© ISO 2016 Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 5 Functional requirements and testing Éléments en élastomère pour administration parentérale et dispositifs à[.]
INTERNATIONAL STANDARD ISO 8871-5 Second edition 2016-10-15 Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 5: Functional requirements and testing Éléments en élastomère pour administration parentérale et dispositifs usage pharmaceutique — Partie 5: Exigences fonctionnelles et essais Reference number ISO 8871-5:2016(E) © ISO 2016 ISO 8871-5:2016(E) COPYRIGHT PROTECTED DOCUMENT © ISO 2016, Published in Switzerland All rights reserved Unless otherwise specified, no part o f this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission Permission can be requested from either ISO at the address below or ISO’s member body in the country o f the requester ISO copyright o ffice Ch de Blandonnet • CP 401 CH-1214 Vernier, Geneva, Switzerland Tel +41 22 749 01 11 Fax +41 22 749 09 47 copyright@iso.org www.iso.org ii © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Contents Page Foreword iv Introduction v Scope Normative references Terms and definitions Requirements 4.2 4.3 4.4 Fragmentation Self-sealing and aqueous solution tightness Aqueous solution tightness Penetrab ility Preparation of elastomeric closures for testing 5.1 Sampling 5.2 Cleaning 5.3 Sterilization Annex A (normative) Test for penetrability Annex B (normative) Test for fragmentation Annex C (normative) Test for self-sealing and dye solution tightness Annex D (normative) Test for dye solution tightness Bibliography 10 © ISO 2016 – All rights reserved iii ISO 8871-5:2016(E) Foreword ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies) The work o f 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 o f electrotechnical standardization The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part In particular the different approval criteria needed for the di fferent types o f ISO documents should be noted This document was dra fted in accordance with the editorial rules of the ISO/IEC Directives, Part (see www.iso.org/directives) Attention is drawn to the possibility that some o f the elements o f this document may be the subject o f patent rights ISO shall not be held responsible for identi fying any or all such patent rights Details o f any patent rights identified during the development o f the document will be in the Introduction and/or on the ISO list of patent declarations received (see www.iso.org/patents) Any trade name used in this document is in formation given for the convenience o f users and does not constitute an endorsement For an explanation on the meaning o f ISO specific terms and expressions related to formity assessment, as well as information about ISO’s adherence to the WTO principles in the Technical Barriers to Trade (TBT) see the following URL: Foreword - Supplementary in formation The committee responsible for this document is ISO/TC 76, Tran sfusion , infusion an d injection , an d blood processin g equipm ent for m edical an d ph arm aceutical use This second edition cancels and replaces the first edition (ISO 8871-5:2005), which has been technically revised ISO 8871 consists of the following parts, under the general title : — — Part 2: Identification and characterization — — — Elastom eric parts for parenterals an d for devices for ph arm aceutical use Part : Extractables in aqueous autoclavates Part 3: Determin ation of released-particle count Part 4: Biological requirem ents an d test m eth ods Part 5: Fun ction al requirem ents an d testin g iv © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Introduction E l as tomeric or rub b er clo s u re s for ph armaceutic a l u s e are u s e d i n combi nation with vi a l s a nd many ti me s i n conj u nc tion with pierci ng device s T here are th re e to the pierc i ng pro ce s s T he s e a re p ene trabi l ity, fu nc tiona l fragmentation p arame ters wh ich a re i mp or tant and s el f- s e a l i ng T he th re e fu nc tiona l tests described in this part of ISO 8871 can be used as a reference method for testing elastomeric clo s u re s th at a re pierce d u s i ng i nj e c tion ne e d le s made from me ta l I n add ition, the aque ou s s olution tightne s s te s t c an b e u s e d to veri fy the e ffe c tivene s s o f the s e a l i ng o f a s p e ci fic clo s u re/vi a l combi nation © ISO 2016 – All rights reserved v INTERNATIONAL STANDARD ISO 8871-5:2016(E) Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 5: Functional requirements and testing Scope T h i s p a r t o f I S O 8 71 s p e ci fie s re qu i rements and te s t me tho d s for func tiona l p ara me ters o f el as tomeric clo s u re s us e d i n combi nation with vi a l s and when pierce d by an i nj e c tion ne e d le NO TE Fu nc tio n a l te s ti n g with s p i ke s i s s p e c i fie d i n I S O -2 a nd i n I S O - Normative references T he fol lowi ng i nd i s p en s able c u ments , i n whole or i n p ar t, are normatively re ference d i n th i s c u ment a nd are for its appl ic ation For date d re ference s , on ly the e d ition cite d appl ie s For u ndate d re ference s , the late s t e d ition o f the re ference d c u ment (i nclud i ng any amend ments) appl ie s ISO 7864, ISO 8362-1, ISO 8362-3, ISO 8362-4, ISO 8362-6, Sterile h ypodermic n eedles for sin gle use Injection contain ers an d accessories — Part : Injection vials m ade of glass tubin g Injection contain ers an d accessories — Part 3: Alumin ium caps for injection vials Injection contain ers an d accessories — Part 4: Injection vials m ade of m oulded glass Injection contain ers an d accessories — Part 6: Caps m ade of alumin ium-plastics com bin ation s for injection vials Terms and definitions For the pu r p o s e s o f th i s c u ment, the fol lowi ng term s and defi n ition s apply 3.1 penetrability force required for piercing an elastomeric closure 3.2 fragmentation me as u re o f the nu mb er o f ela s tomeric p a r ticle s wh ich are generate d b y the pierci ng pro ce s s 3.3 self-sealing me a s u re o f the re s e a l i n g e ffic ienc y o f el a s to mer ic clo s u re s a needle fo l lo wi n g p ene tratio n a nd wi thd rawa l o f 3.4 aqueous solution tightness me as u re for the e ffe c tive s e a l i ng o f a s p e ci fic el as tomeric clo s u re/vi a l combi nation © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Requirements 4.1 Penetrability When tested in accordance with Annex A, the force required for piercing shall not be greater than 10 N for each closure 4.2 Fragmentation When tested in accordance with Annex B, the number of elastomeric fragments per 48 piercings visible with the na ke d eye s l l no t b e gre ater tha n 4.3 Self-sealing and aqueous solution tightness f f When tested in accordance with Annex C containers which utilize elastomeric closures that are pierced multiple times Materials that meet the requirements are not required to undergo further testing in accordance with 4.4 , none o when ob s er ve d with the na ke d eye T his the via l s s l l conta i n any trace o re qu i rement appl ie s to mu lti- s e coloure d s olution conta i ners on ly, i.e 4.4 Aqueous solution tightness When tested in accordance with Annex D , none o f the vi a l s s l l contai n a ny trace o f colou re d s olution when ob s er ve d with the na ke d eye Preparation of elastomeric closures for testing 5.1 Sampling The number of closures required for each test is as follows — 10 — Fragmentation: 12 — Self-sealing and aqueous solution tightness: 10 — Aqueous solution tightness: 10 In practice, it is recommended that more than the minimum required number of closures be prepared for testing Pene trabi l ity: 5.2 Cleaning Closures shall be sterilized in the as-delivered condition If samples from regular production cleaning processes are not available, the stoppers shall be cleaned in accordance with the following procedure Introduce an appropriate number of rubber closures in a suitable glass container, cover with particlefre e water, b oi l for m i n, then ri n s e five ti me s with cold p a r ticle - fre e water 5.3 Sterilization T he clo s u re s sh a l l b e te s te d a fter havi ng b e en s ubj e c te d to the s teri l i z ation me tho d ac tua l ly u s e d © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Annex A (normative) Test for penetrability A.1 General M a ny ela s tomeric clo s u re s force for pha rmaceutic a l u s e are u s e d i n conj u nc tion with i nj e c tion ne e d le s T he ne ce s s a r y to p ene trate or pierce a rubb er clo s u re i s a n i mp or tant p ara me ter i n eva luati ng the s uitabi l ity o f the clo s u re for its i ntende d u s e A.2 Principle T he force ne ce s s ar y to comple tely pierce an el as tomeric clo s u re i s me as u re d u s i ng a s u itab le app a ratu s A.3 Apparatus, equipment and reagents A.3.1 10 closures , prepared in accordance with Clause A.3.2 10 clean vials , in acco rdance with I S O - o r I S O 62 - 4, neck finis h s ize to match the s ize o f closures (A.3.1) (e.g 13 mm, 20 mm) A.3.3 10 aluminium or plastic/aluminium crimp seals , in accordance with ISO 8362-3 or ISO 83626, sized to match the size of closures (A.3.1) (e.g 13 mm, 20 mm), and crimping apparatus 10 lubricated long-bevel [bevel angle (11 ± 2)°] metal hypodermic needles , external diameter of 0,8 mm in accordance with ISO 7864 A.3.4 A.3.5 Apparatus , cap ab le o f meas uring a fo rce o f N with an accuracy o f ± , N A.4 Procedure A.4.1 Close the vials (A.3.2) with the closures (A.3.1) to be tested and secure with a crimp seal (A.3.3) Fit the force-measuring apparatus (A.3.5 A.3.4) and pierce a closure perpendicular to the surface Record the maximum force Use a new needle for each of the remaining closures and repeat the procedure A.4.2 ) with a hyp o dermic needle ( A.5 Expression of results Record the force required for piercing each closure and compare the test results with the requirement in 4.1 © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Annex B (normative) Test for fragmentation B.1 General M a ny el a s tomer ic clo s u re s E la s to meric fragments and s i z e o f the s e are used for ph a rmaceutic a l u s e a re u s e d i n co nj u nc tion with i nj e c tio n ne e d le s m ay b e rele a s e d up o n p ene tration with the s e i nj e c tion ne e d le s T he nu mb er fragments c a n a ffe c t the qua l ity o f d r ug pro duc ts with wh ich the el a s tomeric clo s u re s B.2 Principle E la s tomeric clo s u re s for i nj e c tion vi a l s are pierce d with a n i nj e c tion ne e d le E la s tomeric fragments wh ich h ave b e en c au s e d b y pierc i ng a re col le c te d on a fi lter and cou nte d B.3 Apparatus, equipment and reagents B.3.1 12 closures , prepared in accordance with Clause B.3.2 12 clean vials , in acco rdance with I S O - o r I S O - 4, neck finis h s ize to match the s ize o f closures (B.3.1) (e.g 13 mm, 20 mm) B.3.3 12 aluminium or plastic/aluminium crimp seals , in accordance with ISO 8362-3 or ISO 83626, size to match the size of closures (B.3.1) (e.g 13 mm, 20 mm), and crimping apparatus B.3.4 Particle-free water, to fit the fill vo lumes o f the vials (B.3.2 ) and syringe (B.3.6) B.3.5 12 lubricated long-bevel [bevel angle (11 ± 2)°] metal hypodermic needles , external diameter of 0,8 mm in accordance with ISO 7864 B.3.6 Syringe , cap ab le o f b eing fitted with the needles in B.3.5 B.3.7 Filter, with a pore size of 0,5 µm B.3.8 Filtering apparatus , cap ab le o f ho lding a filter (B.3.7) with a pore size of 0,5 µm B.3.9 Laboratory microscope or a magnification glass , with a minimum magnificatio n o f B.4 Procedure Place in each of the 12 clean vials (B.3.2) a volume of particle-free water (B.3.4) equivalent to the nominal volume minus ml (e.g place 21 ml in a 25 ml vial) Close the vials with the closures (B.3.1) to be tested and secure with a crimp seal (B.3.3) B.4.1 B.4.2 Pierce each clo s ure us ing a hyp o dermic needle ( particle-free water (B.3.4 B.3.5 ) fitted to a clean syringe ( B.3.6 ) filled with ) , and inj ect into the vial ml o f water and remove ml o f air C arry o ut this © ISO 2016 – All rights reserved ISO 8871-5:2016(E) operation four times for each closure, piercing each time at a different site Use a new needle for each closure and check that the needle is not blunted during the test B.4.3 Pas s the liquid fro m each o f the vials thro ugh a filter ( B.3.7) having a pore size of 0,5 µm and co unt the numb er o f p articles vis ib le with the naked eye The co unt is b as ed o n the as s ump tio n that fragments with a diameter equal to o r greater than µm are vis ib le with the naked eye I n cas es o f ub t o r dis p ute, co unt the rub b er their size and nature fragments with a micro s co p e o r magni fying glas s ( B.3.9 ) to veri fy B.5 Expression of results Record the total number of fragments and compare to the limit given in 4.2 © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Annex C (normative) Test for self-sealing and dye solution tightness C.1 General E la s tomeric clo s ure s for pha rmaceutic a l u s e are com mon ly u s e d i n conj u nc tion with vi a l s T he clo s u re en s u re s an appropri ate s e a l with the vi a l Po or clo s u re/via l s e a l i ntegrity and/or p o or s el f- s e a l i ng c an a ffe c t the s teri l ity o f the via l contents , pro duc t volume a nd concentration o f s e s M any ela s tomeric clo s u re s for ph armaceutic a l u s e a re u s e d i n conj unc tion with i nj e c tion ne e d le s For mu ltiple - s e conta i ners , the clo s u re s may b e pierce d many ti me s over the cou rs e o f del iveri ng a l l the s e s S el f- s e a l i ng or re s e a l o f the i nci s ion made b y the ne e d le i s i mp or tant to the contai ner i ntegrity C.2 Principle E la s tomeric clo s ure s for le a kage force d for i nj e c tion vi a l s are pierce d s evera l ti me s with a n i nj e c tion ne e d le and exam i ne d b y a pre s s u re d i fferentia l ac ro s s the clo s u re C.3 Apparatus, equipment and reagents C.3.1 10 closures , prepared in accordance with Clause C.3.2 10 clean vials , in acco rdance with I S O - o r I S O - 4, neck finis h s ize to match the s ize o f closures (C.3.1) (e.g 13 mm, 20 mm) C.3.3 10 aluminium or plastic/aluminium crimp seals , in accordance with ISO 8362-3 or ISO 83626, size to match the size of closures (C.3.1) (e.g 13 mm, 20 mm), and crimping apparatus C.3.4 Particle-free water, to fit the fill vo lumes o f the vials (C.3.2) C.3.5 Solution of methylene blue , g/l NOTE The presence of surfactants can change the leaking behaviour of a liquid, and therefore, it is advisable to avoid it 10 lubricated long-bevel [bevel angle (11 ± 2)°] metal hypodermic needles , external diameter of 0,8 mm in accordance with ISO 7864 C.3.6 C.3.7 Vacuum chamber, for 10 capable of maintaining a pressure (27 kPa below atmospheric pressure) C.4 Procedure Place in each of the 10 clean vials (C.3.2) a volume of particle-free water (C.3.4) equivalent to the nominal volume (e.g place 25 ml in a 25 ml vial) Close the vials with the closures (C.3.1) to be tested and secure with a crimp seal (C.3.3) C.4.1 © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Using a new hypodermic needle (C.3.6) for each closure, pierce each closure 10 times, piercing each time at a different site within the target area Immerse the vials upright in a container holding the solution o f methylene blue (C.3.5 ) Ensure that the vials are completely immersed in the solution Place the container of vials in a vacuum chamber (C.3.7 ) and reduce the pressure by 27 kPa Hold the vacuum for 10 min, then restore to atmospheric pressure Allow the vials to remain immersed in the methylene blue solution for an additional 30 min, then remove them from the chamber Rinse the outside of the vials with C.4.2 water Inspect the vial contents visually for any traces o f the blue-coloured solution o f methylene blue C.5 Expression of results Report i f the vials contain any trace o f coloured solution and compare to the requirements in 4.3 © ISO 2016 – All rights reserved ISO 8871-5:2016(E) Annex D (normative) Test for dye solution tightness D.1 General Elastomeric closures for pharmaceutical use are commonly used in conjunction with vials The closure ensures an appropriate seal with the vial Poor closure/vial seal integrity can a ffect the sterility o f the vial contents, product volume and concentration of doses D.2 Principle Vials that are filled with liquid, stoppered and capped are submerged in a coloured solution The vials are inspected for leakage as a result of a pressure differential across the closure/vial interface D.3 Apparatus, equipment and reagents D.3.1 10 closures , prepared in accordance with Clause D.3.2 10 clean vials , in accordance with ISO 8362-1 or ISO 8362-4, neck finish size to match the size o f closures (e.g 13 mm, 20 mm) 10 aluminium or plastic/aluminium crimp seals , in accordance with ISO 8362-3 or ISO 83626, size to match the size of closures (e.g 13 mm, 20 mm), and crimping apparatus D.3.3 D.3.4 Particle-free water, to fit the fill volumes o f the vials D.3.5 Solution of methylene blue , g/l D.3.6 Vacuum chamber, for 10 capable of maintaining a pressure of 27 kPa below atmospheric pressure D.4 Procedure Place in each of the 10 clean vials (D.3.2) a volume of particle-free water (D.3.4) equivalent to the nominal volume (e.g place 25 ml in a 25 ml vial) Close the vials with the closures (D.3.1) to be tested and secure with a crimp seal (D.3.3) D.4.1 D.4.2 Immerse the vials upright in a container holding the solution o f methylene blue (D.3.5) Ensure that the vials are completely immersed in the solution Place the container o f vials in a vacuum chamber (D.3.6 ) and reduce the pressure by 27 kPa Hold the vacuum for 10 min, then restore to atmospheric pressure Allow the vials to remain immersed in the methylene blue solution for an additional 30 min, then remove them from the chamber Rinse the outside of the vials with water Inspect the vial contents visually for any traces o f the blue-coloured solution o f methylene blue © ISO 2016 – All rights reserved ISO 8871-5:2016(E) D.5 Expression of results Rep or t i f the vi a l s contai n a ny trace o f coloure d s olution a nd comp a re to the re qu i rement i n © ISO 2016 – All rights reserved 4.4 ISO 8871-5:2016(E) Bibliography [1] [2] ISO 8536-2, ISO 8536-6,1) In fusion equipment for medical use — Part 6: Freeze drying closures for in fusion bottles Infusion equipm ent for m edical use — Part 2: Closures for infusion bottles 1) To be published (revision of ISO 8536-6:2009) 10 © ISO 2016 – All rights reserved ISO 8871-5:2016(E) I CS 1 40 Price based on 10 pages © ISO 2016 – All rights reserved