CHAPTER 5 PRODUCTION

EUROPEAN COMMISSION
HEALTH AND CONSUMERS DIRECTORATE-GENERAL Public Health and Risk Assess ent Medicinal products quality sa!ety and e!!icacy

Brussels, <date> EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinar Use Part ! "hapter #$ Production

Legal %asis for pu%lishing the detailed guidelines$ Article 47 of Directive 2001/83/EC on the Community co e rel!tin" to me icin!l #ro ucts for hum!n use !n Article $1 of Directive 2001/82/EC on the Community co e rel!tin" to veterin!ry me icin!l #ro ucts% &his ocument #rovi es "ui !nce for the inter#ret!tion of the #rinci#les !n "ui elines of "oo m!nuf!cturin" #r!ctice '()*+ for me icin!l #ro ucts !s l!i o,n in Directive 2003/-4/EC for me icin!l #ro ucts for hum!n use !n Directive -1/412/EEC for veterin!ry use% &tatus of the document. /evision% Reasons for changes. Ch!n"es h!ve 0een m! e to sections 17 to 20 to im#rove the "ui !nce on #revention of cross1cont!min!tion !n to refer to to2icolo"ic!l !ssessment "ui !nce% Ch!n"es ,ere !lso intro uce in sections 23 to 28 on the 4u!lific!tion of su##liers in or er to reflect the le"!l o0li"!tion of m!nuf!cturin" !uthoris!tion hol ers to ensure th!t !ctive su0st!nces !re #ro uce in !ccor !nce ,ith ()*% &he ch!n"es inclu e su##ly ch!in tr!ce!0ility% 5ection '33+ is inserte to cl!rify !n h!rmonise e2#ect!tions of m!nuf!cturers re"!r in" the testin" of st!rtin" m!teri!ls ,hile section '38+ intro uces "ui !nce on notific!tion of restrictions in su##ly% De! line for comin" into o#er!tion. 3 months from #u0lic!tion

C!

issi!n Eu"!#$enne% &-'()* &"u+elles , Eu"!#ese C!

issie% &-'()* &"ussel - &el.iu / Tele#h!ne0 123-34 3** '' ''

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Principle *ro uction o#er!tions must follo, cle!rly efine #roce ures6 they must com#ly ,ith the #rinci#les of (oo )!nuf!cturin" *r!ctice in or er to o0t!in #ro ucts of the re4uisite 4u!lity !n 0e in !ccor !nce ,ith the relev!nt m!nuf!cturin" !n m!r7etin" !uthoris!tions% General $%1 $%2 *ro uction shoul 0e #erforme !n su#ervise 0y com#etent #eo#le% All h!n lin" of m!teri!ls !n #ro ucts, such !s recei#t !n 4u!r!ntine, s!m#lin", stor!"e, l!0ellin", is#ensin", #rocessin", #!c7!"in" !n istri0ution shoul 0e one in !ccor !nce ,ith ,ritten #roce ures or instructions !n , ,here necess!ry, recor e % All incomin" m!teri!ls shoul 0e chec7e to ensure th!t the consi"nment corres#on s to the or er% Cont!iners shoul 0e cle!ne ,here necess!ry !n l!0elle ,ith the #rescri0e !t!% D!m!"e to cont!iners !n !ny other #ro0lem ,hich mi"ht ! versely !ffect the 4u!lity of ! m!teri!l shoul 0e investi"!te , recor e !n re#orte to the 8u!lity Control De#!rtment% 9ncomin" m!teri!ls !n finishe #ro ucts shoul 0e #hysic!lly or ! ministr!tively 4u!r!ntine imme i!tely !fter recei#t or #rocessin", until they h!ve 0een rele!se for use or istri0ution% 9nterme i!te !n 0ul7 #ro ucts #urch!se !s such shoul 0e h!n le on recei#t !s thou"h they ,ere st!rtin" m!teri!ls% All m!teri!ls !n #ro ucts shoul 0e store un er the !##ro#ri!te con itions est!0lishe 0y the m!nuf!cturer !n in !n or erly f!shion to #ermit 0!tch se"re"!tion !n stoc7 rot!tion% Chec7s on yiel s, !n reconcili!tion of 4u!ntities, shoul 0e c!rrie out !s necess!ry to ensure th!t there !re no iscre#!ncies outsi e !cce#t!0le limits% :#er!tions on ifferent #ro ucts shoul not 0e c!rrie out simult!neously or consecutively in the s!me room unless there is no ris7 of mi21u# or cross1 cont!min!tion%

$%3

$%4

$%$

$%3 $%7

$%8 $%-

$%10 At every st!"e of #rocessin", #ro ucts !n m!teri!ls shoul 0e #rotecte from micro0i!l !n other cont!min!tion% $%11 ;hen ,or7in" ,ith ry m!teri!ls !n #ro ucts, s#eci!l #rec!utions shoul 0e t!7en to #revent the "ener!tion !n issemin!tion of ust% &his !##lies #!rticul!rly to the h!n lin" of hi"hly !ctive or sensitisin" m!teri!ls% $%12 At !ll times urin" #rocessin", !ll m!teri!ls, 0ul7 cont!iners, m!<or items of e4ui#ment !n ,here !##ro#ri!te rooms use shoul 0e l!0elle or other,ise i entifie ,ith !n in ic!tion of the #ro uct or m!teri!l 0ein" #rocesse , its stren"th ',here !##lic!0le+ !n 0!tch num0er% ;here !##lic!0le, this in ic!tion shoul !lso mention the st!"e of #ro uction%
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$%13 =!0els !##lie to cont!iners, e4ui#ment or #remises shoul 0e cle!r, un!m0i"uous !n in the com#!ny>s !"ree form!t% 9t is often hel#ful in ! ition to the ,or in" on the l!0els to use colours to in ic!te st!tus 'for e2!m#le, 4u!r!ntine , !cce#te , re<ecte , cle!n %%%+% $%14 Chec7s shoul 0e c!rrie out to ensure th!t #i#elines !n other #ieces of e4ui#ment use for the tr!ns#ort!tion of #ro ucts from one !re! to !nother !re connecte in ! correct m!nner% $%1$ Any evi!tion from instructions or #roce ures shoul 0e !voi e !s f!r !s #ossi0le% 9f ! evi!tion occurs, it shoul 0e !##rove in ,ritin" 0y ! com#etent #erson, ,ith the involvement of the 8u!lity Control De#!rtment ,hen !##ro#ri!te% $%13 Access to #ro uction #remises shoul 0e restricte to !uthorise #ersonnel% Prevention of cross'contamination in production $%17 ?orm!lly, the #ro uction of non1me icin!l #ro ucts shoul 0e !voi e in !re!s !n ,ith e4ui#ment estine for the #ro uction of me icin!l #ro ucts 0ut in e2ce#tion!l circumst!nces coul 0e !llo,e ,here the me!sures to #revent cross cont!min!tion ,ith me icin!l #ro ucts escri0e 0elo, !n in Ch!#ter 3 c!n 0e !##lie % &he #ro uction of technic!l #oisons, such !s #estici es !n her0ici es, shoul not 0e !llo,e in #remises use for the m!nuf!cture of me icin!l #ro ucts% $%18 Cont!min!tion of ! st!rtin" m!teri!l or of ! #ro uct 0y !nother m!teri!l or #ro uct must 0e !voi e % &his ris7 of !cci ent!l cross1cont!min!tion !rises from the uncontrolle rele!se of ust, "!ses, v!#ours, s#r!ys, "enetic m!teri!l or or"!nisms from !ctive su0st!nces, other st!rtin" m!teri!ls, #ro ucts in #rocess, from resi ues on e4ui#ment, !n from o#er!tors> clothin"% &he si"nific!nce of this ris7 v!ries ,ith the ty#e of cont!min!nt !n of #ro uct 0ein" cont!min!te % *ro ucts in ,hich cross cont!min!tion is li7ely to 0e most si"nific!nt !re those ! ministere 0y in<ection !n those "iven over ! lon" time% Cross cont!min!tion shoul 0e !voi e 0y ro0ust esi"n of the #remises, e4ui#ment !n #rocesses ,hich t!7e #l!ce ,ithin ! m!nuf!cturin" f!cility% &his shoul 0e su##orte 0y !##ro#ri!te #roce ures !n technic!l or or"!ni@!tion!l me!sures, inclu in" re#ro uci0le cle!nin" !n econt!min!tion #rocesses of v!li !te effectiveness% $%1- A to2icolo"ic!l ev!lu!tion shoul 0e the 0!sis for the est!0lishment of threshol v!lues in rel!tion to the #ro ucts m!nuf!cture 'see (ui eline on settin" he!lth 0!se e2#osure limits for use in ris7 i entific!tion in the m!nuf!cture of ifferent me icin!l #ro ucts in sh!re f!cilities+% ;here the to2icolo"ic!l ev!lu!tion su##orts ! threshol v!lue, this shoul 0e use !s !n in#ut #!r!meter in ris7 !ssessment% A 8u!lity /is7 )!n!"ement !##ro!ch shoul 0e use 0!se u#on this to2icolo"ic!l ev!lu!tion !n the #otenti!l cross cont!min!tion ris7s #resente 0y the #ro ucts m!nuf!cture % A!ctors inclu in"6 f!cility/e4ui#ment esi"n, #ersonnel flo,, #hysico1chemic!l ch!r!cteristics of the !ctive su0st!nce, #rocess ch!r!cteristics, cle!nin" #rocesses !n !n!lytic!l c!#!0ilities rel!tive to the threshol v!lues for #ro ucts shoul !lso 0e t!7en into !ccount% &he outcome of the 8u!lity /is7 )!n!"ement #rocess shoul 0e the 0!sis for eterminin" the necessity for !n e2tent to ,hich e4ui#ment !n f!cilities shoul 0e e ic!te to ! #!rticul!r
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#ro uct or #ro uct f!mily% &his m!y r!n"e from e ic!tin" s#ecific #ro uct cont!ct #!rts to e ic!tion of the entire m!nuf!cturin" f!cility% 9t m!y 0e !cce#t!0le to confine m!nuf!cturin" !ctivities to ! se"re"!te , self cont!ine #ro uction !re! ,ithin ! multi#ro uct f!cility, ,here <ustifie % $%20 &echnic!l !n or"!nis!tion!l me!sures to miti"!te ris7s of cross1cont!min!tion coul inclu e, 0ut !re not limite to, the follo,in". &echnic!l )e!sures e ic!te f!cilities, self1cont!ine #ro uction !re!s h!vin" se#!r!te #rocessin" e4ui#ment !n se#!r!te BCAC systems% 9t m!y !lso 0e esir!0le to isol!te cert!in utilities from those use in other !re!s% esi"n of m!nuf!cturin" #rocess, f!cility !n e4ui#ment to minimi@e o##ortunities for cross cont!min!tion urin" #rocessin", m!inten!nce !n cle!nin"

use of Dclose systemsE for #rocessin" !n m!teri!l / #ro uct tr!nsfer 0et,een e4ui#ment, use of #hysic!l 0!rrier systems, inclu in" isol!tors, !s cont!inment me!sures Controlle remov!l of ust close to source of the cont!min!nt e%"% throu"h loc!lise e2tr!ction e ic!tion of #rocessin" e4ui#ment, e ic!tion of #ro uct cont!ct #!rts or e ic!tion of selecte #!rts ,hich !re h!r er to cle!n 'e%"% filters+, e ic!tion of m!inten!nce tools

use of is#os!0le technolo"ies use of e4ui#ment esi"ne for e!se of cle!nin" !##ro#ri!te use of !ir1loc7s !n #ressure c!sc! e to confine #otenti!l !ir0orne cont!min!nt ,ithin ! s#ecifie !re! minimisin" the ris7 of cont!min!tion c!use 0y recircul!tion or re1 entry of untre!te or insufficiently tre!te !ir

use of !utom!tic cle!n in #l!ce systems of v!li !te effectiveness, for common "ener!l ,!sh !re!s, se#!r!tion of e4ui#ment ,!shin", ryin" !n stor!"e !re!s,

:r"!nis!tion!l )e!sures De ic!tin" the ,hole m!nuf!cturin" f!cility or ! self cont!ine #ro uction !re! on ! c!m#!i"n 0!sis ' e ic!te 0y se#!r!tion in time+ follo,e 0y ! cle!nin" #rocess of v!li !te effectiveness,

Fee#in" #rotective clothin" insi e !re!s ,here #ro ucts ,ith hi"h ris7 of cross cont!min!tion !re #rocesse , Cle!nin" verific!tion !fter e!ch #ro uct c!m#!i"n inste! of ! cle!nin" v!li !tion shoul 0e consi ere !s ! etect!0ility tool to su##ort effectiveness of the 8u!lity /is7 )!n!"ement !##ro!ch, Cle!nin" of ,or7in" !re!s !n surf!ces follo,e 0y e2ecution of ! com#rehensive s!m#lin" #rotocol for critic!l surf!ces Gse of !ir s!m#les !n ,i#e/s,!0 s!m#les t!7en in ! <oinin" !re!s outsi e the ,or7in" !re! to emonstr!te the efficiency of miti"!tion me!sures for !ir0orne !n mech!nic!l tr!nsfer of cont!min!nt, 5#ecific me!sures for ,!ste h!n lin", cont!min!te rinsin" ,!ter !n soile "o,nin", /ecor in" of s#ills, !cci ent!l events or evi!tions from #roce ures Desi"n of cle!nin" #rocesses for m!nuf!cturin" e4ui#ment !n 0uil in" f!cilities such th!t the cle!nin" #rocesses in themselves o not #resent ! cross cont!min!tion ris7% Desi"n of et!ile recor s for cle!nin" #rocesses to !ssure com#letion of cle!nin" in !ccor !nce ,ith !##rove #roce ures !n use of cle!nin" st!tus l!0els on e4ui#ment !n m!nuf!cturin" !re!s, Gse of common "ener!l ,!sh !re!s on ! c!m#!i"n 0!sis% )onitorin" of ,or7in" 0eh!viour to ensure tr!inin" effectiveness !n com#li!nce ,ith the relev!nt #roce ur!l controls%

$%21 )e!sures to #revent cross1cont!min!tion !n their effectiveness shoul 0e chec7e #erio ic!lly !ccor in" to set #roce ures% Validation $%22 C!li !tion stu ies shoul reinforce (oo )!nuf!cturin" *r!ctice !n 0e con ucte in !ccor !nce ,ith efine #roce ures% /esults !n conclusions shoul 0e recor e % $%23 ;hen !ny ne, m!nuf!cturin" formul! or metho of #re#!r!tion is ! o#te , ste#s shoul 0e t!7en to emonstr!te its suit!0ility for routine #rocessin"% &he efine #rocess, usin" the m!teri!ls !n e4ui#ment s#ecifie , shoul 0e sho,n to yiel ! #ro uct consistently of the re4uire 4u!lity% $%24 5i"nific!nt !men ments to the m!nuf!cturin" #rocess, inclu in" !ny ch!n"e in e4ui#ment or m!teri!ls, ,hich m!y !ffect #ro uct 4u!lity !n /or the re#ro uci0ility of the #rocess, shoul 0e v!li !te % $%2$ *rocesses !n #roce ures shoul un er"o #erio ic critic!l re1v!li !tion to ensure th!t they rem!in c!#!0le of !chievin" the inten e results% &tarting materials
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$%23 &he selection, 4u!lific!tion, !##rov!l !n m!inten!nce of su##liers of st!rtin" m!teri!ls, to"ether ,ith their #urch!se !n !cce#t!nce, shoul 0e ocumente !s #!rt of the #h!rm!ceutic!l 4u!lity system% &he level of su#ervision shoul 0e #ro#ortion!te to the ris7s #ose 0y the in ivi u!l m!teri!ls, t!7in" !ccount of their source, m!nuf!cturin" #rocess, su##ly ch!in com#le2ity !n the fin!l use to ,hich the m!teri!l is #ut in the me icin!l #ro uct% &he su##ortin" evi ence for e!ch su##lier / m!teri!l !##rov!l shoul 0e m!int!ine % 5t!ff involve in these !ctivities shoul h!ve ! current 7no,le "e of the su##liers, the su##ly ch!in !n the !ssoci!te ris7s involve % ;here #ossi0le st!rtin" m!teri!ls shoul 0e #urch!se irectly from the m!nuf!cturer of the st!rtin" m!teri!l%% &he 4u!lity re4uirements est!0lishe 0y the m!nuf!cturer for the st!rtin" m!teri!ls shoul 0e iscusse !n !"ree ,ith the su##liers% A##ro#ri!te !s#ects of the #ro uction, !n control, inclu in" h!n lin", l!0ellin", #!c7!"in" !n istri0ution re4uirements, com#l!ints, rec!lls !n re<ection #roce ures shoul 0e ocumente in ! 4u!lity !"reement or s#ecific!tion% $%27 Aor the !##rov!l !n m!inten!nce of su##liers of !ctive su0st!nces !n e2ci#ients, the follo,in" is re4uire . Active su0st!nces 5u##ly ch!in tr!ce!0ility shoul 0e est!0lishe !n the !ssoci!te ris7s, from !ctive su0st!nce st!rtin" m!teri!ls to the finishe me icin!l #ro uct, shoul 0e form!lly !ssesse !n #erio ic!lly verifie % A##ro#ri!te me!sures shoul 0e #ut in #l!ce to re uce ris7s to the 4u!lity of the !ctive su0st!nce% &he su##ly ch!in !n tr!ce!0ility recor s for e!ch !ctive su0st!nce 'inclu in" !ctive su0st!nce st!rtin" m!teri!ls+ shoul 0e !v!il!0le !n 0e ret!ine 0y the EEA 0!se m!nuf!cturer or im#orter of the me icin!l #ro uct% Au its shoul 0e c!rrie out !t the m!nuf!cturers !n istri0utors of !ctive su0st!nces to confirm th!t they com#ly ,ith the relev!nt "oo m!nuf!cturin" #r!ctice !n "oo istri0ution #r!ctice re4uirements% &he hol er of the m!nuf!cturin" !uthori@!tion sh!ll verify such com#li!nce either 0y himself or throu"h !n entity !ctin" on his 0eh!lf un er ! contr!ct% Aor veterin!ry me icin!l #ro ucts, !u its shoul 0e con ucte 0!se on ris7% Au its shoul 0e of !n !##ro#ri!te ur!tion !n sco#e to ensure th!t ! full !n cle!r !ssessment of ()* is m! e6 consi er!tion shoul 0e "iven to #otenti!l cross1 cont!min!tion from other m!teri!ls on site% &he re#ort shoul fully reflect ,h!t ,!s one !n seen on the !u it ,ith !ny eficiencies cle!rly i entifie % Corrective !n #reventive !ctions shoul 0e im#lemente % Aurther !u its shoul 0e un ert!7en !t interv!ls efine 0y the 4u!lity ris7 m!n!"ement #rocess to ensure the m!inten!nce of st!n !r s !n continue use of the !##rove su##ly ch!in% E2ci#ients E2ci#ients ,hich !re consi ere to #ose ! #!rticul!r ris7 to the 4u!lity of the me icin!l #ro uct, 0!se on form!lise 4u!lity ris7 m!n!"ement, shoul 0e "iven simil!r !ttention to those for !ctive su0st!nces% $%28 Aor e!ch elivery of st!rtin" m!teri!l the cont!iners shoul 0e chec7e for inte"rity of #!c7!"e, inclu in" t!m#er evi ent se!l ,here relev!nt, !n for corres#on ence 0et,een
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the elivery note, the su##lier>s l!0els !n !##rove su##lier inform!tion m!int!ine 0y the me icin!l #ro uct m!nuf!cturer% &he receivin" chec7s on e!ch elivery shoul 0e ocumente % $%2- 9f one m!teri!l elivery is m! e u# of ifferent 0!tches, e!ch 0!tch must 0e consi ere !s se#!r!te for s!m#lin", testin" !n rele!se% $%30 5t!rtin" m!teri!ls in the stor!"e !re! shoul 0e !##ro#ri!tely l!0elle 'see Ch!#ter $, item 13+% =!0els shoul 0e!r !t le!st the follo,in" inform!tion. 1 &he esi"n!te n!me of the #ro uct !n the intern!l co e reference ,here !##lic!0le6 ! 0!tch num0er "iven !t recei#t6 1 ;here !##ro#ri!te, the st!tus of the contents 'e%"% in 4u!r!ntine, on test, rele!se , re<ecte +6 1 ;here !##ro#ri!te, !n e2#iry !te or ! !te 0eyon ,hich retestin" is necess!ry% ;hen fully com#uterise stor!"e systems !re use , !ll the !0ove inform!tion nee not necess!rily 0e in ! le"i0le form on the l!0el% $%31 &here shoul 0e !##ro#ri!te #roce ures or me!sures to !ssure the i entity of the contents of e!ch cont!iner of st!rtin" m!teri!l% Bul7 cont!iners from ,hich s!m#les h!ve 0een r!,n shoul 0e i entifie 'see Ch!#ter 3, item 13+% $%32 :nly st!rtin" m!teri!ls ,hich h!ve 0een rele!se 0y the 8u!lity Control De#!rtment !n ,hich !re ,ithin their shelf life shoul 0e use % $%33 )!nuf!cturers of finishe #ro ucts !re res#onsi0le for !ny testin" of st!rtin" m!teri!ls !s escri0e in the m!r7etin" !uthoris!tion ossier% &hey c!n utilise #!rti!l or full test results from the !##rove st!rtin" m!teri!l m!nuf!cturer 0ut must, !s ! minimum, #erform i entific!tion testin" of e!ch 0!tch themselves !ccor in" to !nne2 8% &he r!tion!le for the outsourcin" of this testin" shoul 0e <ustifie !n the follo,in" re4uirements shoul 0e fulfille . ocumente !n

!+ A form!l !"reement shoul 0e si"ne , !ccor in" to ch!#ter 7, 0et,een the finishe #ro uct m!nuf!cturer !n the st!rtin" m!teri!l m!nuf!cturer% Amon" the res#ective res#onsi0ilities escri0e in the form!l !"reement, s#eci!l !ttention shoul 0e #!i to those rel!te to the istri0ution con itions 'tr!ns#ort, ,holes!lin", stor!"e !n elivery+ in or er to m!int!in the 4u!lity ch!r!cteristics of the st!rtin" m!teri!ls !n to ensure th!t test results rem!in !##lic!0le to the elivere m!teri!l% 0+ &he finishe #ro uct m!nuf!cturer shoul #erform !u its !t !##ro#ri!te interv!ls !t the site's+ c!rryin" out the testin" 'inclu in" s!m#lin"+ of the st!rtin" m!teri!ls in or er to !ssure com#li!nce ,ith (oo )!nuf!cturin" *r!ctice !n ,ith the s#ecific!tions !n testin" metho s escri0e in the )!r7etin" Authoris!tion ossier% c+ &he certific!te of !n!lysis #rovi e 0y the st!rtin" m!teri!l m!nuf!cturer shoul 0e si"ne 0y ! esi"n!te #erson ,ith !##ro#ri!te 4u!lific!tions !n e2#erience% &his #erson shoul ensure th!t e!ch 0!tch h!s 0een m!nuf!cture !n chec7e for com#li!nce ,ith the re4uirements of the form!l !"reement% + &he finishe #ro uct m!nuf!cturer shoul h!ve ! si"nific!nt e2#erience in e!lin" ,ith the st!rtin" m!teri!l m!nuf!cturer inclu in" !ssessment of 0!tches #reviously
7

receive !n the history of com#li!nce 0efore re ucin" in1house testin"% Any si"nific!nt ch!n"e in the m!nuf!cturin" or testin" #rocesses shoul 0e consi ere % e+ &he finishe #ro uct m!nuf!cturer shoul !lso #erform ! full !n!lysis !t !##ro#ri!te interv!ls !n com#!re the results ,ith the su##lier>s certific!te of !n!lysis in or er to chec7 the reli!0ility of the l!tter% 5houl this testin" i entify !ny iscre#!ncy then !n investi"!tion shoul 0e #erforme !n !##ro#ri!te me!sures t!7en% &he !cce#t!nce of certific!te of !n!lysis from the su##lier shoul 0e iscontinue until these me!sures !re com#lete % ?otes. 1% A simil!r !##ro!ch shoul !##ly to #!c7!"in" m!teri!ls !s st!te in ()* #!rt 9, $%41% 2% 9 entity testin" of st!rtin" m!teri!ls shoul 0e #erforme !ccor in" to the metho s !n the s#ecific!tions of the relev!nt )!r7etin" Authoris!tion ossier% $%34 5t!rtin" m!teri!ls shoul only 0e is#ense 0y esi"n!te #ersons, follo,in" ! ,ritten #roce ure, to ensure th!t the correct m!teri!ls !re !ccur!tely ,ei"he or me!sure into cle!n !n #ro#erly l!0elle cont!iners% $%3$ E!ch is#ense m!teri!l !n its ,ei"ht or volume shoul 0e in e#en ently chec7e !n the chec7 recor e % $%33 )!teri!ls is#ense for e!ch 0!tch shoul 0e 7e#t to"ether !n cons#icuously l!0elle !s such% Processing operations$ intermediate and %ul( products $%37 Before !ny #rocessin" o#er!tion is st!rte , ste#s shoul 0e t!7en to ensure th!t the ,or7 !re! !n e4ui#ment !re cle!n !n free from !ny st!rtin" m!teri!ls, #ro ucts, #ro uct resi ues or ocuments not re4uire for the current o#er!tion% $%38 9nterme i!te !n 0ul7 #ro ucts shoul 0e 7e#t un er !##ro#ri!te con itions% $%3- Critic!l #rocesses shoul 0e v!li !te 'see HC!li !tionH in this Ch!#ter+% $%40 Any necess!ry in1#rocess controls !n environment!l controls shoul 0e c!rrie out !n recor e % $%41 Any si"nific!nt evi!tion from the e2#ecte yiel shoul 0e recor e !n investi"!te % Pac(aging materials $%42 &he #urch!se, h!n lin" !n control of #rim!ry !n #rinte #!c7!"in" m!teri!ls sh!ll 0e !ccor e !ttention simil!r to th!t "iven to st!rtin" m!teri!ls% $%43 *!rticul!r !ttention shoul 0e #!i to #rinte m!teri!ls% &hey shoul 0e store in ! e4u!tely secure con itions such !s to e2clu e un!uthorise !ccess% Cut l!0els !n other loose #rinte m!teri!ls shoul 0e store !n tr!ns#orte in se#!r!te close cont!iners so !s to !voi mi21u#s% *!c7!"in" m!teri!ls shoul 0e issue for use only 0y !uthorise #ersonnel follo,in" !n !##rove !n ocumente #roce ure%

$%44 E!ch elivery or 0!tch of #rinte or #rim!ry #!c7!"in" m!teri!l shoul 0e "iven ! s#ecific reference num0er or i entific!tion m!r7% $%4$ :ut !te or o0solete #rim!ry #!c7!"in" m!teri!l or #rinte #!c7!"in" m!teri!l shoul 0e estroye !n this is#os!l recor e %

Pac(aging operations $%43 ;hen settin" u# ! #ro"r!mme for the #!c7!"in" o#er!tions, #!rticul!r !ttention shoul 0e "iven to minimisin" the ris7 of cross1cont!min!tion, mi21u#s or su0stitutions% Different #ro ucts shoul not 0e #!c7!"e in close #ro2imity unless there is #hysic!l se"re"!tion% $%47 Before #!c7!"in" o#er!tions !re 0e"un, ste#s shoul 0e t!7en to ensure th!t the ,or7 !re!, #!c7!"in" lines, #rintin" m!chines !n other e4ui#ment !re cle!n !n free from !ny #ro ucts, m!teri!ls or ocuments #reviously use , if these !re not re4uire for the current o#er!tion% &he line1cle!r!nce shoul 0e #erforme !ccor in" to !n !##ro#ri!te chec71list% $%48 &he n!me !n 0!tch num0er of the #ro uct 0ein" h!n le shoul 0e is#l!ye !t e!ch #!c7!"in" st!tion or line% $%4- All #ro ucts !n #!c7!"in" m!teri!ls to 0e use shoul 0e chec7e on elivery to the #!c7!"in" e#!rtment for 4u!ntity, i entity !n conformity ,ith the *!c7!"in" 9nstructions% $%$0 Cont!iners for fillin" shoul 0e cle!n 0efore fillin"% Attention shoul 0e "iven to !voi !n remove !ny cont!min!nts such !s "l!ss fr!"ments !n met!l #!rticles% $%$1 ?orm!lly, fillin" !n se!lin" shoul 0e follo,e !s 4uic7ly !s #ossi0le 0y l!0ellin"% 9f it is not the c!se, !##ro#ri!te #roce ures shoul 0e !##lie to ensure th!t no mi21u#s or misl!0ellin" c!n occur% $%$2 &he correct #erform!nce of !ny #rintin" o#er!tion 'for e2!m#le co e num0ers, e2#iry !tes+ to 0e one se#!r!tely or in the course of the #!c7!"in" shoul 0e chec7e !n recor e % Attention shoul 0e #!i to #rintin" 0y h!n ,hich shoul 0e re1chec7e !t re"ul!r interv!ls% $%$3 5#eci!l c!re shoul 0e t!7en ,hen usin" cut1l!0els !n ,hen over1#rintin" is c!rrie out off1line% /oll1fee l!0els !re norm!lly #refer!0le to cut1l!0els, in hel#in" to !voi mi21u#s% $%$4 Chec7s shoul 0e m! e to ensure th!t !ny electronic co e re! ers, l!0el counters or simil!r evices !re o#er!tin" correctly% $%$$ *rinte !n em0osse inform!tion on #!c7!"in" m!teri!ls shoul resist!nt to f! in" or er!sin"% 0e istinct !n

$%$3 :n1line control of the #ro uct urin" #!c7!"in" shoul inclu e !t le!st chec7in" the follo,in".
*

!+ (ener!l !##e!r!nce of the #!c7!"es6 0+ ;hether the #!c7!"es !re com#lete6 c+ ;hether the correct #ro ucts !n #!c7!"in" m!teri!ls !re use 6 + ;hether !ny over1#rintin" is correct6 e+ Correct functionin" of line monitors% 5!m#les t!7en !,!y from the #!c7!"in" line shoul not 0e returne % $%$7 *ro ucts ,hich h!ve 0een involve in !n unusu!l event shoul only 0e reintro uce into the #rocess !fter s#eci!l ins#ection, investi"!tion !n !##rov!l 0y !uthorise #ersonnel% Det!ile recor shoul 0e 7e#t of this o#er!tion% $%$8 Any si"nific!nt or unusu!l iscre#!ncy o0serve urin" reconcili!tion of the !mount of 0ul7 #ro uct !n #rinte #!c7!"in" m!teri!ls !n the num0er of units #ro uce shoul 0e investi"!te !n s!tisf!ctorily !ccounte for 0efore rele!se% $%$- G#on com#letion of ! #!c7!"in" o#er!tion, !ny unuse 0!tch1co e #!c7!"in" m!teri!ls shoul 0e estroye !n the estruction recor e % A ocumente #roce ure shoul 0e follo,e if unco e #rinte m!teri!ls !re returne to stoc7% )inished products $%30 Ainishe #ro ucts shoul 0e hel in 4u!r!ntine until their fin!l rele!se un er con itions est!0lishe 0y the m!nuf!cturer% $%31 &he ev!lu!tion of finishe #ro ucts !n ocument!tion ,hich is necess!ry 0efore rele!se of #ro uct for s!le !re escri0e in Ch!#ter 3 '8u!lity Control+% $%32 After rele!se, finishe #ro ucts shoul est!0lishe 0y the m!nuf!cturer% Re*ected+ recovered and returned materials $%33 /e<ecte m!teri!ls !n #ro ucts shoul 0e cle!rly m!r7e !s such !n store se#!r!tely in restricte !re!s% &hey shoul either 0e returne to the su##liers or, ,here !##ro#ri!te, re#rocesse or estroye % ;h!tever !ction is t!7en shoul 0e !##rove !n recor e 0y !uthorise #ersonnel% $%34 &he re#rocessin" of re<ecte #ro ucts shoul 0e e2ce#tion!l% 9t is only #ermitte if the 4u!lity of the fin!l #ro uct is not !ffecte , if the s#ecific!tions !re met !n if it is one in !ccor !nce ,ith ! efine !n !uthorise #roce ure !fter ev!lu!tion of the ris7s involve % /ecor shoul 0e 7e#t of the re#rocessin"% $%3$ &he recovery of !ll or #!rt of e!rlier 0!tches ,hich conform to the re4uire 4u!lity 0y incor#or!tion into ! 0!tch of the s!me #ro uct !t ! efine st!"e of m!nuf!cture shoul 0e !uthorise 0eforeh!n % &his recovery shoul 0e c!rrie out in !ccor !nce ,ith ! efine #roce ure !fter ev!lu!tion of the ris7s involve , inclu in" !ny #ossi0le effect on shelf life% &he recovery shoul 0e recor e %
'(

0e store

!s us!0le stoc7 un er con itions

$%33 &he nee for ! ition!l testin" of !ny finishe #ro uct ,hich h!s 0een re#rocesse , or into ,hich ! recovere #ro uct h!s 0een incor#or!te , shoul 0e consi ere 0y the 8u!lity Control De#!rtment% $%37 *ro ucts returne from the m!r7et !n ,hich h!ve left the control of the m!nuf!cturer shoul 0e estroye unless ,ithout ou0t their 4u!lity is s!tisf!ctory6 they m!y 0e consi ere for re1s!le, re1l!0ellin" or recovery in ! su0se4uent 0!tch only !fter they h!ve 0een critic!lly !ssesse 0y the 8u!lity Control De#!rtment in !ccor !nce ,ith ! ,ritten #roce ure% &he n!ture of the #ro uct, !ny s#eci!l stor!"e con itions it re4uires, its con ition !n history, !n the time el!#se since it ,!s issue shoul !ll 0e t!7en into !ccount in this !ssessment% ;here !ny ou0t !rises over the 4u!lity of the #ro uct, it shoul not 0e consi ere suit!0le for re1issue or re1use, !lthou"h 0!sic chemic!l re#rocessin" to recover !ctive in"re ient m!y 0e #ossi0le% Any !ction t!7en shoul 0e !##ro#ri!tely recor e % Product shortage due to manufacturing constraints $%38 H&he hol er of ! m!r7etin" !uthoris!tion for ! me icin!l #ro uct shoul , ,ithin the limits of their res#onsi0ilities, ensure !##ro#ri!te !n continue su##lies of th!t me icin!l #ro uct to #h!rm!cies !n #ersons !uthorise to su##ly me icin!l #ro ucts 1% &he m!r7etin" !uthoris!tion hol er shoul 0e informe in ! timely m!nner in c!se of !ny constr!ints in m!nuf!cturin" o#er!tions ,hich m!y result in !n !0norm!l restriction in the su##ly of ! me icin!l #ro uct% &he hol er shoul !lso notify the com#etent !uthority if the #ro uct ce!ses to 0e #l!ce on the m!r7et of the )em0er 5t!te, either tem#or!rily or #erm!nently% 5uch notific!tion sh!ll, other,ise th!n in e2ce#tion!l circumst!nces, 0e m! e no less th!n 2 months 0efore the interru#tion in the #l!cin" on the m!r7et of the #ro uct2

1 2

Article 81 of Directive 2001/83/EC, !s !men e Article 23! of Directive 2001/83/EC

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