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
`
`Reference number
`ISO 11040-5:2012(E)
`
`© ISO 2012
`
`Regeneron Exhibit 1233.001
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`ISO 11040-5:2012(E)
`
`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
`
`ii
`
`
`
`© ISO 2012 – All rights reserved
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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
`
`© ISO 2012 – All rights reserved
`
`
`
`iii
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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.
`
`iv
`
`
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`© ISO 2012 – All rights reserved
`
`Regeneron Exhibit 1233.004
`Regeneron v. Novartis
`IPR2021-00816
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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.
`
`The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be
`NOTE
`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 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 11040-4, Prefilled syringes — Part 4: Glass barrels for injectables
`
`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.
`
`© ISO 2012 – All rights reserved
`
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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
`
`2
`
`
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`© ISO 2012 – All rights reserved
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`Dimensions of plunger stoppers
`
`Nominal
`volume
`
`Type
`
`d1a
`
`d2a
`
`d3a
`
`tol.
`
`tol.
`
`nom.
`
`tol.
`
`Nominal
`inner
`diameter
`d2b
`
`4,65 ± 0,1
`
`ml
`
`0,5
`
`PSL
`
`nom.
`nom.
`5,2
`4,1
`to
`to
`5,3
`4,2
`5,9
`6,8
`to
`to
`6
`7
`7,6
`9,05
`to
`to
`8
`9,25
`10,5
`12,5
`to
`to
`11,15
`12,7
`13,5
`15
`to
`to
`13,75
`15,3
`18,4
`19,9
`to
`to
`18,6
`20,1
`The nominal diameter shall be agreed upon between the manufacturer and the user within the given range.
`
`6,35 ± 0,1
`
`1 (long)
`
`8,65 ± 0,2
`
`1 to 3
`
`±0,1
`
`PST
`
`11,85 ± 0,2
`
`14,25 ± 0,2
`
`19,05 ± 0,2
`
`5
`
`10
`
`20
`
`a
`b
`
`In accordance with ISO 11040-4.
`
`±0,15
`
`2,5
`
`2,6
`
`±0,2
`
`±0,15
`
`4,7
`
`5,2
`to
`5,6
`7,4
`to
`7,6
`
`10,7
`
`±0,25
`
`ISO 11040-5:2012(E)
`
`Dimensions in millimetres
`h1a
`h2a
`
`nom.
`6,85
`to
`7,0
`7,65
`to
`7,85
`7,7
`to
`7,85
`
`8,5
`
`8,5
`to
`10
`13,45
`to
`13,50
`
`tol.
`
`nom.
`
`tol.
`
`5,3
`
`±0,35
`
`±0,4
`
`4,5
`
`4
`
`6,0
`
`6
`to
`6,2
`
`7
`
`±0,3
`
`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.
`
`Designation of a plunger stopper with snap lip for a glass barrel of 0,5 ml nominal volume, complying with
`EXAMPLE 1
`the requirements in this part of ISO 11040:
`
`Plunger ISO 11040-5 - PSL - 0,5
`
`Designation of a threaded plunger stopper for a glass barrel of 1 ml nominal volume, long version,
`EXAMPLE 2
`complying with the requirements in this part of ISO 11040:
`
`Plunger ISO 11040-5 - PST - 1 - lg
`
`© ISO 2012 – All rights reserved
`
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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.
`
`4
`
`
`
`© ISO 2012 – All rights reserved
`
`Regeneron Exhibit 1233.008
`Regeneron v. Novartis
`IPR2021-00816
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`

`

`ISO 11040-5:2012(E)
`
`Bibliography
`
`[1]
`
`[2]
`
`[3]
`
`[4]
`
`[5]
`
`[6]
`
`ISO 48, Rubber, vulcanized or thermoplastic — Determination of hardness (hardness between 10 IRHD
`and 100 IRHD)
`
`ISO 2230, Rubber products — Guidelines for storage
`
`ISO 3302-2, Rubber — Tolerances for products — Part 2: Geometrical tolerances
`
`ISO 8362-5, Injection containers for injectables and accessories — Part 5: Freeze drying closures for
`injection vials
`
`ISO 9997, Dental cartridge syringes
`
`ISO 15378, Primary packaging materials for medicinal products — Particular requirements for the
`application of ISO 9001:2008, with reference to Good Manufacturing Practice (GMP)
`
`© ISO 2012 – All rights reserved
`
`
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`5
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`ISO 11040-5:2012(E)
`
`ICS 11.040.25
`Price based on 5 pages
`
`© ISO 2012 – All rights reserved
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