Reference number ISO 1 5747 201 0(E) © I SO 201 0 I NTERNATI ON AL STANDARD ISO 1 5747 Second edition 201 0 04 1 5 Plastic containers for intravenous injections Récipients en plastique pour injections[.]
I N TE RN ATI ON AL S TAN D ARD ISO 5747 Second ed i ti on 201 0-04-1 Plastic containers for intravenous injections Récipients en plastique pour injections intraveineuses Referen ce n u mber I SO 5747: 201 0(E) © I SO 201 I SO 5747: 201 0(E) PDF d i sclai m er Th i s PDF sh al l n ot fi l e be e d i te d d o wn l o a d i n g a cce pts Ad o b e no is D e ta i l s a of th i s co n ta i n u n l es s fi l e , l i a b i l i ty i n em b e d d e d th e p a rti e s th i s th e s o ftwa re we re acce p t wh i ch th e re i n In a re th e a cco rd a n ce em b e d d e d re s p o n s i b i l i ty wi th a re of Ad o b e ' s l i ce n s e d n ot to l i ce n s i n g an d i n fri n g i n g p o l i cy, i n s ta l l e d Ad o b e ' s on th i s th e l i ce n s i n g fi l e m ay com p u te r p o l i cy be p ri n te d p e rfo rm i n g Th e I SO or vi e we d th e C e n tra l bu t e d i ti n g In S e cre ta ri a t a re a S ys tem s p ro d u cts o p ti m i ze d u n l i ke l y e ve n t th a t a typ e fa ces type fa ces tra d em a rk o f Ad o b e p a m e te rs th e m ay u sed to fo r p ri n ti n g p ro b l em I n co rp o te d cre a te E ve ry re l a ti n g to it th i s ca re is PDF h as fo u n d , fi l e been pl e a s e ca n take n be fo u n d to e n s u re i n fo rm th e in th e th at C e n tra l G e n e l th e fi l e is I n fo re l ati ve s u i ta b l e S ecre ta ri a t a t th e for to u se a d d re s s th e by fi l e; I SO g i ve n th e P D F -cre a ti o n m em b e r b o d i es In b e l o w COPYRI G H T PROTECTED DOCU M EN T © I SO Al l ri g h ts 201 res e rve d e l e ctro n i c I S O's U n l e ss m e ch a n i ca l , m em b e r b o d y i n I SO o th e rwi s e i n cl u d i n g th e co u n try s p eci fi e d , no p h o to co p yi n g o f th e p a rt an d of th i s p u b l i ca ti o n m i cro fi l m , wi th o u t m ay be re p ro d u ce d p e rm i s s i o n in wri ti n g or u ti l i ze d from in ei th e r an y I SO fo rm at th e or by an y a d d re s s m ean s, b el ow or re q u e s te r co p yri g h t o ffi ce Ca s e p o s ta l e 56 • CH -1 1 Te l + 41 22 749 01 1 Fax + 41 22 749 09 47 E -m a i l W eb G e n eva 20 co p yri g h t@ i s o o rg www i s o o rg P u bl i sh ed ii or in S wi tze rl a n d © I SO 201 – Al l ri g h ts res e rve d I SO 5747: 201 0(E) Con ten ts Pag e Foreword i v I n trod u cti on v Scope N orm ati ve referen ces Term s an d d efi n i ti on s Req u i rem en ts Ph ysi cal req u i rem en ts Ch em i cal req u i rem en ts Bi ol og i cal req u i rem en ts I d en ti fi cati on Appl i cati on of tests An n ex A (n orm ati ve) Ph ysi cal tests An n ex B (n orm ati ve) Ch em i cal tests An n ex C (n orm ati ve) Bi ol og i cal tests Bi bl i og raph y © I S O 201 – Al l ri g h ts reserved iii I SO 5747: 201 0(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies) The work of preparing International Standards is normally carried out through ISO technical committees Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization International Standards are drafted in accordance with the rules given in the ISO/IEC Directives, Part The main task of technical committees is to prepare International Standards Draft International Standards adopted by the technical committees are circulated to the member bodies for voting Publication as an International Standard requires approval by at least 75 % of the member bodies casting a vote Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights ISO shall not be held responsible for identifying any or all such patent rights ISO 5747 was prepared by Technical Committee ISO/TC 76, This second edition cancels and replaces the first edition (ISO 5747:2003), which has been technically revised Especially Annex C was totally revised in order to refer to the International Standards of the ISO 0993 series, which specifies the biological assessment of medical products Transfusion, infusion and injection equipment for medical and pharmaceutical use iv © ISO 201 – All rights reserved I SO 5747: 201 0(E) I n trodu cti on In s om e cou n tri es , n a ti on a l or re g i on al p h arm a copoe i a s or oth e r g o ve rn m e n t re g u l a ti on s are l eg al l y bi n d i n g a n d th e s e re q u i re m e n ts take p re ce d en ce o ver th i s I n te rn a ti o n a l S ta n d ard © I S O – Al l ri g h ts res erved v I N TERN ATI ON AL STAN D ARD I SO 5747: 201 0(E) Pl asti c tai n ers for i n traven ou s i n j ecti on s Scope Th i s I n tern ati on al Stan d ard tai n s req u i rem en ts th at rel ate to th e safe h an d l i n g an d th e ph ysi cal , ch em i cal an d bi ol og i cal testi n g of pl asti c tai n ers for paren teral s Th i s I n tern ati on al Stan d ard i s appl i cabl e to pl asti c tai n ers for paren teral s h avi n g on e or m ore ch am bers an d h avi n g a total n om i n al capaci ty i n th e ran g e of 50 m l to 000 m l su ch as fi l m bag s or bl ow-m ou l d ed pl asti c bottl es for d i rect ad m i n i strati on of i n fu si on (i n j ecti on ) sol u ti on s Th e N orm ati ve referen ces fol l owi n g referen ces, referen ced on l y th e d ocu m en ts ed i ti on ci ted are appl i es i n d i spen sabl e For u n d ated for th e appl i cati on referen ces, th e of th i s l atest d ocu m en t ed i ti on of th e For d ated referen ced d ocu m en t (i n cl u d i n g an y am en d m en ts) appl i es Sampling procedures for inspection by attributes — Part 1: Sampling schemes indexed by acceptance quality limit (AQL) for lot-by-lot inspection I SO 2859-1 , I SO 8536-4, Infusion equipment for medical use — Part 4: Infusion sets for single use, gravity feed I SO 0993 (al l parts), Biological evaluation of medical devices Term s an d defi n i ti on s For th e pu rposes of th i s d ocu m en t, th e fol l owi n g term s an d d efi n i ti on s appl y access port area of th e i n fu si on tai n er si sti n g of th e i n serti on poi n t an d th e i n j ecti on poi n t, i f appl i cabl e cover part th at protects th e access port d u ri n g storag e an d al so provi d es evi d en ce th at th e i n fu si on tai n er h as been tam pered wi th N OTE Th e cover can al so en velop the en ti re tai n er (e g ou ter bag ) 3 em pty tai n er raw tai n er wi th i d en ti fi cati on , wh i ch i s su i tabl e for th e acceptan ce, storag e an d ad m i n i strati on of th e i n j ecti on sol u ti on h an g er th at part of th e tai n er th at i s u sed to h an g i t u p © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) i d en ti fi cati on paper or foi l l abel or pri n ti n g or em bossi n g i n fu si on tai n er tai n er fi l l ed to i ts n om i n al capaci ty wi th paren teral i n j ecti on prod u ct an d wi th i d en ti fi cati on for th e storag e an d ad m i n i strati on of th e paren teral i n j ecti on prod u ct i n j ecti on poi n t poi n t for i n j ecti n g ph arm aceu ti cal s N OTE Th e i n j ection poi n t an d th e i nserti on poi n t can be id en ti cal N OTE Som e tai ners i n ten tion al l y d o n ot h ave an i n j ection poi n t i n serti on poi n t poi n t wh i ch accepts th e i n serti on part of th e i n fu si on d evi ce n om i n al capaci ty i n ten d ed or d ecl ared fl u i d vol u m e of a tai n er raw tai n er em pty tai n er th at h as n ot yet been steri l i zed an d h as n o i d en ti fi cati on 1 sh eeti n g pl asti c fi l m , foi l or sh eeti n g i n ten d ed for th e prod u cti on of em pty tai n ers Req u i rem en ts 4 Ph ysi cal req u i rem ents M an ufactu ri n g process com pati bi l i ty Th e i n fu si on tai n er sh al l com pl y wi th th e req u i rem en ts g i ven i n to an d to after th e m an u factu ri n g process (su ch as steri l i zati on ) Resi stan ce to tem peratu re, pressu re an d l eakag e Th e i n fu si on tai n er sh al l wi th stan d al tern ati n g th erm al stress, sh al l be resi stan t to pressu re an d sh al l be l eak-free wh en tested as speci fi ed i n A Resi stan ce to d roppi n g Th e i n fu si on tai n er sh al l su stai n n o d am ag e after bei n g d ropped wh en tested as speci fi ed i n A 4 Tran sparen cy Th e i n fu si on tai n er sh al l be su ffi ci en tl y tran sparen t so th at su spen d ed parti cl es, tu rbi d i ty an d d i scol orati on can be recog n i sed wh en tested as speci fi ed i n A Al tern ati ve proced u res m ay be u sed N OTE Bl ocki n g of U V rad iati on sh ou l d be consi d ered d epen d i n g on th e ten t of th e tai n er © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) Water vapou r perm eabi l i ty Unless otherwise defined for specific applications or uses, the packed infusion container shall not lose more than % of its mass during the period of usability, when tested as specified in A.6 NOTE Permeability of other gases (e.g oxygen) should be taken into account depending on the content of the container Parti cu l ate tam i n ati on Infusion containers shall be manufactured so that contamination with particles is avoided When empty infusion containers are tested as specified in A.7, no more than 25 particles with a diameter W µm and no more than particles with a diameter W 25 µm shall be found per millilitre of nominal capacity Finished parenteral solutions in the infusion containers shall comply with relevant pharmacopoeial requirements for finished product particulate matter Cover The access port shall be protected by a cover Its intactness is determined by visual inspection It shall be possible to remove the cover without using mechanical aids Access port It shall be possible to pierce the insertion point with the insertion part of an infusion device as specified in ISO 8536-4 The force shall not exceed 200 N at an insertion rate of 500 mm·min −1 , when tested as specified in A.8 Ad h esi on stren g th of th e i n fu si on d evi ce an d i m perm eabi l i ty of th e i n serti on poi n t The material and design of the access port shall be suitable for accepting the insertion part of an infusion device in accordance with ISO 8536-4, for sealing off the insertion point and for holding the insertion part firmly when subject to tensile load When tested as specified in A.9 no leakage shall occur and the insertion part shall not slide out from the insertion point The removal force shall be greater than N I n j ecti on poi n t If the container has an injection point, this shall not leak after puncturing and removal of the cannula when tested as specified in A.1 1 H an g er It shall be possible to hang the infusion container up when it is in use The hanger shall withstand a tensile load when tested as specified in A.1 I d en ti fi cati on The identification characters shall be clearly legible, and affixed labels shall not become detached when tested as specified in A.1 4 Ch emi cal req ui rem en ts Req u i rem en ts for th e raw tai n er or th e sh eeti n g The sheeting shall fulfil the requirements given in the relevant pharmacopoeias Alternatively, it may be tested as described in Table © ISO 201 – All rights reserved I SO 5747: 201 0(E) Tabl e — Req u i rem en ts for th e raw tai n er or th e sh eeti n g M axim u m Req u i rem en ts Test as speci fi ed i n perm i ssi bl e val u e Resi d u e on i gn i ti on : pol yol efi ns m g /g pol yvi n yl chl ori d e, contai ni n g pl asti ci zers m g /g Metal s: Ba, Cd , Cr, Cu , Pb, Sn 2 B for each m etal , m g /kg B Req u i rem en ts for th e test fl u i d Th e test fl u i d sh al l be prepared as speci fi ed i n B N o col orati on , bu t weak opal escen ce of th e test fl u i d , i s perm i ssi bl e I t sh al l fu l fi l th e req u i rem en ts speci fi ed i n Tabl e Tabl e — Req u i rem en ts for th e test fl u i d Req u i rem en ts M axim u m perm i ssi bl e val u e Test as speci fi ed i n 0, ml sod i u m h yd roxi d e solu tion [ c(N aOH ) = 0, 01 m ol/l ] Aci d ity or al kal i n i ty B 0, ml h yd roch lori c aci d [ c(H Cl ) = 0, 01 m ol /l ] i n the ran g e of 230 nm to 360 n m : U V absorban ce u 0, 25 for i n fu si on tai ners wi th a n omi n al capaci ty u 00 m l u 0, for i n fu si on tai n ers wi th a n om i n al capaci ty > 00 ml B Evaporati on resi d u e mg B Oxi d i zabl e sti tu en ts , ml B Am m on i a 0, mg /l B B 1 Metal s: Ba, Cr, Cu , Pb for each m etal , m g /l Sn , Cd for each m etal , 0, mg /l Al 0, 05 m g /l H eavy m etals 4 m g /l B Bi ol og i cal req u i rements I m perm eabi l i ty for m i croorg an i sm s Th e i n fu si on tai n er sh al l be i m perm eabl e to m i croorg an i sm s wh en tested as speci fi ed i n C M i g rati on /tol eran ce Th e m ateri al s u sed for th e m an u factu re of i n fu si on tai n ers (e g fi l m s, wrappi n g s, ad h esi ves, ad h esi on prom oters, pri n ti n g i n ks) shal l n ot rel ease i n to th e i n fu si on sol u ti on an y su bstan ces i n su ch q u an ti ti es th at th ey h ave a pyrog en i c or toxi c effect wh en tested as speci fi ed i n C 3, C an d th e I SO 0993 seri es © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) I d en ti fi cati on I d en ti fi ca ti on s h a l l be i n a ccord a n ce wi th th e re l e va n t l a ws a n d s p e ci fi ca ti o n s Appl i cati on of tests A d i s ti n cti o n te s ti n g is m ad e Th e y s h a l l be be twe e n re pe a te d typ e te s ti n g i f on e an d or m ore b a tch of th e tes ti n g fol l o wi n g Al l tes ts s p eci fi ed d i ti on s is in An n e xe s A to ch an g ed C s i g n i fi ca n tl y s o a re typ e th at th e re q u i rem e n ts as s p e ci fi e d i n Cl a u s e m i g h t b e a ffe cted : ⎯ ⎯ ⎯ ⎯ th e d es i g n ; th e p l a s ti c com p os i ti on ; th e p roce s s of m a n u fa ctu ri n g th e i n fu s i on co n ta i n e r; th e s te ri l i za ti o n p roce s s © I S O – Al l ri g h ts res erved I SO 5747: 201 0(E) An n ex A (n orm ati ve) Ph ysi cal tests A G en eral Ph ys i cal testi n g sh al l be perform ed u si n g an i n fu si on tai n er fi l l ed u p to th e n om i n al capaci ty wi th i n fu si on sol u ti on or wi th water A Sam pl i n g Take sam pl es req u i red for th e tests speci fi ed i n A to A i n accord an ce wi th th e req u i rem en ts of stati sti cal q u al i ty trol for sam pl i n g for th e type test, e g accord i n g to I SO 2859-1 A Resi stance to tem peratu re stabi li ty, pressu re an d leakag e − Store i n fu si on tai n ers for 24 h at ( 25 ± 5) ° C an d su bseq u en tl y for 24 h at (50 ± 5) ° C, an d th en su bj ect th em to an i n tern al pressu re of 50 kPa between two pl an e paral l el pl ates at (20 to 30) ° C M n tai n th i s pressu re for m i n An eq u i val en t test m eth od m ay be u sed i n wh i ch an extern al pressu re, su ch as a pressu re cu ff, i s appl i ed to th e bag i n ord er to g en erate an eq u i val en t i n tern al pressu re Th e test i s passed i f n o l eakag e can be d eterm i n ed on vi su al i n specti on Th e test d oes n ot appl y to th e i n tern al seal s separati n g ch am bers wi th i n a tai n er For i n fu si on tai n ers l abel l ed “protect from freezi n g ” , om i t storag e at −25 ° C A Resi stance to d roppin g Drop i n fu si on tai n ers on a h ard , ri g i d , sm ooth su rface at a tem peratu re of (20 to 30) ° C D eterm i n e th e h ei g h t of d rop i n accord an ce wi th Tabl e A , d epen d i n g u pon th e n om i n al capaci ty of th e i n fu si on tai n er Th e test i s passed i f n o i n fu si on tai n er i s broken an d n o l eakag e can be d eterm i n ed on vi su al i n specti on Tabl e A N om i n al capaci ty H ei g h t of d rop ml m 50 to 749 , 00 750 to 499 0, 75 500 to 499 0, 50 500 an d above 0, 25 © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) A Tran sparency Prepare a stem suspension as follows: a) Dissolve 6,0 g hydrazine sulfate for analysis in 400 ml clear water b) Dissolve 60,0 g hexamethylenetetramine for analysis in 400 ml clear water c) The two solutions are poured consecutively into a l measuring flask, filled to l with clear water d) Leave the solution to stand for 48 h at (20 to 30) °C so that a formazine suspension can develop Dilute the stem suspension according to a) to d) :1 00 Fill an empty infusion container to nominal capacity with the diluted suspension, and fill an additional emptied infusion container with clear water In the case of infusion containers which have been sterilized, allow them to remain undisturbed for h prior to inspection The test is passed if, on visual inspection, the turbidity of the formazine suspension in comparison with water is clearly detectable against a black, dull-finished background Conduct the inspection at an illumination intensity in the range (8 000 to 000) lx provided by incandescent light sources directly above and below the container, which illuminate the container at an angle of approximately 90° to the axis of observation The light sources shall illuminate the infusion container directly, i.e be shielded from the analyst's eyes Instead of the above-mentioned formazine suspension an equivalent standard and/or method may be used A Water vapou r perm eabi l i ty Store infusion containers in final packaging at (20 to 30) °C, with a relative humidity of (40 ± 5) %, and without exposure to direct light Unless otherwise defined for specific applications or uses, the test is passed if the rate of decrease in mass for each individual infusion container does not exceed % during the period of usability Suitable methods for shortening the testing duration are permissible (e.g accelerated testing as specified in ICH ) guidelines[1 ] ) A Parti cu l ate tam i nati on Fill empty containers, under cleanroom conditions to the nominal capacity, with water for injection which has been filtered previously through a membrane filter with a pore size of 0,2 µm Process the containers according to their intended use (filling, sterilization) and store for at least h Then determine the particle content of the container's contents using a particle-counting device that functions according to the light blockage method Take into account the values of the blank sample A Pen etrati on abi l i ty Pierce the infusion containers at the insertion point with a test spike in accordance with ISO 8536-4 ) ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use © ISO 201 – All rights reserved I SO 5747: 201 0(E) A Ad h esi on stren g th of th e i n fu si on d evi ce an d i m perm eabi l i ty of th e i n serti on poi n t After pi erci n g th e i n fu si on tai n ers as d escri bed i n A 8, each test spi ke sh al l rem n i n th e i n serti on poi n t for h Th en pl ace th e i n fu si on tai n ers between two pl an e paral l el pl ates, l oad ed wi th an i n tern al pressu re of 20 kPa for s, an d i n spect for an y l eakag e After com pl eti n g th e pressu re test, m easu re th e force n eed ed for rem oval of each test spi ke from th e i n serti on poi n t at a speed of 00 m m · m i n −1 I f th e i n fu si on tai n er i s i n ten d ed to be u sed wi th a pressu re cu ff, perform th e test wi th an i n tern al pressu re of 50 kPa for m i n A Ti g h tn ess of th e i n j ecti on poi n t Pu n ctu re th e i n j ecti on poi n t of th e tai n er wi th a can n u l a h avi n g an ou ts i d e d i am eter of 0, m m or 23 g au g e Keep th e can n u l a i n posi ti on for s After th e can n u l a i s rem oved , test th e i n j ecti on poi n t i n water su bj ected to a pressu re of 20 kPa for s Exam i n e th e i n j ecti on poi n t for si g n s of r l eakag e A 1 H an g er H an g u p th e i n fu si on tai n er (as d efi n ed i n 6) u si n g th e h an g er (as d efi n ed i n 4), an d th en appl y an ad d i ti on al ten si l e force of N for 60 m i n A I d en ti fi cati on Store th e i n fu si on tai n ers com pl etel y su bm erg ed i n water for 24 h at (20 to 30) ° C Th e ch aracters sh al l rem n cl earl y l eg i bl e Paper or foi l l abel s sh al l n ot d etach © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) An n ex B (n orm ati ve) Ch emi cal tests B G en eral Ch em i cal tests appl y to th e em pty tai n er or th e sh eeti n g For al l ch em i cal tests speci fi ed , eq u i val en t m eth od s as d escri bed i n ph arm acopoei as m ay be u sed B Determ i n ati on of th e resi d u e on i g n i ti on Wei g h , 00 g to 2, 00 g of th e tai n er m ateri al (i n sm al l pi eces) i n a su i tabl e cru ci bl e th at h as been previ ou sl y i g n i ted , cool ed an d wei g h ed H eat to (1 00 to 05) ° C for h Th en i g n i te to (550 ± 25) ° C Al l ow to cool i n a d esi ccator an d wei g h Repeat i g n i ti on u n ti l stan t m ass i s attai n ed Cal cu l ate m ass of resi d u e on i g n i ti on per g ram of starti n g m ateri al Eq u i val en t m eth od s as d escri bed i n ph arm acopoei as m ay be u sed B Determ i n ati on of m etal s i n th e pl asti c Determ i n e th e m etal s presen t b y atom i c spectrom etri c an al ysi s of a h yd roch l ori c aci d l each of th e i g n i ti on resi d u e Eq u i val en t m eth od s as d escri bed i n ph arm acopoei as m ay be u sed B Preparati on of th e test fl u i d Fi l l th e em pty tai n er twi ce to th e n om i n al capaci ty wi th water for i n j ecti on , sh ake for approxi m atel y m i n an d th en em pty After th e ri n se water h as d rai n ed off, fi l l th e em pty tai n er to th e n om i n al capaci ty wi th water for i n j ecti on Th en com press th e tai n er so th at th e rem n i n g r escapes from th e tai n er, an d su bseq u en tl y cl ose i t Extract th e tai n er for at l east 30 m i n i n pressu ri zed , satu rated steam at (1 ± 2) ° C U se 250 m l water for i n j ecti on as a com parator fl u i d (bl an k sam pl e) H eati n g -u p an d cool i n g ti m es are not i n cl u d ed i n th e 30 m i n cycl e ti m e req u i rem en t I f appropri ate, th e extracti on m ay be perform ed on pi eces of sh eeti n g or raw tai n er U se pi eces wi th a total su rface area of 500 cm Wash th i s m ateri al twi ce wi th 00 m l water for i n j ecti on an d d i scard th e water after u se Drai n th e pi eces, satu rated steam at (1 21 cover th em wi th 250 m l water for i n j ecti on an d extract for 30 m i n i n pressu ri zed , ± 2) ° C As a com pari son fl u i d (bl an k sam pl e), treat water for i n j ecti on i n th e sam e m an n er I f th e tai n er i s n ot i n ten d ed for steri l i zati on at tem peratu res of at l east ° C, th en th e extracti on m ay al so be perform ed at (1 00 ± 2) ° C for a d u rati on of h or at (70 ± 2) ° C for a d u rati on of (24 ± 2) h , i n wh i ch case th e sel ected tem peratu re sh ou l d n ot be l ower th an th at at wh i ch th e i n fu si on tai n er i s u sed I n th e even t th at th e sol u ti on resu l ti n g from extracti on of a si n g l e tai n er or si n g l e sam pl e of sh eeti n g h as i n su ffi ci en t vol u m e to al l ow for al l of th e req u i red testi n g , th e sol u ti on s from two or m ore extracti on s m ay be com bi n ed to prod u ce a com posi te test sol u ti on I n case al tern ati ve steri l i zati on m eth od s oth er th an th erm al steri l i zati on are to be appl i ed to th e tai n er, e g γ-i rrad i ati on , eth yl en e oxi d e or e-beam , u se steri l i zed tai n ers for preparati on of th e test fl u i d © I S O 201 – Al l ri g h ts reserved I SO 5747: 201 0(E) B Determ i n ati on of tu rbi d i ty an d col orati on D e te rm i n e m ay be tu rb i d i t y an d co l o ti o n by vi s u a l i n s p e cti o n Ap p ro p ri a te p ro ce d u re s a cco rd i n g to p h a rm a co p o e i a s u sed B Determ i n ati on of aci di ty or al kal i ni ty Afte r th e a d d i ti o n H o we ve r, Afte r th e a d d i ti o n on of th e a d d i ti o n of d ro p s a d d i ti o n of 0, d ro p s ml m e th yl of of p h e n o l p h th a l e i n l ess th a n 0, h yd ro ch l o ri c re d s o l u ti o n , ml a ci d th e [ s o l u ti o n , ca u s ti c c (H Cl ) s o l u ti o n sod a = [ 0, 01 sh al l ml c of th e (N aO H ) m o l /l ] , h a ve th i s an te s t = fl u i d 0, 01 sh al l m o l /l ] , co l o ti o n o n g e - re d sh ow re d s h al l no re d co l o ti o n d i sap pear co l o ti o n sh al l ag a i n o ccu r On th e co l o ti o n B Determ i n ati on of th e U V absorpti on D e te rm i n e p h o to m e tri ca l l y th e U V a b s o rb a n ce o f th e te s t fl u i d a g a i n s t th e co m p a ri s o n fl u i d in a cm cu ve tte B Determ i n ati on of th e evaporati on resi d u e E va p o te 00 ml o f th e te s t fl u i d on a wa te r b a th and d ry a t 05 °C to co n s ta n t m a s s B Determ i n ati on of th e oxi d i zabl e sti tu ents B oi l fo r an d ,0 m in, ml th i o s u l fa te u n ti l 20, s u l fu ri c s o l u ti o n C a l cu l a te B M a ke th e c c (N a (H S 2 co n s u m p ti o n a l ka l i n e (N H th e + ) th e n Afte r Th e wa te r to P re p a re an d [ [ te s t fl u i d SO ) O ) = = wi th 20, m o l /l ] 0, 01 m o l /l ] ml Ad d p o ta s s i u m ,0 u n ti l g p e rm a n g a n a te o f p o ta s s i u m light b ro wn i od i d e Th e n ad d s o l u ti o n an d [ ti tra te d ro p s of c ( KM n O th e ) = s o l u ti o n s ta rch 0, 02 wi th s o l u ti o n m o l /l ] sod i u m an d ti tra te of p o ta s s i u m d i ffe re n ce p e rm a n g a n a te b e twe e n th e two s o l u ti o n va l u e s sh al l [ c ( KM n O n o t be ) = 0, 01 g re a te r th a n m o l /l ] ,5 fo r th e te s t fl u i d an d m l Determ i n ati on of amm on i a d i s ti l l e d ρ o f th e co l o u rl e s s com p a to r fl u i d [ ml aci d 30 = ad d s, ml of ml th e an d te s t th e n fl u i d ad d by 0, th e ml a d d i ti o n N e s s l e r' s co m p a to r s o l u ti o n s i m u l ta n e o u s l y m g /l ] a d d i ti o n of 0, by ml e xa m i n e th e N e s s l e r' s th e ml ca u s ti c of ml re a g e n t by of m a ki n g sod a [ c ca u s ti c sod a [ c (N aO H ) = m o l /l ] , d i l u te wi th 2) a l ka l i n e (N aOH ) = ml m o l /l ] , of am m on i u m d i l u te wi th s ta n d a rd d i s ti l l e d wa te r s o l u ti o n to ml re a g e n t s o l u ti o n , wh i ch sh al l n ot be m o re s tro n g l y ye l l o w- co l o u re d th a n th e co m p a to r s o l u ti o n B 1 Th e Determ i n ati on of m etal s m e ta l s d e te cti o n ca s e 2) 10 2, See Ba, lim it ml Cd , ca n C r, be h yd ro ch l o ri c E u rop e a n Cu , Pb, i s e d a ci d by Sn an d Al a re co n ce n tra ti n g s o l u ti o n [ ρ (H C l ) d e te rm i n e d th e = te s t g /l ] fl u i d a re by by a to m i c a b s o rp ti o n e va p o ti o n ad d ed to 50 ml in s p e ctro m e tri c a c co rd a n ce wi th a n a l ys i s B 4, in Th e wh i ch te s t fl u i d P h a rm a co p o e i a © I SO 201 – Al l ri g h ts res e rve d I SO 5747: 201 0(E) B Testi n g for h eavy m etal s Ch em i cal d eterm i n ati on of th e total of h eavy m etal s can be u sed i n stead of th e atom i c absorpti on spectrom etri c d eterm i n ati on of m etal s i n th e test fl u i d accord i n g to B Ad d ,2 ml th i oacetam i d e reag en t to m l of th e test fl u i d an d ml am m on i u m acetate bu ffer sol u ti on (pH = 3, 5) an d i m m ed i atel y m i x Prepare th e com parator sol u ti on prod u ced i n th e sam e m an n er, u si n g m l l ead sol u ti on [ ρ (Pb 2+ ) = m g /l ] an d ad d m l of th e test fl u i d After m i n , exam i n e th e sol u ti on ; i t sh al l n ot be a d eeper sh ad e of brown th an th e com parator sol u ti on © I SO 201 – Al l ri g hts reserved 11 I SO 5747: 201 0(E) An n ex C (n orm ati ve) Bi ol ogi cal tests C Preparati on of th e test fl u i d s C G en eral For bi ol og i cal tests see speci fi c parts of I SO 0993 C Test fl ui d I (pol ar extractan t) Fi l l th e em pty tai n er twi ce to n om i n al capaci ty wi th water for i n j ecti on , sh ake for approxi m atel y m i n an d ρ th en em pty After th e ri n se water h as d rai n ed off, fi l l th e em pty tai n er wi th en ou g h steri l e en d otoxi n -free sod i u m ch l ori d e sol u ti on 3) [ (N aCl ) = g /l ] so th at th e rati o of th e i n n er su rface of th e em pty tai n er, expressed i n sq u are cen ti m etres, to th e vol u m e of sod i u m ch l ori d e sol u ti on , expressed i n m l , i s at l east 6: ± ± Th en com press th e tai n er so th at th e rem n i n g r escapes from th e tai n er, an d cl ose i t Extract i t for (60 2) m i n i n pressu ri zed , satu rated steam at (1 2) ° C Perform th e extracti on on a su ffi ci en t n u m ber of tai n ers so th at at l east approxi m atel y 50 m l of extract i s avai l abl e M i x th e extracts from th e i n d i vi d u al tai n ers after th e y h ave cool ed U se 50 m l of th e steri l e, en d otoxi n -free i soton i c sod i u m ch l ori d e sol u ti on u sed as com parator fl u i d (bl an k sam pl e) ± 4) ± I f th e tai n er i s n ot i n ten d ed for steri l i zati on at tem peratu res of at l east ° C, th en th e extracti on m ay al s o be perform ed at (70 2) ° C for a d u rati on of (24 2) h C Test fl ui d I I (n on -pol ar extractant) Prepare test fl u i d I I i n th e sam e m an n er as test fl u i d I accord i n g to C 2, bu t: ⎯ ⎯ d ry th e em pty tai n ers or th e pl asti c pi eces after bei n g ri n sed wi th water for i n j ecti on u n ti l m oi stu re can n o l on g er be d eterm i n ed by vi su al i n specti on ; u se sesam e oi l for paren teral u se or cotton seed oi l as extracti on ag en t; N OTE ⎯ ⎯ 3) I f n ecessary protect th e sam ple from i n fl u en ces of U V l ig h t by m eans of al u m i ni u m foi l u se sesam e oi l for paren teral u se or cotton seed oi l as com parator fl u i d , 4) d epen d i n g on th e extracti on ag en ts u sed ; i f th e speci fi c bi ol og i cal test m eth od d escri bes a d i fferen t test fl u i d th i s wi l l su persed e th e above 3) See U n i ted States Ph arm acopei a (U SP) 4) E xam pl es of su i table n egati ve an d positi ve trol sam pl es are H D-PE (U SP n eg ati ve bi oreacti on RS) an d PVC wi th org anoti n ad d i ti ves (U SP posi ti ve bi oreacti on RS), avai l abl e from U S Ph armacopei a, Rockvi ll e, MD 20852, U SA Th is i n form ati on i s g i ven for the ven i en ce of th e u ser of thi s stan d ard an d d oes not consti tu te an end orsemen t by I SO of th e prod u ct n am ed Eq u i val en t prod u cts may be u sed i f th ey can be sh own to l ead to th e sam e resu lts 12 © I SO 201 – Al l ri g hts reserved I SO 5747: 201 0(E) C Testi n g for i m permeabi l i ty to m i croorg an i sm s Fi l l em pty tai n ers to th ei r n om i n al capaci ty u n d er steri l e d i ti on s, wi th a cu l tu re m ed i u m , e g casei n pepton e-soybean fl ou r pepton e bou i l l on (CaSo), an d s eal I m m erse th e tai n ers, or th e appropri ate parts of th e tai n ers, i n a su spen si on (~1 CFU /m l ) of ch al l en g e org an i sm (e g Bacillus subtilis, see n ati on al ph arm acopoei as) for at l east 30 m i n N eg ati ve trol s m u st n ot be i m m ersed i n th e bacteri al su spen si on Rem ove th e tai n ers from th e ch al l en g e su spen si on an d ri n se wi th steri l e water I n cu bate th e tai n er for at l east d at a tem peratu re appropriate for th e ch al l en g e org an i sm (e g 37 ° C for Bacillus subtilis) A tai n er th at i s prepared i n th e sam e m an n er, an d th e ten ts of wh i ch are i n ocu l ated wi th m l of a cu l tu re of ch al l en g e org an i sm , serves as th e posi ti ve trol arti cl e Al tern ati vel y, prepare th e posi ti ve trol arti cl e by com prom i si n g a u n i t fi l l ed wi th cu l tu re m ed i u m Th i s m ay be accom pl i sh ed by pu n ctu ri n g th e parti cu l ar area of th e tai n er bei n g ch al l en g ed Exam i n e th e ten ts for m i crobi al g rowth Posi ti ve trol s sh al l exh i bi t tu rbi d i ty Test arti cl es sh al l n ot be tu rbi d C Testi n g for bacteri al en d otoxi n s Perform tests for bacteri al en d otoxi n s accord i n g to th e rel evan t ph arm acopoei a C Testi n g for cytotoxi ci ty I SO 0993-5 d escri bes vari ou s m eth od s for cytotoxi ci ty testi n g Th e m ost su i tabl e test sh ou l d be sel ected i n rel ati on to i n ten d ed u se of th e tai n er I n stead of oi l test fl u i d I I (see C 3) u se cu l tu re m ed i u m wi th seru m or an oth er su i tabl e fl u i d © I SO 201 – Al l ri g hts reserved 13 I SO 5747: 201 0(E) Bi bl i ograph y [1 ] I CH , H arm on i zed Tri parti te G u i d el i n e, Stability Testing of New Drug Substa nces and Products, , (www i ch org ) Recommended for A doption on November 2000 [2] U n i ted States Ph arm acopei a (U SP) [3] Eu ropean Ph arm acopoei a [4] J apan ese Ph arm acopei a 14 © I SO 201 – Al l ri g hts reserved