ISO 11040 Prefilled Syringes Series (Parts 1-8): General and Specific Requirements for Prefilled Syringes

=== ISO 11040-1 ===

INTERNATIONAL STANDARD

ISO 11040-1 Second edition 2015-12-01

Prefilled syringes — Part 1: Glass cylinders for dental local anaesthetic cartridges Seringues préremplies — Partie 1: Tubes en verre pour cartouches dentaires d’anesthésie locale

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Reference number ISO 11040-1:2015(E)

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ISO 11040-1:2015(E)

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COPYRIGHT PROTECTED DOCUMENT © ISO 2015, Published in Switzerland All rights reserved. Unless otherwise specified, no part of 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 of the requester. ISO copyright office Ch. de Blandonnet 8 • 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

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ISO 11040-1:2015(E)

Contents

Page

Foreword......................................................................................................................................................................................................................................... iv

Scope.................................................................................................................................................................................................................................. 1

Normative references....................................................................................................................................................................................... 1

Dimensions and designation.................................................................................................................................................................... 1

3.1 Dimensions.................................................................................................................................................................................................. 1

3.2 Designation................................................................................................................................................................................................. 2

Requirements........................................................................................................................................................................................................... 2

4.1 Material.......................................................................................................................................................................................................... 2

4.2 Performance............................................................................................................................................................................................... 2

Marking........................................................................................................................................................................................................................... 2

Bibliography................................................................................................................................................................................................................................. 4

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iii

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ISO 11040-1:2015(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. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). 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. Details of any patent rights identified during the development of 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 information given for the convenience of users and does not constitute an endorsement. For an explanation on the meaning of ISO specific terms and expressions related to conformity 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 information. The committee responsible for this document is ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This second edition cancels and replaces the first edition (ISO 11040-1:1992), which has been technically revised with the following changes: — including glass cylinders of 2,2 ml size; — amending the requirements on performance and marking; — editorial revision of this part of ISO 11040-1. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plungers stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling — Part 5: Plunger stoppers for injectables — Part 6: Plastics barrels for injectables — Part 7: Packaging systems for sterilized subassembled syringes ready for filling — Part 8: Requirements and test methods for finished prefilled syringes

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INTERNATIONAL STANDARD

ISO 11040-1:2015(E)

Prefilled syringes — Part 1: Glass cylinders for dental local anaesthetic cartridges 1 Scope This part of ISO 11040 specifies the design, dimensions, materials, performance and test methods for glass cylinders for dental local anaesthetic cartridges with a volume of 1,7 ml, 1,8 ml and 2,2 ml intended for single use only. NOTE 1 Cartridges of 1,0 ml size are described in ISO 11499. It applies to primary packs used in direct contact with a drug. NOTE 2 The potency, purity, stability and safety of a drug during its manufacture and storage can be strongly affected by the nature and performance of the primary pack. 2 Normative references The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 720, Glass — Hydrolytic resistance of glass grains at 121 degrees C — Method of test and classification ISO 4802–1, Glassware — Hydrolytic resistance of the interior surfaces of glass containers — Part 1: Determination by titration method and classification ISO 4802–2, Glassware — Hydrolytic resistance of the interior surfaces of glass containers — Part 2: Determination by flame spectrometry and classification 3 Dimensions and designation 3.1 Dimensions The dimensions of the glass cylinder shall be as shown in Figure 1. Variations of the design of the truncated cone are allowed, if at the same time, the following conditions are fulfilled: — truncated cone has the height of the neck length (5 ± 0,2) mm; — stated tolerances of the neck opening are maintained; — diameter of the neck opening at the inner end and at the cone may be a maximum of 0,3 mm smaller than the top (3,15 ± 0,15) mm.

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ISO 11040-1:2015(E)

3.2 Designation

Glass cylinders for dental local anaesthetic cartridges shall be designated by a reference to this part of ISO 11040, followed by the colour of the glass. EXAMPLE A glass cylinder for dental local anaesthetic cartridges (cylinder), made of clear glass (cl) tubing of hydrolytic resistance container class ISO 4802–1 and ISO 4802–2 HC 1, in accordance with this part of ISO 11040 is designated as follows: Glass cylinders for dental local anaesthetic cartridges ISO 11040–1 – cl

4 Requirements 4.1 Material The material shall be colourless (cl) glass of hydrolytic resistance grain class ISO 720 HGA 1. A change in the chemical composition of the glass material should be notified to the user at least nine months in advance.

4.2 Performance

4.2.1 Glass cylinders made of glass tubing should have a sealing surface at the open end of the neck which is flat and free from ripples or undulations which would affect the sealing performance. 4.2.2 Glass cylinders should not contain seed or bubbles to an extent which will interfere with the visual examination of the contents. 4.2.3 Glass cylinders should not have open air lines on the inside surface which can lead to leakages. 4.2.4 When tested in accordance with ISO 4802-1 or ISO 4802-2, the hydrolytic resistance of the internal surface of the glass cylinder shall comply with the requirements of the hydrolytic resistance container class ISO 4802 HC 1. Before conducting the test, the bottom end of the cylinder shall be sealed with a suitable closure element, e.g. silicon rubber. 4.2.5 If the glass cylinder is annealed, the maximum residual stress shall not produce an optical retardation exceeding 40 nm/mm of glass thickness. The test method shall be agreed upon between the glass manufacturer and the customer.

5 Marking

The outer packaging of the glass cylinders shall be marked with the following information: a) size of the glass cylinder; b) number of cylinders it contains; c) designation of the cylinders; d) name or symbol of the manufacturer; e) lot number (only if the cylinder is printed) or date of production. Other markings on the outer packaging are subject to agreement between the manufacturer and the customer.

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ISO 11040-1:2015(E) Dimensions in millimetres

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Key l length of the glass cylinder are as follows: (62,4 ± 0,4) mm for 1,7 ml/1,8 ml glass cylindersc (75,0 ± 0,4) mm for 2,2 ml glass cylindersc a Dimension 3,15 mm ± 0,15 mm over a depth of 5 mm ± 0,2 mm, but see also 3.1. b Slightly rounded. c Designation of volume either as filled-in volume or removable volume. NOTE Any deviations are subject to agreement between the manufacturer and the customer.

[Figure 1 — Typical glass cylinder for dental local anaesthetic cartridges]

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ISO 11040-1:2015(E)

Bibliography

[1] ISO 11499, Dentistry — Single-use cartridges for local anaesthetics

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ISO 11040-1:2015(E)

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=== ISO 11040-2 ===

INTERNATIONAL STANDARD

ISO 11040-2 Second edition 2011-04-01

Prefilled syringes — Part 2: Plunger stoppers for dental local anaesthetic cartridges Seringues préremplies — Partie 2: Bouchons-pistons pour cartouches dentaires d'anesthésie locale

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Reference number ISO 11040-2:2011(E)

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ISO 11040-2:2011(E)

COPYRIGHT PROTECTED DOCUMENT © ISO 2011 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO's member body in the country of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyright@iso.org Web www.iso.org Published in Switzerland

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ISO 11040-2:2011(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 2. 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 11040-2 was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This second edition cancels and replaces the first edition (ISO 11040-2:1994), which has been technically revised by: ⎯ aligning this International Standard with the ISO 8871 series; ⎯ separating requirements on plunger stoppers (this part of ISO 11040) and seals; the latter are now completely covered by ISO 11040-3; ⎯ revising Table 1 on dimensions of plunger stoppers; ⎯ revising the requirements on material, hardness, freedom from leakage and sliding characteristics; ⎯ adding requirements on resistance to ageing. ISO 11040 consists of the following parts, under the general title Prefilled syringes: ⎯ Part 1: Glass cylinders for dental local anaesthetic cartridges ⎯ Part 2: Plunger stoppers for dental local anaesthetic cartridges ⎯ Part 3: Seals for dental local anaesthetic cartridges ⎯ Part 4: Glass barrels for injectables ⎯ Part 5: Plunger stoppers for injectables ⎯ Part 6: Plastic barrels for injectables

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ISO 11040-2:2011(E) Introduction Primary packaging components made of elastomeric materials are an integral part of medicinal products. As such, the principles of current Good Manufacturing Practices (cGMP) are applicable to the manufacturing of these components. Principles of cGMP are described in ISO 15378, and in GMP Guidelines published by the European Community[5] and the United States of America[6].

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INTERNATIONAL STANDARD

ISO 11040-2:2011(E)

Prefilled syringes — Part 2: Plunger stoppers for dental local anaesthetic cartridges 1 Scope This part of ISO 11040 specifies the shape, dimensions, material, performance requirements and labelling of plunger stoppers for dental local anaesthetic cartridges intended for single use only. NOTE The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be affected significantly by the nature and performance of the primary packaging. 2 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 or thermoplastic — Determination of hardness (hardness between 10 IRHD and 100 IRHD) [alternative normative reference to ISO 7619-1] ISO 3302 (all parts), Rubber — Tolerances for products ISO 7619-1, Rubber, vulcanized or thermoplastic — Determination of indentation hardness — Part 1: Durometer method (Shore hardness) [alternative normative reference to ISO 48] ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmaceutical 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 ISO 11040-1, Prefilled syringes — Part 1: Glass cylinders for dental local anaesthetic cartridges ISO 11040-3, Prefilled syringes — Part 3: Seals for dental local anaesthetic cartridges 3 Classification Plunger stoppers shall be classified as follows: ⎯ Type A: plunger stoppers without cavities; ⎯ Type B: plunger stoppers with one cavity; ⎯ Type C: plunger stoppers with two cavities.

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ISO 11040-2:2011(E) 4 Shape and dimensions 4.1 Shape and dimensions of plunger stoppers shall be as shown in Figure 1 and as given in Table 1.

a) Type A

b) Type B

c) Type C

Key d1, d2 diameters of plunger stoppers

[Figure 1 — Shape and dimensions of plunger stoppers showing positions of cavities]

Table 1 — Dimensions of plunger stoppers

Dimensions in millimetres

Nominal inner diameter of the glass cylindera

Typeb

Diameter

min.

max.

6,85 ± 0,15

7,1

6,65

6,85 ± 0,15

7,2

6,65

6,85 ± 0,15

a In accordance with ISO 11040-1. b See Clause 3.

7,4

6,65

4.2 In order to avoid adhesion of the plunger stoppers to each other, there shall be spacers. The height of the spacers shall not exceed 0,3 mm. The shape of the spacers should be agreed between manufacturer and cartridge assembler. 4.3 If not otherwise specified, general dimensional tolerances shall be in accordance with ISO 3302.

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ISO 11040-2:2011(E)

5 Designation

Plunger stoppers can be designated according to their type; see Clause 3 and Figure 1. The designation shall be expressed as the word “plunger”, followed by a reference to this part of ISO 11040, followed by the letter designating the type.

EXAMPLE

Designation of a plunger stopper of Type C (i.e. with two cavities):

Plunger ISO 11040-2 – C

6 Material The elastomeric material used shall meet the requirements specified in Clause 7. Plunger stoppers shall be made from the elastomeric formulation originally tested and approved by the enduser. The manufacturer of plunger stoppers shall ensure the conformance of each delivery with the type sample and compliance with previously agreed functional and compendial requirements. The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at (121 ± 2) °C for 30 min without impairment of its function under the conditions of normal use. In case of other sterilization methods, e.g. irradiation, the suitability of the material shall be evaluated.

7 Requirements

7.1 General

The requirements specified in 7.2 to 7.4 represent minimum requirements which refer to the condition of the elastomeric plunger stoppers on receipt by the user.

7.2 Physical requirements

7.2.1 Hardness

The hardness agreed between manufacturer and user shall not differ from the 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 plunger stoppers in accordance with ISO 48. If tested in accordance with ISO 48, the microhardness shall not differ by more than ±5 IRHD from the type sample. The manufacturer should provide suitable test specimens upon request.

7.2.2 Freedom from leakage

The cartridges shall be free from leakage at the plunger when tested in accordance with the method given in Annex A.

7.2.3 Sliding characteristics

The sliding characteristics are influenced by all components of the container closure systems and process parameters, e.g. siliconization. The testing of complete systems is described in ISO 11499. The results depend on the configuration and the pretreatment (dry, kind of liquid, storage time, etc.).

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ISO 11040-2:2011(E) 7.2.4 Resistance to ageing The maximum time between the date of manufacture and the pharmaceutical use should be agreed upon between the manufacturer of the plunger stoppers and the user. The plunger stoppers shall maintain their performance characteristics throughout the entire shelf life of the medicinal product. The shelf life is determined by the stability test conducted by the user. NOTE Ageing depends upon the storage and handling conditions. A guide to storage of vulcanized rubber is given in ISO 2230. 7.3 Chemical requirements The requirements in ISO 8871-1 apply. 7.4 Biological requirements The requirements in ISO 8871-4 apply. 8 Labelling Packed plunger stoppers which meet the requirements of this part of ISO 11040 can be labelled with the designation given in Clause 5.

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Annex A (normative) Leakage test

ISO 11040-2:2011(E)

A.1 Principle Water-filled cartridges are prepared using the plunger stoppers to be tested. By means of a suitable device, force is applied to the plunger stopper during a defined time interval. Any observed leakage is recorded. The leakage test of the plunger stoppers and the seals (see ISO 11040-3) can be combined. A.2 Apparatus A.2.1 Cartridge cylinders, in accordance with ISO 11040-1. A.2.2 Plunger stoppers, to be tested. A.2.3 Seals, in accordance with ISO 11040-3. A.2.4 Suitable equipment, to prepare water-filled cartridges. A.2.5 Cartridge holder, for example as specified in ISO 9997 or ISO 11499. A.2.6 Pressurizing device, capable of applying a force of (30 ± 3) N. A.3 Procedure A.3.1 Fill 10 cartridges completely with water, ensuring that they are free of any air, using the plunger stoppers to be tested. The water may be replaced by a coloured solution in order to improve the visibility of the leakage. A.3.2 Place the first cartridge, mounted in the cartridge holder (A.2.5), into the pressurizing device (A.2.6), and apply a force of (30 ± 1) N for 1 min. Check for leakage at the plunger stopper. SAFETY PRECAUTIONS — Ensure that adequate safety measures are in place to protect the operator. A.3.3 Repeat the operation described in A.3.2 on the remaining cartridges. A.4 Expression of results Report the number of leakages observed at the plunger stopper. Report whether the testing of the plunger stoppers and the seals (see ISO 11040-3) has been combined.

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ISO 11040-2:2011(E) Bibliography [1] ISO 2230, Rubber products — Guidelines for storage [2] ISO 9997, Dental cartridge syringes [3] ISO 11499, Dentistry — Single-use cartridges for local anaesthetics [4] ISO 15378, Primary packaging materials for medicinal products — Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP) [5] EC Guide to Good Manufacturing Practice for Medicinal Products, III/2244/87, Rev. 3 – January 1998 as amended [6] US/FDA Code of Federal Regulations

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ISO 11040-2:2011(E)

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=== ISO 11040-3 ===

INTERNATIONAL STANDARD

ISO 11040-3 Second edition 2012-01-15

Prefilled syringes — Part 3: Seals for dental local anaesthetic cartridges Seringues préremplies — Partie 3: Rondelles d’étanchéité pour cartouches dentaires d’anesthésie locale

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Reference number ISO 11040-3:2012(E)

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ISO 11040-3:2012(E)

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COPYRIGHT PROTECTED DOCUMENT © ISO 2012 All rights reserved. Unless otherwise specified, no part of this publication may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and microfilm, without permission in writing from either ISO at the address below or ISO’s member body in the country of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyright@iso.org Web www.iso.org Published in Switzerland

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ISO 11040-3:2012(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 2. 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 11040‑3 was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This second edition cancels and replaces the first edition (ISO 11040‑3:1993), which has been technically revised. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plunger stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges — Part 4: Glass barrels for injectables and ready-to-use prefillable syringes — Part 5: Plunger stoppers for injectables — Part 6: Plastics barrels for injectables The following parts are under preparation: — Part 7: Packaging systems for prefillable ready-to-use syringes

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iii

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ISO 11040-3:2012(E) Introduction Primary packaging components made of elastomeric materials are an integral part of medicinal products. Therefore, the principles of current good manufacturing practices (cGMP) apply to the manufacturing of these components. Principles of cGMP are described in ISO 15378 or in the GMP Guidelines published by the European Community and the United States of America.

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INTERNATIONAL STANDARD

ISO 11040-3:2012(E)

Prefilled syringes — Part 3: Seals for dental local anaesthetic cartridges

1 Scope

This part of ISO 11040 specifies the shape, dimensions, material, performance requirements and labelling of seals for dental local anaesthetic cartridges intended for single use only.

NOTE

The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be

significantly affected by the nature and performance of the primary packaging.

2 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 3302-1, Rubber — Tolerances for products — Part 1: Dimensional tolerances ISO 7619-1, Rubber, vulcanized or thermoplastic — Determination of indentation hardness — Part 1: Durometer method (Shore hardness) ISO 7885:2010, Dentistry — Sterile dental injection needles for single use ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmaceutical 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 ISO 8871-5:2005, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 5: Functional requirements and testing ISO 8872, Aluminium caps for transfusion, infusion and injection bottles — General requirements and test methods ISO 11040-1, Prefilled syringes — Part 1: Glass cylinders for dental local anaesthetic cartridges ISO 11040-2, Prefilled syringes — Part 2: Plunger stoppers for dental local anaesthetic cartridges

3 Classification Seals shall be classified as follows: — type A: seals with a mono-layer disc; — type B: seals with a double-layer disc.

4 Shape and dimensions 4.1 The shape and dimensions of seals shall be as shown in Figure 1 and given in Table 1.

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ISO 11040-3:2012(E)

Dimensions in millimetres

Type A: Seal with a mono-layer disc

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Type B: Seal with a double-layer disc Shape and dimensions of seals for dental local anaesthetic cartridges

Dimensions of seals

Nominal size

Type

Total cap heighta

Thickness of disc

±0,15

7,5

4,85 to 4,9

1,3 to 1,5

7,5

4,85 to 5,3

1,45 to 1,95

a The height of the seal depends on the thickness and hardness of the disc.

Dimensions in millimetres

Inner cap diameter d1 ±0,05 7,5 7,5

Bore diameter d2 ±0,3 3,0 3,0

4.2 For type B seals, both single layers shall be continuous. The thickness ratio of the single layers shall be agreed upon between the supplier and user. 4.3 The diameter of the rubber discs shall be such that a sufficient press-fit in the aluminium cap is achieved and that the discs cannot fall out. 4.4 If not otherwise specified, general dimensional tolerances shall be in accordance with ISO 3302-1.

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ISO 11040-3:2012(E)

5 Designation

Seals are designated according to their type (see Clause 3 and Figure 1). The designation shall comprise, in the following order, the descriptor “Seal”, a reference to this part of ISO 11040 and the type letter.

EXAMPLE

Designation of a seal of type A (i.e. trimmed):

Seal ISO 11040-3 - A

6 Material

6.1 Cap

General requirements for aluminium caps shall be in accordance with ISO 8872. In addition, the cap shall be anodized or suitably lacquered.

6.2 Discs

Discs shall be made from the elastomeric formulation originally tested and approved by the end user. The manufacturer of the discs shall ensure the conformance of each delivery with the type sample and the compliance with previously agreed functional and compendial requirements. The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at (121 ± 2) °C for 30 min without impairment of its function under conditions of normal use. If other sterilization methods are used, e.g. irradiation, the suitability of the material shall be evaluated.

7 Requirements 7.1 General The requirements specified in 7.2 to 7.4 constitute minimum requirements concerning the condition of the elastomeric seals on receipt by the user.

7.2 Physical requirements

7.2.1 Hardness of the disc The hardness agreed between the manufacturer and the user shall not differ from the nominal value by more than ±5 Shore A when tested in accordance with ISO 7619-1 on a special test specimen. Alternatively, hardness can be tested on the discs in accordance with ISO 48. If tested according to ISO 48, the microhardness shall not differ by more than ±5 IRHD from the type sample. The manufacturer should provide suitable test specimens upon request. 7.2.2 Fragmentation The requirements and test method of ISO 8871-5:2005, 4.2 and Annex B, shall apply, using a needle with an outer diameter of 0,4 mm that conforms to the butt-end requirements in ISO 7885:2010, 5.3.

Schematic representation of butt-end angle

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ISO 11040-3:2012(E)

7.2.3 Freedom from leakage The seal of the cartridge shall show no signs of leakage when tested in accordance with Annex A.

7.2.4 Resistance to ageing

The maximum time between the date of manufacture of the seals and their pharmaceutical use should be agreed upon between the manufacturer and the user.

The seals 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 on storage and handling conditions. A guide to storage of vulcanized rubber is given in ISO 2230.

7.3 Chemical requirements The requirements of ISO 8871-1 shall apply for the disc.

7.4 Biological requirements The requirements of ISO 8871-4 shall apply. Toxicity tests apply to the disc only.

8 Labelling Packed seals that meet the requirements of this part of ISO 11040 can be labelled with the designation given in Clause 5.

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Annex A (normative) Leakage test

ISO 11040-3:2012(E)

A.1 Principle Water-filled cartridges are prepared using the seals to be tested. By means of a suitable device, a force is applied to the seal during a defined time interval. Any observed leakage is recorded. The leakage tests for seals and plunger stoppers (see ISO 11040-2) can be combined.

A.2 Apparatus A.2.1 Cartridge cylinders, in accordance with ISO 11040-1. A.2.2 Seals to be tested. A.2.3 Plunger stoppers, in accordance with ISO 11040-2. A.2.4 Suitable equipment, to prepare water-filled cartridges. A.2.5 Cartridge holder, e.g. as specified in ISO 9997 or ISO 11499. A.2.6 Pressurizing device, capable of applying a force of (30 ± 1) N.

A.3 Procedure

A.3.1 Take 10 cartridges and fill them with water until they are practically air-free using the seals to be tested.

NOTE

The water may be replaced by a coloured solution in order to improve the visibility of the leakage.

A.3.2 Place the first cartridge, mounted in the cartridge holder (A.2.5), into the pressurizing device (A.2.6), and apply a force of (30 ± 1) N for 1 min. Check for leakage at the seal. SAFETY PRECAUTIONS — Adequate safety measures should be in place to protect the operator.

A.3.3 Repeat the operation described in A.3.2 on the remaining cartridges.

A.4 Expression of results Report the number of leakages observed at the seal. Report whether the testing of the seals and plunger stoppers (see ISO 11040-2) has been combined.

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ISO 11040-3:2012(E) Bibliography [1] ISO 48, Rubber, vulcanized or thermoplastic — Determination of hardness (hardness between 10 IRHD and 100 IRHD) [2] ISO 2230, Rubber products — Guidelines for storage [3] ISO 3302-2, Rubber — Tolerances for products — Part 2: Geometrical tolerances [4] ISO 7405, Dentistry — Evaluation of biocompatibility of medical devices used in dentistry [5] ISO 9997, Dental cartridge syringes [6] ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process [7] ISO 11499, Dentistry — Single-use cartridges for local anaesthetics [8] ISO 13926-2, Pen systems — Part 2: Plunger stoppers for pen-injectors for medical use [9] ISO 15378, Primary packaging materials for medicinal products — Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP)

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ISO 11040-3:2012(E)

ICS 11.040.10;11.040.25;11.060.20 Price based on 6 pages Copyright In©ternISatiOona2l O0rg1a2niz–atioAnlflorrSigtahndtasrdrizeastioenrved Provided by IHS Markit under license with ANSI No reproduction or networking permitted without license from IHS

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=== ISO 11040-4 ===

INTERNATIONAL STANDARD

ISO 11040-4 Third edition 2015-04-01

Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling Seringues préremplies — Partie 4: Cylindres en verre pour produits injectables et seringues préassemblées stérilisées préremplissables

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Reference number ISO 11040-4:2015(E)

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ISO 11040-4:2015(E)

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COPYRIGHT PROTECTED DOCUMENT © ISO 2015 All rights reserved. Unless otherwise specified, no part of 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 of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyright@iso.org Web www.iso.org Published in Switzerland

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ISO 11040-4:2015(E)

Contents

Page

Introduction.................................................................................................................................................................................................................................vi

Terms and definitions...................................................................................................................................................................................... 2

General requirements...................................................................................................................................................................................... 3

4.1 Quality systems........................................................................................................................................................................................ 3

4.2 Testing............................................................................................................................................................................................................. 3

4.3 Documentation........................................................................................................................................................................................ 3

Syringe barrel........................................................................................................................................................................................................... 4

5.1 Design including dimensions....................................................................................................................................................... 4

5.2 Functional testing of Luer connection................................................................................................................................. 7

5.3 Material.......................................................................................................................................................................................................... 7

5.4 Performance requirements........................................................................................................................................................... 7

5.4.1 Hydrolytic resistance.................................................................................................................................................... 7

5.4.2 Annealing quality............................................................................................................................................................. 7

5.4.3 Lubrication of the inner surface.......................................................................................................................... 7

5.4.4 Flange breakage resistance..................................................................................................................................... 7

5.4.5 Luer cone breakage resistance............................................................................................................................. 8

Sterilized subassembled syringes ready for filling........................................................................................................... 8

6.1 General............................................................................................................................................................................................................ 8

6.2 Sterility........................................................................................................................................................................................................... 8

6.3 Pyrogenicity/endotoxins................................................................................................................................................................ 9

6.4 Particles.......................................................................................................................................................................................................... 9

6.5 Additional requirements to specific components of sterilized subassembled

syringes ready for filling.................................................................................................................................................................. 9

6.5.1 Barrel.......................................................................................................................................................................................... 9

6.5.2 Needle..................................................................................................................................................................................... 10

6.5.3 Closure system................................................................................................................................................................. 11

6.6 Closure system barrel integrity.............................................................................................................................................. 12

Packaging...................................................................................................................................................................................................................12

Labelling......................................................................................................................................................................................................................12

Annex A (informative) Examples of types of sterilized subassembled syringes ready for filling.......13

Annex B (informative) Head designs..................................................................................................................................................................15

Annex C (normative) Test methods for syringe barrels.................................................................................................................17

Annex D (informative) Sample preparation for endotoxin and particulate determination.....................23

Annex E (informative) Glide force test method to evaluate syringe lubrication...................................................27

Annex F (informative) Needle penetration test.......................................................................................................................................30

Annex G (normative) Test methods for closure systems...............................................................................................................33

Annex H (informative) Dye solution tightness test............................................................................................................................48

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iii

ISO 11040-4:2015(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. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). 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. Details of any patent rights identified during the development of 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 information given for the convenience of users and does not constitute an endorsement. For an explanation on the meaning of ISO specific terms and expressions related to conformity 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 information The committee responsible for this document is ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This third edition cancels and replaces the second edition (ISO 11040‑4:2007), which has been technically revised and contains the following changes: — Scope has been extended by adding sterilized subassembled syringes ready for filling and appropriate requirements, as well as test methods, have been included; — general requirements have been added on quality systems, testing, and documentation; — requirements on labelling have been revised; — requirements on packaging have been added; — requirements on syringes barrels have been revised by — adding requirements and related test methods for flange breakage resistance and Luer cone breakage resistance, — adding requirements on lubrication, — adding requirements and guidance on tolerances for Luer conical fittings, as well as on functional testing of Luer connections, and — deleting the clause on designation. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plunger stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges

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ISO 11040-4:2015(E) — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling — Part 5: Plunger stoppers for injectables — Part 6: Plastics barrels for injectables — Part 7: Packaging systems for sterilized subassembled syringes ready for filling — Part 8: Requirements and test methods for finished prefilled syringes

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ISO 11040-4:2015(E) Introduction In the past, ampoules and injection vials were mainly used for (parenteral) injectable products. However, for the injection of the products contained in those ampoules and vials, a hypodermic syringe combined with the appropriate injection needle is also needed. This means the injectable product has to be transferred by the user into the hypodermic syringe before its final use. This procedure is not only time-consuming, but also presents a great number of possibilities for contamination. To ensure safe use of an injectable product, prefilled syringes for single use are on the market for many years. Without a doubt, such prefilled syringes permit immediate injection of the product contained after relatively simple handling. These syringes can also be used in injectors with automated functions where further and particular requirements apply. Based on the diameter of the prefilled syringes, appropriate components, such as rubber plungers, tip caps, needle shields, and other closure systems can also be standardized. In conjunction with the right sealing components, they offer a system for (parenteral) injectable use. The producers of filling machines can apply this part of ISO 11040 to achieve a degree of standardization in the equipment of the machines. At the start of prefilled syringe processing by the pharmaceutical industry, syringes made of tubing glass were delivered to the pharmaceutical companies in the form of so called non-sterile “bulkware” only. The process steps washing, drying, inner lubrication, sealing the syringe with a closure system, sterilization, as well as filling and closing, were then performed in the pharmaceutical companies. Processing of “bulkware” is performed like this until today. Sterilized subassembled syringes have partially replaced non-sterile “bulkware”. In the case of sterilized subassembled syringes ready for filling, responsibility for the aforementioned process steps relevant to the injectable product lies with the manufacturer of the primary packaging material. Following the assembly of the needle shield on syringes with a staked needle or tip caps for the Luer cone version, the subassembled syringes are placed into so called nests. The nests, in turn, are placed into a plastic tub. The syringes in the nest are protected by means of an insert liner and the tub itself is sealed by a sealing lid (which is currently and, so far, primarily achieved using a porous material). Thus, the tub properly sealed with the sealing lid represents the “sterile barrier system”. The sealed tub is then wrapped into a sealable bag and, thus, ready for sterilization which is currently and, so far, primarily performed using ethylene oxide. In this form, the sterilized subassembled syringes ready for filling are delivered to the pharmaceutical companies in a sterile condition, where they are processed on suitable machines.

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INTERNATIONAL STANDARD

ISO 11040-4:2015(E)

Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling

1 Scope This part of ISO 11040 applies to — tubing-glass barrels (single-chamber design) for injection preparations, and — sterilized subassembled syringes ready for filling. It specifies materials, dimensions, quality, and performance requirements, as well as relevant test methods. This part of ISO 11040 also specifies those components that are part of the sterilized subassembled syringe ready for filling. Glass barrels and sterilized subassembled syringes ready for filling in accordance with this part of ISO 11040 are intended for single use only. Components to complete the subassembled syringe, such as plunger and rod, are not specified in this part of ISO 11040. NOTE Attention is drawn to applicable national or regional regulations such as Ph. Eur., USP, or JP. Where relevant, specific references to Ph. Eur., USP, and JP have been given in specific clauses or subclauses of this part of ISO 11040.

2 Normative references The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 594‑1,1) Conical fittings with a 6 % (Luer) taper for syringes, needles and certain other medical equipment — Part 1: General requirements ISO 594‑2,1) Conical fittings with 6 % (Luer) taper for syringes, needles and certain other medical equipment — Part 2: Lock fittings ISO 720:1985, Glass — Hydrolytic resistance of glass grains at 121 degrees C — Method of test and classification ISO 4802‑1, Glassware — Hydrolytic resistance of the interior surfaces of glass containers — Part 1: Determination by titration method and classification ISO 4802‑2, Glassware — Hydrolytic resistance of the interior surfaces of glass containers — Part 2: Determination by flame spectrometry and classification ISO 7864, Sterile hypodermic needles for single use ISO 7886‑1:1993, Sterile hypodermic syringes for single use — Part 1: Syringes for manual use

ISO 594-1 and ISO 594-2 will be replaced by ISO 80369-7 (currently in preparation by ISO/TC 210).

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ISO 11040-4:2015(E)

ISO 8871‑1, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 1: Extractables in aqueous autoclavates ISO 9626, Stainless steel needle tubing for the manufacture of medical devices ISO 10993‑7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals ISO 11040‑5, Prefilled syringes — Part 5: Plunger stoppers for injectables ISO 80369‑1, Small-bore connectors for liquids and gases in healthcare applications — Part 1: General requirements 3 Terms and definitions For the purposes of this document, the following terms and definitions apply. 3.1 customer business entity which purchases syringe barrels or sterilized subassembled syringes ready for filling and conducts further processing or filling as appropriate 3.2 manufacturer business entity which performs or is otherwise responsible for the manufacturing of the syringe barrels (bulkware) or for the sterilized subassembled syringes ready for filling by the customer 3.3 needle shield syringe closure used with staked needle subassembled syringes that is designed to protect the needle point/bevel from damage, to allow sterilization of the needle, and to maintain sterility of the contents of the syringe and of the needle up to the time of injection 3.4 prefilled syringe container system filled with the injectable product ready for injection Note 1 to entry: Components of syringes are barrel, needle, closure system, plunger, and rod. Examples of sterilized subassembled syringes ready for filling including components are illustrated in Annex A. 3.5 syringe barrel cylindrical glass body with front end and finger flange Note 1 to entry: See Figure 1. Note 2 to entry: The syringe barrel can be equipped with a staked needle. 3.6 sterilized subassembled syringe ready for filling subassembly that has been pre-treated, consisting of a syringe barrel and a closure system Note 1 to entry: The subassembly has been pre-treated by applying the following processes, as applicable: — assembling/lubricating a needle; — final washing/pyrogen reduction; — drying; — applying lubricant to the inner surface; — sealing the syringe with a closure system;

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ISO 11040-4:2015(E) — packing (see ISO 11040‑7); — sterilization. Note 2 to entry: Examples of sterilized subassembled syringes ready for filling including components are illustrated in Annex A. 3.7 syringe closure system component or multi-component system designed to close the syringe system at the front end that is designed to allow sterilization of the glass tip and maintain sterility of the contents of the syringe up to the time of injection EXAMPLE Tip cap, needle shield, tamper-evident closure system. Note 1 to entry: See 3.3. 3.8 user patient or health care provider (clinical personnel, doctor, or lay person) who uses or applies the injectable product contained in the syringe 4 General requirements

4.1 Quality systems

The activities described within this part of ISO 11040 shall be carried out within a formal quality system. NOTE ISO 15378 contains requirements for a suitable quality management system for primary packaging materials for medicinal products.

4.2 Testing

4.2.1 Any suitable test system can be used when the required accuracy (calibration) and precision (gauge repeatability and reproducibility) can be obtained. The gauge repeatability and reproducibility of the test apparatus shall be no greater than 20 % of the allowed tolerance range for any given measurement. For destructive test measurements, the gauge repeatability and reproducibility shall be no greater than 30 % of the allowed tolerance range. At a minimum, the gauge repeatability and reproducibility should cover ±2 standard deviations (thereby covering approximately 95 % of the variation). EXAMPLE A measurement system with a measurement specification limit of ±0,01 ml (range of 0,02 ml) comes out of the gauge repeatability and reproducibility with a gauge repeatability and reproducibility/tolerance range ratio of 20 %, which means that the gauge repeatability and reproducibility (four standard uncertainties) equals 0,02 ml/5 = 0,004 ml. The uncertainty of the measurement is ±2 standard deviations (see Reference [22]), which equals to 0,002 ml. 4.2.2 The sampling plans used for the selection and testing of sterilized subassembled syringes ready for filling or components thereof shall be based upon statistically valid rationale. NOTE Examples of suitable sampling plans are given in ISO 2859‑1 and ISO 3951‑ series; see also Reference [25]. 4.2.3 Unless agreed otherwise, testing shall be performed at ambient laboratory conditions.

4.3 Documentation

4.3.1 Demonstration of compliance with the requirements of this part of ISO 11040 shall be documented.

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ISO 11040-4:2015(E) 4.3.2 All documentation shall be retained for a specified period of time. The retention period shall consider factors such as regulatory requirements, expiration date, and traceability. 4.3.3 Documentation of compliance with the requirements can include, but is not limited to, performance data, specifications, and test results from validated test methods. 4.3.4 Electronic records, electronic signatures, and handwritten signatures executed to electronic records that contribute to validation, process control, or other quality decision-making processes shall be reliable. 5 Syringe barrel

5.1 Design including dimensions

5.1.1 The dimensions of the syringe barrel shall be as shown in Figure 1 and as given in Table 1, except for the total barrel length and the wall thickness that are given for information only. The type of head design shall be agreed upon between the manufacturer and the customer. For the Luer and the Luer lock design, ISO 594‑1, ISO 594‑2, and ISO 80369‑1 apply, with the addition that the dimension of the Luer conical fitting shall comply with Figure 2. NOTE Commercially developed glass Luer cone and Luer lock prefilled syringes routinely mate with Luer devices in order to effectively administer the medication stored within the syringe. Examples are disposable needles, needleless connector devices, and other forms of Luer access. The current state of the art syringe tip glass forming technology for manufacturing glass prefilled syringes cannot conform completely to the standards on Luer connectors (see ISO 594 series). The ISO 594 series has been developed using ground glass, metal, and injection moulded technology, as well as plastic resins, as the baseline rationale for compliance and capabilities. Differences in the manufacturing methodologies and the need for expanded tolerances in the glass forming manufacturing process are acknowledged. This is why dimensional tolerances are different. While these tolerances are outside of the range of ISO 594 with respect to some of the dimensions, the glass formed tip does successfully mate with the injection moulded female counterparts. See 5.2 and ISO 594:1986 for functional test methods that accommodate for the formed tip manufacturing process. Luer tip dimensions mentioned in the following figures can be checked by means of camera measurements or indirectly by using a gauge similar to the one described in ISO 594. 5.1.2 If printing of the barrel is required, it shall be agreed between the manufacturer and the customer.

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d2 s1

ISO 11040-4:2015(E)

l1 h1

d3 a) cut-ϐlange

d3 b)round ϐlange

d4 c) small-round ϐlange

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Key 1 front end 2 back end NOTE 1 The bore diameter of the tip is subject to agreement between the manufacturer and the customer. For examples of commonly used head designs, see Annex B. NOTE 2 The design of the finger flange is subject to agreement between the manufacturer and the customer.

[Figure 1 — Typical example of a glass syringe barrel and examples of glass finger flanges]

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ISO 11040-4:2015(E)

Table 1 — Syringe barrel dimensions (see Figure 1) Dimensions in millimetres

Nominal

volume

Glass barrel

Finger flange

s1c

nom tol nom tol min. nom. tol. nom. tol. ≈ nom. tol. nom. nom. nom. tol. ml

0,5 6,85

4,65 ±0,1 4,40 47,6

57,5

1,1 1,8 ±0,5 13,4 ±0,4 10,5 ±0,4

8,15

6,35

6,05 54

64,0 ±0,5 0,9 1,9

13,8

1b 10,85 ±0,1 8,65

8,25 35,7 ±0,5 46,7

1,1 2,2

17,75

14,7

2 10,85

8,65

8,25 49

60,0

1,1 2,2

17,75 ±0,75 14,7

2,25 10,85

8,65

8,25 54,4

66,6 ±0,75 1,1 2,2 ±0,5 17,75

14,7 ±0,5

3 10,85

8,65 ±0,2 8,25 72,2

84,4 ±1,0 1,1 2,2

17,75

14,7

14,45

11,85

11,45 66,7 ±0,75 80,0 ±0,75 1,3 2,4

19,5

10 17,05 ±0,2 14,25

13,85 87,25

100,5 ±1,0 1,4 2,5 ±0,6 27 ±1 21,5

20 22,05

19,05

18,40 96,8

114,9 ±1,0 1,5 3,1

32,25

25,9 ±0,6

a Long version.

b Short/standard version.

c Dimension on total barrel length and wall thickness are for information only.

Dimensions in millimetres

Key a Through bore diameter to be agreed between the manufacturer and the customer. b Luer cone length, Luer version. c Luer cone length, Luer lock version. d Length of the Luer lock groove. e Depth of the Luer lock groove. NOTE The above dimensions are not applicable to glass barrel tip designs with a staked needle.

[Figure 2 — Luer conical fitting]

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ISO 11040-4:2015(E)

5.2 Functional testing of Luer connection

The functional performance of the glass prefilled syringe barrel with regard to the conical connection to a 6 % Luer female connector fitting shall be demonstrated through performance testing with female reference connectors made of plastic instead of steel. NOTE The forming process of glass prefillable syringes results in a “wavy” Luer connector surface finish that is incompatible with the use of steel reference connectors for liquid and air leakage, separation force, and unscrewing torque type tests. In addition, male Luer connectors of glass prefillable syringes are often roughened on customer request. For the purpose of demonstrating the functional performance of the syringe Luer connection and the equivalent safety of the connection, the plastic reference connectors shall be verified for compliance with the dimensional requirements of ISO 594‑1. The selected plastic material for the reference connectors shall be chosen for being representative for the normal clinical conditions of use. A rationale shall be developed for the selection of material(s).

5.3 Material

The material shall be colourless (cl) or amber (br) glass of the hydrolytic resistance grain class HGA 1 in accordance with ISO 720:1985. Material requirements are also covered by national or regional pharmacopoeias. See requirements for glass type Ι as given in Ph. Eur. 3.2.1[32], USP <660>[39] and requirements in JP 7.01[47].

5.4 Performance requirements

5.4.1 Hydrolytic resistance

When tested in accordance with ISO 4802‑1 or ISO 4802‑2, the hydrolytic resistance of the internal surface of the glass barrel shall comply with the requirements of hydrolytic resistance container class ISO 4802-HC 1. Before conducting the test, the back end of the barrel shall be sealed with a suitable closure element, e.g. a rubber closure.

5.4.2 Annealing quality

The maximum residual stress shall not produce an optical retardation exceeding 40 nm/mm of glass thickness when the glass barrel is viewed in a strain viewer. The test method for residual stress is subject to agreement between the manufacturer and the customer.

5.4.3 Lubrication of the inner surface

For barrels whose inner surfaces have been lubricated, 6.5.1.2 applies.

5.4.4 Flange breakage resistance

Syringe barrels shall provide an appropriate flange breakage resistance. Limit values are subject to agreement between the manufacturer and the customer. The flange breakage resistance shall be determined in accordance with C.1. NOTE The flange breakage resistance test method is a reference test to provide a consistent measure for comparison of the performance of different syringes and can potentially be used as a quality measure to assess changes and monitor production. The test method might need to be adjusted to simulate specific use conditions of the syringe system, e.g. use in auto-injectors.

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ISO 11040-4:2015(E)

5.4.5 Luer cone breakage resistance

Syringe barrels shall provide an appropriate Luer cone breakage resistance. Limit values are subject to agreement between the manufacturer and the customer. The Luer cone breakage resistance shall be determined in accordance with C.2. NOTE The Luer cone breakage resistance test method is a reference test to provide a consistent measure for comparison of the performance of different syringes and can potentially be used as a quality measure to assess changes and monitor production. The test method might need to be adjusted to simulate specific use conditions of the syringe system, e.g. use in auto-injectors. 6 Sterilized subassembled syringes ready for filling

6.1 General

6.1.1 The design of sterilized subassembled syringes ready for filling varies due to their intended use. The requirements and test methods in the following subclauses and related annexes are based on common design features and syringe components. NOTE Common types of sterilized subassembled syringes ready for filling are illustrated in Annex A. 6.1.2 The following properties should be considered when selecting the raw materials or components and the design of the sterilized subassembled syringe ready for filling: a) microbial barrier; b) biocompatibility and toxicological attributes; c) physical and chemical properties; d) ability for sterilization and compatibility with respect to the intended sterilization process; e) maintenance of sterility of the subassembly; f) shelf-life limitations; g) functionality for their intended use; h) robustness of the closure system during transport from the manufacturer to the user. 6.1.3 The manufacturer shall have documented procedures for the design and development of sterilized subassembled syringes ready for filling. NOTE ISO 15378 contains requirements for a suitable quality management system for primary packaging materials for medicinal products.

6.2 Sterility

Sterilized subassembled syringes ready for filling shall have been sterilized to a sterility assurance level (SAL) of 10−6 using a suitable validated sterilization method (see ISO 11135‑1, ISO 17665‑1, ISO 11137, or ISO 14937). The sterilization process shall not compromise the safety and performance (i.e. changing of colours, dimensions, forms, closing or sealing, blooming or detachment of components, etc.) of the subassembled syringe. Sterility testing is subject of national or regional pharmacopoeias. See the methods given in Ph Eur, 2.6.1[27], USP <71>[34] and JP 4.06[44].

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ISO 11040-4:2015(E) For ethylene oxide sterilization, the requirements for residuals of ISO 10993‑7 apply. See also Reference [26]. NOTE See also other applicable parts of ISO 10993. 6.3 Pyrogenicity/endotoxins For pyrogenicity, the limit value for syringes shall be <0,25 EU/ml considering the nominal volume according to Table 1. NOTE 1 For rationale, see USP monograph on sterile water for injection according to USP <1231>[41]. Extraction method and testing are specified in regional and national pharmacopoeias: — for extraction method, see USP <161>[37]; — for testing, see Ph Eur, 2.6.14, method c)[28], USP <85>[35] and JP 4.01[43]. NOTE 2 A sample preparation is given in D.1. This is based on applicable pharmacopoeias. The subassembled syringes ready for filling shall be processed to remove pyrogenic properties to ensure that they are suitable for their intended use. Such processes shall be validated for three log endotoxin reduction.

6.4 Particles

Sterilized subassembled syringes ready for filling shall be manufactured by processes that reduce the risk of particulate contamination. Current pharmacopoeias identify visible particulates as undesirable but do not define the size or put a limit on the allowable number. It is recommended that the manufacturer and the customer agree upon the size and number of visible particles and the test method. The particle-related specifications given in pharmacopoeias (e.g. Ph. Eur, USP, JP) do not apply to empty containers. For sub-visible particles, the following applies: — particles ≥10 µm: 600 max. per syringe; — particles ≥25 µm: 60 max. per syringe. NOTE 1 These limits have been derived from the USP <788>[40] (small volume parenterals) limit values for filled containers with a nominal volume of less than 100 ml. The limit of the subassembly, which is 10 % of the USP <788>[40], supports the customer to fulfil the USP requirements on the syringe system. This value has been chosen based on historical proven capability using the light obscuration method as given in D.2. NOTE 2 See also Ph. Eur. 2.9.19 [29], Ph. Eur. 2.9.20 [30], USP <788>[40], JP 6.06[45], as well as JP 6.07[46].

6.5 Additional requirements to specific components of sterilized subassembled syringes ready for filling

6.5.1 Barrel

6.5.1.1 The requirements given in Clause 5 apply. Specific design features of the glass barrel should be agreed between the manufacturer and the customer. 6.5.1.2 The inner surface of the syringe barrel may be lubricated. Limit values of the amount of lubricant are subject to agreement between the manufacturer and the customer.

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ISO 11040-4:2015(E)

NOTE 1 Lubrication of the inner surface of the syringe barrel is applied in order to improve gliding properties. This is usually done by siliconization (e.g. by application of a high-viscosity silicone oil to the inner glass surface or with silicone emulsion followed by heat treatment). If silicone oil is used, attention is drawn to applicable requirements in respective pharmacopoeias (see Reference [31] and Reference [42]). NOTE 2 Annex E includes a suitable test method for the determination of the quality and consistency of the lubrication using a gliding force test. NOTE 3 For test methods for verifying the internal siliconization and for defect evaluation list for tubing-glass receptacles, see Reference [25]. NOTE 4 The following are examples of test methods for visualization of the quality of the inner surface treatment: — test method to check the homogeneity of the siliconization by using aluminium oxide powder or alternative powder of a defined quality; in this test, a defined powder is distributed within the syringe by shaking. Spots with no aluminium oxide or powder indicate insufficient siliconization; — optical test methods.

6.5.1.3 When tested in combination with the selected piston/plunger in accordance with ISO 11040‑5, the dead space in the barrel and the nozzle with the piston/plunger fully inserted shall be determined as given in ISO 7886‑1:1993, Annex C. NOTE The test method is a reference test to provide a consistent measure for comparison of the performance of different syringes and can potentially be used as a quality measure to assess changes and monitor production. It is not a design verification test intended to simulate the use condition of the syringe system.

6.5.2 Needle

6.5.2.1 If the sterilized subassembled syringe ready for filling is delivered with a staked needle, the requirements in 6.5.2.2 to 6.5.2.4 apply.

6.5.2.2 The needle shall fulfil the following material, dimensional, and design requirements:

— material and dimensions of the needle tubing shall comply with ISO 9626; — bevel, dimensions, and bond between the glass and the needle shall comply with ISO 7864; — actual needle length shall be in accordance with ISO 7864 (see l in ISO 7864:1993, Figure 1). When there are particular requirements on needle tip height from the flange or the shoulder, which are both common when a syringe with staked needle is used in injectors, the dimension should be agreed upon between the manufacturer and the customer. Specific design features of the needle should be agreed upon between the manufacturer and the customer.

6.5.2.3 The needle shall be surface-treated using a lubricant (e.g. silicone oil). NOTE 1 This is to minimize the pain when the needle penetrates the skin during injection. For silicone oil, attention is drawn to applicable requirements in respective pharmacopoeias (see Reference [31] and Reference [42]). Limit values on needle penetration force might need to be established using a risk assessment and usability engineering process. Needle penetration force measurements can be useful to detect needle point and lubrication defects, but might not be correlated with injection pain. NOTE 2 A suitable test method for the determination of the needle penetration force is given in Annex F.

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ISO 11040-4:2015(E) 6.5.2.4 The needle lumen patency shall be as specified in ISO 7864, if applicable. 6.5.2.5 The adhesive used for fixing the needle inside the glass cone shall fulfil the requirements of relevant pharmacopoeias and/or other national or regional requirements. See also ISO 10093‑1 and UV curing liquid adhesive according to USP class V[36]. The fixation of the needle in the glass cone shall be tested in accordance with G.1. This test method does not specify a limit for the pull-out force because this is subject to agreement between the manufacturer and the customer. See also limit values specified in ISO 7864.

6.5.3 Closure system

6.5.3.1 The material that can contact the injectable product shall meet applicable requirements of ISO 8871‑1. For additional regional or national requirements of pharmacopoeias, see type I or type II requirements of Ph. Eur. 3.2.9[33], USP <381>[38] and JP 7.03[48] that is applicable to volumes >100 ml. 6.5.3.2 The closure system shall allow for sterilization. Compliance shall be demonstrated by suitable methods. NOTE For ethylene oxide sterilization and/or steam sterilization, the design, including the material of the closure system, ensures that all components have sufficient ethylene oxide gas and water vapour permeation so that during sterilization, these gases reach both the cone of the Luer syringe and the needle through the sealing components. 6.5.3.3 The closure system shall provide an appropriate liquid leakage resistance when tested in accordance with G.2. Limit values are subject to agreement between the manufacturer and the customer. 6.5.3.4 Luer conical fittings, if used, shall comply with ISO 594‑1, ISO 594‑2, and ISO 80369‑1. 6.5.3.5 Luer lock adaptor (LLA) collar systems shall withstand a pull-off force of at least 22 N when tested in accordance with G.3. NOTE This pull-off force is consistent with the minimum needle pull-off force as specified in ISO 7864, Table 2, for needles with an outer diameter of 0,5 mm and smaller. 6.5.3.6 Luer lock adaptor (LLA) collar systems shall withstand a specified torque resistance when tested in accordance with G.4. The minimum torque resistance is subject to agreement between the manufacturer and the customer.

6.5.3.7 The design of closure systems shall be such that

— tip caps (if used) can be removed from the syringe with a reasonable torque, — tip caps or needle shields (as applicable) can be removed from the syringe with a reasonable pull- off force, and — tip caps or needle shields maintain the sterility of the cone or needle. The maximum allowed torque and the pull-off force, respectively, shall be agreed upon between the manufacturer and the customer. The test(s) shall be performed in accordance with G.5 and G.6, respectively.

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ISO 11040-4:2015(E) 6.6 Closure system barrel integrity The components of sterilized subassembled syringes ready for filling shall provide sealing against each other during filling, applicable final sterilizations (moist heat by autoclaving), and throughout storage and transport, also through or in different external air pressures. The dye solution tightness test in Annex H is a valuable method to test the tightness of a sterilized subassembled syringe ready for filling in the design development phase. 7 Packaging Non-sterile glass barrels shall be packed in plastic trays as agreed upon between the manufacturer and the customer. For packaging systems for sterilized subassembled syringes ready for filling, see ISO 11040‑7. 8 Labelling For labelling of packaging for sterilized subassembled syringes ready for filling, see ISO 11040‑7. Labelling of packaging of bulkware is subject to agreement between the manufacturer and the customer.

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ISO 11040-4:2015(E) Annex A (informative) Examples of types of sterilized subassembled syringes ready for filling

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A.1 Components

Figure A.1 a), Figure A.1 b), and Figure A.1 c) illustrate common components of sterilized subassembled syringes ready for filling.

a) Syringe with staked needle b) Syringe with Luer cone

c) Syringe with Luer lock cone and Luer lock adaptor

Key 1 needle shield 2 needle 3 syringe barrel 4 tip cap 5 plunger 6 plunger rod

7 Luer lock adaptor 8 rigid sleeve 9 protective tamper-evident cap 10 front end of the syringe 11 back end of the syringe

NOTE Plunger (5) and plunger rod (6) are not within the scope of this part of ISO 11040.

Figure A.1 — Examples of sterilized subassembled syringes ready for filling including components of closure systems

A.2 Description of closure systems

A.2.1 General Closure components close the syringe such that the injectable product remains entirely enclosed and that microbiological contamination of the content of the syringe is avoided. The closure components

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ISO 11040-4:2015(E) are mounted onto the syringe body of the sterilized subassembled syringe ready for filling by the manufacturer. This subassembly is then packed in a suitable packaging system and then sterilized by ethylene oxide or another method. The closure system can comprise of — Luer cone, with or without lock, that can be closed using a tip cap, and — needle and needle shield. Examples are given in Figure A.1 a), Figure A.1 b), and Figure A.1 c). A.2.2 Closures for syringes with Luer cone in accordance with ISO 594‑1 Syringes with Luer cones are closed with a tip cap of an appropriate elastomeric material. The seating of the tip cap is ensured by static friction between the female cone of the tip cap and the male cone of the glass syringe and can be improved by ceramic coating or roughening of the cone surface. For schematic illustration, see Figure A.1 b). A.2.3 Closures for syringes with Luer lock cone in accordance with ISO 594‑2 Syringes with Luer lock cone are closed with a tip cap of an appropriate elastomeric material that is, after assembly with a plastic Luer lock adapter comprising a thread standardized in accordance with ISO 594‑2, snapped onto the Luer cone of the syringe such that both parts together form the conical Luer lock. If the closure/closure system is additionally intended to be prevented from falling off or from slipping, it is mounted into a plastic sleeve which is firmly connected with the Luer lock adapter. For simplicity, such closure systems which consist of the Luer lock adapter, the tip cap, and the plastic sleeve are premounted and then snapped together onto the Luer cone of the syringe. This system ensures a safe closure of the syringe by means of the tip cap which is now held in place not just by friction forces but by form-locking. These closure systems are available with or without tamper evidence in various designs. For schematic illustration, see Figure A.1 c). A.2.4 Syringe with staked needle Syringes with a staked needle are closed with a needle shield. It is important that the needle tip, and particularly the opening of this tip, is completely embedded into the elastomer of the needle shield to ensure sealing. For schematic illustration, see Figure A.1 a).

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Annex B (informative) Head designs a b

ISO 11040-4:2015(E)

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Key a To be agreed upon between the manufacturer and the customer. b Cone tolerance deviating from ISO 594‑1 (see also 5.1). NOTE Particular requirements on Luer tip height from the flange or shoulder, which both are common when a syringe is used in injectors, are subject to agreement between the manufacturer and the customer. Figure B.1 — Model A: head design of a glass barrel with a 6 % Luer cone a

b c Key a To be agreed upon between the manufacturer and the customer. b Cone tolerance deviating from ISO 594‑2 (see also 5.1). c Undercut min. 0,03 mm, edges clear formed. NOTE Particular requirements on Luer tip height from the flange or shoulder, which both are common when a syringe is used in injectors, are subject to agreement between the manufacturer and the customer. Figure B.2 — Model B: head design of a glass barrel with a 6 % Luer cone for Luer lock

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ISO 11040-4:2015(E) a Key a Depending on needle diameter. Figure B.3 — Model C: head design of a glass barrel for syringe with staked needle

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ISO 11040-4:2015(E) Annex C (normative) Test methods for syringe barrels

C.1 Flange breakage resistance C.1.1 Principle The test is used to determine the flange breakage resistance by applying a force on a syringe barrel that has been placed in a cylinder holder under the flange. C.1.2 Materials

C.1.2.1 Syringe barrels to be tested, numbers as required. C.1.3 Apparatus

C.1.3.1 Universal tensile and compression testing machine, (attention shall be paid on bench overall rigidity for high-level resistance) complying with the following: — load cell 2 500 N or as appropriate to the force to be measured; — test speed of 100 mm/min or as appropriate; — sampling rate of at least 100 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer.

C.1.3.2 Syringe holder, made of an appropriate material [e.g. polyether ether ketone (PEEK)] and of appropriate dimensions. NOTE Materials and design depend upon the intended use. This is subject to agreement between the manufacturer and the customer. Table C.1 and Figure C.1 include examples for dimensions of a syringe holder.

Table C.1 — Examples for dimensions of the syringe holder and loading pin Dimensions in millimetres

Syringe barrel outer diameter 6,85 8,15 10,85 14,45 17,05 22,05

Diameter A (see Figure C.1) 7,3 8,6 11,4 15,0 17,5 22,5

Diameter b (see Figure C.2) 4 5 7 10 12 16

Radius c (see Figure C.2) 2 2,5 6 8 9 11

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ISO 11040-4:2015(E)

Dimensions in millimetres

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NOTE

For diameter A, see Table C.1 Figure C.1 — Example of a syringe holder

C.1.3.3 Loading pin, made of an appropriate material and of appropriate dimensions. NOTE 1 Materials and design (e.g. radius of curvature adjusted to the internal syringe shoulder design) depend upon the intended use. This is subject to the agreement between the manufacturer and the customer. Table C.1 and Figure C.2 include examples for dimensions of the loading pin. NOTE 2 Polyacetale, shore hardness D according to ISO 7619‑1 between 80 and 90 is a suitable material of the contact area of the loading pin. The rod can be made of stainless steel. C.1.4 Preparation and preservation of test samples Attention shall be paid not to shock the test samples before testing. Inspect the syringe holder and the loading pin for damage prior to testing and change regularly. C.1.5 Procedure C.1.5.1 Place the syringe barrel to be tested in the syringe holder and position the loading pin close to the syringe barrel depth as illustrated in Figure C.2.

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ISO 11040-4:2015(E) Dimensions in millimetres Key 1 syringe holder 2 syringe barrel 3 loading pin NOTE For diameter b and radius c, see Table C.1. Figure C.2 — Placement of the syringe barrel and the loading pin C.1.5.2 Start the test by applying a test speed of 100 mm/min or as appropriate and a sampling rate of at least 100 Hz. C.1.5.3 Record the force versus displacement and prepare a graph. An example is given in Figure C.3.

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ISO 11040-4:2015(E) F

118,5

119,5

Key F force in Newton l distance in millimetre

Figure C.3 — Example of a force versus displacement curve

C.1.6 Expression of results Determine the peak value from the displacement curve. This corresponds to the flange resistance (flange strength). C.1.7 Test report The test report shall include the following: — the test speed (mm/min); — the sampling rate (Hz); — the peak value from the force versus displacement curve for each sample (N); — the numbers of samples tested; — any deviations or observations.

C.2 Luer cone breakage resistance C.2.1 Principle Many Luer syringes are equipped with a Luer lock connector. Especially for syringes for diluents or syringes for water for injections, the Luer connector is often used to connect to a vial adapter in order to provide a safe reconstitution of a lyophylised vial. This subassembly (syringe barrel, vial adapter, and vial) is big in axial size and therefore, during reconstitution and handling charged by mechanical load through the user. The weakest point of this subassembly is the front end of the syringe that can be charged by a side load. The Luer cone breakage resistance test is used to determine the strength of the cone that is determined by the geometry and glass characteristics like residual tension.

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ISO 11040-4:2015(E) The test can be used for an incoming goods inspection. C.2.2 Materials C.2.2.1 Luer syringe barrels to be tested, numbers as required. C.2.3 Apparatus C.2.3.1 Universal tensile and compression testing machine complying with the following: — load cell appropriate to the force to be measured; — test speed of 25 mm/min or as appropriate; — sampling rate of at least 100 Hz. NOTE Definition of load cell, test speed, and sampling is subject to agreement between the manufacturer and the customer. C.2.3.2 Material holder and rod made of stainless steel, for dimensions, see Figure C.4. Dimensions in millimetres

Key 1 compression testing machine with loading pin 2 syringe holder 3 syringe barrel Figure C.4 — Example of a tensile and compression testing machine including holder with the syringe barrel inserted

C.2.3.3 Set of adapter parts that fit in to the syringe format geometry. C.2.4 Procedure

C.2.4.1 Setup the test apparatus as follows:

— check the adapters for damage and correctness;

— assemble the adapters to the tensile and compression testing machine;

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ISO 11040-4:2015(E) — check for security elements, glass breakage will occur; — install and open correct software to the tensile and compression testing machine, if required. C.2.4.2 Perform the test as follows: — place the syringe barrel in the tensile and compression testing machine (see Figure C.4); — close the security elements; — start the measurement applying a test speed of 25 mm/min, or as appropriate, and a sampling rate of at least 100 Hz; — charge the syringe barrel until the cone breaks; apply the force at a distance of approximately 2 mm from the tip of the syringe barrel; — remove the syringe barrel from the adapter; — clean the adapter from glass residuals; — make sure that it breaks at the tip. C.2.5 Expression of results Record the maximum force at which the Luer cone breaks. C.2.6 Test report The test report shall include the following: — sampling rate (the higher the sampling rate, the more accurate the results) (Hz); — test speed (mm/min); — distance from the tip of the point where the syringe is charged (mm) (approximately 2 mm); — maximum force at breakage (N); — number of samples tested; — any deviations or observations.

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ISO 11040-4:2015(E) Annex D (informative) Sample preparation for endotoxin and particulate determination

D.1 Endotoxins D.1.1 General The sample preparation for endotoxin determination is based on the following documents: — Guidance for industry, pyrogen and endotoxins testing, questions and answers [49]; — USP <161>[37]; — USP <85>[35]; — AAMI ST72:2011[23]. D.1.2 Materials and equipment D.1.2.1 Sterilized syringes (i.e. sterilized by ethylene oxide or moist heat), not less than 3 and not more than 10 syringes. D.1.2.2 Plunger stopper, endotoxin-free or has a vendor-certified maximum endotoxin level. D.1.2.3 Endotoxin-free water of injection or Limulus Amebocyte Lysate (LAL) reagents, as extraction fluid having a temperature of (37 ± 1) °C or at least room temperature. D.1.2.4 Shaker. D.1.2.5 Endotoxin-free container. D.1.3 Procedure D.1.3.1 Protect the endotoxin-free container from environmental contamination until analysed, i.e. work in a controlled environment like ISO 5 according to ISO 14644‑1. D.1.3.2 Fill the syringes with extraction fluid up to the nominal fill volume of the syringe. D.1.3.3 Close the syringes with the plunger stopper. D.1.3.4 Store the filled and closed syringes for not less than 1 h at room temperature. D.1.3.5 Shake the syringes vigorously for 10 min on a horizontal shaker (or similar device). D.1.3.6 Pool the extract into an endotoxin-free container by pushing the plunger stopper and empty the syringes through the front end (Luer Cone, staked needle).

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ISO 11040-4:2015(E)

D.1.3.7 Determine the number of endotoxin units (EU/ml) of the extract using the method as given in USP <85>[35] including “positive” and “negative” samples.

The limit of the extraction fluid can be calculated according to USP <161>[37] using Formula (D.1):

K ×N V

(D.1)

where

K is the amount of endotoxin allowed per syringe;

N is the number of devices tested;

V is the total volume of extract rinse.

NOTE Ensure that the sensitivity of test reagent is high enough to allow a proper detection limit of endotoxins for pooled samples. EXAMPLE For 1 ml nominal fill volume and an endotoxin limit <0,25 EU/ml and a sensitivity of the reagent of 0,02 EU/ml, the “alarm” limit for 10 pooled syringes would be 0,20 EU/ml which is <0,25 EU/ml.

D.2 Particulates D.2.1 General The sample preparation for endotoxin determination of particulates is based on USP <788>[40] and Ph. Eur. 2.9.19[29]. D.2.2 Materials and equipment

D.2.2.1 Sterilized syringes (i.e. sterilized by ethylene oxide or moist heat), numbers as required.

D.2.2.2 Plunger stopper and plunger rod, numbers as required.

D.2.2.3 Water, for injection or any grade of purified water.

D.2.2.4 Container. D.2.3 Procedure

D.2.3.1 Protect the container from environmental contamination until analysed, i.e. work in a controlled environment, e.g. ISO 5 according to ISO 14644‑1.

D.2.3.2 Prepare particle-free water by filtration of water for injection or any grade of purified water through a 0,2 µm to 0,8 µm filter unit.

D.2.3.3 Rinse all the needed equipment (e.g. beakers, dosage systems) with particle-free water.

D.2.3.4 Transfer a minimum of 30 ml of particle-free water into a cleaned container and let it rest undisturbed for a minimum of 2 min to allow degassing of air bubbles.

D.2.3.5 Determine the particle content of the particle-free water but disregard the first measurement as it is only used to clean the measurement system.

D.2.3.6 The limits for the particle-free water by light obscuration are

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ISO 11040-4:2015(E) — 10 particles ≥10 µm, and — 2 particles ≥25 µm. If the particle content is within the limit, continue with the sample preparation. If the particle content is not within the limit, repeat the filtration and measurement until the particlefree water is within specification (D.2.3.2 to D.2.3.5). D.2.3.7 Fill the syringes with nominal volume and close with clean plunger stopper. D.2.3.8 Invert the syringes 20 times. NOTE It can be necessary to agitate the solution more vigorously to suspend the particles properly. D.2.3.9 Remove the tip cap/needle shield and dispense the contents of the syringes into a cleaned container by depressing the plunger with a plunger rod. D.2.3.10 Let the solution rest un-disturbed for a minimum of 2 min to allow degassing of air bubbles. D.2.3.11 Determine the particle content per syringe but disregard the first measurement as it is only used to clean the measurement system. The limits for the containers by light obscuration are — 600 particles ≥10 µm, and — 60 particles ≥25 µm NOTE A minimum pooled sample volume of 25 ml is needed to perform four runs of 5 ml each. The first run is always discarded. The average is calculated for the remaining three test runs. Depending on the nominal fill volume of the syringes, a certain amount of syringes is needed for 1 pool: — 25 syringes 1ml 25ml pool; — 13 syringes 2ml 25ml pool; — 12 syringes 2,25ml 25ml pool; — 9 syringes 3ml 25ml pool; — 5 syringes 5ml 25ml pool. To avoid air bubbles in the measuring device, it is recommended to add an extra 5 ml to the pool (30 ml pool volume). Depending on the batch size of the syringes produced, multiple pools can be required.

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ISO 11040-4:2015(E) The number of particles in each container can be calculated using Formula (D.2): P ×Vt Va ×n where P is the average particle count obtained from the portion of container; Vt is the volume of pooled sample (ml); Va is the nominal volume of the syringe (ml); N is the number of containers pooled.

(D.2)

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ISO 11040-4:2015(E) Annex E (informative) Glide force test method to evaluate syringe lubrication

E.1 Purpose This test method is used to measure the gliding force of empty syringe barrels to assess the quality and consistency of silicone oil lubrication within the inner syringe barrel. The ability to assess the quality and consistency of silicone oil lubrication can be dependent on the test speed used. NOTE Typically, a test speed of 100 mm/min (similar to ISO 7886‑1) is used; however, it can be insufficient to detect lubrication defects. The test speed is subject to agreement between the manufacturer and the customer. This test method applies to any siliconized, sterilized subassembled syringes ready for filling. Break loose force is not part of this test method because break loose force is applicable to the syringe (complete system). E.2 Materials E.2.1 Empty sterilized subassembled syringes ready for filling, numbers as required. E.2.2 Plunger stoppers (piston) in ready-to-use format, to be agreed upon between the manufacturer and the customer (dimensions, compound, siliconization level, sterilization). E.2.3 Plunger rods, appropriate for use with selected plunger stopper, to be agreed upon between the manufacturer and the customer. E.3 Apparatus E.3.1 Universal tensile and compression testing machine complying with the following: — test speed of 100 mm/min or as appropriate; — force range up to 50 N or as appropriate. NOTE Definition of test speed and force range is subject to agreement between the manufacturer and the customer. E.3.2 Syringe support and syringe adaptor plates, appropriately sized for the sterilized subassembled syringes ready for filling to be tested. E.3.3 Vent tube stoppering tool or machine. E.4 Procedure E.4.1 Set the plunger stopper in the empty syringe barrel by using the vent tube insertion method. Select stopper position(s) based on the following areas of concern:

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ISO 11040-4:2015(E) — focus on front portion of barrel; sensitive area for auto-injector performance: Select a position corresponding to 50 % of nominal fill volume (e.g. 27 mm from back of barrel flange to back of plunger stopper, 1 ml-long syringe); — characterization of entire barrel: Select a position corresponding to nominal fill volume (e.g. 10 mm from back of barrel flange to back of plunger stopper, 1 ml-long syringe). E.4.2 Install the plunger rod into or onto the plunger-stopper. NOTE The plunger rod can be with or without thread. E.4.3 Remove the needle shield or other front closure from the sterilized subassembled syringe ready for filling. E.4.4 Place the sterilized subassembled syringe ready for filling in the adaptor plate on the forcemeasurement instrument. E.4.5 Start the compression at the designated speed. E.4.6 End the test when the plunger stopper comes into contact with the shoulder of the syringe barrel. E.4.7 Repeat the steps E.4.1 to E.4.6 for additional test samples. E.4.8 Record the maximum force in the glide force test region (see b in Figure E.1). The glide force test region is defined as the region between the break loose until the sharp increase of the force at the end of the stroke. See Figure E.1. Limit values should be agreed between the manufacturer and the customer.

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F a

ISO 11040-4:2015(E)

l Key 1 start of stopper movement 2 end of testing condition F force in Newton l distance in millimetre a break loose region b glide force test region c end of stroke region Figure E.1 — Example illustrating gliding characteristics E.5 Test report The test report should include the following: — maximum gliding force in the glide force test region (b) (N); — calculated average gliding force (N); — numbers of tested samples; — any deviations or observations.

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ISO 11040-4:2015(E)

Annex F (informative) Needle penetration test

F.1 Principle This test method is used to determine the needle penetration force by piercing a test foil with a needle. The test has been derived from DIN 13097-4. NOTE A test method on needle penetration is currently in preparation by ISO/TC 84. It is intended to harmonize this test method with that prepared by ISO/TC 84 when it becomes available.

F.2 Apparatus F.2.1 Universal tensile and compression testing machine complying with the following: — measuring range up to 50 N or as appropriate; — test speed within the range 20 mm/min to 200 mm/min or as appropriate. NOTE Definition of measuring range and test speed is subject to agreement between the manufacturer and the customer. F.2.2 Needle holder.

F.3 Materials F.3.1 Test foil, specification to be agreed upon between the manufacturer and the customer. F.3.2 Needles and syringes with a staked needle as supplied or with pre-treatment, i.e. siliconized, (in accordance with ISO 9626), numbers as appropriate, to be agreed upon between the manufacturer and the customer.

F.4 Procedure F.4.1 Fix the test foil tension-free in the holder. F.4.2 Fix the needle in the needle holder perpendicular to the test foil and with the tip to the geometric centre of the free area of the test foil. F.4.3 Start the test and penetrate the test foil with the needle. F.4.4 Record the force versus displacement curve. F.4.5 Use a new (not perforated) foil section for each penetration test. Examples on penetration force behaviour and force versus displacement curve are given in Figure F.1 and Figure F.2.

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ISO 11040-4:2015(E)

1. The needle tip meets the test foil. 2. The tip presses the foil, the force increases to F0. 3. The tip penetrates the foil, the cutting phase starts. 4. The cutting edges make the cut. 5. The cut is finished with the force maximum F1. 6. Dilatation of the cut via the primary bevel. 7. Heel passes the foil, the force with maximum F2. 8. The needle tube slides through the enlarged cut.

mm N

N F0 mm

F1 F2

Figure F.1 — Stages of the penetration process

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ISO 11040-4:2015(E) N F0

F1 F2

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Key F0 force for passing the tip (piercing force) F1 force for cutting with the cutting edges (cutting force) F2 force where the heel passes the foil F3 drag penetration force

NOTE foils.

The given illustration is an example only. This curve might not be representative of all needles and test

Figure F.2 — Example of a force versus displacement curve

F.5 Test report The test report should include the following: — specification of the test foil; — test speed (mm/min); — force versus displacement curves; — numbers of tested samples; — any deviations or observations.

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ISO 11040-4:2015(E) Annex G (normative) Test methods for closure systems G.1 Needle pull-out force G.1.1 Principle The test is used to assess the fixation of the needle to the syringe. It is mainly designed to verify whether the needle bonding process is appropriate to show that the staked needle withstands a needle size (gauge) dependent pull-out force according to ISO 7864. G.1.2 Materials G.1.2.1 Sterilized subassembled syringes ready for filling with a staked needle, numbers as required. G.1.3 Apparatus G.1.3.1 Universal tensile and compression testing machine complying with the following: — load cell of max 500 N or as appropriate for the force to be measured; — test speed of 50 mm/min or as appropriate; — sampling rate of minimum 65 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer. G.1.3.2 Syringe holder (syringe can be fixed by shoulder or finger flange during testing). G.1.3.3 Needle gripper device, designed to avoid slippage and to avoid an influence on the measurement itself. G.1.4 Preparation and preservation of test samples The test samples shall follow the same process as the product delivered. G.1.5 Procedure G.1.5.1 Insert the test sample vertically positioned on the testing machine (see Figure G.1).

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ISO 11040-4:2015(E)

F 1 3

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Key 1 needle gripper attached to a testing machine 2 syringe with staked needle 3 syringe holder/base plate Figure G.1 — Position of the test sample in the tensile testing machine G.1.5.2 Grip as much as possible of the needle to avoid slippage. G.1.5.3 Release the test sample. G.1.5.4 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when the “zero” is set. G.1.5.5 Apply a test speed of 50 mm/min or as appropriate, at an appropriate sampling rate [Hz]. G.1.5.6 Start the test. G.1.5.7 Record the force versus displacement. G.1.5.8 Stop the test once the needle is clearly removed from the syringe or broken. G.1.6 Expression of results Record the maximum load peak from the force versus displacement curve. This corresponds to the pullout force of the needle system of the syringe.

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ISO 11040-4:2015(E)

G.1.7 Test report The test report shall include the following: — test speed (mm/min); — sampling rate (Hz); — force versus displacement curve; — peak value according to the maximum force (N); — number of tested samples; — any deviations or observations.

G.2 Closure system liquid leakage test G.2.1 Principle The test is used to assess the liquid leakage resistance of the closure systems (needle shield or tip cap/barrel assembly). It is mainly designed to verify whether the closure system is able to withstand any potential overpressure inside the syringe during the filling process or during transportation. The test pressure of 110 kPa has been selected based on process conditions during the fill finish process. G.2.2 Reagents and materials

G.2.2.1 Reagents of recognized analytical grade and distilled water or water of equivalent purity.

G.2.2.2 Sterilized subassembled syringes ready for filling, numbers as required. G.2.3 Apparatus

G.2.3.1 Universal tensile and compression testing machine or pressurization through the application of compressed air. NOTE Application of pressure via universal tensile and testing machine [(see Figure G.2 a)] is preferred when wall friction can be neglected. In this case, it is assumed that equilibrium is reached between the applied force and the internal pressure. If wall friction cannot be neglected, preference is given to the test as indicated in Figure G.2 b) where the pressures are applied on the closure system through the application of compressed air on the filled media.

G.2.3.2 Syringe holder.

G.2.3.3 Piston and piston rod. G.2.4 Preparation and preservation of test samples The retention time/waiting time between closure setting and leakage testing shall be at least 12 h. Attention shall be paid not to damage and/or loosen the closure system/syringe tip prior to testing. G.2.5 Procedure

G.2.5.1 Insert the test sample into the holder. See Figure G.2.

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ISO 11040-4:2015(E)

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G.2.5.2 Fill the test sample to between 1/3 and 2/3 of the nominal fill volume with the reagent (see G.2.2.1).

G.2.5.3 In case of pressurization, close the holder with the lid and secure the device.

G.2.5.4 Apply a pressure of 110 kPa and hold the pressure for 5 s.

The correlation between the test force and the cross-sectional area of the syringe that is determined by the nominal inner diameter of the syringe can be calculated using Formula (G.1), Formula (G.2), and Formula (G.3) (see also Table G.1):

from

F = p×A

(G.1)

and A= π ×d2 4 follows F = p× π ×d 2 ×10−3 4 where F is the force in Newton; p is the target internal pressure (kPa) (i.e. 110 kPa); A is the cross-sectional area of the syringe barrel (mm2); d is the nominal inner diameter of the syringe barrel (mm).

(G.2) (G.3)

Table G.1 — Correspondence between the inner diameter of the syringe barrel and the test force

Nominal volume of the syringe barrel ml

Nominal inner diameter of the syringe barrel mm

0,5

4,65

6,35

1 to 3

8,65

(short/standard)

11,85

14,25

19,05

a Calculated for the target internal pressure of 110 kPa.

Calculated test forcea N 1,87 3,48 6,46 12,13 17,54 31,35

G.2.5.5 Release the pressure.

G.2.5.6 Monitor the test samples for leakage during and after the test. G.2.6 Expression of results The test is passed if the tip caps are not falling off and/or if no droplets are visible around the external surfaces of the closure system (wet surface of tip cap or needle shield).

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Visually examine if the test samples have passed or failed the test. G.2.7 Test report The test report shall include the following: — applied pressure (kPa) or force (N); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations. F

ISO 11040-4:2015(E)

3 1

a) pressure applied via piston rod and piston through a tensile testing machine Key 1 syringe holder 2 syringe with closure system 3 piston rod and piston

b) pressure supplied by compressed air directly on filled media

NOTE This illustration includes a syringe with a needle shield as an example. The testing is equally applicable to syringes with a tip cap.

Figure G.2 — Examples of testing devices for the determination of closure system liquid leakage

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ISO 11040-4:2015(E) G.3 Luer lock adaptor collar pull-off force G.3.1 Principle The test is used to assess the pull-off force of a Luer lock adaptor (LLA) collar system of sterilized subassembled syringes ready for filling. It is mainly designed to verify whether the LLA collar system is able to withstand an axial pull-off force in order to avoid detachment of the LLA collar system from the syringe barrel by the insertion of a female 6 % (Luer) conical lock fitting. G.3.2 Materials G.3.2.1 Sterilized subassembled syringes ready for filling with LLA, number as required. G.3.3 Apparatus G.3.3.1 Universal tensile and compression testing machine complying with the following: — test speed of 20 mm/min or as appropriate (see ISO 594‑2); — load cell appropriate to the force to be measured, typical range of load cell is between 10 N and 100 N; — sampling rate of at least 65 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer. G.3.3.2 Syringe holder (see Figure G.3) and gripper device.

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1 2

Key 1 LLA gripper plate 2 syringe with LLA/LLA systems 3 syringe holder/base plate Figure G.3 — Example of a testing device for the determination of the Luer lock adapter collar pull-off force

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ISO 11040-4:2015(E) G.3.4 Preparation and preservation of test samples The test samples shall follow the same process as the product delivered. G.3.5 Procedure G.3.5.1 Remove the tip cap. G.3.5.2 Insert the test sample vertically positioned on the testing machine between the holder (finger flange side) and the gripper (LLA collar side). G.3.5.3 Make sure that no pressure/movement is applied to the LLA collar system during test assembling. G.3.5.4 Release the test sample. G.3.5.5 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when “zero” is set. G.3.5.6 Apply a test speed of 20 mm/min or as appropriate at an appropriate sampling rate. G.3.5.7 Record the force versus displacement. G.3.5.8 Stop the test once the LLA collar system is clearly removed from the syringe tip. G.3.6 Expression of results Determine the load peak from the force versus displacement curve. The peak value corresponds to the pull-off force of the LLA collar system of the syringe. G.3.7 Test report The test report shall include the following: — sampling rate (Hz); — test speed (mm/min); — peak value (pull-off force) (N); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations. G.4 Luer lock adaptor collar torque resistance G.4.1 Principle The test is used to assess the torque resistance of a LLA collar system of a sterilized subassembled syringe ready for filling. It is mainly designed to verify whether the LLA collar system is able to withstand an applied torque while inserting a female 6 % (Luer) conical lock fitting (i.e. needle hub).

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ISO 11040-4:2015(E) G.4.2 Materials G.4.2.1 Sterilized subassembled syringes ready for filling with LLA, number as required. G.4.3 Apparatus G.4.3.1 Torque tester combined with a rotation device (see Figure G.4) complying with the following: — torque cell 35 Ncm with 0,05 Ncm resolution or as appropriate to the torque to be measured; — sampling rate of at least 65 Hz; — rotation speed of 20 r/min or as appropriate. NOTE 1 Definition of torque cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer. NOTE 2 For this test, either the syringe barrel or the closure can be rotated. G.4.3.2 Adapter: LLA collar gripper. G.4.3.3 Syringe holder (rotatable, if this alternative is used).

Key 1 LLA gripper inclusive torque sensor 2 syringe with LLA 3 syringe holder/base plate (rotatable) NOTE For this test, either the syringe barrel or the closure can be rotated. Figure G.4 — Example of testing device for the determination of the Luer lock adapter collar torque resistance, with rotatable syringe holder G.4.4 Preparation and preservation of test samples and test pieces The test samples shall follow the same process as the product delivered.

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ISO 11040-4:2015(E) G.4.5 Procedure G.4.5.1 Insert the test sample vertically positioned into the syringe holder of the testing device. See Figure G.4. G.4.5.2 Remove the tip cap. NOTE This can be done manually. G.4.5.3 Mount the adapter onto the LLA collar. G.4.5.4 Set the torque cell to “zero”. Attention shall be paid that no significant pre-torque is applied. G.4.5.5 Set the rotation speed at 20 rotations per minute or as appropriate. G.4.5.6 Start the test by either rotating the turntable 90° clockwise or counter clockwise, depending on the system. Alternatively, rotate the closure. G.4.5.7 Record the peak of the applied torque. G.4.6 Expression of results Record the maximum torque peak. This corresponds to the torque where the LLA collar starts to rotate on the syringe. G.4.7 Test report The test report shall include the following: — rotation speed (°/s or r/min); — sampling rate (Hz); — maximum torque (Ncm); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations. G.5 Luer lock rigid tip cap unscrewing torque G.5.1 Principle The test is used to assess the torque of a rigid tip cap of a sterilized subassembled syringe ready for filling. It is mainly designed to verify whether the rigid tip cap can be removed from the syringe with a reasonable torque. G.5.2 Materials G.5.2.1 Sterilized subassembled syringes ready for filling with a tip cap, numbers as required.

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ISO 11040-4:2015(E)

G.5.3 Apparatus G.5.3.1 Torque tester combined with a rotation device complying with the following: — torque cell 35 Ncm with 0,05 Ncm resolution or as appropriate to the torque to be measured; — sampling rate of at least 65 Hz; — rotation speed of 20 r/min or as appropriate. NOTE 1 Definition of torque cell, sampling rate, and rotation speed is subject to agreement between the manufacturer and the customer. NOTE 2 For this test, either the syringe barrel or the closure can be rotated. G.5.3.2 Adapter: tip cap gripper. G.5.3.3 Syringe holder (rotatable, if this alternative is used). G.5.4 Preparation and preservation of test samples and test pieces The test samples shall follow the same process as the product delivered. G.5.5 Procedure G.5.5.1 Insert the test sample vertically positioned into the syringe holder of the testing device (see Figure G.5). G.5.5.2 Mount the adapter onto the tip cap. G.5.5.3 Set the torque cell to “zero”. Attention shall be paid that no significant pre-torque is applied. G.5.5.4 Set the rotation speed at 20 r/min or as appropriate. G.5.5.5 Start the test by either rotating the turntable 90° clockwise or counter clockwise depending on system. Alternatively, rotate the closure. G.5.5.6 Record the peak load of the applied torque. G.5.6 Expression of results Record the maximum torque peak. This corresponds to the torque where the tip cap starts to rotate on the syringe. G.5.7 Test report The test report shall include the following: — rotation speed (°/s or r/min), — sample rate (Hz); — maximum torque (N·cm); — number of tested samples; — number of passed/failed samples according to specification;

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— any deviations or observations.

ISO 11040-4:2015(E)

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2 3

Key 1 gripper inclusive torque sensor 2 syringe with tip cap 3 syringe holder/base plate (rotatable) NOTE For this test, either the syringe or the closure can be rotated. Figure G.5 — Example of a testing device for the determination of the Luer lock rigid tip cap removal unscrewing torque G.6 Pull-off force of the tip cap or the needle shield G.6.1 Method 1 G.6.1.1 Principle This test is used to assess the removal force of the tip cap or the needle shield of a sterilized subassembled syringe ready for filling. This method can be customized depending on the intended use of the syringe (e.g. manual use, use in an auto-injector). An alternative procedure is described in G.6.2. G.6.1.2 Materials G.6.1.2.1 Sterilized subassembled syringes ready for filling, numbers as required.

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ISO 11040-4:2015(E)

G.6.1.3 Apparatus

G.6.1.3.1 Universal tensile and compression testing machine complying with the following: — load cell 50 N to 100 N, appropriate to the force to be measured; — sampling rate of at least 40 Hz; — test speed between 100 mm/min and 1 000 mm/min or as appropriate. NOTE Definition of load cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer.

G.6.1.3.2 Syringe holder.

G.6.1.3.3 Tip cap/needle shield gripper.

G.6.1.4 Procedure

G.6.1.4.1 Position the test sample vertically with the closure oriented upwards see Figure G.6.

G.6.1.4.2 Apply the grip pressure such that the grip does not slide against or distort/deform the closure system.

G.6.1.4.3 With the syringe otherwise unconstrained, set the load cell to “zero”.

G.6.1.4.4 Position the syringe holder such that the syringe will be captured by the holder when an axial tension force is applied.

G.6.1.4.5 Apply a sampling rate of at least 40 Hz.

G.6.1.4.6 Set the bench displacement rate between 100 mm/min and 1 000 mm/min or as appropriate.

G.6.1.4.7 Record the force versus displacement.

G.6.1.4.8 Stop the test once the closure system is completely removed from the syringe tip.

G.6.1.5 Expression of results The closure system (tip cap /needle shield) pull-out force corresponds to the maximum load recorded in the force versus displacement curve.

G.6.1.6 Test report

The test report shall include the following:

— sampling rate (Hz);

— test speed (mm/min);

— load cell (N);

— maximum load recorded in the force versus displacement curve (N);

— number of tested samples;

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ISO 11040-4:2015(E) Dimensions in millimetres F

2 2

3 3

a) syringe with needle shield Key 1 gripper attached to tensile testing machine 2 syringe with needle shield/tip cap 3 syringe holder/base plate

b) syringe with tip cap

Figure G.6 — Examples of testing devices for the determination of the pull-off force of the tip cap or the needle shield – Method 1

G.6.2 Method 2

G.6.2.1 Principle This test is used to assess the removal force of the tip cap or the needle shield of a sterilized subassembled syringe ready for filling. This test allows the pull-out force to be evaluated without pinching the needle shield and/or the needle. It prevents deformation of the rubber part. An alternative procedure is described in G.6.1.

G.6.2.2 Materials

G.6.2.2.1 Sterilized subassembled syringes ready for filling, numbers as required.

G.6.2.3 Apparatus

G.6.2.3.1 Universal tensile testing and compression machine complying with the following:

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ISO 11040-4:2015(E) — load cell up to 500 N; — sampling rate as appropriate; — test speed as appropriate. NOTE Definition of load cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer. G.6.2.3.2 Pulling device, see Figure G.7. G.6.2.4 Procedure G.6.2.4.1 Position the test sample vertically, syringe flange, and tip cap or needle-shield in their respective holder. G.6.2.4.2 Release the test sample. G.6.2.4.3 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when “zero” is set. G.6.2.4.4 Start the test. G.6.2.4.5 Record the force versus displacement. G.6.2.4.6 Stop the test once the closure is removed from the tip of the syringe. G.6.2.5 Test report The test report shall include the following: — load cell (N); — test speed (mm/min); — sampling rate (Hz); — mean, minimum, and maximum value recorded in the force versus displacement curve (N); — number of tested samples; — any deviations or observations.

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1 2

ISO 11040-4:2015(E)

1 2

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a) syringe with needle shield Key 1 pull-off device attached to tensile testing machine 2 syringe with needle shield/tip cap 3 syringe holder/base plate

b) syringe with tip cap

Figure G.7 — Examples of testing devices for the determination of the pull-off force of the tip cap or the needle shield – Method 2

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ISO 11040-4:2015(E)

Annex H (informative) Dye solution tightness test

H.1 General Sterilized subassembled syringes ready for filling with the injectable product consist of a syringe barrel with a Luer cone or a staked needle on the side facing the patient (front end) commonly sealed with a tip cap in case of a Luer syringe or a needle shield in case of a syringe with staked needle. The back end is sealed with a plunger stopper that allows the delivery of the drug by pushing the plunger stopper towards the liquid with a plunger rod. The tip cap or needle shield on the one side and the plunger stopper on the other side ensure appropriate sealing of the syringe. The dye solution tightness test is a valuable method to test the tightness of a sterilized subassembled syringe ready for filling in the design development phase. This test method alone is not sufficient to ensure container closure integrity of the system. The customer should assume responsibility to properly validate a suitable physical, chemical, or microbiological container closure integrity test method to qualify their chosen container closure system (including injectable product). H.2 Principle Subassembled syringes that are filled with liquid and stoppered with a plunger stopper are submerged in a dye solution. The subassembled syringes are inspected for leakage by checking the presence or absence of ingress of the dye solution into the syringe after applying a depressurisation/re-pressurization cycle. H.3 Apparatus, equipment, and reagents H.3.1 Syringe barrels, according to this part of ISO 11040, preferably prepared as being used in regular production. H.3.2 Tip caps, needle shields, or any other front end closure, to match the front end opening of the syringe, preferably prepared as being used in regular production. H.3.3 Plunger stoppers, according to ISO 11040‑5 to match the inner diameter of the syringe, preferably prepared as being used in regular production. H.3.4 Particle-free water to fill the syringes. H.3.5 Appropriate dye solution, including a colorant and possibly a surfactant. NOTE Suitable dyes are methylene blue, rhodamine B, and fluorescein; possible surfactants are Triton X-100 and Tween 80.2) It is recommended that the dye solution be filtered through a filter (pore size <1 µm) and stored in a clean, particulate-free container until use.

Triton X‑100 and Tween 80 are examples of suitable products available commercially. This information is given for the convenience of users of this document and does not constitute an endorsement by ISO of these products.

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ISO 11040-4:2015(E) H.3.6 Vacuum chamber, capable of maintaining a pressure of min. 270 mbar below atmospheric pressure for 30 min. H.3.7 Hypodermic needle(s), according to ISO 7864 and of size 27 g × 0,5 in. H.4 Preparation and preservation of test samples and test pieces H.4.1 Fill the syringes to nominal volume with particle-free water. H.4.2 Assemble the plunger stopper, leaving an air gap of 2 mm to 5 mm, preferably use the standard piston placement method intended for the future filling process (vent tube or vacuum piston placement). NOTE This method might not work without an air bubble. H.4.3 Discard any syringes with liquid beyond or between the ribs. H.4.4 Create one or more positive leak control samples by creating an open fluid path to the syringe content (e.g. by placing a hypodermic needle or similar device between the front end of the syringe and the corresponding closure or in case of needle shields, by removing the needle shield). H.4.5 Keep one syringe as a reference sample for comparison (not immersed in dye solution). H.5 Procedure H.5.1 Fill the vacuum chamber or an appropriate container with dye solution to a level that all syringes can be completely immersed in the solution. H.5.2 Immerse the syringes in the dye solution. Ensure that the syringes are completely immersed. Reduce the pressure by 270 mbar. Hold the pressure for 30 min then restore to atmospheric pressure. Allow the syringes to remain immersed in the dye solution for an additional 30 min, then remove them carefully from the solution, rinse the syringes with water until all dye solution is completely removed from the outside, and dry the syringes. H.5.3 Inspect all syringe contents visually for any traces of the dye solution. Compare the syringes to the positive and reference controls. The positive control should show the presence of dye in the syringe contents. Spectroscopy might also be used to detect dye. H.6 Test report The test report should include the following information: — colour change of the positive leak sample; — that the reference sample did not show any colour change; — number of syringes that show a colour change and thus, leaked; — any deviations or observations.

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ISO 11040-4:2015(E)

Bibliography

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[1] ISO 180, Plastics — Determination of Izod impact strength [2] ISO 178, Plastics — Determination of flexural properties [3] ISO 527‑2, Plastics — Determination of tensile properties — Part 2: Test conditions for moulding and extrusion plastics [4] ISO 554, Standard atmospheres for conditioning and/or testing — Specifications [5] ISO 2039‑2, Plastics — Determination of hardness — Part 2: Rockwell hardness [6] ISO 2859‑1, Sampling procedures for inspection by attributes — Part 1: Sampling schemes indexed by acceptance quality limit (AQL) for lot-by-lot inspection [7] ISO 3951 (all parts), Sampling procedures and charts for inspection by variables for percent nonconforming [8] ISO 7619‑1, Rubber, vulcanized or thermoplastic — Determination of indentation hardness — Part 1: Durometer method (Shore hardness) [9] ISO 10993‑1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process [10] ISO 11040‑7,3)Prefilled syringes — Part 7: Packaging systems for sterilized subassembled syringes ready for filling [11] ISO 11608‑2, Needle-based injection systems for medical use — Requirements and test methods — Part 2: Needles [12] ISO 11135‑1, Sterilization of health care products — Ethylene oxide — Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices [13] ISO 11137 (all parts), Sterilization of health care products — Requirements for validation and routine control — Radiation sterilization [14] ISO 11140 (all parts), Sterilization of health care products — Chemical indicators [15] ISO 14644‑1, Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness by particle concentration [16] ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices [17] ISO 15378, Primary packaging materials for medicinal products - Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP) [18] ISO 17665‑1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices [19] ISO 11608‑5, Needle-based injection systems for medical use — Requirements and test methods — Part 5: Automated functions [20] ISO 23908, Sharps injury protection — Requirements and test methods — Sharps protection features for single-use hypodermic needles, introducers for catheters and needles used for blood sampling

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ISO 11040-4:2015(E) [21] ISO 80369‑74), Small-bore connectors for liquids and gases in healthcare applications — Part 7: Connectors with 6% (Luer) taper for intravascular or hypodermic applications [22] ISO/IEC Guide 98‑3, Uncertainty of measurement — Part 3: Guide to the expression of uncertainty in measurement (GUM:1995) [23] AAMI ST72:2011, Bacterial endotoxins — Test methodologies, routine monitoring, and alternatives to batch testing [24] DIN 13097-4, Medizinische Kanülen — Teil 4: Anschliffarten, Anforderungen und Prüfung [25] Cantor Verlag, Defect evaluation list for containers made of tubular glass, 4th edition, Vol. 19, Editio 88322 Aulendorf, Germany [26] CPMP/QWP. 159/01, Note for Guidance on limitations to the use of ethylene oxide in the manufacture of medicinal products, www.ema.europa.eu [27] Ph E. 2.6.1, Sterility, www.edqm.eu [28] Ph E. 2.6.14, Bacterial endotoxins, www.edqm.eu [29] Ph E. 2.9.19, Particulate contamination: sub-visible particles, www.edqm.eu [30] Ph E. 2.9.20, Particulate contamination: visible particles, www.edqm.eu [31] Ph E. 3.1.8, Silicone oil used as a lubricant, www.edqm.eu [32] Ph E. 3.2.1, Glass containers for pharmaceutical use, www.edqm.eu [33] Ph E. 3.2.9, Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders, www.edqm.eu [34] USP <71>, Sterility tests, www.usp.org/ [35] USP <85>, Bacterial endotoxins test www.usp.org/ [36] USP <88>, Biological reactivity tests, in vivo, www.usp.org/ [37] USP <161>, Transfusion and infusion assemblies and similar medical devices [38] USP <381>, Elastomeric closures of injections, www.usp.org/ [39] USP <660> Containers – Glass, www.usp.org/ [40] USP <788>, Particulate matter in Injections, www.usp.org/ [41] USP <1231>, Water for pharmaceutical purposes, www.usp.org/ [42] USP NF <>, www.usp.org/ [43] JP 4.01, Bacterial endotoxins tests, http:/jpdb.nihs.gojp/jp16e [44] JP 4.06, Sterility test, http:/jpdb.nihs.gojp/jp16e [45] JP 6.06, Foreign insoluble matter test for injections, http:/jpdb.nihs.gojp/jp16e [46] JP 6.07, Insoluble particulate matter test for injections, http:/jpdb.nihs.gojp/jp16e [47] JP 7.01, Test for glass containers for injections [48] JP 7.03, Test for rubber closure for aqueous infusions, http:/jpdb.nihs.gojp/jp16e

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ISO 11040-4:2015(E) [49] Guidance for industry, pyrogen and endotoxins testing, questions and answers, June 2012, www. fda.gov

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ISO 11040-4:2015(E)

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=== ISO 11040-5 ===

INTERNATIONAL STANDARD

ISO 11040-5 Third edition 2012-01-15

Prefilled syringes — Part 5: Plunger stoppers for injectables Seringues préremplies — Partie 5: Bouchons-pistons pour produits injectables

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Reference number ISO 11040-5:2012(E)

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ISO 11040-5:2012(E)

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ISO 11040-5:2012(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 2. 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 11040-5 was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This third edition cancels and replaces the second edition (ISO 11040-5:2001), which has been technically revised by: — adjusting the title of this part of ISO 11040; — aligning this International Standard with the ISO 8871 series; — revising the requirements on the height of the spacers and requirements on material and hardness; — adding requirements on resistance to ageing. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plunger stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges — Part 4: Glass barrels for injectables and ready-to-use prefillable syringes — Part 5: Plunger stoppers for injectables — Part 6: Plastics barrels for injectables The following parts are under preparation: — Part 7: Packaging systems for prefillable ready-to-use syringes

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ISO 11040-5:2012(E) Introduction Primary packaging components made of elastomeric materials are an integral part of medicinal products. Therefore, the principles of current good manufacturing practices (cGMP) apply to the manufacturing of these components. Principles of cGMP are described in e.g. ISO 15378 or in the GMP Guidelines published by the European Community and the United States of America.

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INTERNATIONAL STANDARD

ISO 11040-5:2012(E)

Prefilled syringes — Part 5: Plunger stoppers for injectables

1 Scope

This part of ISO 11040 specifies the shape, dimensions, material, performance requirements and labelling of plunger stoppers for glass barrels (single-chamber design) for injection preparations in accordance with ISO 11040-4.

Plunger stoppers specified in this part of ISO 11040 are intended for single use only.

This part of ISO 11040 is not applicable to barrier-coated plunger stoppers.

NOTE

The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be

significantly affected by the nature and performance of the primary packaging.

3 Classification Plunger stoppers shall be classified as follows: — type PSL: plunger stoppers with snap lid; — type PST: plunger stoppers with thread.

4 Shape and dimensions 4.1 The shape and dimensions of plunger stoppers shall be as shown in Figure 1 and given in Table 1.

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ISO 11040-5:2012(E)

Dimensions in millimetres

a) Plunger stopper with snap lid (PSL)

NOTE

Thread: 16 pitch on 25,4 mm; for 1 ml (long), 17 pitch on 25,4 mm. b) Plunger stopper with thread (PST)

Shape and dimensions of plunger stoppers for a prefilled syringe

ISO 11040-5:2012(E)

Dimensions of plunger stoppers

Dimensions in millimetres

Nominal inner diameter d2b

Nominal Type

d1a

volume

nom.

tol.

d2a

nom.

tol.

d3a

nom.

tol.

h1a nom. tol.

5,2

4,1

6,85

4,65 ± 0,1

0,5

PSL

2,5

5,3

4,2

7,0

6,8

5,9

7,65

6,35 ± 0,1

1 (long)

2,6

±0,2

7,85

8,65 ± 0,2 11,85 ± 0,2

1 to 3 5

9,05

7,6

±0,1

4,7

9,25 12,5

±0,15

10,5

5,2

PST

12,7

11,15

5,6

7,7 to 7,85 ±0,4 8,5

14,25 ± 0,2

13,5

15,3

13,75

7,4

8,5

±0,25

7,6

19,05 ± 0,2

19,9

18,4

±0,15

20,1

18,6

13,45

10,7

13,50

a The nominal diameter shall be agreed upon between the manufacturer and the user within the given range.

b In accordance with ISO 11040-4.

h2a nom. tol. 5,3 ±0,35 4,5 6,0 ±0,3 6 to 6,2 7

4.2 If not otherwise specified, general dimensional tolerances shall be Class M3 in accordance with ISO 3302-1. 4.3 In order to prevent the plunger stoppers from adhering to each other, there shall be spacers. The height of the spacers shall not exceed 0,3 mm. The shape of the spacers should be agreed upon between the manufacturer and the cartridge assembler. 4.4 Sprues, if present on the surface of the plunger stopper, shall not protrude beyond the surface of the plunger stopper. 4.5 The performance and dimensions of the plunger stopper thread shall be compatible with the plunger rod. The plunger stopper shall not detach itself from the rod under normal use, e.g. aspiration. 5 Designation Plunger stoppers are designated according to their type. The designation shall comprise, in the following order, the descriptor “Plunger”, a reference to this part of ISO 11040, the type of plunger [snap lip (PSL) or threaded (PST)], the volume of the barrel for which the plunger stopper is intended, and the letters “lg” if it is the long version. EXAMPLE 1 Designation of a plunger stopper with snap lip for a glass barrel of 0,5 ml nominal volume, complying with the requirements in this part of ISO 11040: Plunger ISO 11040-5 - PSL - 0,5 EXAMPLE 2 Designation of a threaded plunger stopper for a glass barrel of 1 ml nominal volume, long version, complying with the requirements in this part of ISO 11040: Plunger ISO 11040-5 - PST - 1 - lg

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ISO 11040-5:2012(E)

6 Material The elastomeric material used shall meet the requirements specified in Clause 7. Plunger stoppers shall be made from the elastomeric formulation originally tested and approved by the end user. The manufacturer of the plunger stopper shall ensure the conformance of each delivery with the type sample and compliance with previously agreed functional and compendial requirements. The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at (121 ± 2) °C for 30 min without impairment of its function under conditions of normal use. If other sterilization methods are used, e.g. irradiation, the suitability of the material shall be evaluated.

7 Requirements

7.1 General

The requirements specified in 7.2 to 7.4 constitute minimum requirements concerning the condition of the elastomeric plunger stopper on receipt by the user.

7.2 Physical requirements

7.2.1 Hardness

The hardness agreed between the manufacturer and the user shall not differ from the 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 plunger stoppers in accordance with ISO 48. If tested according to ISO 48, the microhardness shall not differ by more than ±5 IRHD from the type sample. The manufacturer should provide suitable test specimens upon request.

7.2.2 Resistance to ageing

The maximum time between the date of manufacture of the plunger stoppers and their pharmaceutical use should be agreed upon between the manufacturer and the user.

The plunger stoppers 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 on storage and handling conditions. A guide to storage of vulcanized rubber is given in ISO 2230.

7.3 Chemical requirements

The aqueous extractables of the plunger stopper material shall not exceed the limits specified for elastomeric parts defined in ISO 8871-1.

7.4 Biological requirements The requirements in ISO 8871-4 shall apply.

8 Labelling Packed plunger stoppers that meet the requirements of this part of ISO 11040 can be labelled with the designation given in Clause 5.

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ISO 11040-5:2012(E) Bibliography [1] ISO 48, Rubber, vulcanized or thermoplastic — Determination of hardness (hardness between 10 IRHD and 100 IRHD) [2] ISO 2230, Rubber products — Guidelines for storage [3] ISO 3302-2, Rubber — Tolerances for products — Part 2: Geometrical tolerances [4] ISO 8362-5, Injection containers for injectables and accessories — Part 5: Freeze drying closures for injection vials [5] ISO 9997, Dental cartridge syringes [6] ISO 15378, Primary packaging materials for medicinal products — Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP)

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ISO 11040-5:2012(E)

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=== ISO 11040-6 ===

INTERNATIONAL STANDARD

ISO 11040-6 Second edition 2019-01

Prefilled syringes — Part 6: Plastic barrels for injectables and sterilized subassembled syringes ready for filling Seringues préremplies — Partie 6: Cylindres en plastique pour produits injectables et seringues pré-assemblées stérilisées préremplissables

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ISO 11040-6:2019(E)

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COPYRIGHT PROTECTED DOCUMENT © ISO 2019 All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of 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 of the requester. ISO copyright office CP 401 • Ch. de Blandonnet 8 CH-1214 Vernier, Geneva Phone: +41 22 749 01 11 Fax: +41 22 749 09 47 Email: copyright@iso.org Website: www.iso.org Published in Switzerland

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ISO 11040-6:2019(E)

Contents

Page

Dimensions and designation.................................................................................................................................................................... 4

5.1 Design including dimensions....................................................................................................................................................... 4

5.2 Design requirements.......................................................................................................................................................................... 7

5.2.1 Head design........................................................................................................................................................................... 7

5.2.2 Dead space............................................................................................................................................................................. 7

5.2.3 Functional testing of Luer cone/Luer lock connection.................................................................... 7

5.2.4 Flange breakage resistance..................................................................................................................................... 7

5.2.5 Syringe tip breakage resistance........................................................................................................................... 7

6.2 Material.......................................................................................................................................................................................................... 8

6.2.1 General...................................................................................................................................................................................... 8

6.2.2 Duty of notification concerning modifications to polymers........................................................ 8

6.2.3 Needle........................................................................................................................................................................................ 8

6.2.4 Closure system.................................................................................................................................................................... 9

6.2.5 Closure system integrity......................................................................................................................................... 10

6.3 Physical requirements.................................................................................................................................................................... 10

6.3.1 Sterilization........................................................................................................................................................................ 10

6.3.2 Clarity and transparency........................................................................................................................................ 10

6.3.3 Particulate contamination..................................................................................................................................... 10

6.3.4 Lubricants............................................................................................................................................................................ 11

6.4 Chemical requirements................................................................................................................................................................. 11

6.5 Endotoxins and biological requirements....................................................................................................................... 11

Graduation................................................................................................................................................................................................................12

Packaging and labelling..............................................................................................................................................................................12

Annex A (informative) Examples of types of sterilized subassembled syringes ready for filling.......13

Annex B (informative) Head designs..................................................................................................................................................................16

Annex C (normative) Test methods for syringe barrels.................................................................................................................18

Annex D (informative) Sample preparation for endotoxin and particulate determination.....................24

Annex E (informative) Evaluation of syringe lubrication by glide force test method......................................28

Annex F (informative) Needle penetration test.......................................................................................................................................31

Annex G (normative) Test methods for syringe closure systems..........................................................................................34

Annex H (informative) Dye solution tightness test..............................................................................................................................49

Annex I (informative) Guidance on materials...........................................................................................................................................51

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iii

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ISO 11040-6:2019(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. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). 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. Details of any patent rights identified during the development of 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 information given for the convenience of users and does not constitute an endorsement. For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see www.iso .org/iso/foreword.html. This document was prepared by Technical Committee ISO/TC 76 Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. This second edition cancels and replaces the first edition (ISO 11040-6:2012), which has been technically revised. The main changes compared to the previous edition are as follows: — Scope has been extended by adding sterilized subassembled syringes ready for filling. Appropriate requirements and test methods have been included; — general requirements have been added on quality systems, testing, and documentation; — requirements on labelling have been revised; — requirements on packaging have been added; — requirements on syringes barrels have been revised by: — adding requirements and related test methods for flange breakage and tip breakage (cone or staked in needle head) resistance, and — adding requirements on lubrication. A list of all parts in the ISO 11040 series can be found on the ISO website. Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

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ISO 11040-6:2019(E) Introduction Ampoules and injection bottles have been mainly used as primary packaging material for the administration of injectables. However, for the injection of the liquid medicinal products stored in these containers, a hypodermic syringe combined with the appropriate injection cannula is also needed. This requires that the medicinal product be transferred into the hypodermic syringe before its final use. This procedure is not only time-consuming; it can also easily result in mix-ups and possible contamination. In conjunction with the appropriate sealing components, prefilled single-use syringes conforming to this document form a safe system for the transport, storage and administration of medicine. Due to relatively simple handling procedures, they permit fast injection of the medicinal products contained within them. Such prefilled syringes permit immediate injection of the product contained after relatively simple handling. These syringes can also be used in injectors with automated functions where further and particular requirements apply. In more recent years, new technological developments have been made to provide prefilled syringes on the basis of polymers as a material for the barrel of a prefilled syringe system; these developments have been spurred by progress in polymer science and introduction of novel polymers. This document can also be used by engineers as a basis for the development and marketing of standardized filling and processing equipment, e.g. so-called tub and nest filling presentations. Manufacturers of filling equipment and ancillary processing equipment can use this document to achieve a certain degree of unification with regard to the design of these standardized items of equipment. Based on the dimensions of the prefilled syringes, appropriate components, such as rubber plungers, tip caps, needle shields, and other closure systems can also be standardized. In conjunction with the right sealing components, they offer a system for (parenteral) injectable use. It is advised to contact the component and system provider for verifying the component compatibility, e.g. for silicone-oil free or lubricant free systems or if specific matching of components is required. The producers of filling machines can apply this document to achieve a degree of standardization in the equipment of the machines. For sterilized sub-assembled syringes ready for filling, the responsibility for the process steps relevant to the injectable product lies with the manufacturer1). Following the assembly of the needle shield on syringes with a staked needle or tip caps for the Luer cone version, the subassembled syringes are placed into nests. The nests, in turn, are placed into a plastic tub. The syringes in the nest are protected by means of an insert liner and the tub itself is sealed by a sealing lid (which is currently and, so far, primarily achieved using a porous material). Thus, the tub properly sealed with the sealing lid represents the “sterile barrier system”. The sealed tub is then wrapped into a sealable bag and, thus, ready for sterilization. Various sterilization methods can be applied with polymer syringes e.g. Gamma, E-beam, X-Ray irradiation, Moist Heat (autoclave), ethylene oxide. The sterilized subassembled syringes ready for filling are delivered to the pharmaceutical companies in a sterile condition, where they are processed on suitable machines. Compatibility tests with the intended drug product are carried out under the responsibility of the market authorization holder before the final approval is granted. This is described in 11040-8. NOTE Primary packaging materials are an integral part of medicinal products. Thus, the principles of the current Good Manufacturing Practices (cGMP) apply to the manufacturing of these components (e.g. ISO 15378).

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Washing after injection moulding for endotoxin reduction can be eliminated provided that the moulding,

assembling and packaging steps into the sealed sterile barrier system (tub and nest) takes place in a monitored

cleanroom (ISO 14644) and accompanied by microbial cleanroom monitoring.

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INTERNATIONAL STANDARD

ISO 11040-6:2019(E)

Prefilled syringes — Part 6: Plastic barrels for injectables and sterilized subassembled syringes ready for filling 1 Scope This document specifies materials, dimensions, quality, and performance requirements, as well as test methods for polymer barrels and sterilized subassembled syringes ready for filling, intended for single use only. This document also specifies those components that are part of the sterilized subassembled syringe ready for filling. Polymer barrels and sterilized subassembled syringes ready for filling in accordance with this document are intended for single use only. Components to complete the subassembled syringe, such as plunger and rod, are not specified in this document. Prefilled syringes can be produced on dedicated and specifically designed processing equipment such as inline moulding and filling. This document does not apply but can be used also for such dedicated prefilled syringes. 2 Normative references The following documents are referred to in the text in such a way that some or all of their content constitutes requirements 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 7864:2016, Sterile hypodermic needles for single use — Requirements and test methods ISO 7886-1, Sterile hypodermic syringes for single use — Part 1: Syringes for manual use ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 1: Extractables in aqueous autoclavates ISO 9626, Stainless steel needle tubing for the manufacture of medical devices — Requirements and test methods ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process ISO 14971, Medical devices — Application of risk management to medical devices ISO 80369-1, Small-bore connectors for liquids and gases in healthcare applications — Part 1: General requirements ISO 80369-7, Small-bore connectors for liquids and gases in healthcare applications — Part 7: Connectors for intravascular or hypodermic applications

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ISO 11040-6:2019(E)

3 Terms and definitions For the purposes of this document, the following terms and definitions apply. ISO and IEC maintain terminological databases for use in standardization at the following addresses: — ISO Online browsing platform: available at https:/ /www.iso.org/obp — IEC Electropedia: available at http://www.electropedia.org/ 3.1 customer business entity which purchases syringe barrels (3.6) or sterilized subassembled syringes ready for filling (3.7) and conducts further processing or filling as appropriate 3.2 manufacturer business entity which performs or is otherwise responsible for the manufacturing of the syringe barrels (3.6) (plastic barrels for injectables) or for the sterilized subassembled syringes ready for filling (3.7) by the customer (3.1) 3.3 needle shield syringe closure used with staked needle subassembled syringes that is designed to protect the needle point/bevel from damage, to allow sterilization of the needle, and to maintain sterility of the contents of the syringe and of the needle up to the time of injection 3.4 prefilled syringe container system filled with the injectable product ready for injection Note 1 to entry: Components of prefilled syringes are barrel, needle, closure system, plunger, and rod. Examples of sterilized subassembled syringes ready for filling including components are given in Annex A. 3.5 staked needle syringe syringe with a needle integrated into the barrel Note 1 to entry: The fixation can be done by insert moulding, gluing or other bonding methods. 3.6 syringe barrel cylindrical polymer body with front end and finger flange Note 1 to entry: See Figure 1. Note 2 to entry: The syringe barrel can be equipped with a staked needle. 3.7 sterilized subassembled syringe ready for filling subassembly that has been pre-treated, consisting of a syringe barrel (3.6) and a closure system Note 1 to entry: The subassembly has been pre-treated by applying the following processes, as applicable: — injection moulding; — assembling/lubricating needle; — applying a lubricant to syringe barrel inner surface; — sealing the syringe with a closure system; — packaging (see ISO 11040-7);

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ISO 11040-6:2019(E)

— sterilization. Note 2 to entry: Examples of sterilized subassembled syringes ready for filling including components are given in Annex A. 3.8 syringe closure system component or multi-component system designed to close the syringe system at the front end that is designed to allow sterilization of the syringe tip and maintain sterility of the contents of the syringe up to the time of injection EXAMPLE Tip cap, needle shield (3.3), tamper-evident closure system.

4 General requirements

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4.1 Quality systems

The activities described within this document shall be carried out within a formal quality system. NOTE 1 ISO 15378 contains requirements for a suitable quality management system for primary packaging materials for medicinal products. NOTE 2 ISO 14971 can be used as a tool for conducting risk assessment. NOTE 3 ISO 13485 can be used as a tool for design control during development phase and contains requirements for a suitable quality management system.

4.2 Testing

4.2.1 Any suitable test system can be used when the required accuracy (calibration) and precision (gauge repeatability and reproducibility) can be obtained. The gauge repeatability and reproducibility of the test apparatus shall be no greater than 20 % of the allowed tolerance range for any given measurement. For destructive test measurements, the gauge repeatability and reproducibility shall be no greater than 30 % of the allowed tolerance range. At a minimum, the gauge repeatability and reproducibility should cover ±2 standard deviations (thereby covering approximately 95 % of the variation). EXAMPLE A measurement system with a measurement specification limit of ±0,01 ml (range of 0,02 ml) comes out of the gauge repeatability and reproducibility with a gauge repeatability and reproducibility/ tolerance range ratio of 20 %, which means that the gauge repeatability and reproducibility (four standard uncertainties) equals 0,02 ml/5 = 0,004 ml. The uncertainty of the measurement is ±2 standard deviations (see ISO/IEC Guide 98-3), which equals to 0,002 ml.

4.2.2 The sampling plans used for the selection and testing of sterilized subassembled syringes ready for filling or components thereof shall be based upon statistically valid rationale. NOTE Examples of suitable sampling plans are given in ISO 2859-1 and ISO 3951 (all parts).

4.2.3 Unless agreed otherwise, testing shall be performed at ambient laboratory conditions.

4.3 Documentation

4.3.1 Demonstration of conformity with the requirements of this document shall be documented.

4.3.2 All documentation shall be retained for a specified period of time. The retention period shall consider factors such as regulatory requirements, expiration date, and traceability.

4.3.3 Documentation of conformity with the requirements can include, but is not limited to, performance data, specifications, and test results from validated test methods.

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ISO 11040-6:2019(E) 4.3.4 Electronic records, electronic signatures, and handwritten signatures executed to electronic records that contribute to validation, process control, or other quality decision-making processes shall be reliable. 5 Dimensions and designation

5.1 Design including dimensions

5.1.1 The dimensions of the syringe barrel shall be as shown in Figure 1 and as given in Table 1. The type of head design shall be agreed upon between the manufacturer and the customer. For the Luer tip and the Luer lock design, ISO 80369-1 shall apply, and ISO 80369-7 apply. 5.1.2 If printing of the barrel is required, it shall be agreed between the manufacturer and the customer.

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Key 1 front end 2 back end NOTE 1 Edges can be slightly rounded. NOTE 2 The design of the finger flange is agreed between the manufacturer and the customer.

[Figure 1 — Typical example of a barrel and polymer finger flange for a prefilled syringe]

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ISO 11040-6:2019(E) The dimensions of the barrel shall be in accordance with Figure 1 and Table 1. These are the minimum required dimensions. Depending on the application, any other dimensions should be agreed between the manufacturer and the customer. Head designs of polymer barrels are shown in Annex B. When there are particular dimensional requirements, which are common when a syringe is used in combination with injectors, it is recommended that these requirements be agreed between the supplier and the customer.

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ISO 11040-6:2019(E)

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Table 1 — Barrel dimensions

Dimensions in millimetres

Nominal volume

Nominal dimension tolerances

d2a

0,5

6,8 to 8,2 ± 0,1 6,8 to 9,7 ± 0,1b

4,6 to 4,8 ± 0,1 57,0 to 64,8 ± 0,2 47,5 to 54,1 ± 0,2

1,8 to 2,1 ± 0,1 13,4 to 13,8 ± 0,1 10,5 to 11,0 ± 0,1

8,1 to 9,7 ± 0,1

6,3 to 6,5 ± 0,1 64,0 to 64,5 ± 0,2 54,0 to 54,5 ± 0,2 1,9 to 2,3 ± 0,1 13,7 to 13,8 ± 0,1 10,5 to 11,0 ± 0,1

10,8 to 11,4 ± 0,1 8,5 to 8,75 ± 0,1 45,9 to 46,9 ± 0,2 35,2 to 35,9 ± 0,2 1,9 to 2,3 ± 0,1

17,75 ± 0,1

14,70 ± 0,1

2,25

10,8 to 11,4 ± 0,1 8,5 to 8,75 ± 0,1 64,4 to 66,8 ± 0,2 53,9 to 54,6 ± 0,2 1,9 to 2,3 ± 0,1

17,75 ± 0,1

14,70 ± 0,1

10,8 to 11,6 ± 0,1 8,5 to 8,75 ± 0,1 82,4 to 84,6 ± 0,2 71,7 to 72,4 ± 0,2 1,9 to 2,3 ± 0,1

17,75 ± 0,1

14,70 ± 0,1

14,4 to 15,0 ± 0,1 11,7 to 12,2 ± 0,1 76,5 to 80,0 ± 0,2 64,3 to 66,7 ± 0,2 2,0 to 3,1 ± 0,15 22,9 to 23,1 ± 0,1 19,40 to 19,9 ± 0,1

16,6 to 18,0 ± 0,1 14,1 to 14,7 ± 0,1 97,7 to 100,5 ± 0,3 86,2 to 87,3 ± 0,2 2,0 to 3,1 ± 0,15 26,9 to 27,4 ± 0,1 21,50 to 21,9 ± 0,1

21,2 to 22,7 ± 0,15 18,2 to 19,1 ± 0,15 107,3 to 120,2± 0,3 95,6 to 109,1 ± 0,2 2,0 to 3,1 ± 0,15 32,25 to 39,0 ± 0,15 25,15 to 26,1± 0,15

29,2 to 32,3 ± 0,2 26,4 to 29,3 ± 0,2

128,8 to 151,2e ± 0,5

118,7 to 128,2e ± 0,5 2,0 to 3,5 ± 0,2 45,00 to 50,1 ± 0,2 33,2 to 39,10 ± 0,2

35,2 to 35,5 ± 0,2 31,8 to 32,2 ± 0,2

169,8 ± 0,5

156,4 ± 0,5

2,7 to 3,1 ± 0,2

47,65 ± 0,2

41,45 ± 0,2

a For the specification of the inner diameter, the specification of the plunger shall be considered with regard to break loose force and sustaining force as well as for plunger/ barrel seal tightness. The size of the inner diameter also depends on the polymer material.

b This range is dedicated to barrels with an integrated Luer lock.

c Long.

d Short or standard.

e This range is required in order to consider particular applications, such as pumps and injectors.

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ISO 11040-6:2019(E)

5.2 Design requirements

5.2.1 Head design

The type of head design shall be agreed upon between the provider of the barrel component and the customer responsible for filling and finishing the polymer prefilled syringe. For the Luer tip and the Luer lock design, ISO 80369-7 shall apply. Annex B includes certain examples of head designs.

5.2.2 Dead space

When tested in combination with the selected plunger stopper, the dead space in the barrel and the tip with the plunger stopper fully inserted shall be determined as given in ISO 7886-1. Specification should be agreed upon between the manufacturer and customer.

5.2.3 Functional testing of Luer cone/Luer lock connection

The functional performance of the polymer prefilled syringe barrel with regard to the Luer tip or Luer lock connection shall be demonstrated through performance testing in accordance with ISO 80369-7.

5.2.4 Flange breakage resistance

Syringe barrels shall provide an appropriate flange breakage resistance. Limit values are subject to agreement between the manufacturer and the customer. The flange breakage resistance shall be determined in accordance with C.1. NOTE The flange breakage resistance test method is a reference test to provide a consistent measure for comparison of the performance of different syringes and can potentially be used as a quality measure to assess changes and monitor production. The test method can be adjusted to simulate specific use conditions of the syringe system, e.g. use in auto-injectors.

5.2.5 Syringe tip breakage resistance

Syringe barrels shall provide an appropriate syringe tip breakage resistance. Limit values are subject to agreement between the manufacturer and the customer. The syringe tip breakage resistance shall be determined in accordance with C.2. Diameter of syringe holder according to Figure C.4 shall be adjusted to the syringe outer diameter given in Table C.1. NOTE The syringe tip breakage resistance test method is a reference test to provide a consistent measure for comparison of the performance of different syringes and can potentially be used as a quality measure to assess changes and monitor production. The test method can be adjusted to simulate specific use conditions of the syringe system, e.g. use in auto-injectors. 6 Requirements

6.1 General

The attention of the provider of the barrel component and the customer responsible for filling and finishing the plastic prefilled syringe is drawn to applicable performance requirements in monographs of, for example, the European Pharmacopoeia (Ph. Eur.), the United States Pharmacopoeia (USP) or the Japanese Pharmacopoeia (JP).

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ISO 11040-6:2019(E) The manufacturer shall have documented procedures for the design and development of sterilized subassembled syringes ready for filling. NOTE ISO 15378 and ISO 13485 contain requirements for a suitable quality management system for primary packaging materials for medicinal products.

6.2 Material

6.2.1 General

The following properties should be considered when selecting the raw materials or components and the design of the sterilized subassembled syringe ready for filling: a) microbial barrier; b) biocompatibility and toxicological attributes; c) physical and chemical properties; d) ability for sterilization and compatibility with respect to the intended sterilization process; e) maintenance of sterility of the subassembly; f) shelf-life limitations; g) functionality regarding fill-finish; h) robustness of the closure system during transport from the manufacturer to the customer. The material shall exhibit the appropriate performance properties, e.g. oxygen and water vapour permeability. NOTE For guidance on materials, as well as polymer material codification, see Annex I.

6.2.2 Duty of notification concerning modifications to polymers

Change control and notification procedures, need to be in place between the company transforming the polymer into a syringe and the pharmaceutical company using it for injectable drug products. NOTE 1 Requirements are given in ISO 15378 and ISO 13485. NOTE 2 Particular attention is drawn to change control procedures and notification of changes by suppliers of raw material.

6.2.3 Needle

6.2.3.1 If the sterilized subassembled syringe ready for filling is delivered with a staked needle, the requirements in 6.2.3.2 to 6.2.3.5 apply. 6.2.3.2 The needle shall fulfil the following material, dimensional, and design requirements: — material and dimensions of the needle tubing shall be in accordance with ISO 9626; For tapered needles, needle manufacturers shall define how to apply the functional tests, specifically needle stiffness and resistance to breakage on the basis of a specific risk assessment carried out in accordance with ISO 14971; — the bonding strength between the syringe and the needle shall be in accordance with ISO 7864; — actual needle length shall be in accordance with ISO 7864:2016, Figure 2.

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ISO 11040-6:2019(E)

When there are particular requirements on needle tip height from the flange or the shoulder, which are both common when a syringe with staked needle is used in injectors, the dimension should be agreed upon between the manufacturer and the customer. Specific design features of the needle should be agreed upon between the manufacturer and the customer. 6.2.3.3 The needle shall be surface-treated using a lubricant (e.g. silicone oil). NOTE 1 This is to minimize the pain when the needle penetrates the skin during injection. For silicone oil, attention is drawn to applicable requirements in respective pharmacopoeias Ph. Eur.3.1.8, USP NF <> and silicone oil standards. Limit values on needle penetration force may need to be established using a risk assessment and usability engineering process. Needle penetration force measurements can be useful to detect needle point and lubrication defects, but might not be correlated with injection pain. NOTE 2 A suitable test method for the determination of the needle penetration force is given in Annex F. 6.2.3.4 The needle lumen patency shall be as specified in ISO 7864, if applicable. 6.2.3.5 If adhesive is used for fixing the needle inside the tip, attention is drawn to the requirements of relevant pharmacopoeias and/or other national or regional requirements. See also ISO 10993-1. The fixation of the needle in the tip shall be tested in accordance with Clause G.1. This test method does not specify a limit for the pull-out force because this is subject to agreement between the manufacturer and the customer. See also limit values specified in ISO 7864.

6.2.4 Closure system

6.2.4.1 The material that can contact the injectable product shall meet applicable requirements of ISO 8871-1. For additional regional or national requirements of pharmacopoeias, see type I or type II requirements of Ph. Eur. 3.2.9, USP <381> and JP 7.03 that is applicable to volumes >100 ml. 6.2.4.2 The closure system shall allow for sterilization. Conformity shall be demonstrated by suitable methods. NOTE For ethylene oxide sterilization and/or steam sterilization, the design, including the material of the closure system, ensures that all components have sufficient ethylene oxide gas and water vapour permeation so that during sterilization, these gases reach both the cone of the Luer syringe and the needle through the sealing components. The closure system shall provide an appropriate liquid leakage resistance when tested in accordance with G.2. Limit values are subject to agreement between the manufacturer and the customer. 6.2.4.3 Luer conical fittings, if used, shall be in accordance with ISO 80369-7, ISO 80369-20, and ISO 80369-1.

6.2.4.4 Luer Lock Adaptor (LLA) collar systems shall withstand a pull-off force of at least 22 N when tested in accordance with G.3. NOTE This pull-off force is consistent with the minimum needle pull-off force as specified in ISO 7864:2016, Table 2, for needles with an outer diameter of 0,5 mm and smaller.

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ISO 11040-6:2019(E) 6.2.4.5 Luer Lock Adaptor (LLA) collar systems shall withstand a specified torque resistance when tested in accordance with G.4. The minimum torque resistance is subject to agreement between the manufacturer and the customer.

6.2.4.6 The design of closure systems shall be such that

— tip caps (if used) can be removed from the syringe with a reasonable torque force, — tip caps or needle shields (as applicable) can be removed from the syringe with a reasonable pull-off force, and — tip caps or needle shields maintain the sterility of the Luer cone or needle. The maximum allowed torque and the pull-off force, respectively, shall be agreed upon between the manufacturer and the customer. The test(s) shall be performed in accordance with G.5 and G.6, respectively.

6.2.5 Closure system integrity

The components of sterilized subassembled syringes ready for filling shall provide sealing against each other during filling, applicable final sterilizations, and throughout storage and transport, also through or in different external air pressures. Closure system integrity shall be demonstrated with a validated method. The dye solution tightness test in Annex H is a valuable method to test the tightness of a sterilized subassembled syringe ready for filling in the design development phase. NOTE Deterministic methods such as helium-leakage, high voltage leak detection as well as probabilistic methods such as microbial ingress can be considered.

6.3 Physical requirements

6.3.1 Sterilization

Sterilized subassembled syringes ready for filling shall have been sterilized to a Sterility Assurance Level (SAL) of 10−6 using a suitable validated sterilization method (e.g. ISO 11135, ISO 17665-1, ISO 11137 (all parts) or ISO 14937).

6.3.2 Clarity and transparency

Clarity and transparency requirements before and after sterilization as well as test methodology need to be agreed upon between manufacturer and customer. Any possible colouring, for example regarding light shielding, shall be agreed between the customer and the manufacturer of the primary packaging material.

6.3.3 Particulate contamination

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ISO 11040-6:2019(E)

For sub-visible particles, the following applies: — particles ≥10 µm: 600 max. per syringe; — particles ≥25 µm: 60 max. per syringe. NOTE 1 These limits have been derived from the USP <788> (small volume parenterals) limit values for filled containers with a nominal volume of less than 100 ml. The limit of the subassembly, which is 10 % of the USP <788>, supports the customer to fulfil the USP requirements on the syringe system. This value has been chosen based on historical proven capability using the light obscuration method as given in D.2. NOTE 2 See also Ph. Eur. 2.9.19, Ph. Eur. 2.9.20, USP <788>, JP 6.06, as well as JP 6.07.

6.3.4 Lubricants

For silicone oil, attention is drawn to applicable quality and quantity requirements in respective pharmacopoeias. For other lubricants, appropriate in-house monographs shall be applied. If the interior surfaces of the syringe barrel are lubricated, the lubricant shall not be visible, under normal or corrected-to-normal vision, as droplets or particles. Limit values and distribution of the amount of lubricant are subject to agreement between the manufacturer and the customer. NOTE 1 Lubrication of the inner surface of the syringe barrel is applied in order to improve gliding properties. This is usually done by siliconization (e.g. by application of a high-viscosity silicone oil to the inner syringe surface or with silicone followed by curing treatment). If silicone oil is used, attention is drawn to applicable requirements in respective pharmacopoeias pharmacopoeias Ph. Eur.3.1.8, USP NF <>. NOTE 2 Annex E includes a suitable test method for the determination of the quality and consistency of the lubrication using a gliding force test.

6.4 Chemical requirements

The materials used for manufacturing the syringes shall be chosen such that the risk of them releasing chemical constituents that can migrate into the injectables is minimized. NOTE 1 For test methods, see regional or national pharmacopoeias or the EMA Guideline for chemical constituents of extracts[30]. For investigation of extractables of the sterilized sub-assembled syringe, the impact of all packaging materials around the syringe as provided to the customer shall be considered. NOTE 2 The investigation can insure that printing inks or adhesive labels used on the polymer syringes do not affect the performance of the syringe and do not pose an unacceptable risk towards the contents and/or the patient.

6.5 Endotoxins and biological requirements

The material shall conform to biological requirements, i.e. toxic, cytotoxic, bacteriostatic, bactericidal, pyrogenic or haemolytic reactions. NOTE 1 In many countries, national or regional pharmacopoeias, state regulations or standards specify in detail suitable tests for assessing biological safety. Examples are the Ph. Eur., USP and JP. The required tests shall be agreed in accordance with ISO 10993-1 between the manufacturer of the primary packaging material and the customer. For endotoxins, the limit value for syringes shall be <0,25 EU/ml considering the nominal volume according to Table 1. NOTE 2 For rationale, see USP monograph on sterile water for injection according to USP <1231>.

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ISO 11040-6:2019(E) Extraction method and testing are specified in regional and national pharmacopoeias: — for extraction method, see USP <161>; — for testing, see Ph Eur, 2.6.14, method c), USP <85> and JP 4.01. NOTE 3 A sample preparation is given in Annex D. This is based on applicable pharmacopoeias. 7 Graduation If fill-lines or graduation marks are applied, ISO 7886-1 can be considered. 8 Packaging and labelling For packaging systems and labelling requirements for sterilized subassembled syringes ready for filling, see ISO 11040-7. Labelling of packaging of plastic barrels for injectables is subject to agreement between the manufacturer and the customer.

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ISO 11040-6:2019(E) Annex A (informative) Examples of types of sterilized subassembled syringes ready for filling A.1 Components Figure A.1 a) to Figure A.1 d) illustrate common components of sterilized subassembled syringes ready for filling.

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ISO 11040-6:2019(E)

a) Syringe with staked needle

b) Syringe with Luer cone c) Syringe with Luer d) Syringe with intelock cone and Luer lock grated Luer lock adaptor

Key 1 needle shield 2 needle 3 syringe barrel 4 tip cap 5 plunger 6 plunger rod

7 Luer lock adaptor 8 rigid sleeve 9 protective tamper-evident cap 10 front end of the syringe 11 back end of the syringe 12 integrated Luer lock

NOTE Plunger (5) and plunger rod (6) are not within the scope of this document.

Figure A.1 — Examples of sterilized subassembled syringes ready for filling including components of closure systems

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ISO 11040-6:2019(E) A.2 Description of closure systems A.2.1 General Closure components close the syringe such that the injectable product remains entirely enclosed and that microbiological contamination of the content of the syringe is avoided. The closure components are mounted onto the syringe body of the sterilized subassembled syringe ready for filling by the manufacturer. This subassembly is then packed in a suitable packaging system and then sterilized by ethylene oxide or another method. The closure system can comprise of — Luer cone, with or without lock, that can be closed using a tip cap, and — needle and needle shield. Examples are given in Figure A.1 a) to Figure A.1 d). A.2.2 Closures for syringes with Luer cone in accordance with ISO 80369-7 Syringes with Luer cone are closed with a tip cap of an appropriate closure material. For schematic illustration, see Figure A.1 b). A.2.3 Closures for syringes with Luer lock adaptor in accordance with ISO 80369-7 Syringes with Luer lock adaptor are closed with a tip cap of an appropriate closure material which is, after assembly with a polymer Luer lock adapter comprising a thread standardized in accordance with ISO 80369-7, snapped onto the Luer cone of the syringe such that both parts together form the conical Luer lock. These closure systems are available with or without tamper evidence in various designs. For schematic illustration, see Figure A.1 c). A.2.4 Closures for syringes with integrated Luer lock in accordance with ISO 80369-7 Syringes with integrated Luer Lock are closed with a tip cap of an appropriate closure material. For schematic illustration, see Figure A.1 d). A.2.5 Syringe with staked needle Syringes with a staked needle are closed with a needle shield or rigid needle shield. It is important that the needle tip, and particularly the opening of this tip, is completely embedded into the elastomer of the needle shield to ensure sealing. For schematic illustration, see Figure A.1 a).

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ISO 11040-6:2019(E)

Annex B (informative) Head designs

Figure B.1 shows a head design of a barrel for syringe with staked needle.

a Depending on needle diameter. NOTE Bore can also be cylindrical. Figure B.1 — Model A: Head design of a barrel for syringe with staked needle Figure B.2 shows a head design of a barrel with a 6 % Luer cone according to ISO 80369-7.

Figure B.2 — Model B: Head design of a barrel with a 6 % Luer cone according to ISO 80369-7 Figure B.3 shows a head design of a barrel with a 6 % Luer cone for Luer Lock according to ISO 80369-7.

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ISO 11040-6:2019(E) a To be agreed upon between the manufacturer and the customer. NOTE Particular requirements on Luer tip height from the flange or shoulder, which both are common when a syringe is used in injectors, are subject to agreement between the manufacturer and the customer. Figure B.3 — Model C: Head design of a barrel with a 6 % Luer cone for Luer Lock according to ISO 80369-7 Figure B.4 shows a head design of a barrel with an integrated Luer Lock according to ISO 80369-7. Figure B.4 — Model D: Head design of a barrel with an integrated Luer Lock according to ISO 80369-7

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ISO 11040-6:2019(E) Annex C (normative) Test methods for syringe barrels

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C.1.3.1 Universal tensile and compression testing machine, (attention shall be paid on bench overall rigidity for high-level resistance) in accordance with the following: — load cell 2 500 N or as appropriate to the force to be measured; — test speed of 100 mm/min or as appropriate; — sampling rate of at least 100 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer.

C.1.3.2 Syringe holder, made of an appropriate material [e.g. polyether ether ketone, (PEEK)] or stainless steel and of appropriate dimensions. Materials and design depend upon the intended use. This is subject to agreement between the manufacturer and the customer. Table C.1 and Figure C.1 include examples for dimensions of a syringe holder.

Table C.1 — Examples for dimensions of the syringe holder and loading pin

Dimensions in millimetres

Syringe barrel outer diameter

Diameter A (see Figure C.1)

Diameter b (see Figure C.2)

Radius c (see Figure C.2)

(OD) OD

OD + 0,5

80% of inner diameter of

b/2

syringe (ID)

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ISO 11040-6:2019(E) Dimensions in millimetres

NOTE

For diameter A, see Table C.1 Figure C.1 — Example of a syringe holder

C.1.3.3 Loading pin, made of an appropriate material and of appropriate dimensions. NOTE 1 Materials and design (e.g. radius of curvature adjusted to the internal syringe shoulder design) depend upon the intended use. This is subject to the agreement between the manufacturer and the customer. Table C.1 and Figure C.2 include examples for dimensions of the loading pin. NOTE 2 Polyacetale, shore hardness D according to ISO 7619-1 between 80 and 90 is a suitable material of the contact area of the loading pin. The rod can be made of stainless steel. C.1.4 Preparation and preservation of test samples Attention shall be paid not to shock the test samples before testing. Inspect the syringe holder and the loading pin for damage prior to testing and change regularly. C.1.5 Procedure C.1.5.1 Place the syringe barrel to be tested in the syringe holder and position the loading pin close to the syringe barrel depth as illustrated in Figure C.2.

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ISO 11040-6:2019(E)

Dimensions in millimetres

Key 1 syringe holder 2 syringe barrel 3 loading pin NOTE For diameter b and radius c, see Table C.1. Figure C.2 — Placement of the syringe barrel and the loading pin C.1.5.2 Start the test by applying a test speed of 100 mm/min or as appropriate and a sampling rate of at least 100 Hz. C.1.5.3 Record the force versus displacement and prepare a graph. An example is given in Figure C.3.

Key F force in newtons l distance in millimetre

Figure C.3 — Example of a force versus displacement curve

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ISO 11040-6:2019(E) C.1.6 Expression of results Determine the peak value from the displacement curve. This corresponds to the flange resistance (flange strength). C.1.7 Test report The test report shall include the following: — the test speed (mm/min); — the sampling rate (Hz); — the peak value from the force versus displacement curve for each sample (N); — the numbers of samples tested; — any deviations or observations. C.2 Luer cone breakage resistance C.2.1 Principle Many Luer syringes are equipped with a Luer connector. Especially for syringes with diluents or syringes for water for injections, the Luer connector is often used to connect to a vial adapter in order to provide a safe reconstitution of a lyophilized vial. This subassembly (syringe barrel, vial adapter and vial) is big in axial size and therefore, during reconstitution and handling charged by mechanical load through the user. The weakest point of this subassembly is the front end of the syringe that can be charged by a side load. The Luer cone breakage resistance test is used to determine the strength of the cone that is determined by the geometry and plastic material characteristics. C.2.2 Materials Luer syringe barrels to be tested, numbers as required. C.2.3 Apparatus C.2.3.1 Universal tensile and compression testing machine, (attention shall be paid on bench overall rigidity for high-level resistance) in accordance with the following: — load cell 2 500 N or as appropriate to the force to be measured; — test speed of 25 mm/min or as appropriate; — sampling rate of at least 100 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer. C.2.3.2 Material holder and loading pin made of stainless steel, for dimensions, see Figure C.4.

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ISO 11040-6:2019(E)

Dimensions in millimetres

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C.2.3.3 Adapter set which fits syringe geometries. C.2.4 Procedure C.2.4.1 Set up the test apparatus as follows: — Check the adapters for damage and correctness. — Assemble the adapters to the tensile and compression testing machine. — Check for security elements, plastic breakage will occur. — Install and open correct software to the tensile and compression testing machine, if required. C.2.4.2 Perform the test as follows: — Place the syringe barrel in the tensile and compression testing machine (see Figure C.4.). — Close the security elements. — Start the measurement applying a test speed of 25 mm/min, or as appropriate, and a sampling rate of at least 100 Hz. — Charge the syringe barrel until cone breaks; apply the force at a distance of approximately 2 mm from the tip of the syringe barrel. — Remove the syringe barrel from the adapter. — Clean the adapter from plastic residues. — Make sure that it breaks at the tip.

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ISO 11040-6:2019(E) C.2.5 Expression of results Record the maximum force at which the Luer cone breaks. C.2.6 Test report The test report shall include the following: — the test speed (mm/min); — the sampling rate (Hz); (the higher the sampling rate the more accurate the results); — distance from the tip of the point where the syringe is charged (mm); (approximately 2 mm); — maximum force at breakage (N); — the numbers of samples tested; — any deviations or observations.

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ISO 11040-6:2019(E) Annex D (informative) Sample preparation for endotoxin and particulate determination

D.1 Endotoxins D.1.1 General The sample preparation for endotoxin determination is based on the following documents: — Guidance for industry, pyrogen and endotoxins testing, questions and answers; — USP <161>; — USP <85>; — AAMI ST72:2011. D.1.2 Materials and equipment D.1.2.1 Sterilized syringes (i.e. sterilized by ethylene oxide or moist heat), not less than 3 and not more than 10 syringes. D.1.2.2 Plunger stopper, endotoxin-free or has a vendor-certified maximum endotoxin level. D.1.2.3 Endotoxin-free water of injection or Limulus Amebocyte Lysate (LAL) reagents, as extraction fluid having a temperature of (37 ± 1) °C. D.1.2.4 Shaker. D.1.2.5 Endotoxin-free container. D.1.3 Procedure D.1.3.1 Protect the endotoxin-free container from environmental contamination until analyzed, i.e. work in a controlled environment such as ISO 5 according to ISO 14644-1. D.1.3.2 Fill the syringes with extraction fluid up to the nominal fill volume of the syringe. D.1.3.3 Close the syringes with the plunger stopper. D.1.3.4 Store the filled and closed syringes for not less than 1 h at least at room temperature. D.1.3.5 Shake the syringes vigorously for 10 min on a horizontal shaker (or similar device). D.1.3.6 Pool the extract into an endotoxin-free container by pushing the plunger stopper and empty the syringes through the front end (Luer cone, staked needle).

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ISO 11040-6:2019(E)

D.1.3.7 Determine the number of endotoxin units (EU/ml) of the extract using the method as given in USP <85> including “positive” and “negative” samples.

The limit of the extraction fluid can be calculated according to USP <161> using Formula (D.1):

K ×N V

(D.1)

where

K is the amount of endotoxin allowed per syringe; N is the number of devices tested; V is the total volume of extract rinse. Ensure that the sensitivity of test reagent is high enough to allow a proper detection limit of endotoxins for pooled samples. EXAMPLE For 1 ml nominal fill volume and an endotoxin limit <0,25 EU/ml and a sensitivity of the reagent of 0,02 EU/ml, the “alarm” limit for 10 pooled syringes would be 0,20 EU/ml which is <0,25 EU/ml.

D.2 Particulates D.2.1 General The sample preparation for particulate matter determination is based on USP <788> and Ph. Eur. 2.9.19. D.2.2 Materials and equipment D.2.2.1 Sterilized syringes (i.e. sterilized by ethylene oxide or moist heat), numbers as required. D.2.2.2 Plunger stopper and plunger rod, numbers as required. D.2.2.3 Water, for injection or any grade of purified water. D.2.2.4 Container. D.2.3 Procedure D.2.3.1 Protect the container from environmental contamination until analyzed, i.e. work in a controlled environment, e.g. ISO 5 according to ISO 14644-1. D.2.3.2 Prepare particle-free water by filtration of water for injection or any grade of purified water through a 0,2 µm to 0,8 µm filter unit. D.2.3.3 Rinse all the needed equipment (e.g. beakers, dosage systems) with particle-free water. D.2.3.4 Transfer a minimum of 30 ml of particle-free water into a cleaned container and let it rest undisturbed for a minimum of 2 min to allow degassing of air bubbles. D.2.3.5 Determine the particle content of the particle-free water but disregard the first measurement as it is only used to clean the measurement system.

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ISO 11040-6:2019(E)

D.2.3.6 The limits for the particle-free water by light obscuration are — 10 particles ≥10 µm, and — 2 particles ≥25 µm. If the particle content is within the limit, continue with the sample preparation. If the particle content is not within the limit, repeat the filtration and measurement until the particlefree water is within specification (D.2.3.2 to D.2.3.5).

D.2.3.7 Fill the syringes with nominal volume and close with clean plunger stopper.

D.2.3.8 Invert the syringes 20 times. NOTE It can be necessary to agitate the solution more vigorously to suspend the particles properly.

D.2.3.9 Remove the tip cap/needle shield and dispense the contents of the syringes into a cleaned container by depressing the plunger with a plunger rod.

D.2.3.10 Let the solution rest un-disturbed for a minimum of 2 min to allow degassing of air bubbles.

D.2.3.11 Determine the particle content per syringe but disregard the first measurement as it is only used to clean the measurement system.

The limits for the containers by light obscuration are

— 600 particles ≥10 µm, and

— 60 particles ≥25 µm

NOTE A minimum pooled sample volume of 25 ml is needed to perform four runs of 5 ml each. The first run is always discarded. The average is calculated for the remaining three test runs. Depending on the nominal fill volume of the syringes, a certain amount of syringes is needed for 1 pool:

— 25 syringes 1 ml 25 ml pool;

— 13 syringes 2 ml 25 ml pool;

— 12 syringes 2,25 ml 25 ml pool;

— 9 syringes 3 ml 25 ml pool;

— 5 syringes 5 ml 25 ml pool.

To avoid air bubbles in the measuring device, it is recommended to add an extra 5 ml to the pool (30 ml pool volume).

Depending on the batch size of the syringes produced, multiple pools can be required.

The number of particles in each container can be calculated using Formula (D.2):

P ×Vt Va ×n

(D.2)

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ISO 11040-6:2019(E) where P is the average particle count obtained from the portion of container; Vt is the volume of pooled sample (ml); Va is the nominal volume of the syringe (ml); n is the number of containers pooled.

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ISO 11040-6:2019(E) Annex E (informative) Evaluation of syringe lubrication by glide force test method E.1 Purpose This test method is used to assess the quality and consistency of lubrication within the inner syringe barrel by measuring the glide force of the empty syringe barrel. The ability to assess the quality and consistency of lubrication can be dependent on the test speed used. NOTE Typically, a test speed of 100 mm/min (similar to ISO 7886-1) is used; however, it can be insufficient to detect lubrication defects. The test speed is subject to agreement between the manufacturer and the customer. Break loose force is not part of this test method because break loose force is applicable to the syringe (complete system). E.2 Materials E.2.1 Empty sterilized subassembled syringes ready for filling, adequate sample size corresponding to the sampling plan in 4.2.2 is required. E.2.2 Plunger stoppers (piston) in ready-to-use format, to be agreed upon between the manufacturer and the customer (dimensions, compound, siliconization level, sterilization). E.2.3 Plunger rods, appropriate for use with selected plunger stopper, to be agreed upon between the manufacturer and the customer. E.3 Apparatus E.3.1 Universal tensile and compression testing machine in accordance with the following: — test speed of 100 mm/min or as appropriate; — force range up to 50 N or as appropriate; — sampling rate as appropriate NOTE Definition of test speed and force range is subject to agreement between the manufacturer and the customer. E.3.2 Syringe support stand and syringe adaptor plates, appropriately sized for the sterilized subassembled syringes ready for filling to be tested. E.3.3 Vent tube stoppering tool or machine.

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ISO 11040-6:2019(E) E.4 Procedure E.4.1 Set the plunger stopper in the empty syringe barrel by using the vent tube insertion method. Select stopper position(s) based on the following areas of concern: — focus on front portion of barrel; sensitive area for auto-injector performance: Select a position corresponding to 50 % of nominal fill volume (e.g. 27 mm from back of barrel flange to back of plunger stopper, 1 ml-long syringe); — characterization of entire barrel: Select a position corresponding to nominal fill volume (e.g. 10 mm from back of barrel flange to back of plunger stopper, 1 ml-long syringe). E.4.2 Install the plunger rod into or onto the plunger-stopper. NOTE The plunger rod can be with or without thread. E.4.3 Remove the needle shield or other front closure from the sterilized subassembled syringe ready for filling. E.4.4 Place the sterilized subassembled syringe ready for filling in the adaptor plate on the forcemeasurement instrument. E.4.5 Start the compression at the designated speed. E.4.6 End the test when the plunger stopper comes into contact with the shoulder of the syringe barrel. E.4.7 Repeat the steps E.4.1 to E.4.6 for additional test samples. E.4.8 Record the maximum force in the glide force test region (see footnote b in Figure E.1). The glide force test region is defined as the region between the break loose and the sharp increase of the force at the end of the stroke. See Figure E.1. Limit values should be agreed between the manufacturer and the customer.

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ISO 11040-6:2019(E)

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Key 1 start of stopper movement 2 end of testing condition F force in newtons l distance in millimetre a Break loose region. b Glide force test region. c End of stroke region. Figure E.1 — Example illustrating gliding characteristics E.5 Test report The test report should include the following: — maximum gliding force in the glide force test region (footnote b) (N); — sampling rate (Hz); — calculated average gliding force (N); — numbers of tested samples; — any deviations or observations.

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Annex F (informative) Needle penetration test

ISO 11040-6:2019(E)

F.1 Principle This test method is used to determine the needle penetration force by piercing a test foil with a needle. The test has been derived from ISO 7864. F.2 Apparatus F.2.1 Universal tensile and compression testing machine in accordance with the following: — measuring range up to 50 N or as appropriate; — test speed within the range 20 mm/min to 200 mm/min or as appropriate; — sampling rate as appropriate. NOTE Definition of measuring range and test speed is subject to agreement between the manufacturer and the customer. F.2.2 Needle holder. F.3 Materials F.3.1 Test foil, specification to be agreed upon between the manufacturer and the customer. F.3.2 Syringes with a staked needle as supplied, i.e. siliconized. F.4 Procedure F.4.1 Fix the test foil tension-free in the holder. F.4.2 Fix the needle in the needle holder perpendicular to the test foil and with the tip to the geometric centre of the free area of the test foil. F.4.3 Start the test and penetrate the test foil with the needle. F.4.4 Record the force versus displacement curve.

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ISO 11040-6:2019(E) F.4.5 Use a new (not perforated) foil section for each penetration test. Examples on penetration force behaviour and force versus displacement curve are given in Figure F.1 and Figure F.2.

The needle tip meets the test foil.
The tip presses the foil, the force increases to F0.
The tip penetrates the foil, the cutting phase starts.
The cutting edges make the cut.
The cut is finished with the force maximum F1.
Dilatation of the cut via the primary bevel.

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Heel passes the foil, the force with maximum F2.
The needle tube slides through the enlarged cut.

Figure F.1 — Stages of the penetration process

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ISO 11040-6:2019(E)

Key F0 force for passing the tip (piercing force) F1 force for cutting with the cutting edges (cutting force) F2 force where the heel passes the foil F3 drag penetration force NOTE The illustration given is an example only. This curve might not be representative of all needles and test foils. Figure F.2 — Example of a force versus displacement curve F.5 Test report The test report should include the following: — specification of the test foil; — test speed (mm/min); — sampling rate (Hz); — force versus displacement curves; — numbers of tested samples; — any deviations or observations.

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ISO 11040-6:2019(E) Annex G (normative) Test methods for syringe closure systems G.1 Needle pull-out force G.1.1 Principle The test is used to assess the fixation of the needle to the staked needle syringe. It is mainly designed to verify whether the needle fixation process is appropriate to show that the staked needle withstands a needle size (gauge) dependent pull-out force according to ISO 7864. G.1.2 Materials Sterilized subassembled syringes ready for filling with a staked needle, numbers as required. G.1.3 Apparatus G.1.3.1 Universal tensile and compression testing machine in accordance with the following: — load cell of max 500 N or as appropriate for the force to be measured; — test speed of 50 mm/min or as appropriate; — sampling rate of minimum 65 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer. G.1.3.2 Syringe holder (syringe can be fixed by shoulder or finger flange during testing). G.1.3.3 Needle gripper device, designed to avoid slippage and to avoid an influence on the measurement itself. G.1.4 Preparation and preservation of test samples The test samples shall follow the same process as the product delivered.

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ISO 11040-6:2019(E) G.1.5 Procedure G.1.5.1 Insert the test sample vertically positioned on the testing machine (see Figure G.1).

Key 1 needle gripper attached to a testing machine 2 syringe with staked needle 3 syringe holder/base plate F force in newtons Figure G.1 — Position of the test sample in the tensile testing machine G.1.5.2 Grip as much as possible of the needle to avoid slippage. G.1.5.3 Release the test sample. G.1.5.4 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when the “zero” is set. G.1.5.5 Apply a test speed of 50 mm/min or as appropriate, at an appropriate sampling rate (Hz). G.1.5.6 Start the test. G.1.5.7 Record the force versus displacement. G.1.5.8 Stop the test once the needle is clearly removed from the syringe or broken.

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ISO 11040-6:2019(E)

G.1.6 Expression of results Record the maximum load peak from the force versus displacement curve. This corresponds to the pull-out force of the needle system of the syringe. G.1.7 Test report The test report shall include the following: — test speed (mm/min); — sampling rate (Hz); — force versus displacement curve; — peak value according to the maximum force (N); — number of tested samples; — any deviations or observations. G.2 Syringe closure system liquid leakage test G.2.1 Principle The test is used to assess the liquid leakage resistance of the closure systems (needle shield or tip cap/ barrel assembly). It is mainly designed to verify whether the closure system is able to withstand any potential overpressure inside the syringe during the filling process or during transportation. The test pressure of 110 kPa has been selected based on process conditions during the fill finish process. G.2.2 Reagents and materials G.2.2.1 Reagents of recognized analytical grade and distilled water or water of equivalent purity. G.2.2.2 Sterilized subassembled syringes ready for filling, numbers as required. G.2.3 Apparatus G.2.3.1 Universal tensile and compression testing machine or pressurization through the application of compressed air. NOTE Application of pressure via universal tensile and testing machine [see Figure G.2 a)] is preferred when wall friction can be neglected. In this case, it is assumed that equilibrium is reached between the applied force and the internal pressure. If wall friction cannot be neglected, preference is given to the test as indicated in Figure G.2 b) where the pressures are applied on the closure system through the application of compressed air on the filled media. G.2.3.2 Syringe holder. G.2.3.4 Plunger stopper and plunger rod. G.2.4 Preparation and preservation of test samples The retention time/waiting time between closure setting and leakage testing shall be at least 12 h. Attention shall be paid not to damage and/or loosen the closure system/syringe tip prior to testing.

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ISO 11040-6:2019(E)

G.2.5 Procedure

G.2.5.1 Insert the test sample into the holder. See Figure G.2.

G.2.5.2 Fill the test sample to between 1/3 and 2/3 of the nominal fill volume with the reagent (see G.2.2.1).

G.2.5.3 In case of pressurization, close the holder with the lid and secure the device.

G.2.5.4 Apply a pressure of 110 kPa and hold the pressure for 5 s.

from

F = p× A

(G.1)

and A= π×d2 4 follows F = p× π ×d 2 ×10−3 4 where

(G.2) (G.3)

F is the force in newtons; p is the target internal pressure (kPa) (i.e. 110 kPa); A is the cross-sectional area of the syringe barrel (mm2); d is the nominal inner diameter of the syringe barrel (mm).

Table G.1 — Correspondence between the inner diameter of the syringe barrel and the test force

Nominal volume of the syringe barrel

Nominal inner diameter of the syringe barrel

Calculated test forcea

0,5

e.g. 4,65

1,87

a Calculated for the target internal pressure of 110 kPa.

NOTE Formula (G.3) calculation example: 110 kPa × 3,14/4 × (4,65 mm)2 × 10−3 = 1,87 N.

G.2.5.5 Release the pressure.

G.2.5.6 Monitor the test samples for leakage during and after the test.

G.2.6 Expression of results

The test is passed if the tip caps are not falling off and/or if no droplets are visible around the external surfaces of the closure system (wet surface of tip cap or needle shield).

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ISO 11040-6:2019(E) Visually examine if the test samples have passed or failed the test. G.2.7 Test report The test report shall include the following: — applied pressure (kPa) or force (N); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations.

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a) Pressure applied via plunger rod and plunger stopper a tensile testing machine

b) Pressure supplied by compressed air directly on filled media

Key 1 syringe holder 2 syringe with closure system 3 plunger rod and plunger stopper F force in newtons

NOTE This illustration includes a syringe with a needle shield as an example. The testing is equally applicable to syringes with a tip cap.

Figure G.2 — Examples of testing devices for the determination of closure system liquid leakage

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ISO 11040-6:2019(E) G.3 Luer lock adaptor collar pull-off force G.3.1 Principle The test is used to assess the pull-off force of a Luer Lock Adaptor (LLA) collar system of sterilized subassembled syringes ready for filling. It is mainly designed to verify whether the LLA collar system is able to withstand an axial pull-off force in order to avoid detachment of the LLA collar system from the syringe barrel by the insertion of a female 6 % (Luer) conical lock fitting. G.3.2 Materials Sterilized subassembled syringes ready for filling with LLA, number as required. G.3.3 Apparatus G.3.3.1 Universal tensile and compression testing machine in accordance with the following: — test speed of 20 mm/min or as appropriate (10 N/s) (see ISO 80369-20); — load cell appropriate to the force to be measured, typical range of load cell is between 10 N and 100 N; — sampling rate of at least 65 Hz. NOTE Definition of load cell, test speed, and sampling rate is subject to agreement between the manufacturer and the customer. G.3.3.2 Syringe holder (see Figure G.3) and gripper device.

Key 1 LLA gripper plate 2 syringe with LLA/LLA systems 3 syringe holder/base plate Figure G.3 — Example of a testing device for the determination of the Luer lock adapter collar pull-off force

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ISO 11040-6:2019(E) G.3.4 Preparation and preservation of test samples The test samples shall follow the same process as the product delivered. G.3.5 Procedure G.3.5.1 Remove the tip cap. G.3.5.2 Insert the test sample vertically positioned on the testing machine between the holder (finger flange side) and the gripper (LLA collar side). G.3.5.3 Make sure that no pressure/movement is applied to the LLA collar system during test assembling. G.3.5.4 Release the test sample. G.3.5.5 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when “zero” is set. G.3.5.6 Apply a test speed of 20 mm/min or as appropriate at an appropriate sampling rate. G.3.5.7 Record the force versus displacement. G.3.5.8 Stop the test once the LLA collar system is clearly removed from the syringe tip. G.3.6 Expression of results Determine the load peak from the force versus displacement curve. The peak value corresponds to the pull-off force of the LLA collar system of the syringe. G.3.7 Test report The test report shall include the following: — sampling rate (Hz); — test speed (mm/min); — peak value (pull-off force) (N); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations. G.4 Luer lock adaptor collar torque resistance G.4.1 Principle The test is used to assess the torque resistance of a LLA collar system of a sterilized subassembled syringe ready for filling. It is mainly designed to verify whether the LLA collar system is able to withstand an applied torque while inserting a female 6 % (Luer) conical lock fitting (i.e. needle hub).

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ISO 11040-6:2019(E) G.4.2 Materials Sterilized subassembled syringes ready for filling with LLA, number as required. G.4.3 Apparatus G.4.3.1 Torque tester combined with a rotation device (see Figure G.4) in accordance with the following: — torque cell 35 Ncm with 0,05 Ncm resolution or as appropriate to the torque to be measured; — sampling rate of at least 65 Hz; — rotation speed of 20 r/min or as appropriate. NOTE 1 Definition of torque cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer. NOTE 2 For this test, either the syringe barrel or the closure can be rotated. G.4.3.2 Adapter: LLA collar gripper. G.4.3.3 Syringe holder (rotatable, if this alternative is used).

Key 1 LLA gripper inclusive torque sensor 2 syringe with LLA 3 syringe holder/base plate (rotatable) T rotation NOTE For this test, either the syringe barrel or the closure can be rotated. Figure G.4 — Example of testing device for the determination of the Luer lock adapter collar torque resistance, with rotatable syringe holder

G.4.4 Preparation and preservation of test samples and test pieces The test samples shall follow the same process as the product delivered.

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ISO 11040-6:2019(E) G.4.5 Procedure G.4.5.1 Insert the test sample vertically positioned into the syringe holder of the testing device. See Figure G.4. G.4.5.2 Remove the tip cap. NOTE This can be done manually. G.4.5.3 Mount the adapter onto the LLA collar. G.4.5.4 Set the torque cell to “zero”. Attention shall be paid that no significant pre-torque is applied. G.4.5.5 Set the rotation speed at 20 rotations per minute or as appropriate. G.4.5.6 Start the test by either rotating the turntable 90° clockwise or counter clockwise, depending on the system. Alternatively, rotate the closure. G.4.5.7 Record the peak of the applied torque. G.4.6 Expression of results Record the maximum torque measured. This corresponds to the torque where the LLA collar starts to rotate on the syringe. G.4.7 Test report The test report shall include the following: — rotation speed (°/s or r/min); — sampling rate (Hz); — maximum torque (Ncm); — number of tested samples; — number of passed/failed samples according to specification; — any deviations or observations. G.5 Luer lock rigid tip cap unscrewing torque G.5.1 Principle The test is used to assess the torque of a rigid tip cap of a sterilized subassembled syringe ready for filling. It is mainly designed to verify whether the rigid tip cap can be removed from the syringe with a reasonable torque. G.5.2 Materials Sterilized subassembled syringes ready for filling with a tip cap, numbers as required.

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ISO 11040-6:2019(E) G.5.3 Apparatus G.5.3.1 Torque tester combined with a rotation device in accordance with the following: — torque cell 35 Ncm with 0,05 Ncm resolution or as appropriate to the torque to be measured; — sampling rate of at least 65 Hz; — rotation speed of 20 r/min or as appropriate. NOTE 1 Definition of torque cell, sampling rate, and rotation speed is subject to agreement between the manufacturer and the customer. NOTE 2 For this test, either the syringe barrel or the closure can be rotated. G.5.3.2 Adapter: tip cap gripper. G.5.3.3 Syringe holder (rotatable, if this alternative is used). G.5.4 Preparation and preservation of test samples and test pieces The test samples shall follow the same process as the product delivered. G.5.5 Procedure G.5.5.1 Insert the test sample vertically positioned into the syringe holder of the testing device (see Figure G.5). G.5.5.2 Mount the adapter onto the tip cap. G.5.5.3 Set the torque cell to “zero”. Attention shall be paid that no significant pre-torque is applied. G.5.5.4 Set the rotation speed at 20 r/min or as appropriate. G.5.5.5 Start the test by either rotating the turntable 90° clockwise or counter clockwise depending on system. Alternatively, rotate the closure. G.5.5.6 Record the peak load of the applied torque. G.5.6 Expression of results Record the maximum torque peak. This corresponds to the torque where the tip cap starts to rotate on the syringe. G.5.7 Test report The test report shall include the following: — rotation speed (°/s or r/min); — sample rate (Hz); — maximum torque (Ncm); — number of tested samples; — number of passed/failed samples according to specification;

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ISO 11040-6:2019(E) — any deviations or observations.

Key 1 gripper inclusive torque sensor 2 syringe with tip cap 3 syringe holder/base plate (rotatable) T rotation NOTE For this test, either the syringe or the closure can be rotated. Figure G.5 — Example of a testing device for the determination of the Luer lock rigid tip cap removal unscrewing torque

G.6 Pull-off force of the tip cap or the needle shield G.6.1 Method 1 G.6.1.1 Principle This test is used to assess the removal force of the tip cap or the needle shield of a sterilized subassembled syringe ready for filling. This method can be customized depending on the intended use of the syringe (e.g. manual use, use in an auto-injector). An alternative procedure is described in G.6.2. Figure G.6 shows examples of testing devices for the determination of the pull-off force of the tip cap or the needle shield. G.6.1.2 Materials Sterilized subassembled syringes ready for filling, numbers as required.

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ISO 11040-6:2019(E)

G.6.1.3 Apparatus

G.6.1.3.1 Universal tensile and compression testing machine in accordance with the following: — load cell 50 N to 100 N, appropriate to the force to be measured; — sampling rate of at least 40 Hz; — test speed between 100 mm/min and 1 000 mm/min or as appropriate. NOTE Definition of load cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer.

G.6.1.3.2 Syringe holder.

G.6.1.3.3 Tip cap/needle shield gripper.

G.6.1.4 Procedure

G.6.1.4.1 Position the test sample vertically with the closure oriented upwards.

G.6.1.4.2 Apply the grip pressure such that the grip does not slide against or distort/deform the closure system.

G.6.1.4.3 With the syringe otherwise unconstrained, set the load cell to “zero”.

G.6.1.4.4 Position the syringe holder such that the syringe will be captured by the holder when an axial tension force is applied.

G.6.1.4.5 Apply a sampling rate of at least 40 Hz.

G.6.1.4.6 Set the bench displacement rate between 100 mm/min and 1 000 mm/min or as appropriate.

G.6.1.4.7 Record the force versus displacement.

G.6.1.4.8 Stop the test once the closure system is completely removed from the syringe tip.

G.6.1.5 Expression of results The closure system (tip cap /needle shield) pull-out force corresponds to the maximum load recorded in the force versus displacement curve.

G.6.1.6 Test report

The test report shall include the following:

— sampling rate (Hz);

— test speed (mm/min);

— load cell (N);

— maximum load recorded in the force versus displacement curve (N);

— number of tested samples;

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ISO 11040-6:2019(E)

Dimensions in millimetres

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a) Syringe with needle shield Key 1 gripper attached to tensile testing machine 2 syringe with needle shield/tip cap 3 syringe holder/base plate F force in newtons

b) Syringe with tip cap

Figure G.6 — Examples of testing devices for the determination of the pull-off force of the tip cap or the needle shield — Method 1

G.6.2 Method 2 G.6.2.1 Principle This test is used to assess the removal force of the tip cap or the needle shield of a sterilized subassembled syringe ready for filling. This test allows the pull-out force to be evaluated without pinching the needle shield and/or the needle. It prevents deformation of the rubber part. An alternative procedure is described in G.6.1. G.6.2.2 Materials Sterilized subassembled syringes ready for filling, numbers as required.

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ISO 11040-6:2019(E) G.6.2.3 Apparatus G.6.2.3.1 Universal tensile testing and compression machine in accordance with the following: — load cell up to 500 N; — sampling rate as appropriate; — test speed as appropriate. NOTE Definition of load cell, sampling rate, and test speed is subject to agreement between the manufacturer and the customer. G.6.2.3.2 Pulling device, see Figure G.7. G.6.2.4 Procedure G.6.2.4.1 Position the test sample vertically, syringe flange, and tip cap or needle-shield in their respective holder. G.6.2.4.2 Release the test sample. G.6.2.4.3 Set the load cell to “zero”. Attention shall be paid that no significant pre-load is applied when “zero” is set. G.6.2.4.4 Start the test. G.6.2.4.5 Record the force versus displacement. G.6.2.4.6 Stop the test once the closure is removed from the tip of the syringe. G.6.2.5 Test report The test report shall include the following: — load cell (N); — test speed (mm/min); — sampling rate (Hz); — mean, minimum, and maximum value recorded in the force versus displacement curve (N); — number of tested samples; — any deviations or observations.

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ISO 11040-6:2019(E)

a) Syringe with needle shield Key 1 pull-off device attached to tensile testing machine 2 syringe with needle shield/tip cap 3 syringe holder/base plate F force in newtons

b) Syringe with tip cap

Figure G.7 — Examples of testing devices for the determination of the pull-off force of the tip cap or the needle shield — Method 2

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ISO 11040-6:2019(E) Annex H (informative) Dye solution tightness test

H.1 General Sterilized subassembled syringes ready for filling with the injectable product consist of a syringe barrel with a Luer cone or a staked needle on the side facing the patient (front end) commonly sealed with a tip cap in case of a Luer syringe or a needle shield in case of a syringe with staked needle. The back end is sealed with a plunger stopper that allows the delivery of the drug by pushing the plunger stopper towards the liquid with a plunger rod. The tip cap or needle shield on the one side and the plunger stopper on the other side ensure appropriate sealing of the syringe. The dye solution tightness test is a valuable method to test the tightness of a sterilized subassembled syringe ready for filling in the design development phase. This test method alone is not sufficient to ensure container closure integrity of the system. The customer should assume responsibility to properly validate a suitable physical, chemical, or microbiological container closure integrity test method to qualify their chosen container closure system (including injectable product). H.2 Principle Subassembled syringes that are filled with liquid and stoppered with a plunger stopper are submerged in a dye solution. The subassembled syringes are inspected for leakage by checking the presence or absence of ingress of the dye solution into the syringe after applying a depressurisation/repressurization cycle. H.3 Apparatus, equipment, and reagents H.3.1 Syringe barrels, according to this document, preferably prepared as being used in regular production. H.3.2 Tip caps, needle shields, or any other front end closure, to match the front end opening of the syringe, preferably prepared as being used in regular production. H.3.3 Plunger stoppers, according to ISO 11040-5 to match the inner diameter of the syringe, preferably prepared as being used in regular production. H.3.4 Particle-free water to fill the syringes. H.3.5 Appropriate dye solution, including a colorant and possibly a surfactant. NOTE Suitable dyes are methylene blue, rhodamine B, and fluorescein; possible surfactants is Tween 802). It is recommended that the dye solution be filtered through a filter (pore size <1 µm) and stored in a clean, particulate-free container until use.

Tween 80 is an example of a suitable product available commercially. This information is given for the

convenience of users of this document and does not constitute an endorsement by ISO of these products.

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ISO 11040-6:2019(E) H.3.6 Vacuum chamber, capable of maintaining a pressure of min 270 mbar below atmospheric pressure for 30 min. H.3.7 Hypodermic needle(s), according to ISO 7864 and of size 27 g × 0,5 in. H.4 Preparation and preservation of test samples and test pieces H.4.1 Fill the syringes to nominal volume with particle-free water. H.4.2 Assemble the plunger stopper, leaving an air gap of 2 mm to 5 mm, preferably use the standard placement method intended for the future filling process (vent tube or vacuum placement). NOTE This method might not work without an air bubble. H.4.3 Discard any syringes with liquid beyond or between the ribs. H.4.4 Create one or more positive leak control samples by creating an open fluid path to the syringe content (e.g. by placing a hypodermic needle or similar device between the front end of the syringe and the corresponding closure or in case of needle shields, by removing the needle shield). H.4.5 Keep one syringe as a reference sample for comparison (not immersed in dye solution). H.5 Procedure H.5.1 Fill the vacuum chamber or an appropriate container with dye solution to a level that all syringes can be completely immersed in the solution. H.5.2 Immerse the syringes in the dye solution. Ensure that the syringes are completely immersed. Reduce the pressure by 270 mbar. Hold the pressure for 30 min then restore to atmospheric pressure. Allow the syringes to remain immersed in the dye solution for an additional 30 min, then remove them carefully from the solution, rinse the syringes with water until all dye solution is completely removed from the outside, and dry the syringes. H.5.3 Inspect all syringe contents visually for any traces of the dye solution. Compare the syringes to the positive and reference controls. The positive control should show the presence of dye in the syringe contents. Spectroscopy might also be used to detect dye. H.6 Test report The test report should include the following information: — colour change of the positive leak sample; — that the reference sample did not show any colour change; — number of syringes that show a colour change and thus, leaked; — any deviations or observations.

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Annex I (informative) Guidance on materials

ISO 11040-6:2019(E)

Materials used in the construction of syringe barrels for use in prefilled syringes should be suitable for the process to be used, the sterilization method to be applied and for the specific requirements as primary packaging for injectable drug products. Materials used in the construction of prefilled syringes should not cause the syringes to be detrimentally affected, physically or chemically, by the normal use of injectable preparations and should be safe for the intended use. Certain grades of polypropylene (homo-polymer and/or co-polymer polypropylene), cyclo-olefin copolymer and cyclo-olefin polymer have been used for the barrels of prefilled syringes in applications with a variety of injectable products (drugs and biologics). The organization responsible for the marketing approval of the injectable drug product should demonstrate the appropriateness and compatibility of the selected material and the suitability of the prefillable syringe as a container closure system. This includes, among others, the verification of drug/ container interactions (leachable, extractable and sorption assessments) in reference to regulatory guidance (e.g. FDA and EMA), pharmacopoeias and other guidelines (e.g. ICH). To develop the necessary data as outlined above, a collaborative approach is recommended between the pharmaceutical company that holds the marketing authorization of the injectable product and the supplier of the packaging system, with reference to ISO 15378. For polymer materials codification, see Table I.1.

Table I.1 — Polymer materials codification

Type of polymer Cyclo-olefin copolymer Cyclo-olefin polymer Polypropylene Other polymer

Codification COC COP PP OTH

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ISO 11040-6:2019(E)

Bibliography

[1] ISO 2859-1, Sampling procedures for inspection by attributes -- Part 1: Sampling schemes indexed by acceptance quality limit (AQL) for lot-by-lot inspection [2] ISO 3826-1, Plastics collapsible containers for human blood and blood components — Part 1: Conventional containers [3] ISO 3951 (all parts), Sampling procedures for inspection by variables [4] ISO 7619-1,3)Rubber, vulcanized or thermoplastic -- Determination of indentation hardness -- Part 1: Durometer method (Shore hardness) [5] ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals [6] ISO 11040-4, Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling [7] ISO 11040-5, Prefilled syringes — Part 5: Plunger stoppers for injectables [8] ISO 11040-7, Prefilled syringes — Part 7: Packaging systems for sterilized subassembled syringes ready for filling [9] ISO 11135, Sterilization of health-care products -- Ethylene oxide -- Requirements for the development, validation and routine control of a sterilization process for medical devices [10] ISO 11137 (all parts), Sterilization of health care products — Radiation [11] ISO 13485, Medical devices — Quality management systems — Requirements for regulatory purposes [12] ISO 13926-2, Pen systems — Part 2: Plunger stoppers for pen-injectors for medical use [13] ISO 14644-1, Cleanrooms and associated controlled environments -- Part 1: Classification of air cleanliness by particle concentration [14] ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices [15] ISO 15378, Primary packaging materials for medicinal products — Particular requirements for the application of ISO 9001:2015, with reference to Good Manufacturing Practice (GMP) [16] ISO 15747, Plastics containers for intravenous injections [17] ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices [18] ISO 80369-20, Small-bore connectors for liquids and gases in healthcare applications — Part 20: Common test methods [19] ISO/IEC Guide 98-3, Uncertainty of measurement — Part 3: Guide to the expression of uncertainty in measurement (GUM:1995) [20] ASTM D7210-06, Standard Practice for Extraction of Additives in Polyolefin Plastics [21] AAMI ST72:2011, Bacterial endotoxins — Test methods, routine monitoring, and alternatives to batch testing

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ISO 11040-6:2019(E)

[22] European guide for pharmaceutical products, III/2244/87, rev. 3 – January 1989 as amended

[23] Guideline I.C.H. Harmonized Tripartite Guideline, Stability Testing for New Drug Substances and Products, https:/ /www.pmda.go.jp/english/rs-sb-std/standards- development/jp/0019.html

[24] FDA. US Food and Drug Administration, https://www. fda. gov

[25] ICH. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, http:/ /www. ich.org

[26] United States Pharmacopoeia. http://www. usp. org

[27] USP <161>, Transfusion and infusion assemblies and similar medical devices

[28] USP <85>, Bacterial endotoxins test

[29] Japanese

Pharmacopoeia.

-development/jp/0019.html

https://www. pmda. go.jp/english/rs- sb- std/standards

[30] Guideline on Plastic Immediate Packaging Materials, European Medicines Agency,

London,

http:/ /www.ema.europa. eu/docs/en_GB/document_library/Scientific

_guideline/2009/09/WC500003448.pdf

[31] Jenke D. An extractables/leachables strategy facilitated by collaboration between drug product vendors and plastic material/system suppliers, PDA Journal of Pharmaceutical Science and Technology, Vol. 61. No. 1, January-February 2007

[32] Cantor Verlag. Defect evaluation list for containers made of tubular glass, 4th edition, Vol. 19, Edition 88322 Aulendorf, Germany

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ISO 11040-6:2019(E)

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=== ISO 11040-7 ===

INTERNATIONAL STANDARD

ISO 11040-7 First edition 2015-04-01

Prefilled syringes — Part 7: Packaging systems for sterilized subassembled syringes ready for filling Seringues préremplies — Partie 7: Systèmes d’emballage pour les seringues stérilisées prêtes à l’emploi préremplissables

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Reference number ISO 11040-7:2015(E)

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ISO 11040-7:2015(E)

© ISO 2015 All rights reserved. Unless otherwise specified, no part of 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 of the requester. ISO copyright office Case postale 56 • CH-1211 Geneva 20 Tel. + 41 22 749 01 11 Fax + 41 22 749 09 47 E-mail copyright@iso.org Web www.iso.org

Published in Switzerland

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ISO 11040-7:2015(E)

Contents

Page

Requirements for the packaging system...................................................................................................................................... 2

4.1 General............................................................................................................................................................................................................ 2

4.2 Nest.................................................................................................................................................................................................................... 3

4.3 Tub...................................................................................................................................................................................................................... 4

4.4 Insert liner................................................................................................................................................................................................... 4

4.5 Sealing lid..................................................................................................................................................................................................... 4

4.6 Protective bag........................................................................................................................................................................................... 5

Information to be provided by the manufacturer............................................................................................................... 5

Marking of the tub................................................................................................................................................................................................ 5

Packaging of tubs in trading units/bundles.............................................................................................................................. 6

Annex A (informative) Design of nests................................................................................................................................................................ 7

Annex B (informative) Determination of nest deflection.............................................................................................................14

Annex C (informative) Design of tubs................................................................................................................................................................17

Annex D (informative) Schematic illustrations of examples for the orientation of tubs within the protective bag...........................................................................................................................................................................19

Annex E (informative) Design and dimensions of the protective bag..............................................................................21

Annex F (informative) Test method to determine the distance between the edge of the protective bag to the rear end of the tub...................................................................................................................................24

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iii

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ISO 11040-7:2015(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. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). 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. Details of any patent rights identified during the development of 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 information given for the convenience of users and does not constitute an endorsement. For an explanation on the meaning of ISO specific terms and expressions related to conformity 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 information. The committee responsible for this document is ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plunger stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling — Part 5: Plunger stoppers for injectables — Part 6: Plastics barrels for injectables — Part 7: Packaging systems for sterilized subassembled syringes ready for filling The following part is under preparation: — Part 8: Requirements and test methods for finished prefilled syringes

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ISO 11040-7:2015(E) Introduction At the start of prefilled syringe processing by the pharmaceutical industry, syringes made of tubing glass were delivered to the pharmaceutical companies in the form of a so called non-sterile “bulkware” only. The process steps like washing, drying, inner lubrication, sealing the syringe with a closure system, sterilization, as well as filling, and closing were then performed in the pharmaceutical companies. Processing of “bulkware” is still performed like this nowadays. Sterilized subassembled syringes have partially replaced the non-sterile “bulkware”. In the case of sterilized subassembled syringes ready for filling, responsibility for the aforementioned process steps relevant to the injectable product lies within the manufacturer of the primary packaging material. Following the assembly of the needle shield on syringes with a staked needle or tip caps for the luer cone version, the subassembled syringes are placed into so called nests. The nests, in turn, are placed into a plastic tub. The syringes in the nest are protected by means of an insert liner and the tub itself is sealed by a sealing lid (which is currently, and so far, primarily achieved using a porous material). Thus, the tub properly sealed with the sealing lid represents the “sterile barrier system”. The sealed tub is then wrapped into a sealable bag and, thus, ready for sterilization which is currently, and so far, primarily performed using ethylene oxide. In this form, the sterilized subassembled syringes ready for filling are delivered to the pharmaceutical companies in a sterile condition where they are processed on suitable machines. The packaging design and material have to ensure sterility and should be compatible with the process of the customer. The packaging characteristics, material, thickness, shape, and resistance to deformations among others are such that they maintain, up to the point of use, the integrity of the product and a validated barrier against particulate and bacterial contamination. The packaging materials have to fulfil regional and national regulatory requirements.

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INTERNATIONAL STANDARD

ISO 11040-7:2015(E)

Prefilled syringes — Part 7: Packaging systems for sterilized subassembled syringes ready for filling 1 Scope This part of ISO 11040 specifies the packaging system that is used to deliver sterilized subassembled syringes ready for filling in tubs and nests. Downstream processes (processes after filling such as in house/outside transport, reprocessing) can result in specific requirements on the packaging system used to deliver sterilized subassembled syringes ready for filling. However, these requirements are not within the scope of this part of ISO 11040. NOTE 1 Glass barrels and sterilized subassembled syringes ready for filling, plungers, and plastic barrels for injectables are specified in ISO 11040‑4, ISO 11040‑5, and ISO 11040‑6. NOTE 2 ISO 11607‑2 addresses validation requirements of sealing and packaging processes for medical devices. 2 Normative references The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 11607‑1, Packaging for terminally sterilized medical devices — Part 1: Requirements for materials, sterile barrier systems and packaging systems 3 Terms and definitions For the purposes of this document, the following terms and definitions apply. 3.1 customer business entity which purchases syringe barrels or sterilized subassembled syringes ready for filling and conducts further processing or filling as appropriate 3.2 insert liner foil to cover the filled nest 3.3 manufacturer business entity which performs or is otherwise responsible for the manufacturing of the syringe barrels (bulkware) or for the sterilized subassembled syringes ready for filling by the customer 3.4 nest plastic plate with a defined hole pattern for the suspension of the syringe bodies

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ISO 11040-7:2015(E) 3.5 primary packaging material packaging materials used in pharmaceutical packaging which will contain, seal, or be used for dose application of a medicinal product and which will have direct contact with the medicinal product [SOURCE: ISO 15378:2011, definition 3.35.1] 3.6 protective bag plastic bag or sealing around the tub 3.7 sealing lid microbial barrier material for sealing the tub 3.8 packaging system combination of the sterile barrier system and protective packaging [SOURCE: ISO/TS 11139:2006, definition 2.28] 3.9 protective packaging configuration of materials designed to prevent damage to the sterile barrier system and its contents from the time of their assembly until the point of use [SOURCE: ISO/TS 11139:2006, definition 2.37 modified by adding “from the time of their assembly”.] 3.10 sterile barrier system minimum package that prevents ingress of microorganisms and allows aseptic presentation of product at the point of use Note 1 to entry: For packaging systems for sterilized subassembled syringes ready for filling, the sterile barrier system is formed by the tub and sealing lid. [SOURCE: ISO/TS 11139:2006, definition 2.44 modified by adding Note 1 to entry.] 3.11 tub plastic container to accommodate the filled nest 4 Requirements for the packaging system

4.1 General

4.1.1 The introduction of sterilized packaged subassembled syringes into an aseptic filling environment poses a risk of microbiological and/or particulate contamination of the drug product. The packaging system shall have acceptable microbiological and particulate levels to support the introduction of the sterilized subassembled syringes into an aseptic filling environment. Requirements should be agreed upon by the manufacturer and the customer. 4.1.2 The materials, the sterile barrier system, and the packaging system that enable sterilization and maintain sterility until the point of aseptic filling shall comply with the requirements of ISO 11607‑1. The sterile barrier system shall ensure product sterility over its shelf-life (i.e. the time sterility is ensured by the integrity of the sterile barrier system in recommended storage conditions). As a minimum, the protective bag protects the tub from external contaminants like dust or dirt. Ideally, it also maintains product sterility over its shelf-life and allows for bioburden control at the time of use.

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ISO 11040-7:2015(E) 4.1.3 Tubs, nests, and protective bags shall allow general processing and aseptic presentation of the sterilized subassembled syringes over their shelf-life. The process steps to be considered include, but are not limited to the following: a) for tubs including sealing lid and insert liner:

lid sealing and lid opening; 2) conveying; 3) nest insertion and extraction; 4) stacking and destacking; 5) sterilization (e.g. ethylene oxide, gamma) and decontamination (e g. electron beam). b) for nests: 1) barrel insertion and extraction; 2) filling; 3) stoppering; 4) stacking and destacking. c) for protective bag: 1) sealing; 2) folding; 3) decontamination; 4) cutting and opening. NOTE The process steps described include those at the premises of the manufacturer and of the customer.

4.2 Nest

NOTE This subclause covers nests used for sterilized subassembled syringes ready for filling. Nested formats can also be used for plunger stoppers/pistons. 4.2.1 For the nest, the following information shall be provided (information on dimensions including tolerances): — external dimensions; — deflection; — holes for the syringes; — centering openings/lifting openings; — defined free space where the lifting tool can engage. Customer and manufacturer should agree upon the dimensions and tolerances of the finished product as delivered. NOTE For information on dimensions, see Annex A. This annex has the intent to harmonize products coming to the market to facilitate the handling and processing of the prefilled syringes.

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ISO 11040-7:2015(E) 4.2.2 The design of the nest shall facilitate the insertion and removal of the sterilized subassembled syringes ready for filling (e.g. Luer lock adapter (LLA)-syringes) by adding bevels or other means. NOTE For information on design, see Annex A. 4.2.3 The maximum acceptable nest deflection should be agreed upon by the manufacturer and customer. The nest deflection can be determined using the test method as described in Annex B.

4.3 Tub

4.3.1 For tubs, the following information shall be provided (information on dimensions including tolerances):

— external dimensions including reinforcements/beads, radii, and indentations; — dimensions of the reinforcement/bead below the sealing edge, as well the slope of the lateral surfaces. NOTE For information on dimensions, see Annex C. This annex has the intent to harmonize products coming to the market to facilitate the handling and processing of the prefilled syringes. 4.3.2 The tub shall allow the sealing of the lid. The tub flange shall be free of sharp edges to protect the integrity of various packaging layers. NOTE For information on design, see Annex C. 4.3.3 If sterilization indicators are applied to the tubs, they shall comply with the appropriate International Standards (see ISO 11138 and ISO 11140).

4.4 Insert liner

The insert liner that is intended to protect the syringes from particles generated during opening should release a minimum of particles. The insert liner shall be, where appropriate, permeable for the sterilization agent (e.g. made of non-woven material of polyolefine). The insert liner can consist of several layers in order to ensure sufficient shielding of the glass against electron beam irradiation during the decontamination process. To enable proper removal, the layers should be connected with each other (e.g. by means of sealing the points). Edges may be rounded. The shape and dimensions of the insert liner shall comply with the tub.

4.5 Sealing lid

The sealing lid (e.g. made from non-woven polyolefin material) shall be sealable to the tub and completely peelable from the tub while minimizing the risk of releasing particles. The seal properties (e.g. seal strength, seal width) and integrity shall be tested in accordance with a validated test method. NOTE For examples of test methods, see ISO 11607‑1. The sealing lid should be designed to ensure sealing lid overhang beyond the edge of the sealing in order to reduce the risk of delamination. The sealing lid shall be, where appropriate, permeable for the sterilization agent. Considerations should be given to the selection of materials and seals with regard to decontamination processes (e.g. electron beam disinfection) prior to transfer of the packaging into the aseptic filling area.

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ISO 11040-7:2015(E)

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4.6 Protective bag

4.6.1 The protective bag shall be permanently sealed and shall enable the selected sterilization method. Testing of the seal properties (e.g. seal strength, seal width) shall be performed in accordance with a validated test method. NOTE For examples of test methods, see ISO 11607‑1. Considerations should be made to the selection of materials and seals with regard to decontamination processes (e.g. electron beam and H2O2 disinfection) prior to transfer of the packaging into the aseptic filling area. 4.6.2 The protective bag can consist of a single bag or double bags. The following information shall be provided as a minimum to the customer (information on dimensions including tolerances). For single bags: — bag dimensions (inside and outside); — width of the sealing joints, in millimetres, and their positions and type of sealing; — material (type and position, i.e. which material is used at which position); — orientation of the tub inside the bag (for possible configurations, see Annex D). For double bags: — dimensions of the outer bag; — width of the sealing joints, in millimetres, and their positions and type of sealing; — material (type and position, i.e. which material is used at which position) of the outer bag; — orientation of the tub with the bag inside the outer bag (for possible configurations, see Annex D); — folding of the inner bag. NOTE For types of protective bags, including dimensions, see Annex E.

5 Information to be provided by the manufacturer The manufacturer shall provide the following additional information: — information about the location of window(s) in the protective bag, if relevant; — information about specific material characteristics.

6 Marking of the tub The tub shall be marked as agreed upon by the manufacturer of the sterilized subassembled syringe ready for filling and the customer and can contain the following information: a) manufacturer’s name; b) article description; c) quantity of sterilized subassembled syringes ready for filling; d) warning “do not use if packaging is damaged”; e) date of manufacture;

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ISO 11040-7:2015(E) f) manufacturer’s batch number; g) serial number. NOTE 1 Machine-readable codes support automatic processing and tracking. NOTE 2 Symbols according to ISO 7000[1] or ISO 15223‑1[9] can be used. 7 Packaging of tubs in trading units/bundles The packaging system shall provide adequate protection to the product (including the sterile barrier system) through the hazards of handling, distribution, and storage. NOTE See ISO 11607‑1 for guidance on performance testing requirements and references for appropriate testing conditions. For packing the filled tubs, consideration should be given to product orientation in the pack to avoid jeopardizing the performance of the product. Storage conditions, including orientation and shelf life of the packaging system, shall be supported by shipping and ageing tests.

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Annex A (informative) Design of nests

ISO 11040-7:2015(E)

This annex intends to harmonize nests for sterilized subassembled syringes ready for filling, coming to the market, to facilitate the handling and processing of prefilled syringes. For this purpose, Tables A.1, A.2, and A.3 include — the range of typical dimensions of nests that reflect the current market situation and — for further harmonization, the corresponding nominal dimensions that are offered for future packaging developments. The related figures represent examples of the design of nests. Attention is drawn to the fact that certain designs of flange of plastic syringes of 20 ml and 50 ml, according to ISO 11040‑6, do not match with the dimensions given in this annex. Customers and manufacturers should agree upon the dimensions and tolerances of the finished product as delivered.

Table A.1 — Guidance on dimensions of a 160 cavity nest (see Figure A.1) Dimensions in millimetres

Position

Range of dimensiona

Nominal dimensionb

229,2 to 230,8

230,2

197,5 to 199,1

198,5

17,3 to 17,7

17,5

108,7

108,8

18,5 to 19,5

19,05

189,9 to 191,1

190,5

143,8 to 145,0

144,4

11,45

12,5 to 12,9

12,7

19,80

19,85

27,05

7,6

15 to 15,4

15,2

2,5 max.

1 max.

a This range reflects the current market situation.

b These nominal values refer to the finished product as delivered to the customer and are provided for future packaging developments.

c For special version.

NOTE 1 The Committee responsible for this part of ISO 11040 decided not to include any tolerances for the dimensions given in this table, in this edition of this part of ISO 11040, and it is understood that these are subject to agreement between the manufacturer and the customer.

NOTE 2 These dimensions can be used either for mould acceptance by the manufacturer or part acceptance by the customer.

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ISO 11040-7:2015(E)

Table A.1 (continued)

Position

Range of dimensiona

Nominal dimensionb

5 max.

—

9,3 to 9,6

9,4

a This range reflects the current market situation.

b These nominal values refer to the finished product as delivered to the customer and are provided for future packaging developments.

c For special version.

NOTE 2 These dimensions can be used either for mould acceptance by the manufacturer or part acceptance by the customer.

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ISO 11040-7:2015(E)

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B H

Key 1 customized ribbing to reinforce the nest stability against deflection 2 restricted area for suction cups N maximum deflection a 160 × Ø O (see Table A.1). NOTE Compatible barrel sizes 0,5 ml to 1 ml long. Figure A.1 — Guidance on design of a 160 cavity nest

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ISO 11040-7:2015(E)

Table A.2 — Guidance on dimensions of a 100 cavity nest (see Figure A.2) Dimensions in millimetres

Position

Range of dimensiona

Nominal dimensionb

229,1 to 230,9

230,2

197,4 to 199,2

198,5

17,23 to 17,73

17,5

107,40

107,5

18,47 to 19,57

19,05

180,09 to 181,59

147,70 to 149,20

148,6

9,98 to 10,68

10,35

16,49

16,51

24,93

24,95

24,60

9,32 to 9,72

9,53

19,03

19,05

2,5 max.

1 max.

5 max.

—

12,1 to 12,35

12,2

10,3 to 10,5

—

9,3 to 9,6

9,4

a This range reflects the current market situation.

b These nominal values refer to the finished product as delivered to the customer and are provided for future packaging developments.

c For special version.

NOTE 2 These dimensions can be used either for mould acceptance by the manufacturer or part acceptance by the customer.

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A H

ISO 11040-7:2015(E) C N

Oa G

B E D = =

Key 1 customized ribbing to reinforce the nest stability against deflection 2 restricted area for suction cups N maximum deflection a 100 × Ø O (see Table A.2). NOTE Compatible barrel sizes 1 ml to 3 ml long. Figure A.2 — Guidance on design of a 100 cavity nest

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ISO 11040-7:2015(E)

Table A.3 — Guidance on dimensions of a 64, 42, 30, and 20 cavity nest (see Figure A.3) Dimensions in millimetres

Position

5 ml/64 cavities

Range of dimensionsa

10 ml/42 cavities

20 ml/30 cavities

50 ml/20 cavities

228,8 to Nominal 228,8 to Nominal 228,8 to Nominal 228,8 to Nominal

231,2

230,2

231,2

230,2

231,2

230,2

231,2

230,2

197,1 to Nominal 197,1 to Nominal 197,1 to Nominal 197,1 to Nominal

199,5

198,5

199,5

198,5

199,5

198,5

199,5

198,5

17,23 to 17,73

33,37 to 33,87

17,21 to 23,36

88,22

99,50

82,25

98,77

18,47 to 19,57

18,50 to 19,6

18,45 to 26,97

180,32 to 181,62

170,81 to 172,11

166,35 to 167,65

158,05 to 164,65

144,8 to 146,1

142,23 to 143,53

132,95 to 134,25

129,50 to 132,65

9,93

8,72

5,38 to 10,33

20,02 to 21,52

27,82 to 29,32

32,65 to 34,15

42,94 to 44,44

26,45

27,74

31,55

33,1 to 34,29

24,60

29,29

30,81

22 to 35,76

12,06

23,53 to 24,73

27,97 to 29,17

32,8 to 34,0

39,23 to 40,43

5 max.

15,36 to 16,36

18,06 to 19,06

22,56 to 23,56

30,41 to 33,25

a This range reflects the current market situation. At this stage, nominal dimensions are only given for dimensions A and B.

NOTE 2 These dimensions can be used either for mould acceptance by the manufacturer or part acceptance by the customer.

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ISO 11040-7:2015(E)

a) 64 cavity nest for compatible barrel sizes 5 ml long

20 cavity nest for

compatible barrel sizes

50 ml long

42 cavity nest for

compatible barrel sizes

10 ml long

30 cavity nest for

compatible barrel sizes

20 ml long

Key 1 customized ribbing to reinforce the nest stability against deflection 2 restricted area for suction cups N maximum deflection a 64 x Ø O, 20 x Ø O, 42 x Ø O, and 30 x Ø O respectively (see Table A.3).

Figure A.3 — Guidance on design of a 64, 42, 30, and 20 cavity nest

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ISO 11040-7:2015(E) Annex B (informative) Determination of nest deflection B.1 General This annex describes one example of test methods used to determine the nest deflection. Other test methods are available and are equally applicable. The two nest supports described in this annex are also given as examples only. B.2 Principle The nest deflection is measured by using a depth gauge. The deflection of the nest is measured by holding the nests either by its four corners or placing it on a perforated plate with a hole pattern similar to the nest. B.3 Materials and apparatus B.3.1 Nest to be tested, either empty or filled with empty sterilized subassembled syringes ready for filling. B.3.2 Nest support. NOTE Figures B.1 and B.2 describe two alternative nest supports that are suitable for this test. B.3.3 Depth gauge. B.4 Procedure Insert the removable middle pillar in the centre of the nest frame (Figure B.1) and put it in an empty or full nest (if full, remove the sterilized subassembled syringes ready for filling in the middle to clear the area for the measurement). Position the nest support under the depth gauge and move it down until it is in contact with the central point of the nest. Set to zero. Raise the depth gauge, remove the middle pillar, and put back the nest filled with the sterilized subassembled syringes ready for filling. Move down the gauge until it is in contact with the central point of the nest. Measure the depth. The depth measured represents the nest deflection when loaded with sterilized subassembled syringes ready for filling. B.5 Test report The test report shall include the following information: a) the value in millimetres with two numbers after the decimal point; b) the type of test equipment used.

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ISO 11040-7:2015(E)

Key 1 frame 2 pillar 3 removable pillar 4 hole NOTE The nest support consists of a frame with four pillars holding the nest by its four corners. The removable middle pillar is used to hold the nest flat. The hole in the middle accommodates the removable middle pillar. Figure B.1 — Schematic drawing of the frame used to hold the nest by its corners - Example 1

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ISO 11040-7:2015(E)

Key 1 depth gauge 2 syringe 3 nest 4 perforated plate (size part, easy to change) 5 foot NOTE The force of the measuring sensor should not deform the tested nest. Figure B.2 — Schematic drawing nest support - Example 2

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Annex C (informative) Design of tubs

ISO 11040-7:2015(E)

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This annex intends to harmonize tubs for sterilized subassembled syringes ready for filling, coming to the market, to facilitate the handling and processing of prefilled syringes. For this purpose, Table C.1 includes — the range of typical dimensions of tubs that reflect the current market situation and — for further harmonization, the corresponding nominal dimensions that are offered for future packaging developments. The related figure represents an example of the design of tubs. Customers and manufacturers should agree upon the dimensions and tolerances of the finished product as delivered.

Table C.1 — Guidance on dimensions of a commonly called 3” tub (see Figure C.1) Dimensions in millimetres

Remarks

Position Dimensiona

Nominal dimensionb

226,2 to 228,6

259 to 261,2

25,4 to 28

96 to 98,5

97,5

inside

201,3

inside

11,6 to 13,7

12,7

inside

233,3

measuring point angle I = K

26,4

measuring point angle L = J

52,5

measuring point angle

213,1 to 215,1

measuring point angle

216 to 220

measuring point angle

178,2 to 181,6

179,9

measuring point angle

180,9 to 185,1

a This range reflects the current market situation.

b These nominal values refer to the finished product as delivered to the customer and are provided for future packaging developments.

c Has to correspond to the nest with clearance.

NOTE 2 Other tubs commonly on the market are, for example, 4”, 6”, and 6 3/4 ” tubs. These tubs are, at this stage, not defined.

NOTE 3 These dimensions can be used either for mould acceptance by the manufacturer or part acceptance by the customer.

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ISO 11040-7:2015(E) 26,4 F

R16 0,5

Dimensions in millimetres A

G Ma Nb H B

14,5

Ib b

X d c

E P O X

L K C D

Figure C.1 — Guidance on the design of a commonly called 3” tub Key 1 customized stack ribs a J and M checked on reinforced area. b I and N checked on reinforced area. c Flange thickness to be agreed upon with the customer. d Rounded edge recommended on both sides. NOTE The bottom of the tub can be recessed or flat.

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ISO 11040-7:2015(E) Annex D (informative) Schematic illustrations of examples for the orientation of tubs within the protective bag The following schematic illustrations represent examples for the orientation of tubs within the protective bags. The long dimension of the tub should be aligned with the long dimension of the protective bag. For the dimensions of tubs and protective bags, see Annexes C and E. Figure D.1 — Example 1 - Top web porous material Figure D.2 — Example 2 - Header bag upwards NOTE This configuration reduces the permeability for sterilization gases versus the configuration in Figures D.1 and D.2 and can have an impact on sterilization cycles. Figure D.3 — Example 3 - Header bag downwards

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ISO 11040-7:2015(E)

NOTE Header bag or reel bag windows are located on top of each other to allow for sufficient permeability for sterilization gases and air. Figure D.4 — Example 4 - Double bag upwards NOTE Header bag or reel bag windows are located on top of each other to allow for sufficient permeability for sterilization gases and air. Figure D.5 — Example 5 - Double bag downwards

Key 1 tub 2 protective bag

Figure D.6 — Example 6 - Double reel bag

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ISO 11040-7:2015(E) Annex E (informative) Design and dimensions of the protective bag E.1 Design There are many designs of protective bags and the following figures represent only examples of commonly used protective bags. Dimensions are subject to agreement between the manufacturer and the customer. Dimensions in millimetres S1

B --`,,,,,,,,,,,,,,,,```,--,,,,,,,---

Key

Lc length of cutting area

A overall length

B overall width

distance between the seals S2

S1, S2 seals

NOTE The seal S2 is typically made after inserting the tub.

Figure E.1 — Illustration of an example of a reel bag without window

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ISO 11040-7:2015(E) H

Dimensions in millimetres S1

B --`,,,,,,,,,,,,,,,,```,--,,,,,,,---

Key Lc A B C S1, S2, S3, S4

length of cutting area overall length overall width of the bag distance between end of seal S4 and beginning of seal S2 seals

NOTE The seal S2 is typically made after inserting the tub.

Figure E.2 — Illustration of an example of a header bag with window

Table E.1 — Guidance on dimensions Dimensions in millimetres

Position

Range of dimensiona

Reel bag

Header bag

485 to 515

445 to 475

380 to 410

10–16

n.a.b

10–16

n.a.b

10–16

n.a.b

10–16

a These range of values refer to the finished product as delivered to the customer. It reflects the current market situation.

b Not applicable.

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ISO 11040-7:2015(E)

E.2 Determination of the overall length and the cutting area

The length of the cutting area of the protective bag can be calculated as follows:

Lc = C − S4 − Lt

(E.1)

where

is the length of the cutting area in millimetres;

is the distance between the two S2 seals or for header bags, the distance between end of

seal S4 and beginning of seal S2 in millimetres;

is the length of the tub in millimetres;

C and S4 are measured after opening a sealed bag;

is zero for reel bags.

C and S4 are measured after opening a sealed bag.

NOTE A test method to determine the distance from the edge of the protective bag to the rear end of the tub is given in Annex F. This test method can be used to evaluate whether the protective bag can be opened automatically.

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ISO 11040-7:2015(E) Annex F (informative) Test method to determine the distance between the edge of the protective bag to the rear end of the tub F.1 Principle The distance between the edge of the protective bag and the rear end of the tub is measured using a test apparatus as described in this Annex. The test apparatus is given as an example only and similar constructions can be used alternatively. This test method can be used to evaluate whether the protective bag can be opened automatically. F.2 Apparatus, materials F.2.1 Test apparatus, consisting of a moveable slide, crank handle, knee level clamps, and measuring unit, as described in Figure F.1 or similar device. F.2.2 Protective bags, to be tested, number as appropriate. F.3 Procedure Place the test apparatus in an upright and fixed position. Using the crank handle (1), move the moveable slide (6) until it reaches the end stop (starting position). In this position, there is an offset to the actual zero level (4), e.g. 120 mm. Ensure that the moveable slide (6) rests against the mounting of the knee level clamp (2) before carrying on with the procedure. Adjust the measuring unit (7) so that the display shows zero. Set the knee level clamps (2) to an open position and insert the protective bag with the seam facing the knee level clamps (2) and the tub lid facing the support columns (8) (see also Figure 2). If the seam is greater than 40 mm (see Figure F.2), problems might arise during automatic opening. Be sure that the protective bag is inserted correctly and that it is situated against the end stop. Using the crank handle (1), set the moveable slide (6) to the appropriate depth. Ensure that the tub is hanging freely within the protective bag and that there is a small gap between the bottom of the tub and the moveable slide (6). Using the crank handle (1), carefully raise the moveable slide (6) until it reaches the bottom rim of the tub and until it just rests on the moveable slide (6). Read off the measurement from the display and add this value to the offset value (e.g. 120 mm) to obtain the length between the edge of the protective bag and the rear end of the tub.

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ISO 11040-7:2015(E)

F.4 Test report

Report the measured length in millimetres (distance between the edge of the protective bag and the rear end of the tub).

Report the type of the equipment used.

5 6

0,00

Key 1 crank handle 2 knee level clamp 3 adjustable knee level clamp brackets for different tub heights 4 offset (e.g. 120 mm)

5 seam area 6 moveable slide 7 measuring unit 8 support column

Figure F.1 — Example of test apparatus

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ISO 11040-7:2015(E)

Dimensions in millimetres

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Key 1 bag welding 2 cutting device a Safety distance to ensure that cutting is not in or outside the welding area. b Machine parameter. c Safety distance. NOTE Problems might arise during automatic opening if the indicated measure of 40 mm is exceeded. Figure F.2 — Illustration of the position of the tub in the test apparatus

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Bibliography

ISO 11040-7:2015(E)

[1] ISO 7000, Graphical symbols for use on equipment — Registered symbols [2] ISO 11135‑1, Sterilization of health care products — Ethylene oxide — Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices [3] ISO 11137 (all parts), Sterilization of health care products — Radiation [4] ISO 11138 (all parts), Sterilization of health care products — Biological indicators [5] ISO/TS 11139, Sterilization of health care products — Vocabulary [6] ISO 11140 (all parts), Sterilization of health care products — Chemical indicators [7] ISO 11607‑2, Packaging for terminally sterilized medical devices — Part 2: Validation requirements for forming, sealing and assembly processes [8] ISO 14937, Sterilization of health care products — General requirements for characterization of a sterilizing agent and the development, validation and routine control of a sterilization process for medical devices [9] ISO 15223‑1, Medical devices — Symbols to be used with medical device labels, labelling and information to be supplied — Part 1: General requirements [10] ISO 15378, Primary packaging materials for medicinal products - Particular requirements for the application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP) [11] ISO 17665‑1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices

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ISO 11040-7:2015(E)

ICS 11.040.25 Price based on 27 pages Copyright In©ternIaStioOnal2O0rg1an5iza–tionAfolrlSrtaingdhardtiszartioenserved Provided by IHS Markit under license with ANSI No reproduction or networking permitted without license from IHS

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=== ISO 11040-8 ===

INTERNATIONAL STANDARD

ISO 11040-8 First edition 2016-11-15

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Prefilled syringes — Part 8: Requirements and test methods for finished prefilled syringes Seringues préremplies — Partie 8: Exigences et méthodes d’essai pour seringues préremplies prêtes à l’emploi

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Reference number ISO 11040-8:2016(E)

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ISO 11040-8:2016(E)

© ISO 2016, Published in Switzerland All rights reserved. Unless otherwise specified, no part of 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 of the requester. ISO copyright office Ch. de Blandonnet 8 • 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

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ISO 11040-8:2016(E)

Contents

Page

User requirements.............................................................................................................................................................................................. 2

4.1 Definition of intended use.............................................................................................................................................................. 2

4.2 Risk management.................................................................................................................................................................................. 3

4.3 Application of usability engineering..................................................................................................................................... 3

System characterization................................................................................................................................................................................ 3

5.1 Critical dimensions............................................................................................................................................................................... 3

5.2 Description of components and materials....................................................................................................................... 4

5.2.1 General...................................................................................................................................................................................... 4

5.2.2 Barrel.......................................................................................................................................................................................... 4

5.2.3 Plunger stoppers............................................................................................................................................................... 5

5.2.4 Additional components............................................................................................................................................... 5

5.3 Description of the content of the finished prefilled syringe............................................................................. 5

Performance requirements........................................................................................................................................................................ 5

6.2 Break loose and extrusion forces............................................................................................................................................. 5

6.3 Burst resistance....................................................................................................................................................................................... 6

6.4 Break resistance...................................................................................................................................................................................... 6

6.5 Closure system forces and torques......................................................................................................................................... 6

6.6 Connectivity with fluid path connectors............................................................................................................................ 6

6.7 Residual volume...................................................................................................................................................................................... 6

6.8 Needle penetration force................................................................................................................................................................. 6

6.9 Needle pull-out force.......................................................................................................................................................................... 6

6.10 Sharps injury protection requirements.............................................................................................................................. 6

6.11 Liquid leakage beyond plunger................................................................................................................................................. 7

6.12 Markings........................................................................................................................................................................................................ 7

Pharmaceutical requirements................................................................................................................................................................ 7

7.1 General............................................................................................................................................................................................................ 7

7.2 Drug-container interaction........................................................................................................................................................... 7

7.3 Biological requirements................................................................................................................................................................... 7

7.4 Container closure integrity........................................................................................................................................................... 7

7.5 Deliverable volume............................................................................................................................................................................... 8

7.6 Particles (visible and subvisible)............................................................................................................................................. 8

Documentation........................................................................................................................................................................................................ 8

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iii

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ISO 11040-8:2016(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. The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives). 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. Details of any patent rights identified during the development of 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 information given for the convenience of users and does not constitute an endorsement. For an explanation on the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO’s adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following URL: www.iso.org/iso/foreword.html. The committee responsible for this document is ISO/TC 76, Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use. ISO 11040 consists of the following parts, under the general title Prefilled syringes: — Part 1: Glass cylinders for dental local anaesthetic cartridges — Part 2: Plunger stoppers for dental local anaesthetic cartridges — Part 3: Seals for dental local anaesthetic cartridges — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling — Part 5: Plunger stoppers for injectables — Part 6: Plastic barrels for injectables — Part 7: Packaging systems for sterilized subassembled syringes ready for filling — Part 8: Requirements and test methods for finished prefilled syringes

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ISO 11040-8:2016(E) Introduction Historically, injectable (parenteral) liquid pharmaceutical products have been mainly provided in primary containers (i.e. ampoules and vials) which required the liquid to be transferred into a hypodermic syringe and combined with the appropriate injection needle before its final use. This procedure is not only time-consuming, but also presents a great number of possibilities for contamination and use errors. Over the past several years, the presentation of liquid pharmaceutical products in prefilled syringes for single use, many with staked needles, is becoming more prevalent. The simplicity of use that is provided not only benefits their use in the clinical setting, but also enables these to be used by lay users in a home setting. The standardization of the requirements for prefilled syringes has been addressed by ISO/TC 76 in two ways: — the specification of the components of the prefilled syringe prior to filling is included in the previous parts of the ISO 11040 series; — the requirements for the final prefilled syringe, presented to the user as a finished product, are addressed in this part of ISO 11040. Finished prefilled syringes require marketing authorization as a drug, in some regions as a combination product or as a medical device, depending on the content and the intended use. The syringe plays a dual role in the prefilled syringe product — as a container closure system and as a delivery device. Safety, performance and usability need to be considered, as well in case of intended preassembly, copackaging or label reference for use with other devices and equipment. This part of ISO 11040 addresses the content and syringe as a system, with the intent to ensure the successful performance for its intended purpose. There are other international and national standards and guidance publications and, in some countries, national regulations that are applicable to medical devices and pharmaceuticals. Their requirements might supersede or complement this part of ISO 11040. Developers and manufacturers of finished prefilled syringes are encouraged to investigate and determine whether there are any other requirements relevant to the safety or marketability of their products.

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INTERNATIONAL STANDARD

ISO 11040-8:2016(E)

Prefilled syringes — Part 8: Requirements and test methods for finished prefilled syringes

1 Scope This part of ISO 11040 is applicable to aseptically filled or terminally sterilized finished prefilled syringes (intended for single use only) based on ISO 11040-4 or ISO 11040-6, together with ISO 11040-5, for parenteral injection preparations with focus on quality, functional performance and safety requirements, as well as relevant test methods. Finished prefilled syringes which have undergone an additional preparation step by the user before injection (e.g. diluent syringes that have been emptied for reconstitution and in which the reconstituted drug solution has been aspirated after reconstitution) are excluded from the scope of this part of ISO 11040. NOTE 1 This part of ISO 11040 can also be used as a guidance for other types, designs and/or sizes of prefilled syringes, e.g. dual chamber prefilled syringes. NOTE 2 In case the finished prefilled syringes are used in a needle-based injection system, see also ISO 11608-3. NOTE 3 Attention is drawn to applicable national or regional regulations such as Ph. Eur1), USP2) or JP3). NOTE 4 Finished prefilled syringes containing so-called borderline products, e.g. hyaluronic acid, are included in the scope of this part of ISO 11040, though they are not always regulated as a pharmaceutical product.

2 Normative references The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies. ISO 11040-4:2015, Prefilled syringes — Part 4: Glass barrels for injectables and sterilized subassembled syringes ready for filling ISO 11040-5, Prefilled syringes — Part 5: Plunger stoppers for injectables ISO 11040-6, Prefilled syringes — Part 6: Plastic barrels for injectables ISO 23908, Sharps injury protection — Requirements and test methods — Sharps protection features for single-use hypodermic needles, introducers for catheters and needles used for blood sampling ISO 80369-1, Small-bore connectors for liquids and gases in healthcare applications — Part 1: General requirements ISO 80369-7, Small-bore connectors for liquids and gases in healthcare applications — Part 7: Connectors with 6% (Luer) taper for intravascular or hypodermic applications

See http://www.edqm.eu/. 2) See http://www.usp.org/. 3) See http://www.pmda.go.jp.

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ISO 11040-8:2016(E)

ISO 80369-20, Small-bore connectors for liquids and gases in healthcare applications — Part 20: Common test methods ISO 7886-1:2015, Sterile hypodermic syringes for single use — Part 1: Syringes for manual use IEC 62366, Medical devices — Application of usability engineering to medical devices

3 Terms and definitions For the purposes of this document, the following terms and definitions apply. 3.1 finished prefilled syringe prefilled container closure system for parenteral injection preparations as it is marketed, including e.g. assembly of components, terminal sterilization and final packaging 3.2 manufacturer natural or legal person holding the licence for the pharmaceutical product with responsibility for the design, manufacture, packaging, and labelling of a finished prefilled syringe, before it is placed on the market or put into service, regardless of whether these operations are carried out by that person or on that person’s behalf by a third party 3.3 risk management systematic application of management policies, procedures and practices to the tasks of analysing, evaluating, controlling and monitoring risk [SOURCE: ISO 14971:2007, 2.22] 3.4 user patient or health care provider (clinical personnel, doctor, or lay person) who prepares and/or uses the finished prefilled syringe

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4 User requirements 4.1 Definition of intended use The manufacturer shall define the intended use of the finished prefilled syringe. Aspects to be considered shall include the following: — users including their health status; — the route of administration; — target tissue; — additional medical devices or application aids that are used for application, e.g. needle-based injection systems, infusion tubes, reconstitution aids, sterile hypodermic needles, plunger rod/finger flange; — characteristics of the environment during transport, storage and use; — interactions between user, environment and prefilled syringe; — point of use, e.g. hospital, homecare; — frequency of application; — criticality of medication, e.g. medication for acute care or for chronic diseases.

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ISO 11040-8:2016(E)

4.2 Risk management

Manufacturers shall follow a risk-based approach during the design, development, manufacture and life cycle of the finished prefilled syringe like exemplary described by ISO 14971. Risk management shall consider the intended use, interactions between content and container, and environmental conditions. This can result in product-specific requirements and test methods that differ from what is outlined in this part of ISO 11040. If the prefilled syringe is intended to be used in combination with preattached, copackaged or label referenced devices and equipment, the manufacturer shall ensure that the whole combination, including the connection system, is safe, usable and does not impair the specified performances of the devices. NOTE For filling process, see Reference [17].

4.3 Application of usability engineering

The usability of the prefilled syringe shall be considered and validated according to a process compliant with IEC 62366. NOTE 1 For further information, see Reference [16]. NOTE 2 The instructions for use are part of the usability testing. 5 System characterization

5.1 Critical dimensions

Critical dimensions shall be defined considering the intended use of the finished prefilled syringe. Special focus shall be given to: — interfaces with other devices (e.g. sharp injury prevention features or needle-based injection systems, needleless connection devices), components and users; — connectivity with other devices at the point of use (e.g. IV access systems or needles); — plunger stopper position depending on the intended use (e.g. use in needle-based injection systems). Figure 1 includes examples on how to measure the plunger stopper position on finished prefilled syringes.

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ISO 11040-8:2016(E)

a) Example 1

b) Example 2

Key 1 l1 l2 and l3

plunger stopper distance from the plunger stopper to the top of the 90° cone (mechanical or optical gage) distance from the plunger stopper to the back end of the syringe

[Figure 1 — Examples for measuring plunger the stopper position for finished prefilled syringes]

5.2 Description of components and materials

5.2.1 General

The selected components and materials shall be suitable for the intended manufacturing processes (e.g. terminal sterilization if applicable). The interface with other drug delivery devices and/or components, e.g. tubing or needle based injection systems, shall be considered.

5.2.2 Barrel

ISO 11040-4 and ISO 11040-6 shall apply. NOTE 1 If fill lines or graduation marks are printed, ISO 7886-1:2015, Table 1 can be considered. NOTE 2 ISO 11040-6 will be revised to cover plastic subassemblies ready for filling. The barrel can include a staked needle. The needle dimensions including inner and outer diameters shall be consistent with the intended use, considering e.g. route of administration, use in needle-based injection systems and contents viscosity.

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ISO 11040-8:2016(E) 5.2.3 Plunger stoppers ISO 11040-5 shall apply. NOTE 1 Plunger stopper dimensions change by placing it into the syringe. NOTE 2 There can be special aspects for coated or laminated plungers, associated e.g. with plunger placement. 5.2.4 Additional components Additional components supporting the intended use can include the following: — plunger rod; — add-on finger flange; — sharp injury prevention feature according to ISO 23908; — hypodermic needle with 6 % Luer conical fitting according to ISO 7864; — filter; — tubing; — vial adapter. A finished prefilled syringes can be used in needle-based injection systems. The interface to the relevant components shall be considered. 5.3 Description of the content of the finished prefilled syringe Critical parameters of the content shall be defined. These parameters can include the following: — viscosity; — density; — surface tension; — fill volume including tolerances; — pH. These parameters are temperature dependent and can change over time. 6 Performance requirements 6.1 General The manufacturer shall ensure that the finished prefilled syringe meets the appropriate functional requirements until the end of its shelf life. The tests described in the following subclauses should be considered but might not be all inclusive. Limits for the tests shall be defined based on the intended use (see 4.1). 6.2 Break loose and extrusion forces Break loose and extrusion force testing shall be conducted with the final system (including assembled plunger and e.g. attached needle and assembled plunger rod) as intended for use. For the tests, the temperature of the content shall be the same as for application.

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ISO 11040-8:2016(E)

It shall be considered that the forces might change over shelf life, depending on environmental conditions and aging. The test speed shall be defined based on the intended use, considering injection duration requirements, as well as the content properties. For interpretation of test results, see ISO 11040-4:2015, Figure E.1. NOTE ISO 11040-6 will be revised to cover plastic subassemblies ready for filling.

6.3 Burst resistance

The burst resistance for the finished prefilled syringe shall be tested with the test setup as described in ISO 11040-4:2015, G.2 but with a sealing of the front end to allow burst pressure testing. Test pressures and acceptance criteria shall be defined considering the intended use as well as the content properties (e.g. use in needle-based injection systems or prefilled syringes with a high viscosity content). NOTE ISO 11040-6 will be revised to cover plastic subassemblies ready for filling.

6.4 Break resistance

For flange break resistance, ISO 11040-4:2015, 5.4.4 applies and for Luer cone breakage resistance, ISO 11040-4:2015, 5.4.5 applies. NOTE ISO 11040-6 will be revised to cover plastic subassemblies ready for filling.

6.5 Closure system forces and torques Test methods of ISO 11040-4:2015, G.3 to G.6 apply.

6.6 Connectivity with fluid path connectors

Additional fluid path connectors to be used according to the intended use shall be tested for connectivity and leakage following ISO 80369-1, ISO 80369-7 and ISO 80369-20. See also ISO 11040-4 and ISO 11040-6 for Luer connectors.

6.7 Residual volume

The residual volume of the finished prefilled syringe has to be tested in combination with components as considered in the intended use. ISO 11040-4:2015, 6.5.1.3, applies.

6.8 Needle penetration force

Needle penetration force for finished prefilled syringes with a staked needle shall be tested according to ISO 11040-4:2015, Annex F. NOTE Terminal sterilization using moist heat can affect the silicone layer on the needle.

6.9 Needle pull-out force ISO 11040-4:2015, 6.5.2.5 applies.

6.10 Sharps injury protection requirements

If the finished prefilled syringe has integrated sharps injury protection features (or sharps protection devices included in the presentation), it shall meet the requirements of ISO 23908.

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ISO 11040-8:2016(E)

6.11 Liquid leakage beyond plunger

The syringe shall be tested according to ISO 7886-1:2015, Annex B for liquid leakage, with blocked fluid path, by applying an axial force on the plunger stopper by the final plunger rod, consistent with the maximum force generated during use.

6.12 Markings

All graduation markings or indicator lines (e.g. preprinted or on a label) shall be verified to be as accurate as appropriate for their intended use.

7 Pharmaceutical requirements

7.1 General

Pharmaceutical requirements for medicinal products are covered by national or regional regulations such as pharmacopoeias and accompanying applicable guidelines. The container closure system shall be suitable for the content (protection, safety, compatibility and performance), considering the intended use (e.g. transport, storage or use). The tests in 7.2 to 7.6 shall be performed but might not be all inclusive.

7.2 Drug-container interaction

The content of the prefilled syringe shall meet the specified quality attributes throughout the shelf life when transported and stored according to the manufacturer’s instructions. The impact of components (e.g. needle, tubing) on the content at the time of use shall be considered. The following aspects shall be considered but might not be all inclusive: — extractables/leachables, e.g residuals from forming, moulding, assembly process, gluing, sterilization process, rubber ingredients, impurities and degradation products, free silicone, as well as from labels; — compatibility, e.g. loss of potency of the drug, adsorption, degradation of the drug, change of stability indicating parameters; — effect of shear forces during delivery on the drug quality.

7.3 Biological requirements

Biological hazard assessment shall be performed for the finished prefilled syringe following, e.g. ISO 10993-1. The container closure system shall maintain sterility, achieved either by aseptic processing or by terminal sterilization, throughout its shelf life including transportation. Endotoxin levels are specified in pharmacopoeial requirements. NOTE See References [11] and [12].

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7.4 Container closure integrity

The container closure system sealing surfaces shall ensure integrity throughout filling, terminal sterilizations (if applicable, e.g. moist heat by autoclaving), further manufacturing steps, storage and transportation (considering different external air pressures) to ensure content sterility and to prevent leakage. A suitable container closure integrity test method (e.g. physical, microbiological) shall be qualified and validated to assess the finished prefilled syringe.

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ISO 11040-8:2016(E) 7.5 Deliverable volume The deliverable volume from the finished prefilled syringe shall comply with the required or labelled drug dose for the application when used per preparation steps and instructions for use for the finished prefilled syringe considering applicable pharmacopoeia requirements. 7.6 Particles (visible and subvisible) The particulate level is specified in applicable pharmacopoeias. 8 Documentation Test reports shall include — the objective, — the acceptance criteria with a justification if not specified in the standard, — the sample size with a justification if not specified in the standard, — the test method, and — the test results including a discussion thereof and a discussion of any deviations, as well as a conclusion.

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Bibliography

ISO 11040-8:2016(E)

[1] ISO 7864, Sterile hypodermic needles for single use [2] ISO 7886-1:2015, Sterile hypodermic syringes for single use — Part 1: Syringes for manual use [3] ISO 9626, Stainless steel needle tubing for the manufacture of medical devices [4] ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process [5] ISO 11608-1, Needle-based injection systems for medical use — Requirements and test methods — Part 1: Needle-based injection systems [6] ISO 11608-2, Needle-based injection systems for medical use — Requirements and test methods — Part 2: Needles [7] ISO 11608-3Needle-based injection systems for medical use — Requirements and test methods — Part 3: Finished containers [8] ISO 11608-4, Pen-injectors for medical use — Part 4: Requirements and test methods for electronic and electromechanical pen-injectors [9] ISO 11608-5, Needle-based injection systems for medical use — Requirements and test methods — Part 5: Automated functions [10] ISO 14971, Medical devices — Application of risk management to medical devices [11] ISO 13408-1, Aseptic processing of health care products — Part 1: General requirements [12] ISO 17665-1, Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation and routine control of a sterilization process for medical devices [13] ISO 80369-3, Small-bore connectors for liquids and gases in healthcare applications — Part 3: Connectors for enteral applications [14] IEC 80369-5, Small-bore connectors for liquids and gases in healthcare applications — Part 5: Connectors for limb cuff inflation applications [15] ISO 80369-6, Small bore connectors for liquids and gases in healthcare applications — Part 6: Connectors for neuraxial applications [16] ANSI/AAMI HE75, Human Factors Engineering — Design of Medical Devices [17] ICH Q9. Quality risk management, see http://www.ich.org

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ISO 11040-8:2016(E)

ICS 11.040.25 Price based on 9 pages --`,,,,,,,,,,,,,,,,```,--,,,,,,,--- Copyright In©ternIaStioOnal2O0rg1an6iza–tionAfolrlSrtaingdhardtiszartioenserved Provided by IHS Markit under license with ANSI No reproduction or networking permitted without license from IHS

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ISO 11040 Complete

ISO 11040 Prefilled Syringes Series (Parts 1-8): General and Specific Requirements for Prefilled Syringes

3.2 Designation

4.2 Performance

7.1 General

7.2 Physical requirements

7.2.1 Hardness

7.2.2 Freedom from leakage

7.2.3 Sliding characteristics

6.1 Cap

6.2 Discs

7.2 Physical requirements

7.2.4 Resistance to ageing

6.5 Additional requirements to specific components of sterilized subassembled

4.1 Quality systems

4.2 Testing

4.3 Documentation

5.1 Design including dimensions

5.2 Functional testing of Luer connection

5.3 Material

5.4 Performance requirements

5.4.1 Hydrolytic resistance

5.4.2 Annealing quality

5.4.3 Lubrication of the inner surface

5.4.4 Flange breakage resistance

5.4.5 Luer cone breakage resistance

6.1 General

6.2 Sterility

6.4 Particles

6.5 Additional requirements to specific components of sterilized subassembled syringes ready for filling

6.5.1 Barrel

6.5.2 Needle

6.5.2.2 The needle shall fulfil the following material, dimensional, and design requirements:

6.5.3 Closure system

6.5.3.7 The design of closure systems shall be such that

7.1 General

7.2 Physical requirements

7.2.1 Hardness

7.2.2 Resistance to ageing

7.3 Chemical requirements

4.1 Quality systems

4.2 Testing

4.3 Documentation

5.1 Design including dimensions

5.2 Design requirements

5.2.1 Head design

5.2.2 Dead space

5.2.3 Functional testing of Luer cone/Luer lock connection

5.2.4 Flange breakage resistance

5.2.5 Syringe tip breakage resistance

6.1 General

6.2 Material

6.2.1 General

6.2.2 Duty of notification concerning modifications to polymers

6.2.3 Needle

6.2.4 Closure system

6.2.4.6 The design of closure systems shall be such that

6.2.5 Closure system integrity

6.3 Physical requirements

6.3.1 Sterilization

6.3.2 Clarity and transparency

6.3.3 Particulate contamination

6.3.4 Lubricants

6.4 Chemical requirements

6.5 Endotoxins and biological requirements

4.1 General

4.2 Nest

4.3 Tub

4.3.1 For tubs, the following information shall be provided (information on dimensions including tolerances):

4.4 Insert liner

4.5 Sealing lid

4.6 Protective bag

4.2 Risk management

4.3 Application of usability engineering

5.1 Critical dimensions

5.2 Description of components and materials

5.2.1 General

5.2.2 Barrel

6.3 Burst resistance

6.4 Break resistance