1、BS EN ISO8536-2:2010ICS 11.040.20NO COPYING WITHOUT BSI PERMISSION EXCEPT AS PERMITTED BY COPYRIGHT LAWBRITISH STANDARDInfusion equipment formedical usePart 2: Closures for infusion bottlesIncorporating corrigendum May 2010National forewordThis British Standard is the UK implementation of EN ISO 853
2、6-2:2010. It is identical to ISO 8536-2:2010. It supersedes BS EN ISO 8563-2:2002 which is withdrawn.The UK participation in its preparation was entrusted to Technical Committee CH/212, IVDs.A list of organizations represented on this committee can be obtained on request to its secretary.This public
3、ation does not purport to include all the necessary provisions of a contract. Users are responsible for its correct application.Compliance with a British Standard cannot confer immunity from legal obligations.BS EN ISO 8536-2:2010This British Standard was published under the authority of the Standar
4、ds Policy and Strategy Committee on 30 April 2010 BSI 2010Amendments/corrigenda issued since publicationComments Date 31 August 2010 Incorporating corrected version of ISO 8536-2:2010, 15 May 2010; Note in A.3.7 amendedISBN 978 0 580 71529 7EUROPEAN STANDARD NORME EUROPENNE EUROPISCHE NORM EN ISO 85
5、36-2 March 2010 ICS 11.040.20 Supersedes EN ISO 8536-2:2002English Version Infusion equipment for medical use - Part 2: Closures for infusion bottles (ISO 8536-2:2010) Matriel de perfusion usage mdical - Partie 2: Bouchons pour flacons de perfusion (ISO 8536-2:2010) Infusionsgerte zur medizinischen
6、Verwendung - Teil 2: Stopfen fr Infusionsflaschen (ISO 8536-2:2010) This European Standard was approved by CEN on 18 February 2010. CEN members are bound to comply with the CEN/CENELEC Internal Regulations which stipulate the conditions for giving this European Standard the status of a national stan
7、dard without any alteration. Up-to-date lists and bibliographical references concerning such national standards may be obtained on application to the CEN Management Centre or to any CEN member. This European Standard exists in three official versions (English, French, German). A version in any other
8、 language made by translation under the responsibility of a CEN member into its own language and notified to the CEN Management Centre has the same status as the official versions. CEN members are the national standards bodies of Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark,
9、Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and United Kingdom. EUROPEAN COMMITTEE FOR STANDARDIZATION COMIT EUROPEN DE NORMALISATION
10、EUROPISCHES KOMITEE FR NORMUNG Management Centre: Avenue Marnix 17, B-1000 Brussels 2010 CEN All rights of exploitation in any form and by any means reserved worldwide for CEN national Members. Ref. No. EN ISO 8536-2:2010: EBS EN ISO 8536-2:2010EN ISO 8536-2:2010 (E) 3 Foreword This document (EN ISO
11、 8536-2:2010) has been prepared by Technical Committee ISO/TC 76 “Transfusion, infusion and injection equipment for medical and pharmaceutical use“. This European Standard shall be given the status of a national standard, either by publication of an identical text or by endorsement, at the latest by
12、 September 2010, and conflicting national standards shall be withdrawn at the latest by September 2010. Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. CEN and/or CENELEC shall not be held responsible for identifying any or all su
13、ch patent rights. This document supersedes EN ISO 8536-2:2002. According to the CEN/CENELEC Internal Regulations, the national standards organizations of the following countries are bound to implement this European Standard: Austria, Belgium, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Eston
14、ia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Endorsement notice The text of ISO 8536-2:2010 has been approved by CEN
15、 as a EN ISO 8536-2:2010 without any modification. The corrected version of ISO 8536-2:2010 15 May 2010 provided a revised English language text incorporating the following editorial corrections: Page 6, Note in A.3.7: “50 mm” has been replaced by “50 m”. ,BS EN ISO 8536-2:2010ISO 8536-2:2010(E) ISO
16、 2010 All rights reserved vIntroduction The purpose of this part of ISO 8536 is to specify the shape and dimensions of and the requirements for elastomeric closures intended for infusion bottles. In order to provide seal integrity of the container closure systems the dimensions of the elastomeric cl
17、osures have to be compatible with the dimensions of the infusion bottles and the caps as specified in corresponding parts of ISO 8536. Primary packaging components made of elastomeric materials are an integral part of medicinal products and thus the principles of current Good Manufacturing Practice
18、(cGMP) apply to the manufacturing of these components. Principles of cGMP are described in, e.g. ISO 15378 or GMP Guidelines as published by the European Community and the United States of America. BS EN ISO 8536-2:2010BS EN ISO 8536-2:2010INTERNATIONAL STANDARD ISO 8536-2:2010(E) ISO 2010 All right
19、s reserved 1Infusion equipment for medical use Part 2: Closures for infusion bottles 1 Scope This part of ISO 8536 specifies the shape, dimensions, material, performance requirements and labelling of closures for infusion bottles as specified in ISO 8536-1. The dimensional requirements are not appli
20、cable to barrier-coated closures. Closures specified in this part of ISO 8536 are intended for single use only. NOTE The potency, purity, stability and safety of a medicinal product during its manufacture and storage can strongly be affected by the nature and performance of the primary packaging. 2
21、Normative references The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 48, Rubber, vulcanized o
22、r thermoplastic Determination of hardness (hardness between 10 IRHD and 100 IRHD) ISO 3302-1, Rubber Tolerances for products Part 1: Dimensional tolerances ISO 3302-2, Rubber Tolerances for products Part 2: Geometrical tolerances ISO 7619-1, Rubber, vulcanized or thermoplastic Determination of inden
23、tation hardness Part 1: Durometer method (Shore hardness) ISO 8536-1, Infusion equipment for medical use Part 1: Infusion glass bottles ISO 8536-3, Infusion equipment for medical use Part 3: Aluminium caps for infusion bottles ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmac
24、eutical use Part 1: Extractables in aqueous autoclavates ISO 8871-4, Elastomeric parts for parenterals and for devices for pharmaceutical use Part 4: Biological requirements and test methods 3 Shape and dimensions 3.1 The shape and dimensions of closures shall be as shown in Figure 1 and as given in
25、 Table 1. Figure 1 illustrates two typical designs of closure, types A and B. BS EN ISO 8536-2:2010ISO 8536-2:2010(E) 2 ISO 2010 All rights reservedDimensions in millimetres Figure 1 Dimensions and configuration of type A and type B closures Table 1 Dimensions of infusion closures Dimensions in mill
26、imetres Type Nominal size d1 0,2 d2max. d3min. d4min. d5max. d60,3 h10,4 h20,3 h3h4a0,3 h5A 32 23,6 18,2 13 13 14 30,8 12,2 4 5,1 4 B 28 19,6 15,5 6,9 6,1 7,1 27,1 10,2 3,4 4,2 2,5 5,1 aIndentations may reduce the piercing thickness. 3.2 If not otherwise specified, general dimensional tolerances sha
27、ll be in accordance with ISO 3302-1 and ISO 3302-2. 3.3 In order to facilitate the production process, the flange of the closure may have a slightly conical shape (maximum 0,8 mm related to the diameter). The trimming edge of the flange shall comply with the tolerances specified for the diameter of
28、the flange. 3.4 The diameter, d4, which defines the piercing area shall not exceed d3. Marks and indentations may be placed in the piercing area. The height of the marks shall not exceed 0,3 mm. BS EN ISO 8536-2:2010ISO 8536-2:2010(E) ISO 2010 All rights reserved 3NOTE The spacers in Figure 1 for ty
29、pe A and type B closures are shown for illustrative purposes only and do not form part of the requirements of this part of ISO 8536. 3.5 All edges of the closure may be rounded. 4 Designation Closures can be designated according to their type, see Figure 1. The designation is expressed as the number
30、 of this part of ISO 8536 followed by the nominal size of the infusion bottle followed by the type letter. EXAMPLE A type A closure for infusion bottles of nominal size 32 mm complying with the requirements laid down in this part of ISO 8536 is designated as follows: Infusion closure ISO 8536-2 - 32
31、 - A 5 Material The elastomeric material used shall meet the requirements specified in Clause 6. The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at (121 2) C for 30 min without exceeding the specified limits and without the impairment of its perf
32、ormance characteristics under the conditions of normal use. In case of other sterilization methods, e. g. irradiation, the suitability of the material shall be evaluated. NOTE For use with infusion solutions, resistance to two steam sterilization cycles may not be needed because only terminal steril
33、ization is applied. Closures shall be made of elastomeric formulation originally tested and approved by the end-user. The closure manufacturer shall ensure the conformance of each delivery with the type sample and the compliance with previously agreed functional parameters and compendium requirement
34、s. 6 Requirements 6.1 General The requirements specified in 6.2 to 6.4 represent minimum requirements which refer to the condition of the elastomeric closures on receipt by the user. 6.2 Physical requirements 6.2.1 Hardness The hardness agreed between manufacturer and user shall not differ from the
35、nominal value by more than 5 Shore A when tested in accordance with ISO 7619-1 on a special test specimen. Alternatively, the hardness can be tested on the closures according to ISO 48. If tested according to ISO 48, the microhardness shall not differ by more than 5 IRHD from the type sample. 6.2.2
36、Fragmentation When tested for fragmentation in accordance with Annex A, not more than 20 fragments of diameter W 50 m per 10 piercings shall be observed. BS EN ISO 8536-2:2010ISO 8536-2:2010(E) 4 ISO 2010 All rights reserved6.2.3 Spike penetration force When tested for penetrability in accordance wi
37、th Annex B, the force needed to penetrate the closure shall not exceed 80 N, and the average value shall be less than 75 N. No closure shall be pushed into the bottle during piercing. 6.2.4 Spike retention/sealability When tested in accordance with Annex C, complete penetration shall be achieved (no
38、 closure shall be pushed into the bottle) in all cases and no signs of leakage shall appear between the spike and the closure over 4 h; nor shall the spike be pulled from the closure during this time period. 6.2.5 Resistance to ageing The maximum time between the date of manufacture and the pharmace
39、utical use should be agreed upon between the manufacturer of the closures and the user. The closures shall maintain their performance characteristics throughout the entire shelf life of the medicinal product which is tested as part of the stability test by the user. NOTE Ageing depends upon the stor
40、age and handling conditions. A guide to storage of vulcanized rubber is given in ISO 2230. 6.3 Chemical requirements The requirements of ISO 8871-1 shall apply. 6.4 Biological requirements The requirements of ISO 8871-4 shall apply. 7 Labelling Packed closures which meet the requirements of this par
41、t of ISO 8536 can be labelled with the designation given in Clause 4. BS EN ISO 8536-2:2010ISO 8536-2:2010(E) ISO 2010 All rights reserved 5Annex A (normative) Determination of fragments A.1 Principle The purpose of the test is to measure the relative coring tendencies of different ISO rubber closur
42、es. The values obtained can be significantly affected by many factors, such as prior processing of the closures, type of crimping device, sealing force, design of the spike, its sharpness, the amount of lubrication of the spike and the keenness of the operators sight. It is, therefore, necessary to
43、control these variables in order to obtain comparable results. In this context a subsequent test with closures of known fragmentation properties can be included (reference test), i.e. in a first run the closures of which the fragmentation should be evaluated are tested. Immediately afterwards in a s
44、econd run, closures with known fragmentation behaviour are tested (reference). This subsequent testing should be included from time to time to ensure appropriate handling and test system. If the fragmentation of the reference samples is found to be in the range of known results the testing is recogn
45、ised as valid. A.2 Apparatus A.2.1 Ten infusion bottles, in accordance with ISO 8536-1 (20 infusion bottles are required, should reference testing be included). A.2.2 Capping device and aluminium caps, in accordance with ISO 8536-3, and which fit the infusion bottles to be used in the test. A.2.3 Me
46、mbrane filter set. A.2.4 One test spike, in accordance with Annex D. NOTE The same test spike should be used for all reference and sample testing. A.2.5 Steam autoclave, capable of maintaining (121 2) C. A.3 Procedure A.3.1 Collect a sample of ten closures from the type or lot to be tested. A.3.2 Pr
47、epare ten infusion bottles in accordance with ISO 8536-1, of any size, filled with a minimum of 50 % of the nominal volume of water. Close these ten infusion bottles with closures of the type to be tested. A.3.3 Fix the closures with aluminium caps that meet the requirements of ISO 8536-3. Autoclave
48、 the bottles for 30 min at (121 2) C in saturated steam. Allow them to cool to room temperature. A.3.4 Degrease the test spike by means of an appropriate organic solvent and dip it into distilled water. Inspect the spike before use; it shall have its original sharpness and shall not be damaged. BS E
49、N ISO 8536-2:2010ISO 8536-2:2010(E) 6 ISO 2010 All rights reservedA.3.5 Hold the spike vertically by hand and pierce closure No. 1 within the marked area, holding the bottle No.1 firmly in a vertical position. Shake the bottle for a few seconds and withdraw the spike. A.3.6 Repeat A.3.4 and A.3.5 until all ten closures are pierced once. A.3.7 Remove the tested closures from each bottle. Put the content of all the bottles through one membrane filter. Ensure that no fragments remain in the bottles. Co
