commiss direct ec june amend direct ec european parliament council commun code relat medicin product human text eea relev commiss european commun regard treati establish european commun regard direct ec european parliament council novemb commun code relat medicin product human amend direct ec articl thereof medicin product human european commun market grant market authoris deliv compet author view obtain market authoris applic dossier particular document relat result test trial carri medicin product submit detail scientif technic requir annex direct ec adapt account scientif technic progress larg set requir result recent legisl present content market authoris applic dossier improv order facilit assess part dossier common medicin product framework intern confer harmonis ich consensu reach provid harmonis format terminolog common technic document homogen organis present market authoris applic dossier human medicin product achiev standardis market authoris dossier requir introduc order implement common technic document delai standardis market authoris dossier requir harmonis format applic type medicin product human procedur grant market authoris medicin product present specif featur requir fulfil account situat simplifi dossier present provid safeti biolog medicin product reli rigor control start materi requir suitabl human donor test donat start materi plasma deriv medicin product laid direct ec set standard qualiti safeti collect test process storag distribut human blood blood compon amend direct ec articl direct ec amend plasma deriv medicin product se biolog medicin product manufactur base care handl human plasma start materi account fact plasma materi case medicin product result substanti part market authoris dossier common great number dossier total plasma deriv medicin product establish system aim simplifi procedur approv subsequ human plasma deriv medicin product end concept plasma master file pmf introduc order pool nation expertis coordin emea singl evalu pmf serv stand document separ market authoris dossier harmonis control relev inform start materi manufactur plasma deriv medicin product achiev pmf system consist step assess assess pmf carri commun level result certif complianc commun legisl pmf account nation compet author prevent subsequ reassess assess finish plasma deriv medicin product modifi part pmf essenti part content plasma origin plasma qualiti safeti remain task compet author grant market authoris plasma deriv medicin product case vaccin human antigen common medicin product vaccin chang antigen ipso facto impact vaccin authoris procedur order simplifi exist procedur assess vaccin grant market authoris subsequ due modif manufactur process test individu antigen involv combin vaccin system base concept vaccin antigen master file vamf introduc vamf pool nation expertis coordin emea singl evalu concern vaccin antigen vamf serv stand part market authoris dossier provid relev inform biolog chemic natur relat specif antigen constitut activ substanc combin vaccin vamf system consist step assess assess vamf carri commun level result certif complianc commun legisl vamf account nation compet author prevent subsequ reassess assess finish medicin product combin vaccin modifi antigen task compet author grant combin vaccin market authoris herbal medicin product differ substanti convent medicin product intrins notion herbal substanc herbal prepar determin specif requir respect product regard standardis market authoris requir treatment acquir inherit patholog dysfunct human call concept base approach base develop biotechnolog techniqu involv advanc therapi medicin product base process focus gene transfer produc bio molecul gene therapi medicin product manipul process cell cell therapi medicin product activ substanc achiev essenti action metabol physiolog immunolog mean restor correct modifi physiolog function human complex therapeut product repres categori biolog medicin product sens articl direct ec gener principl applic product scientif technic point view specif requir regard standardis market authoris requir determin direct ec amend measur provid direct accord opinion stand committe medicin product human adopt direct articl direct ec amend paragraph articl word quot part quot replac quot part ii point quot annex replac text annex direct articl member state bring forc law regul administr provis compli direct octob latest forthwith inform commiss thereof member state adopt provis refer direct accompani refer occas offici public member state determin refer made direct applic juli articl direct enter forc dai public offici journal european union articl direct address member state brussel june commiss erkki liikanen member commiss oj oj annex annex direct ec replac quot annex analyt pharmacotoxicolog clinic standard protocol respect test medicin product tabl content gt tabl gt introduct gener principl particular document accompani applic market authoris pursuant articl present accord requir set annex follow guidanc publish commiss rule govern medicin product european commun volum notic applic medicin product human present content dossier common technic document ctd particular document present modul modul european commun specif administr data modul qualiti clinic clinic summari modul chemic pharmaceut biolog inform modul clinic report modul clinic studi report present implement common format ich region european commun unit state america japan modul present strict accord format content number system delin detail volum notic applic refer european commun ctd present applic type market authoris applic irrespect procedur appli centralis mutual recognit nation base full abridg applic applic type product includ chemic entiti nce radio pharmaceut plasma deriv vaccin herbal medicin product assembl dossier applic market authoris applic account scientif guidelin relat qualiti safeti efficaci medicin product human adopt committe proprietari medicin product cpmp publish european medicin evalu agenc emea pharmaceut commun guidelin publish commiss volum rule govern medicin product european commun respect qualiti part chemic pharmaceut biolog dossier monograph includ gener monograph gener chapter european pharmacopoeia applic manufactur process compli requir commiss direct eec lai principl guidelin good manufactur practic gmp medicin product human principl guidelin gmp publish commiss rule govern medicin product european commun volum inform relev evalu medicin product concern includ applic favour unfavour product relev detail incomplet abandon pharmaco toxicolog clinic test trial relat medicin product complet trial therapeut indic cover applic clinic trial conduct european commun compli requir direct ec european parliament council approxim law regul administr provis member state relat implement good clinic practic conduct clinic trial medicin product human account assess applic clinic trial conduct european commun relat medicin product intend european commun design implement report good clinic practic ethic principl concern basi principl equival provis direct ec carri accord ethic principl reflect declar helsinki clinic pharmaco toxicolog studi carri conform provis relat good laboratori practic laid council direct eec harmonis regul administr provis relat applic principl good laboratori practic verif applic test chemic substanc eec inspect verif good laboratori practic glp member state ensur test anim conduct accord council direct eec novemb approxim law regul administr provis member state protect anim experiment scientif purpos order monitor benefit risk assess inform origin applic pharmaco vigil inform submit compet author market authoris grant chang data dossier submit compet author accord requir commiss regul ec ec commiss relev accord nation provis requir volum commiss public rule govern medicin product european commun annex divid part part describ applic format summari product characterist label leaflet present requir standard applic modul part ii derog quot specif applic quot establish medicin essenti similar product fix combin similar biolog product except circumst mix applic part bibliograph part studi part iii deal quot applic requir quot biolog medicin product plasma master file vaccin antigen master file radio pharmaceut homeopath medicin product herbal medicin product orphan medicin product part iv deal quot advanc therapi medicin product quot concern specif requir gene therapi medicin product human autolog allogen system xenogen system cell therapi medicin product human anim origin xenogen transplant medicin product part standardis market authoris dossier requir modul administr inform tabl content comprehens tabl content modul dossier submit market authoris applic present applic form medicin product subject applic identifi activ substanc pharmaceut form rout administr strength final present includ packag address applic address manufactur site involv stage manufactur includ manufactur finish product manufactur activ substanc relev address import applic identifi type applic sampl provid annex administr data copi manufactur authoris defin articl list countri authoris grant copi summari product characterist accord articl approv member state list countri applic submit outlin applic form applic provid inter alia detail medicin product subject applic legal basi applic propos market authoris holder manufactur inform orphan medicin product statu scientif advic paediatr develop program summari product characterist label packag leaflet summari product characterist applic propos summari product characterist accord articl label packag leaflet propos label text outer packag packag leaflet provid accord mandatori item list titl label medicin product human articl packag leaflet articl mock up specimen applic provid specimen mock up outer packag label packag leaflet medicin product concern summari product characterist approv member state annex administr data applic form copi summari product characterist accord articl approv member state applic list countri applic submit inform expert accord articl expert provid detail report observ document particular constitut market authoris dossier modul chemic pharmaceut biolog document clinic document clinic document expert requir address critic point relat qualiti medicin product investig carri anim human be bring data relev evalu requir met provid qualiti summari clinic overview data studi carri anim clinic overview locat modul market authoris applic dossier declar sign expert inform educ background train occup experi present modul expert suitabl technic profession qualif profession relationship expert applic declar specif requir type applic specif requir type applic address part ii present annex environment risk assess applic applic market authoris includ risk assess overview evalu risk environ due dispos medicin product make propos label provis environment risk connect releas medicin product consist gmo genet modifi organ mean articl direct ec european parliament council march deliber releas environ modifi organ repeal council direct eec address inform pertain environment risk appendix modul inform present accord provis direct ec take account guidanc document publish commiss connect implement direct inform consist introduct copi written consent consent deliber releas environ gmo research develop purpos part direct ec inform request annex ii iv direct ec includ detect identif method uniqu code gmo addit inform gmo product relev evalu environment risk environ risk assess era report prepar basi inform annex iii iv direct ec accord annex ii direct ec take account inform era conclus propos risk manag strategi includ relev gmo product question post market monitor plan identif special particular summari product characterist label packag leaflet measur order inform public date signatur author inform author educ train occup experi statement author relationship applic includ modul summari modul aim summaris chemic pharmaceut biolog data clinic data clinic data present modul dossier market authoris provid report overview articl direct critic point address analys factual summari includ tabular format provid report provid cross refer tabular format inform contain main document present modul chemic pharmaceut biolog document modul clinic document modul clinic document inform contain modul present accord format content number system delin volum notic applic overview summari compli basic principl requir laid herewith tabl content modul tabl content scientif document submit modul introduct inform pharmacolog class mode action propos clinic medicin product market authoris request suppli qualiti summari review inform relat chemic pharmaceut biolog data provid qualiti summari kei critic paramet issu relat qualiti aspect emphasis justif case relev guidelin document follow scope outlin detail data present modul clinic overview integr critic assess clinic evalu medicin product anim vitro requir discuss justif test strategi deviat relev guidelin includ biolog medicin product assess impur degrad product includ potenti pharmacolog toxicolog effect implic differ chiral chemic form impur profil compound clinic studi product market discuss biolog medicin product compar materi clinic studi clinic studi medicin product market assess excipi subject specif safeti assess characterist medicin product demonstr clinic studi defin implic find safeti medicin product intend clinic human discuss clinic overview clinic overview intend provid critic analysi clinic data includ clinic summari modul approach clinic develop medicin product includ critic studi design decis relat perform studi provid overview clinic find includ import limit evalu benefit risk base conclus clinic studi provid interpret efficaci safeti find support propos dose target indic evalu summari product characterist approach optimis benefit manag risk requir efficaci safeti issu encount develop unresolv issu explain clinic summari result pharmacolog pharmaco kinet toxicolog studi carri anim vitro provid factual written tabul summari present order introduct pharmacolog written summari pharmacolog tabul summari pharmaco kinet written summari pharmaco kinet tabul summari toxicolog written summari toxicolog tabul summari clinic summari detail factual summari clinic inform medicin product includ modul provid includ result bio pharmaceut studi clinic pharmacolog studi clinic efficaci safeti studi synopsi individu studi requir summaris clinic inform present order summari bio pharmaceut analyt method summari clinic pharmacolog studi summari clinic efficaci summari clinic safeti synops individu studi modul chemic pharmaceut biolog inform medicin product chemic biolog activ substanc format present gener outlin modul tabl content bodi data activ substanc gener inform nomenclatur structur gener properti manufactur manufactur descript manufactur process process control control materi control critic step intermedi process valid evalu manufactur process develop characteris elucid structur characterist impur control activ substanc specif analyt procedur valid analyt procedur batch analys justif specif refer standard materi contain closur system stabil stabil summari conclus post approv stabil protocol stabil commit stabil data finish medicin product descript composit medicin product pharmaceut develop compon medicin product activ substanc excipi medicin product formul develop overag physicochem biolog properti manufactur process develop contain closur system microbiolog attribut compat manufactur manufactur batch formula descript manufactur process process control control critic step intermedi process valid evalu control excipi specif analyt procedur valid analyt procedur justif specif excipi human anim origin excipi control finish medicin product specif analyt procedur valid analyt procedur batch analys characteris impur justif specif refer standard materi contain closur system stabil stabil summari conclus post approv stabil protocol stabil commit stabil data appendic facil equip biolog medicin product adventiti agent safeti evalu excipi european commun addit inform process valid scheme medicin product medic devic certif suitabl medicin product manufactur process materi anim human origin tse procedur literatur refer content basic principl requir chemic pharmaceut biolog data provid includ activ substanc finish medicin product relev inform develop manufactur process characteris properti qualiti control oper requir stabil descript composit present finish medicin product main set inform provid deal activ substanc finish medicin product modul addit suppli detail inform start raw materi manufactur oper activ substanc excipi incorpor formul finish medicin product procedur method manufactur control activ substanc finish medicin product suffici detail enabl repeat control test carri request compet author test procedur correspond state scientif progress time valid result valid studi provid case test procedur includ european pharmacopoeia descript replac detail refer monograph gener chapter monograph european pharmacopoeia applic substanc prepar pharmaceut form appear respect substanc member state requir observ nation pharmacopoeia materi european pharmacopoeia pharmacopoeia member state prepar method liabl leav impur control pharmacopoeia monograph impur maximum toler limit declar suitabl test procedur case specif contain monograph european pharmacopoeia nation pharmacopoeia member state insuffici ensur qualiti substanc compet author request specif market authoris holder compet author inform author respons pharmacopoeia question market authoris holder provid author pharmacopoeia detail alleg insuffici addit specif appli case analyt procedur includ european pharmacopoeia descript replac relev section detail refer monograph gener chapter case start raw materi activ substanc excipi european pharmacopoeia pharmacopoeia member state complianc monograph countri pharmacopoeia accept case applic submit copi monograph accompani valid analyt procedur contain monograph translat activ substanc raw start materi excipi subject monograph european pharmacopoeia applic appli certif suitabl grant european director qualiti medicin present relev section modul certif suitabl monograph european pharmacopoeia deem replac relev data section modul manufactur give assur write applic manufactur process modifi grant certif suitabl european director qualiti medicin defin activ substanc activ substanc manufactur applic arrang detail descript manufactur process ii qualiti control manufactur iii process valid suppli separ document directli compet author manufactur activ substanc activ substanc master file case manufactur provid applic data respons medicin product manufactur confirm write applic ensur batch batch consist modifi manufactur process specif inform applic document particular support applic chang suppli compet author document particular suppli applic concern open part activ substanc master file specif measur prevent transmiss anim spongiform encephalopathi materi rumin origin step manufactur process applic demonstr complianc materi note guidanc minimis risk transmit anim spongiform encephalopathi agent medicin product updat publish commiss offici journal european union demonstr complianc note guidanc submit prefer certif suitabl relev monograph european pharmacopoeia grant european director qualiti medicin suppli scientif data substanti complianc adventiti agent inform assess risk respect potenti contamin adventiti agent viral viral laid relev guidelin relev gener monograph gener chapter european pharmacopoeia provid special apparatu equip stage manufactur process control oper medicin product adequ detail applic need ce mark requir commun legisl medic devic provid special attent paid select element activ substanc gener inform inform relat start raw materi inform nomenclatur activ substanc provid includ recommend intern proprietari inn european pharmacopoeia relev chemic structur formula includ rel absolut stereo chemistri molecular formula rel molecular mass provid biotechnolog medicin product schemat amino acid sequenc rel molecular mass provid list provid physicochem relev properti activ substanc includ biolog activ biolog medicin product purpos annex start materi materi activ substanc manufactur extract biolog medicin product start materi substanc biolog origin micro organ organ tissu plant anim origin cell fluid includ blood plasma human anim origin biotechnolog cell construct cell substrat recombin includ primari cell biolog medicin product product activ substanc biolog substanc biolog substanc substanc produc extract biolog sourc characteris determin qualiti combin physico chemic biolog test product process control consid biolog medicin product immunolog medicin product medicin product deriv human blood human plasma defin paragraph articl medicin product fall scope part annex regul eec advanc therapi medicin product defin part iv annex substanc manufactur extract activ substanc activ substanc directli deriv reagent cultur media foetal calf serum addit buffer involv chromatographi raw materi manufactur process activ substanc descript activ substanc manufactur process repres applic commit manufactur activ substanc adequ describ manufactur process process control inform laid guidelin publish agenc provid materi need order manufactur activ substanc list identifi materi process inform qualiti control materi provid inform demonstr materi meet standard intend provid raw materi list qualiti control document address respons manufactur includ contractor propos product site facil involv manufactur test provid biolog medicin product addit requir appli origin histori start materi document specif measur prevent transmiss anim spongiform encephalopathi applic demonstr activ substanc compli note guidanc minimis risk transmit anim spongiform encephalopathi agent medicin product updat publish commiss offici journal european union cell bank cell characterist shown remain unchang passag level product seed materi cell bank pool serum plasma materi biolog origin materi deriv test adventiti agent presenc potenti pathogen adventiti agent inevit materi process ensur elimin inactiv valid vaccin product base seed lot system establish cell bank bacteri viral vaccin characterist infecti agent demonstr seed addit live vaccin stabil attenu characterist demonstr seed proof suffici attenu characterist demonstr product stage medicin product deriv human blood plasma origin criteria procedur collect transport storag start materi document accord provis laid part iii annex manufactur facil equip test accept criteria carri critic step inform qualiti control intermedi process valid evalu studi provid presenc potenti pathogen adventiti agent inevit correspond materi process ensur elimin inactiv valid section deal viral safeti evalu descript discuss signific made manufactur process develop manufactur site activ substanc provid characteris activ substanc data highlight structur characterist activ substanc provid confirm structur activ substanc base physico chemic immuno chemic biolog method inform impur provid control activ substanc detail inform specif routin control activ substanc justif choic specif method analysi valid provid result control carri individu batch manufactur develop present refer standard materi refer prepar standard identifi detail relev chemic biolog refer materi european pharmacopoeia contain closur system activ substanc descript contain closur system specif provid stabil activ substanc type studi conduct protocol result studi summaris detail result stabil studi includ inform analyt procedur gener data valid procedur present format post authoris stabil protocol stabil commit provid finish medicin product descript composit finish medicin product descript finish medicin product composit provid inform includ descript pharmaceut form composit constitu finish medicin product amount unit basi function constitu activ substanc constitu excipi natur quantiti includ colour matter preserv adjuv stabilis thicken emulsifi flavour aromat substanc constitu intend ingest administ patient outer cover medicin product hard capsul soft capsul rectal capsul coat tablet film coat tablet particular supplement relev data type contain manner closur detail devic medicin product administ deliv medicin product quot usual terminolog quot describ constitu medicin product notwithstand applic provis articl respect substanc european pharmacopoeia fail nation pharmacopoeia member state main titl head monograph question refer pharmacopoeia concern respect substanc intern proprietari inn recommend world health organis fail exact scientif design substanc intern proprietari exact scientif design statement prepar supplement relev detail respect colour matter design quot quot code assign council direct eec decemb approxim rule member state colour matter authoris medicin product european parliament council direct ec june colour foodstuff order give quot quantit composit quot activ substanc finish medicin product depend pharmaceut form concern mass number unit biolog activ dosag unit unit mass volum activ substanc activ substanc present form compound deriv design quantit total mass relev mass activ entiti entiti molecul medicin product activ substanc subject applic market authoris member state time quantit statement activ substanc salt hydrat systemat express term mass activ entiti entiti molecul subsequ authoris medicin product member state quantit composit state activ substanc unit biolog activ substanc defin molecularli intern unit biolog activ defin world health organis intern unit defin unit biolog activ express provid unambigu inform activ substanc applic european pharmacopoeia unit pharmaceut develop chapter devot inform develop studi conduct establish dosag form formul manufactur process contain closur system microbiolog attribut usag instruct intend market authoris applic dossier studi chapter distinct routin control test conduct specif critic paramet formul process attribut influenc batch reproduc medicin product perform medicin product qualiti identifi addit support data referenc relev chapter modul clinic studi report modul clinic studi report market authoris applic dossier compat activ substanc excipi kei physicochem characterist activ substanc influenc perform finish product compat activ substanc case combin product document choic excipi rel respect function concentr document descript develop finish product provid take consider propos rout administr usag overag formul warrant physiochem biolog properti concern paramet relev perform finish product address document select optimis manufactur process differ manufactur process es produc pivot clinic batch process manufactur propos finish medicin product provid suitabl contain closur system storag ship finish product document interact medicin product contain consid microbiolog attribut dosag form relat steril steril product accord document prescrib european pharmacopoeia order provid support inform label compat finish product reconstitut diluent dosag devic document manufactur process finish medicin product descript manufactur method accompani applic market authoris pursuant articl draft give adequ synopsi natur oper emploi purpos includ mention stage manufactur includ process control accept criteria assess made process emploi produc pharmaceut form produc advers chang constitu case continu manufactur full detail precaut ensur homogen finish product experiment studi valid manufactur process standard method manufactur critic product steril medicin product detail sterilis process asept procedur detail batch formula address respons manufactur includ contractor propos product site facil involv manufactur test provid particular relat product control test carri intermedi stage manufactur process view ensur consist product process includ test essenti check conform medicin product formula exception applic propos analyt method test finish product includ assai activ substanc excipi constitu subject requir activ substanc appli qualiti control finish product depend process control test medicin product essenti defin method prepar descript document result valid studi critic step critic assai manufactur process provid control excipi materi need order manufactur excipi list identifi materi process inform qualiti control materi provid inform demonstr materi meet standard intend provid colour matter case satisfi requir direct eec ec addit colour matter meet puriti criteria laid direct ec amend excipi specif justif detail analyt procedur duli valid specif attent paid excipi human anim origin specif measur prevent transmiss anim spongiform encephalopathi applic demonstr excipi medicin product manufactur accord note guidanc minimis risk transmit anim spongiform encephalopathi agent medicin product updat publish commiss offici journal european union demonstr complianc aforement note guidanc submit prefer certif suitabl relev monograph transmiss spongiform encephalopathi european pharmacopoeia suppli scientif data substanti complianc excipi excipi time medicin product rout administr full detail manufactur characteris control cross refer support safeti data clinic clinic provid activ substanc format previous document detail chemic pharmaceut biolog inform present inform format order chapter devot activ substanc modul inform excipi present stand document format paragraph applic differ excipi manufactur stand document made applic submiss compet author addit inform toxic studi excipi provid modul dossier clinic studi provid modul control finish medicin product control finish medicin product batch medicin product entiti compris unit pharmaceut form made initi quantiti materi undergon seri manufactur sterilis oper case continu product process unit manufactur period time justif maximum accept deviat activ substanc content finish product exce time manufactur detail inform specif releas shelf life justif choic method analysi valid provid refer standard materi refer prepar standard test finish medicin product identifi detail previous provid section relat activ substanc contain closur finish medicin product descript contain closur system includ ident packag materi specif provid specif includ descript identif pharmacopoei method valid includ function outer packag materi descript provid function outer packag materi addit inform provid stabil finish medicin product type studi conduct protocol result studi summaris detail result stabil studi includ inform analyt procedur gener data valid procedur present format case vaccin inform cumul stabil provid post authoris stabil protocol stabil commit provid modul clinic report format present gener outlin modul tabl content studi report pharmacolog primari pharmaco dynam secondari pharmaco dynam safeti pharmacolog pharmaco dynam interact pharmaco kinet analyt method valid report absorpt distribut metabol excret pharmaco kinet interact clinic pharmaco kinet studi toxicolog singl dose toxic repeat dose toxic genotox vitro vivo includ support toxico kinet evalu carcinogen long term studi short medium term studi studi reproduct development toxic fertil earli embryon develop embryo fetal develop prenat postnat develop studi offspr juvenil anim dose evalu local toler toxic studi antigen immuno toxic mechanist studi depend metabolit impur literatur refer content basic principl requir special attent paid select element pharmacolog toxicolog test show potenti toxic product danger undesir toxic effect occur propos condit human be evalu relat patholog condit concern pharmacolog properti product qualit quantit relationship propos human be result reliabl gener applic mathemat statist procedur design experiment method evalu result addition clinician inform therapeut toxicolog potenti product biolog medicin product immunolog medicin product medicin product deriv human blood plasma requir modul adapt individu product test program carri justifi applic establish test program consider test requir repeat administr product design account induct interfer antibodi examin reproduct function embryo foetal peri natal toxic mutagen potenti carcinogen potenti consid constitu activ substanc incrimin valid remov replac studi toxicolog pharmaco kinet excipi time pharmaceut field investig possibl signific degrad storag medicin product toxicolog degrad product consid pharmacolog pharmacolog studi follow distinct line approach firstli action relat propos therapeut adequ investig recognis valid assai vivo vitro experiment techniqu detail reproduc result express quantit term dose effect curv time effect curv comparison made data relat substanc substanc similar therapeut action applic investig potenti undesir pharmaco dynam effect substanc physiolog function investig perform exposur anticip therapeut rang experiment techniqu standard procedur detail reproduc investig establish valid suspect modif respons result repeat administr substanc investig pharmaco dynam medicin product interact test combin activ substanc prompt pharmacolog premis indic therapeut effect case pharmaco dynam studi demonstr interact make combin therapeut case scientif justif combin sought therapeut experiment investig determin effect expect combin demonstr anim import collater effect investig pharmaco kinet pharmaco kinet mean studi fate activ substanc metabolit organ cover studi absorpt distribut metabol bio transform excret substanc studi phase carri mean physic chemic possibl biolog method observ actual pharmaco dynam activ substanc inform distribut elimin case data indispens determin dosag human respect chemo therapeut substanc antibiot substanc depend pharmaco dynam effect numer diagnost agent vitro studi carri advantag human materi comparison anim materi protein bind metabol drug drug interact pharmaco kinet investig pharmacolog activ substanc case combin substanc investig accord provis direct pharmaco kinet studi requir toxic test therapeut experiment justifi omiss pharmaco kinet program design comparison extrapol anim human toxicolog singl dose toxic singl dose toxic test qualit quantit studi toxic reaction result singl administr activ substanc substanc contain medicin product proport physico chemic state present actual product singl dose toxic test carri accord relev guidelin publish agenc repeat dose toxic repeat dose toxic test intend reveal physiolog anatomo patholog induc repeat administr activ substanc combin activ substanc examin determin relat dosag gener desir test perform short term last week long term durat depend condit clinic purpos describ potenti advers effect attent paid clinic studi durat defin relev guidelin publish agenc geno toxic purpos studi mutagen clastogen potenti reveal substanc genet materi individu cell mutagen substanc present hazard health exposur mutagen carri risk induc germ line mutat possibl inherit disord risk somat mutat includ lead cancer studi obligatori substanc carcino genic test reveal carcinogen effect requir studi perform medicin product expect clinic prolong period patient life continu repeatedli intermitt manner studi recommend medicin product concern carcinogen potenti product class similar structur evid repeat dose toxic studi studi unequivoc geno toxic compound need presum tran speci carcinogen impli hazard human medicin product intend administ chronic human chronic studi detect earli tumorigen effect reproduct development toxic investig impair male femal reproduct function harm effect progeni perform test test compris studi effect adult male femal reproduct function studi toxic teratogen effect stage develop concept sexual matur latent effect medicin product investig administ femal pregnanc omiss test adequ justifi depend medicin product addit studi address develop administ medicin product offspr warrant embryo foetal toxic studi conduct mammalian speci rodent peri postnat studi conduct speci metabol medicin product speci similar man desir includ speci desir speci repeat dose toxic studi state scientif knowledg time applic lodg account determin studi design local toler purpos local toler studi ascertain medicin product activ substanc excipi toler site bodi contact medicin product result administr clinic test strategi mechan effect administr pure physico chemic action product distinguish toxicolog pharmaco dynam local toler test conduct prepar develop human vehicl excipi treat control group posit control refer substanc includ design local toler test choic speci durat frequenc rout administr dose depend problem investig propos condit administr clinic revers local lesion perform relev studi anim substitut valid vitro test provid test result compar qualiti us purpos safeti evalu chemic appli skin dermal rectal vagin sensitis potenti evalu test system guinea pig assai local lymph node assai modul clinic studi report format present gener outlin modul tabl content clinic studi report tabular list clinic studi clinic studi report report bio pharmaceut studi bio avail studi report compar bio avail bio equival studi report vitro vivo correl studi report report bio analyt analyt method report studi pertin pharmaco kinet human bio materi plasma protein bind studi report report hepat metabol interact studi report studi human bio materi report human pharmaco kinet studi healthi subject pharmaco kinet initi toler studi report patient pharmaco kinet initi toler studi report intrins factor pharmaco kinet studi report extrins factor pharmaco kinet studi report popul pharmaco kinet studi report report human pharmaco dynam studi healthi subject pharmaco dynam pharmaco kinet pharmaco dynam studi report patient pharmaco dynam pharmaco kinet pharmaco dynam studi studi report report efficaci safeti studi studi report control clinic studi pertin claim indic studi report uncontrol clinic studi report analys data studi includ formal integr analys meta analys bridg analys studi report report post market experi literatur refer content basic principl requir special attent paid select element clinic particular provid pursuant articl enabl suffici found scientif valid opinion form medicin product satisfi criteria govern grant market authoris essenti requir result clinic trial commun favour unfavour clinic trial preced adequ pharmacolog toxicolog test carri anim accord requir modul annex investig acquaint conclus drawn pharmacolog toxicolog studi applic provid investig brochur consist relev inform prior onset clinic trial includ chemic pharmaceut biolog data toxicolog pharmaco kinet pharmaco dynam data anim result earlier clinic trial adequ data justifi natur scale durat propos trial complet pharmacolog toxicolog report provid request materi human anim origin mean emploi ensur safeti transmiss infecti agent prior commenc trial market authoris holder arrang essenti clinic trial document includ case report form subject medic file owner data year complet discontinu trial year grant market authoris european commun pend contempl market applic european commun year formal discontinu clinic develop investig product subject medic file retain accord applic legisl accord maximum period time permit hospit institut privat practic document retain longer period requir applic regulatori requir agreement sponsor respons sponsor inform hospit institut practic document longer retain sponsor owner data retain document pertain trial long product authoris document includ protocol includ rational object statist design methodolog trial condit perform manag detail investig product refer medicin product placebo standard oper procedur written opinion protocol procedur investig brochur case report form trial subject final report audit certif final report retain sponsor subsequ owner year medicin product longer authoris addit trial conduct european commun market authoris holder make addit arrang archiv document accord provis direct ec implement detail guidelin chang ownership data document data document made request relev author particular clinic trial suffici detail object judgement made protocol includ rational object statist design methodolog trial condit perform manag detail investig medicin product audit certif list investig investig give address appoint qualif clinic duti state trial carri assembl inform respect patient individu includ case report form trial subject final report sign investig multi centr trial investig ordin princip investig particular clinic trial refer forward compet author agreement compet author applic omit part inform complet document provid forthwith request investig conclus experiment evid express opinion safeti product normal condit toler efficaci inform relat indic contra indic dosag averag durat treatment special precaut treatment clinic symptom dosag report result multi centr studi princip investig conclus express opinion safeti efficaci investig medicin product behalf centr clinic observ summaris trial indic number sex subject treat select ag distribut group patient investig compar test number patient withdrawn prematur trial reason withdraw control trial carri condit control group receiv treatment receiv placebo receiv medicin product effect receiv treatment therapi medicin product frequenc observ advers reaction detail patient increas risk elderli peopl children women pregnanc menstruat physiolog patholog condit requir special consider paramet evalu criteria efficaci result term paramet statist evalu result call design trial variabl factor involv addit investig observ sign habitu addict difficulti wean patient medicin product interact observ medicin product administ concomitantli criteria determin exclus patient trial death occur trial follow period particular combin medicin substanc ident requir medicin product substanti safeti efficaci combin total partial omiss data explain unexpect result occur trial pre clinic toxicolog pharmacolog test undertaken review medicin product intend long term administr particular modif pharmacolog action repeat administr establish long term dosag report bio pharmaceut studi bio avail studi report compar bio avail bio equival studi report report vitro vivo correl studi bio analyt analyt method provid addit assess bio avail undertaken demonstr bio equival medicin product refer articl report studi pertin pharmaco kinet human bio materi purpos annex human bio materi protein cell tissu relat materi deriv human sourc vitro vivo assess pharmaco kinet properti drug substanc respect report plasma protein bind studi hepat metabol activ substanc interact studi studi human bio materi provid report human pharmaco kinet studi pharmaco kinet characterist absorpt rate extent distribut metabol excret clinic signific featur includ implic kinet data dosag regimen patient risk differ man anim speci pre clinic studi addit standard multipl sampl pharmaco kinet studi popul pharmaco kinet analys base spars sampl clinic studi address question contribut intrins extrins factor variabl dose pharmaco kinet respons relationship report pharmaco kinet initi toler studi healthi subject patient report pharmaco kinet studi assess effect intrins extrins factor report popul pharmaco kinet studi provid medicin product administ concomitantli medicin product particular joint administr test perform demonstr modif pharmacolog action pharmaco kinet interact activ substanc medicin product substanc investig report human pharmaco dynam studi pharmaco dynam action correl efficaci demonstr includ dose respons relationship time justif dosag condit administr mode action pharmaco dynam action relat efficaci demonstr pharmaco dynam effect human be suffici justifi conclus potenti therapeut effect medicin product administ concomitantli medicin product particular joint administr test perform demonstr modif pharmacolog action pharmaco dynam interact activ substanc medicin product substanc investig report efficaci safeti studi studi report control clinic studi pertin claim indic gener clinic trial quot control clinic trial quot randomis versu placebo versu establish medicin product proven therapeut design justifi treatment control group vari case case depend ethic consider therapeut area instanc pertin compar efficaci medicin product establish medicin product proven therapeut effect placebo trial effect product object measur step avoid bia includ method randomis blind protocol trial includ descript statist method emploi number reason inclus patient includ calcul power trial level signific descript statist unit measur avoid bia method randomis document inclus larg number subject trial regard adequ substitut properli control trial safeti data review take account guidelin publish commiss attent event result dose concomit medic advers event event result withdraw death patient patient group increas risk identifi attent paid potenti vulner patient present small number children pregnant women frail elderli peopl mark abnorm metabol excret implic safeti evalu medicin product studi report uncontrol clinic studi report analys data studi clinic studi report report provid report post market experi medicin product authoris countri inform respect advers reaction medicin product concern medicin product activ substanc relat usag rate case report form individu patient list submit accord relev guidelin publish agenc case report form individu patient data list provid present order clinic studi report index studi part ii specif market authoris dossier requir medicin product present specif featur requir market authoris applic dossier laid part annex adapt account situat adapt present dossier applic establish medicin medicin product activ substanc quot establish medicin quot refer articl ii recognis efficaci accept level safeti specif rule appli applic submit modul part annex modul detail scientif bibliographi address clinic clinic characterist specif rule appli order demonstr establish medicin factor account order establish establish medicin constitu medicin product time substanc quantit aspect substanc degre scientif interest substanc reflect publish scientif literatur coher scientif assess period time establish establish substanc case period time requir establish establish medicin constitu medicin product decad systemat document substanc medicin product commun document submit applic cover aspect safeti efficaci assess includ refer review relev literatur take account pre post market studi publish scientif literatur experi form epidemiolog studi compar epidemiolog studi document favour unfavour commun respect provis quot establish medicin quot clarifi quot bibliograph refer quot sourc evid post market studi epidemiolog studi data relat test trial serv valid proof safeti efficaci product applic explain justifi sourc inform satisfactorili attent paid miss inform justif demonstr accept level safeti efficaci support studi lack clinic clinic overview explain relev data submit concern product product intend market judgement made product studi consid similar product applic market authoris made spite exist differ post market experi product constitu import applic put special emphasi issu essenti similar medicin product applic base articl essenti similar product data modul part annex provid applic grant consent holder origin market authoris cross refer content modul applic base articl iii essenti similar product gener data modul part annex data show bio avail bio equival origin medicin product provid biolog medicin product part ii similar biolog medicin product product clinic clinic overview summari focu element ground claim essenti similar summari impur present batch activ substanc finish medicin product relev decomposit product aris storag propos product market evalu impur evalu bio equival studi justif studi perform respect guidelin quot investig bio avail bio equival quot updat publish literatur relev substanc present applic accept articl quot peer review quot journal annot purpos claim summari product characterist infer properti medicin product therapeut group discuss clinic clinic overview summari substanti publish literatur addit studi applic addit data order demonstr evid equival safeti efficaci properti salt ester deriv authoris activ substanc provid applic claim essenti similar addit data requir specif situat activ substanc essenti similar medicin product therapeut moieti origin authoris product salt ester complex deriv evid chang pharmaco kinet moieti pharmaco dynam toxic chang safeti efficaci profil demonstr case associ consid activ substanc medicin product intend therapeut present pharmaceut form administ rout dose posolog result toxicolog pharmacolog test clinic trial provid similar biolog medicin product provis articl iii suffici case biolog medicin product inform requir case essenti similar product gener permit demonstr similar natur biolog medicin product addit data toxicolog clinic profil provid biolog medicin product defin part paragraph annex refer origin medicin product grant market authoris commun submit market authoris independ applic expiri data protect period approach appli inform suppli limit modul pharmaceut chemic biolog data supplement bio equival bio avail data type amount addit data toxicolog clinic clinic data determin case case basi accord relev scientif guidelin due divers biolog medicin product identifi studi foreseen modul requir compet author take account specif characterist individu medicin product gener principl appli address guidelin take account characterist concern biolog medicin product publish agenc case origin authoris medicin product indic efficaci safeti medicin product claim similar justifi demonstr separ claim indic fix combin medicin product applic base articl relat medicin product made activ substanc previous authoris fix combin medicin product applic full dossier modul provid fix combin medicin product applic inform manufactur site adventiti agent safeti evalu provid document applic except circumst provid articl applic show unabl provid comprehens data efficaci safeti normal condit indic product question intend encount rare applic expect provid comprehens evid present state scientif knowledg comprehens inform provid contrari gener accept principl medic ethic collect inform market authoris grant subject specif oblig oblig includ applic complet identifi programm studi time period compet author result form basi reassess benefit risk profil medicin product question suppli medic prescript case administ strict medic supervis possibl hospit case radio pharmaceut authoris person packag leaflet medic inform draw attent medic practition fact particular medicin product question inadequ respect mix market authoris applic mix market authoris applic market authoris applic dossier modul consist combin report limit clinic clinic studi carri applic bibliograph refer modul accord structur part annex compet author accept propos format present applic case case basi part iii medicin product part lai specif requir relat natur identifi medicin product biolog medicin product plasma deriv medicin product medicin product deriv human blood plasma derog provis modul dossier requir mention quot inform relat start raw materi quot start materi made human blood plasma replac plasma master file certifi accord part principl purpos annex plasma master file stand document separ dossier market authoris relev detail inform characterist entir human plasma start materi raw materi manufactur intermedi fraction constitu excipi activ substanc part medicin product medic devic refer direct ec european parliament council novemb amend council direct ec medic devic incorpor stabl deriv human blood human plasma centr establish fraction process human plasma prepar updat set detail relev inform refer plasma master file plasma master file submit agenc compet author applic market authoris holder market authoris applic market authoris market authoris holder differ holder plasma master file plasma master file made applic market authoris holder submiss compet author case applic market authoris holder respons medicin product compet author evalu market authoris await agenc issu certif decid applic market authoris dossier human plasma deriv constitu refer plasma master file plasma start raw materi content accord provis articl amend direct ec refer requir donor test donat plasma master file includ inform plasma start raw materi plasma origin inform centr establish blood plasma collect carri includ inspect approv epidemiolog data blood transmiss infect ii inform centr establish test donat plasma pool carri includ inspect approv statu iii select exclus criteria blood plasma donor iv system place enabl path donat trace blood plasma collect establish finish product vice versa plasma qualiti safeti complianc european pharmacopoeia monograph ii test blood plasma donat pool infecti agent includ inform test method case plasma pool valid data test iii technic characterist bag blood plasma collect includ inform anticoagul solut iv condit storag transport plasma procedur inventori hold quarantin period vi characteris plasma pool system place plasma deriv medicin product manufactur plasma fraction processor hand blood plasma collect test centr establish hand defin condit interact agre specif addit plasma master file provid list medicin product plasma master file valid medicin product grant market authoris process grant authoris includ medicin product refer articl direct ec european parliament council relat implement good clinic practic conduct clinic trial medicin product human evalu certif medicin product authoris market authoris applic submit full dossier compet author accompani separ plasma master file exist plasma master file subject scientif technic evalu carri agenc posit evalu result certif complianc commun legisl plasma master file accompani evalu report certif issu appli commun plasma master file updat certifi annual basi subsequ introduc term plasma master file follow evalu procedur laid commiss regul ec examin variat term market authoris fall scope council regul eec juli lai commun procedur authoris supervis medicin product human veterinari establish european agenc evalu medicin product condit assess laid regul ec step provis fourth indent compet author grant grant market authoris account certif certif variat plasma master file concern medicin product derog provis indent present point evalu certif plasma master file correspond blood plasma deriv medicin product market authoris restrict singl member state scientif technic evalu plasma master file carri nation compet author member state vaccin vaccin human derog provis modul quot activ substanc quot requir base vaccin antigen master file system appli market authoris applic dossier vaccin human influenza vaccin requir includ vaccin antigen master file vaccin antigen activ substanc vaccin principl purpos annex vaccin antigen master file stand part market authoris applic dossier vaccin relev inform biolog pharmaceut chemic natur activ substanc part medicin product stand part common monoval combin vaccin present applic market authoris holder vaccin distinct vaccin antigen activ substanc vaccin antigen present vaccin combin vaccin distinct vaccin antigen aim prevent singl infecti diseas monoval vaccin vaccin vaccin antigen aim prevent singl infecti diseas content vaccin antigen master file inform extract relev part activ substanc modul quot qualiti data quot delin part annex activ substanc gener inform includ complianc relev monograph european pharmacopoeia inform manufactur activ substanc head cover manufactur process inform start raw materi specif measur tse adventiti agent safeti evalu facil equip characteris activ substanc qualiti control activ substanc refer standard materi contain closur system activ substanc stabil activ substanc evalu certif vaccin vaccin antigen applic submit compet author full market authoris applic dossier includ vaccin antigen master file singl vaccin antigen part vaccin master file exist singl vaccin antigen scientif technic evalu vaccin antigen master file carri agenc posit evalu result certif complianc european legisl vaccin antigen master file accompani evalu report certif appli commun provis indent appli vaccin consist combin vaccin antigen irrespect vaccin antigen part vaccin authoris commun content vaccin antigen master file vaccin authoris commun subject scientif technic evalu carri agenc accord procedur laid commiss regul ec case posit evalu agenc issu certif complianc commun legisl vaccin antigen master file certif issu appli commun derog provis indent present point evalu certif vaccin antigen master file correspond vaccin subject market authoris grant commun procedur provid authoris vaccin includ vaccin antigen evalu commun procedur scientif technic evalu vaccin antigen master file subsequ carri nation compet author grant market authoris step provis fourth indent compet author grant grant market authoris account certif certif variat vaccin antigen master file concern medicin product radio pharmaceut precursor radio pharmaceut purpos chapter applic base articl provid full dossier specif detail includ modul context radio pharmaceut kit radio label suppli manufactur activ substanc consid part formul intend carri bind radio nuclid descript manufactur method radio pharmaceut kit includ detail manufactur kit detail recommend final process produc radioact medicin product specif radio nuclid accord relev gener monograph specif monograph european pharmacopoeia addit compound essenti radio label structur radio label compound radio nuclid nuclear reaction involv discuss gener mother daughter radio nuclid consid activ substanc detail natur radio nuclid ident isotop impur carrier specif activ provid start materi includ irradi target materi consider chemic radiochem puriti relationship bio distribut provid radio nuclid puriti radiochem puriti specif activ gener detail test mother daughter radio nuclid requir gener eluat test mother radio nuclid constitu gener system provid requir express content activ substanc term mass activ entiti onlyappli radio pharmaceut kit radio nuclid radioact express becquerel date time refer time zone type radiat kit specif finish product includ test perform product radio label control radiochem radio nuclid puriti radio label compound includ materi essenti radio label identifi assai inform stabil radio nuclid gener radio nuclid kit radio label product stabil radio pharmaceut multi dose vial document modul appreci toxic radiat dose diagnosi consequ radio pharmaceut therapi properti desir evalu safeti efficaci radio pharmaceut address requir medicin product radiat dosimetri aspect organ tissu exposur radiat document absorb radiat dose estim calcul internation recognis system rout administr modul result clinic trial provid applic justifi clinic overview radio pharmaceut precursor radio label purpos specif case radio pharmaceut precursor intend sole radio label purpos primari object present inform address consequ poor radio label effici vivo dissoci radio label conjug question relat effect produc patient free radio nuclid addit present relev inform relat occup hazard radiat exposur hospit staff environ inform applic provid modul provis modul appli registr radio pharmaceut precursor defin indent applic modul singl dose repeat dose toxic result studi carri conform provis relat good laboratori practic laid council direct eec eec provid justifi mutagen studi radio nuclid consid case inform relat chemic toxic disposit relev quot cold quot nuclid present modul clinic inform gener clinic studi precursor consid relev specif case radio pharmaceut precursor intend sole radio label purpos inform demonstr clinic util radio pharmaceut precursor attach relev carrier molecul present homeopath medicin product section set specif provis applic modul homeopath medicin product defin articl modul provis modul appli document submit accord articl simplifi registr homeopath medicin product refer articl document authoris homeopath medicin product refer articl modif terminolog latin homeopath stock market authoris applic dossier accord latin titl european pharmacopoeia absenc thereof offici pharmacopoeia member state relev tradit member state provid control start materi particular document start materi materi includ raw materi intermedi final dilut incorpor finish medicin product accompani applic supplement addit data homeopath stock gener qualiti requir appli start raw materi intermedi step manufactur process final dilut incorpor finish medicin product assai requir toxic compon present qualiti control final dilut incorpor high dilut degre step manufactur process start materi final dilut incorpor finish medicin product fulli case dilut involv dilut step accord homeopathicmanufactur method laid relev monograph european pharmacopoeia absenc thereof offici pharmacopoeia member state control test finish medicin product gener qualiti requir appli homeopath finish medicin product except duli justifi applic identif assai toxicolog relev constitu carri justifi identif assai toxicolog relev constitu due dilut finish medicin product qualiti demonstr complet valid manufactur dilut process stabil test stabil finish medicin product demonstr stabil data homeopath stock gener transfer dilut tritur obtain thereof identif assai activ substanc due degre dilut stabil data pharmaceut form consid modul provis modul appli simplifi registr homeopath medicin product refer articl specif miss inform justifi justif demonstr accept level safeti support studi lack herbal medicin product applic herbal medicin product provid full dossier specif detail includ modul provis modul includ complianc monograph european pharmacopoeia appli authoris herbal medicin product state scientif knowledg time applic lodg account aspect specif herbal medicin product consid herbal substanc herbal prepar purpos annex term quot herbal substanc prepar quot consid equival term quot herbal drug herbal drug prepar quot defin european pharmacopoeia respect nomencrlatur herbal substanc binomi scientif plant genu speci varieti author chemotyp applic part plant definit herbal substanc name synonym mention pharmacopoeia laboratori code provid respect nomenclatur herbal prepar binomi scientif plant genu speci varieti author chemotyp applic part plant definit herbal prepar ratio herbal substanc herbal prepar extract solvent name synonym mention pharmacopoeia laboratori code provid document section structur herbal substanc herbal prepar applic physic form descript constitu therapeut activ marker molecular formula rel molecular mass structur formula includ rel absolut stereo chemistri molecular formula rel molecular mass constitu provid document section manufactur herbal substanc address respons supplier includ contractor propos site facil involv product collect test herbal substanc provid document section manufactur herbal prepar address respons manufactur includ contractor propos manufactur site facil involv manufactur test herbal prepar provid respect descript manufactur process process control herbal substanc inform provid adequ describ plant product plant collect includ geograph sourc medicin plant cultiv harvest dry storag condit respect descript manufactur process process control herbal prepar inform provid adequ describ manufactur process herbal prepar includ descript process solvent reagent purif stage standardis respect manufactur process develop summari describ develop herbal substanc herbal prepar applic provid take consider propos rout administr usag result compar phyto chemic composit herbal substanc herbal prepar applic support bibliograph data herbal substanc herbal prepar applic contain activ substanc herbal medicin product appli discuss respect elucid structur characterist herbal substanc inform botan macroscop microscop phyto chemic characteris biolog activ provid respect elucid structur characterist herbal prepar inform phyto physicochem characteris biolog activ provid specif herbal substanc herbal prepar applic provid analyt procedur test herbal substanc herbal prepar applic provid respect valid analyt procedur analyt valid inform includ experiment data analyt procedur test herbal substanc herbal prepar applic provid respect batch analys descript batch result batch analys herbal substanc herbal prepar applic provid includ pharmacopoei substanc justif specif herbal substanc herbal prepar applic provid inform refer standard refer materi test herbal substanc herbal prepar applic provid herbal substanc herbal prepar subject monograph applic appli certif suitabl grant european director qualiti medicin herbal medicin product respect formul develop summari describ develop herbal medicin product provid take consider propos rout administr usag result compar phyto chemic composit product support bibliograph data herbal medicin product appli discuss orphan medicin product case orphan medicin product mean regul ec gener provis part ii except circumst appli applic justifi clinic clinic summari reason provid complet inform provid justif benefit risk balanc orphan medicin product concern applic market authoris orphan medicin product invok provis articl ii part ii annex establish medicin systemat document concern substanc refer derog substanc accord provis articl direct part iv advanc therapi medicin product advanc therapi medicin product base manufactur process focuss gene transfer produc bio molecul biolog advanc therapeut modifi cell activ substanc part activ substanc medicin product present market authoris applic dossier fulfil format requir part annex modul appli genet modifi organ deliber releas environ attent paid persist genet modifi organ recipi replic modif genet modifi organ releas environ inform environment risk annex modul gene therapi medicin product human xenogen purpos annex gene therapi medicin product product obtain set manufactur process aim transfer perform vivo vivo prophylact diagnost therapeut gene piec nucleic acid human anim cell subsequ express vivo gene transfer involv express system contain deliveri system vector viral viral origin vector includ human anim cell divers gene therapi medicin product gene therapi medicin product base allogen xenogen cell vector readi prepar store transfer host cell cell obtain previous process cell bank bank collect bank establish procur primari cell limit viabil cell genet modifi vector repres activ substanc addit step carri order obtain finish product essenc medicin product intend administ number patient gene therapi medicin product autolog human cell activ substanc batch readi prepar vector store transfer autolog cell addit step carri order obtain finish medicin product product prepar cell obtain individu patient cell genet modifi readi prepar vector gene prepar advanc constitut activ substanc prepar inject patient definit intend singl patient manufactur process collect cell patient inject patient consid intervent administr readi prepar vector insert prophylact diagnost therapeut genet materi activ substanc batch readi prepar vector addit step carri order obtain finish medicin product type medicin product intend administ patient transfer genet materi carri direct inject readi prepar vector recipi specif requir modul gene therapi medicin product includ nake nucleic acid complex nucleic acid viral vector viral vector genet modifi cell medicin product identifi main element manufactur process start materi materi activ substanc manufactur gene interest express plasmid cell bank viru stock viral vector activ substanc recombin vector viru nake complex plasmid viru produc cell vitro genet modifi cell finish medicin product activ substanc formul final contain intend medic depend type gene therapi medicin product rout administr condit necessit vivo treatment cell patient special attent paid item inform provid relev characterist gene therapi medicin product includ express target cell popul inform sourc construct characteris verif encod gene sequenc includ integr stabil provid therapeut gene complet sequenc gene regulatori element vector backbon provid inform characteris vector transfer deliv gene provid includ physico chemic characteris biolog immunolog characteris medicin product utilis micro organ bacteria virus facilit gene transfer biolog gene transfer data pathogenesi parent strain tropism specif tissu cell type cell cycl depend interact provid medicin product utilis biolog mean facilit gene transfer physico chemic properti constitu individu combin provid principl cell bank seed lot establish characteris appli gene transfer medicin product sourc cell host recombin vector provid characterist human sourc ag sex result microbiolog viral test exclus criteria countri origin document cell anim origin detail inform relat item provid sourc anim anim husbandri care transgen anim method creation characteris transgen cell natur insert gene measur prevent monitor infect sourc donor anim test infecti agent facil control start raw materi descript cell collect methodolog includ locat type tissu oper process transport storag traceabl control carri collect process document evalu viral safeti traceabl product donor finish medicin product essenti part document suppli presenc replic compet viru stock replic compet viral vector exclud somat cell therapi medicin product human xenogen purpos annex somat cell therapi medicin product human autolog eman patient allogen come human xenogen come anim somat live cell biolog characterist substanti alter result manipul obtain therapeut diagnost prevent effect metabol pharmacolog immunolog mean manipul includ expans activ autolog cell popul vivo adopt immuno therapi allogen xenogen cell medic devic vivo vivo micro capsul intrins matrix scaffold bio degrad specif requir cell therapi medicin product modul somat cell therapi medicin product includ cell manipul modifi immunolog metabol function properti qualit quantit aspect cell sort select manipul subsequ undergo manufactur process order obtain finish medicin product cell manipul combin cellular compon biolog inert matrix medic devic exert principl intend action finish product autolog cell deriv express vitro specif cultur condit cell genet modifi manipul express previous unexpress homolog homolog function properti manufactur process collect cell patient autolog situat inject patient consid singl intervent medicin product element manufactur process identifi start materi materi activ substanc manufactur organ tissu bodi fluid cell activ substanc manipul cell cell lysat prolifer cell cell conjunct inert matrix medic devic finish medicin product activ substanc formul final contain intend medic gener inform activ substanc activ substanc cell therapi medicin product consist cell consequ vitro process displai prophylact diagnost therapeut properti origin physiolog biolog section describ type cell cultur concern tissu organ biolog fluid cell deriv autolog allogen xenogen natur donat geograph origin document collect cell sampl storag prior process detail allogen cell special attent paid step process cover select donor type manipul carri physiolog function cell activ substanc provid inform relat start materi activ substanc human somat cell human somat cell therapi medicin product made defin number pool viabl cell deriv manufactur process start level organ tissu retriev human level defin cell bank system pool cell reli continu cell line purpos chapter activ substanc seed pool human cell finish medicin product seed pool human cell formul intend medic start materi step manufactur process fulli document includ viral safeti aspect organ tissu bodi fluid cell human origin characterist human sourc ag sex microbiolog statu exclus criteria countri origin document descript sampl includ site type oper process pool transport storag traceabl control carri sampl document cell bank system relev requir depict part appli prepar qualiti control cell bank system essenti case allogen xenogen cell ancillari materi ancillari medic devic inform provid raw materi cytokin growth factor cultur media ancillari product medic devic cell sort devic biocompat polym matrix fibr bead term bio compat function risk infecti agent anim somat cell xenogen detail inform relat item provid sourc anim anim husbandri care genet modifi anim method creation characteris transgen cell natur insert excis knock gene measur prevent monitor infect sourc donor anim test infecti agent includ vertic transmit micro organ endogen retro virus facil cell bank system control start raw materi inform manufactur process activ substanc finish product step manufactur process organ tissu dissoci select cell popul interest vitro cell cultur cell transform physico chemic agent gene transfer document characteris activ substanc relev inform characteris cell popul interest term ident speci origin band cytogenet morpholog analysi puriti adventiti microbi agent cellular contamin potenc defin biolog activ suitabl karyolog tumorigen test intend medicin provid pharmaceut develop finish medicin product specif method administr intraven infus site inject transplant surgeri inform provid ancillari medic devic bio compat polym matrix fibr bead term bio compat durabl traceabl detail flow chart provid insur traceabl product donor finish medicin product specif requir gene therapi somat cell therapi human xenogen medicin product modul modul gene somat cell therapi medicin product recognis convent requir laid modul clinic test medicin product due uniqu divers structur biolog properti product question includ high degre speci specif subject specif immunolog barrier differ pleiotrop respons rational underpin clinic develop criteria choos relev speci model properli caption modul identifi develop anim model order assist extrapol specif find function endpoint toxic vivo activ product human be scientif justif anim model diseas support safeti proof concept efficaci provid modul efficaci advanc therapi medicin product demonstr modul product therapeut indic perform convent clinic trial deviat exist guidelin justifi modul clinic develop advanc therapi medicin product special featur ow complex labil natur activ substanc requir addit consider issu relat viabil prolifer migrat differenti cell somat cell therapi special clinic circumst product special mode action gene express somat gene therapi special risk product aris potenti contamin infecti agent address applic market authoris advanc therapi medicin product special emphasi put earli stage develop hand includ choic donor case cell therapi medicin product therapeut intervent includ proper handl administr product hand modul applic relev data measur survei control function develop live cell recipi prevent transmiss infecti agent recipi minimis potenti risk public health human pharmacolog efficaci studi human pharmacolog studi provid inform expect mode action expect efficaci base justifi end point bio distribut adequ dose schedul method administr modal desir efficaci studi convent pharmaco kinet studi relev advanc therapi product studi healthi volunt feasibl establish dose kinet difficult determin clinic trial studi distribut vivo behaviour product includ cell prolifer long term function extent distribut gene product durat desir gene express test develop trace cell product cell express desir gene human bodi monitor function cell administ transfect assess efficaci safeti advanc therapi medicin product includ care descript evalu therapeut procedur includ special wai administr transfect cell vivo vitro manipul intervent techniqu test regimen includ immuno suppress antivir cytotox treatment procedur test clinic trial product inform safeti safeti issu aris immun respons medicin product express protein immun reject immuno suppress breakdown immuno isol devic consid advanc gene therapi somat cell therapi medicin product xenogen cell therapi gene transfer product replic compet particl infecti agent patient monitor develop infect patholog sequela pre post authoris phase surveil extend close contact patient includ health care worker risk contamin potenti transmiss agent total elimin somat cell therapi medicin product gene transfer medicin product risk minimis measur modul measur includ product process complement accompani test method qualiti control process surveil method modul advanc somat cell therapi medicin product limit temporarili perman establish document expertis facil assur specif follow safeti patient similar approach relev gene therapi medicin product potenti risk replic compet infecti agent long term monitor aspect develop late complic consid address submiss relev applic submit detail risk manag plan cover clinic laboratori data patient emerg epidemiolog data relev data archiv tissu sampl donor recipi system need ensur traceabl medicin product rapid respons suspici pattern advers event specif statement xeno transplant medicin product purpos annex xeno transplant procedur involv transplant implant infus human recipi live tissu organ retriev anim human bodi fluid cell tissu organ undergon vivo contact live human anim cell tissu organ specif emphasi paid start materi respect detail inform relat item provid specif guidelin sourc anim anim husbandri care genet modifi anim method creation characteris transgen cell natur insert excis knock gene measur prevent monitor infect sourc donor anim test infecti agent facil control start raw materi traceabl intern confer harmonis technic requir registr pharmaceut human oj oj oj oj offici journal offici journal oj oj oj oj oj oj quot