Mansutfaeacroctiftil uvere e pharmacienugtriecdaile nts reb9m9e9c1eD Manufacture of sterile active pharmaceutical ingredients stnetno cf oelbaT 1. tnemegdelwonkcA ...............................................................................................2 2. noitcudortnI ..........................................................................................................3 3. yrassolG ................................................................................................................4 4. Scope ..…………...................................................................................................6 5. s’I PeAlire tfssorerutcafun ae mhr tosfelpicni rlpareneG ............................... 7 6. tnemn ot rndienvman pe,isueqseimerP ………................................................... 8 6.1 .…sesimerP ................................ ................................ ............................ 8 6.1.1 lar e n eg ................................ ................................ ................................ 8 6.1.2 smo ogrnig n a hc ................................ ................................ ................... 8 6.1.3 smetsy sr i a ................................ ................................ ........................... 8 6.2 .…tnempiuqE ................................ ................................ ......................... 9 6.2.1 lar e n eg ................................ ................................ ................................ 9 6.2.2 gninae l c ................................ ................................ ............................... 10 6.2.3 tnempiu q fenooitasili r e ts ................................ ................................ ..... 10 6.3 .…)smo onrael ct(nemnorivnE ................................ ................................ 12 6.3.1 lar e n eg ................................ ................................ ................................ 12 6.3.2 tnempiu q fenooitazitinas ................................ ................................ ..... 13 7. lennosreP ......................................................................................................…..... 14 7.1 .…lareneG ................................ ................................ .............................. 14 7.2 seda rlgaudivid nei hrt odferiuq egrnihtolC ................................ .............. 14 8. gnissecorP ....................................................................................................…..... 16 8.1 .…lareneG ................................ ................................ .............................. 16 8.2 seda rsg’I P fAgonirutcafun acmitpesA ................................ ................... 17 8.2.1 s’I P fAgonisseco rcpitpe s fanooitad i l av ................................ .............. 17 8.3 s’IP Af onoitasiliret slanimreT ................................ ................................ 18 8.3.1 ta eyh r ydIb PeA h ftnooitasili r e ts ................................ ....................... 18 8.3.2 hts i o m I Pe Ahfntooitasilire t)smaet st(ae ................................ ............ 19 8.3.3 noitaid a yrIb PeA h ftnooitasili r e ts ................................ ...................... 19 8.3.4 s a ygIb PeA h ftnooitasili r e ts ................................ .............................. 19 8.4 .…gnildn aIh PeAliretS ................................ ................................ ........... 19 8.5 stneidergn ilacituecamrah pevitc aeliret sf ognihsiniF ............................... 20 9. Quality unit activities .................…..............................................................…...21 10. secnerefeR .....................................................................................................…... 22 1 Manufacture of sterile active pharmaceutical ingredients 1. stnemegdelwonkcA sihT ediug enroutcafu nfao m seltlanicer iieetdtvue sierstcgacanhAmIra hnPee bnettirw yba .CIF EfeCoettimm osCtneiderg nsIlacituecamra hePvit ce Ahmto refcr okfsat :ecr okfs asti h ftsorebm eemr eswnosr egpniwoll oefhT giw d.urLD nnamlhuK n o,itrsahMceoH ynamr el–GessuoR gnagfl o.WrD akcaM airtsu A–Hbm GeimehcoiB nal A.rM ,elppihW oxalG modgni Kdetin U-emoclleW Drs. end asveeC seilV sdnalreh tt een-hNaTtlusnoC .nnroaMTv negnoD ]namriah cs[dnalreht ee N hC-TARUP 2 Manufacture of sterile active pharmaceutical ingredients 2. noitcudortnI evi tlcaAcitu esctanmeriadhePrg n,I)s’IPA( desu sa stneidergni ni elirets lanicidem,stcudorp tsum eb elire tssselnu eht lanif egasod mrof s iy,ldleasniilmirree ttrso decudorp yb assecorp gnidu l ncgon niiait sa.irplteiltrisefts s ’dIePdAnet nriof esu ni laretnerap stcudorp tsumosla n osnoitacificep stnavele rhti wylpmoc lairetc arsbonegoryp .snixotodne ehT erutcafunam fo elirets s’IPA tsum eb yltci rdtesllortnoc ni redro ot esiminim eht ksirfo , snmosiitna anhgitrmioaw-tonroccim snixotodn edn a.selcitrap fI eht lanif egasod mrof siton .selcitr a fpeoe ryfllacitca r epdbluo hss’I PeA h,tnoitartl i yfdbesilire t esobt 3 Manufacture of sterile active pharmaceutical ingredients 3. yrassolG ) ItPnAe(ide rlgancIituecam reavhiPtcA ynA ecnatsbus ro erutxim fo secnatsbus dednetni ot eb desu ni eht erutcafunam fo agurd )lanicidem( tcudorp dna taht nehw desu ni eht noitcudorp fo a gurd semoceb naevitca tneidergni fo eht gurd .tcudorp hcuS secnatsbus era dednetni ot hsinruflacigolocamrahp ytivitca ro rehto tcerid tceffe ni eht ,sisongaid ,eruc ,noitagitim tnemtaert ro noitneverpfo y ndefoohoibttc ndeunrfautcu ret thc este rsfooafteesid :etoN evitcA lacituecamrahp stneidergni era yllausu tsrif deniatbo ni eht edurc .etats tneuqesbuS noitcudorp snoitarepo trevnoc eht edurc lairetam ot eht lanif IPA taht steemeht .stnemeriuq erralim irso/d nlaaieopocamrahp -or ceiv mo smop etegrtnsissec olrapnoit i ddoedttacej bn u eIset ssePalaInibAhihPart AeAts ro/d nsaelcitr a,psmsinagro .snixotodne gnisse ccoirtppesA gnildnaH elirets slairetam ni a dellor t,ntoncemnorivne ni hcihw eht ria ,seilppus,slairetam tnempiuqe dna lennosrep era detaluger ot lortnoc laiborcim dna etalucitra pnoitanimatnocot .slev eellbatpecca met sdyessolC A desolc metsys escialp-ni-desilir ertos desilirets elihw desolc roirp ot ,esu dna sierusserp ro/dna muucav thgit ot emos denifederp kael .etar hcuS a metsys nac eb desilitu rofsti dednetni esoprup tuohtiw hceerb ot eht ytirgetni fo eht ,metsys nac eb detpada rofdiulf srefsnart ni ro/dna tuo elih wgniniat n,isaimspesa dna si elbatcennoc ot rehto desolcsmetsys .ytirget nfsios otluohtiw m entespyOs .mets ydseso leacnif ehdci hawireti rec h fteor o rmeo ntoe e omstli atfa hmtets yAs noitalu msissecorP ahi tdlweaomcriggoloib otrucoihmtiW dohteM fo gnitaulave na citpesa ssecorp gnisu na etairporppa obecalp lairetamgniyolpme .slairet aemlire trs odfe seuso hettamixorp pyaleso lhcci hswdohtem 4 Manufacture of sterile active pharmaceutical ingredients W ah itldwaeocmriggoloib ohrtciim sd oghntieym oml uphim tdelwe aom girsnbgsi o esar ccucgioin trminpp taedaso uahfltoaevMe .slairet aemlire tr sodfe seuso hettamixorp pyaleso ltcaht ngia pemlaicretS seireS fo evitucesnoc sehctab fo eht emas IPA derutcafunam gniwollof noitasilirets foeht erfuot cna of f iue oetn hr laaetotir mh fnrudtseedlimte ps h.iet uhnnqTaoeliptcu deotreplpmoc .sehc teasbeht noitadilaV yt i, vtmrineote tcm,s a ps yngis,so nue eitiqcgr tateonuf chn ridoyAtedpvenmnocauarocpropd .stlus edretcep xe ehodtta e,lecnarus sfeaoerg eh dg hiat hi,wlliw 5 Manufacture of sterile active pharmaceutical ingredients 4. epocS tsoM PMG sediug rof s’IPA od ton edivorp cificeps ecnadiug no eht erutcafunam foelirets .s’IPA sihT CIFEC tnemucod sedivorp siht lanoitidda ecnadiug hcihw si euqinu ot eht eli r d enestisesutaidemr e etIfrnPouiAtcafu ne.ahs mTIePlAi r gefntoisld ndeanrhautcafunam sessec osrlpla fedistuo eht epocs fo sih ttnemucod dna si derevoc yb lareneg PMsGenilediug rof s’IPA hcus sa eht CIFEC tnemucod PMG“ senilediug no erutcafunam fo kluB .69 9t1sug udAet a”dslacime hlCacituecamrahP sA htiw lla CIFE C,stnemucod siht ecnadi utgnemucod sah neeb nettirw ot tsissa yrtsudnini .emig eP rMe Ghrted ngunirutcafun afsmotcep snaiatrec 6 Manufacture of sterile active pharmaceutical ingredients 5. s’IP Aeliret sf oerutcafuna meh tro fselpicnir plareneG tI si deredisnoc a lareneg PMG tnemeriuqer taht eht erutcafunam fo lla setaidemretnidna s’IPA dluohs eb deirrac tuo rednu snoitidnoc taht esiminim eht ksir fo noitanimatnoc ybeht gnirutcafunam .tnemnorivne erutcafunaM fo elirets s’IPA dluohs ekat ecalp ni,tnempiuqe citpe sganimrofr e npdienia rltennosr e ypdbesilire tds ndaenae l,cdetare pyolis a ee obdtengised .sessecorp .tnemuc osdi h otmtudned deA h ntdienif eed rsanoitacifissa lmco onraelC reveneh Weht ssecorp si nepo dna eht elirets IPA si ,desop xseiht dluohs eb nihtiw a edargA .dnuorg ke cdhB a atabericgwalpk rl o a ew acrdnAe ooairalrag er udft eocrr a oilfefuo uhqrlntetaarntmoncem nn o gtrdin insesvaem dndprreioa ufdeqnheaTts .tnemuc osdi hrf6teotpa hndciebircs ende ee brsa’I PeAlirets eliret Ss’IPA nac deebrutcafu nyab mn oliatnaismirleit rreots yb c;igtnpielssasaneicmorrept retp alnhiica tee rddnoeimbirc s eesrdeauqinh c oe ewt.hteTci odfhooch t eenshmoititasilirets .tnemu cso id8fhot 7 Manufacture of sterile active pharmaceutical ingredients 6. tnemnorivn edn atnempiuq e,sesimerP 6.1 sesimerP 6.1.1 lareneG nI naelc ,saera lla desopxe secafrus dluohs eb ,htooms suoivrepmi dna nekorbnuni redr o eosti m gnsienomnhii sitdtsi md a enderlflanhouocgasmi rutrocro-ocaotaprcim .stnatcefnis idd nsatne gganinae l fcnooitacilp pdaetaep eer httimrep oT ecuder noitalumucca fo tsud dna ot etatilicaf ,gninaelc ereht dluohs eb on elbanaelcnu sessecer dna a muminim fo gnitcejorp ,segdel ,sevlehs sdraobpucdna .tnem psiruoqo eDdluohs eb dengised ot diova sgryno aio;mddsielss seelcbearnaelcnu .nosa esri hrt oeflbarised neub .me hetvo beaca pes hmto rnfoitanimatn otcneve r opdtela e esdbluo hssgnili eecslaF ,sepiP ,stcud dna rehto seitilitu dluohs eb dellatsni os taht yeht od ton etaerc,sessecer .nae l octtluciff ied rtaa hstecafr uds nsagnine pdoelaesnu skniS dna sniard dluohs eb detibihorp ni edarg B/A .saera sniarD ni edarg Csaera dluohs eb .elbazitinas roolF sniard ni rewol edarg naelc smoor dluohs eb dettifhtiw spart ro retaw slaes ot tneverp .wolf-kcab riA skaerb dluohs eb dettif neewtebyna .snia red hdt nsakn i rstonempiuqe 6.1.2 s mgonoirgnahC gnignahC smoor gnidael otni ssalc A dna B tnemnorivne dluohs eb dengisedsa .skcolria erehT dluohs eb lacisyhp noitarapes fo eht tnereffid segats fo gnignahcot esiminim laiborcim dna etalucitrap noitanimatnoc fo naelc moor .gnihtolc g nsimgo norydaro l e hf sdehr.Clelvterlsu iiti aso dtwlaeaheecihllsbhefTacsfnufileff egats fo eht gnignahc moor ,dluohs ni eht tser-ta ,etats eb eht emas edarg sa ehtaera otn ihcihw ti .sdae lehT esu fegotnai rgsanmpaoehoscr rgonfire td nngeanivnaaeellc saera si semitem o.selbarised nI ,lareneg dnah gnihsaw seitilicaf dluohs ebdedivorp .smo ogrnigna hec h fteoga ttssr ief h ntyilno 6.1.3 smets yrsiA erehW skcolria era ,desu htob kcolria srood dluohs ton eb .dyelnseupooenatlumniAs gnikcolretni metsys ro a lausiv ro/dna elbidua gninraw metsys dluohs eb detarepoot rgn eeonatfnroi.h aoo odnetteamemnhpietotverp A deretlif ria ylppus dluohs niatniam a evitisop erusserp dna ria wolf evitalerot gnidnuorrus saera fo a rewol edarg rednu lla lanoitare psonoitidnoc dna dluohshsulf eht aera .ylevitceffe tnecajdA smoor fo tnereffid sedarg dluohs evah a erusserp laitn efroeff i0d1 - 51 slac seacPnad i.u)gs (eruallau vcniotirtanPet tdaluohs eb diapot n oeihttce tfoorp eht enoz ftose t,akesri grtaht ,s itn e emetnhaot irndiievmnmheicihw .de s soetprnxaeeno ptmcoa cttncou cddoerspi l ni IardPenAtas 8 Manufacture of sterile active pharmaceutical ingredients ehT suoirav snoitadnemmocer gnidrager ria seilppus dna erusserp slaitnereffidyam deen ot eb deifidom ni eht esac fo ylhgih cixot ro evitcaoidar ,stcudorptslihw gniniatniam eht deriuqer latnemnorivne .lortnoc noitanimatnoceD fo seitilicafdna .snoitare peom ors oyfrassec e enyb aame rnaae lgacniva erl i fatonemtaert tI dluohs eb detartsnomed taht wolf-ria snrettap od ton tneserp a noitanimatnoc,ksir .g.e erac dluohs eb nekat ot erusne taht ria swolf od ton etubirtsid selcitrap morfa . kttsc niuo erdt rm oenepa rnohifrpoiguooztiqahe r,enpo osgrneiptareneg-elcitrap e d r dmsleuge erut lndnto oaAeiiiisto hfcban vyatesoifr.oschd ayritnrwlpdiipnapIus erusserp secnereffid dluohs eb dettif neewteb saera erehw eseht secnereffid era .tnatropmi esehT erusserp secnereffid dluohs eb dedrocer ylraluger ro esiwrehto .detnemucod suounitnoC gnirotinom fo erusserp ecnereffid fo edarg A dna edargB .dednemmoc e srsiaera 6.2 Equipment 6.2.1 lareneG citpesA gnirutcafunam fo elirets s’IPA dluohs ylbareferp ekat ecalp nitnempiuqe detarepo rednu evitisop erusserp evitaler ot eht gnidnuorrus .aera fI ,ton kaelstset ecnanetn irae mtdyfncaaneuq edrefhsil b sa tpt naeslateascit irdroecfmro f drelebupohs .ria pdenra .desilire t esdbluo htsnempiu qdeesilire tes hgtniva e rlgoniret nseess alglA dehsilbat snnt eaoudoeirr aedcbluo hssretl is fad gntan el vlfyaotirget ne ihfgtonitseT .tnemecalp erret fda nyacneuqerf ynA citpesa snoitcennoc edam ot eht elirets tnalp tsum eb deirrac tuo ni a edargA .detadil a evdbluo hsserudeco rhpc u fsyotilibati ues h.Ttnemnorivne retaW tnemtaert stnalp dna noitubirtsid smetsys dluohs eb ,dengised detcurtsnocdna deniatnia mot erusne a elbai leecrruos fo retaw fo neata i.ryptoirlpapua qyehTdluohs ton eb detarepo dnoyeb rieht dengi s.eydticapac retaW rof snoitcejn i)IFW( dluohseb ndoniatanima tlnaoicbo rsc tidn mee ntvtriueae brhnaipt nr datdem snr,iaoddtescudorp .C °e0v7 oebrautar e npt omaaiettaluc rtincats neyolbcpm a rx,oehftworg t nlel mAhpciuusqe sa ,sresili rreita sgnildnah d nnaoi t,asrmteltisfy s,ria tnev dnasag dn slo tmui nceoteoet habijsosdtbyt iuuselbs ga i,avdrtrntnoaset ims,rdtsearteeartwtlif .ecnanetnia mdennal pdna llA troppus smetsys dluohs eb detadilav ro dei fyilllaauuqdividni ot erusne tahthcae metsys si gnimrofrep nihtiw eht deriuqer .snoitacificeps laitnetoP secruos fo noitanimatnoc htiw ,smsinagro-orcim snixotodne dna etalucitrap rettam dluohs eb .detanimil e-elbisso preveneh w-dn adeifitnedi etairporppA evitneverp ecnanetniam dna noitarbilac serudecorp rof tnempiuqedna .lortn onnciiam esrmets ye shtta hetrus noeetca l nepdibluo hssmets ytsroppus 9