNAA/Shang/11/87(H3N2)RefA/Sich/2/87(H3N2)RefA/Taiw/l/86(HINI)RefB/Yam/16/88RefCPMP/BWP/214/969/18A/Shang/11/87Working seedlot No.2.4.Infectivity titre:.Date of tests:.Test results:.MONOVALENT VIRUS POOLMONOVALENT VIRUS POOL1.1.Information on manufactureInformation on manufactureName and address of manufacturer:.1.11.21.31.41.51.61.71.81.9Virus strain:.Lot number(s):.Working seed lots used:.Date of inoculation:.Date of harvesting:.Method of inactivation:.Date of inactivation:.Method of disruption(if any):.Date of disruption(if any):.1.10.Concentration/purification procedure:.1.111.12Added antibiotics:.Filtration details(if any):.CPMP/BWP/214/9610/182.2.2.1Tests on monovalent virus poolTests on monovalent virus poolTest for inactivationDate of test:.Test results:.2.2Test for haemagglutinin antigen contentMethod:.Date of test:.Test results:.2.3Identity of haemagglutininMethod:.Date of test:.Test results:.2.4Purity(for surface antigen vaccines only)Method:.(e.g.type of PAGE system,reducing/non reducing conditions)Date of test:.Test results:.(e.g.HA,M and NP bands must be identified.Comparison between whole virus andsurface antigen preparation must be made)CPMP/BWP/214/9611/18BULK VACCINEBULK VACCINEDate of test:.Test results:.1.1.Information on manufactureInformation on manufactureName and address of manufacturer:.1.11.2Lot number:.Lot number and volume of monovalent pools used to prepare bulk:.1.3Other substances added and volumes:.1.42.2.Date of blending:.Tests on bulk vaccineTests on bulk vaccineAnalytical testsMethod(s):.Test results:.(include test for mercury,if appropriate)CPMP/BWP/214/9612/18FINISHED PRODUCTFINISHED PRODUCT1.1.Information on manufactureInformation on manufactureName and address of manufacturer:.1.11.21.31.41.52.2.2.1Lot number:.Date of filling:.Type of container:.Volume in container:.Number of doses filled:.Tests on finished productTests on finished productIdentity for haemagglutininMethod:.Date of test:.Test results:.2.2SterilityMethod:.Date of test:.Test results:.2.3Haemagglutinin antigen contentMethod:.Date of test:.Test results:.2.4Total protein(this test may be performed on bulk vaccine)Method:.Date of test:.Test results:.CPMP/BWP/214/9613/182.5Abnormal toxicityMethod:.Date of test:.Test results:.2.6Ovalbumin(this test may be performed on bulk vaccine)Method:.Date of test:.Test results:.2.7EndotoxinMethod:.(e.g.type of limulus kit)Date of test:.Test results:.2.8pHDate of test:.Test results:.2.9Preservative contentMethod:.Date of test:.Test results:.2.10Appearance:.CPMP/BWP/214/9614/18E.E.1.1.CLINICALCLINICAL TRIALSTRIALS RELATEDRELATED TOTO YEARLYYEARLY LI