ISO 8536-6:2025

Infusion equipment for medical use - Part 6: Freeze drying closures for infusion bottles

This document specifies the shape, dimensions, material, performance requirements and labelling for the type of closure for infusion bottles, as described in ISO 8536-1, that is used in connection with the freeze-drying (or lyophilization) of drugs and biological materials. The dimensional requirements are not applicable to barrier-coated closures. Closures specified in this document are intended for single use only. NOTE The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be strongly affected by the nature and performance of the primary packaging.

Matériel de perfusion à usage médical — Partie 6: Bouchons à lyophilisation pour flacons de perfusion

General Information

• Status: Published
• Publication Date: 26-Mar-2025
• ICS: 11.040.20 - Transfusion, infusion and injection equipment
• Technical Committee: ISO/TC 76 - Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use
• Drafting Committee: ISO/TC 76 - Transfusion, infusion and injection, and blood processing equipment for medical and pharmaceutical use
• Current Stage: 6060 - International Standard published
• Start Date: 27-Mar-2025
• Due Date: 14-Oct-2025
• Completion Date: 27-Mar-2025

Relations

• Revises: ISO 8536-6:2016 - Infusion equipment for medical use - Part 6: Freeze drying closures for infusion bottles
• Effective Date: 22-Oct-2022

Overview

ISO 8536-6:2025 - Infusion equipment for medical use - Part 6: Freeze drying closures for infusion bottles defines the design, materials, performance requirements and labelling for elastomeric freeze-drying (lyophilization) closures used on infusion glass bottles. The standard covers shape and dimensions (except for barrier‑coated closures), single‑use intent, and specific physical, chemical and biological test criteria to protect the potency, purity and stability of freeze‑dried medicinal products.

Key topics and technical requirements

• Scope & designation
  • Applies to closures used in conjunction with freeze‑drying of drugs and biologicals; designated as “Freeze drying closure ISO 8536-6:2025 – [size]”.
• Shape and dimensions
  • Prescribed dimensions and features (flange, plug, spacers, positioning elements) to allow insertion in a sublimation (halfway) position and final full insertion.
• Materials
  • Elastomeric formulations must meet Clause 7 requirements and be the same formulation approved by the user. Materials should withstand two autoclave cycles (121 ± 2 °C, 30 min) and be evaluated for other sterilization methods.
  • Note: butyl and halogenated butyl rubbers are commonly preferred for low water vapour permeability.
• Physical requirements
  • Hardness: agreed value ±5 IRHD.
  • Fragmentation (coring): ≤ 20 fragments per 10 piercings (Annex A).
  • Spike penetration force: no single penetration > 80 N; average < 75 N (Annex B).
  • Spike retention / sealability: no leakage or spike pull‑out over 4 h; closures must not be pushed into bottle during piercing (Annex C).
  • Resistance to ageing: closures must maintain performance through shelf life as part of stability testing.
  • Residual moisture: specific test method included (Annex E) due to impact on freeze‑dried product stability.
• Testing & normative annexes
  • Annexes cover fragment determination, penetration force, retention/sealability, closure piercing devices and residual moisture measurement.
• Labelling
  • Label requirements and designation rules are specified.

Practical applications and users

Who uses ISO 8536-6:2025:

• Pharmaceutical packaging and closure manufacturers designing freeze‑drying caps
• Lyophilization process engineers and formulation scientists assessing primary packaging impact on product stability
• Quality control, R&D and validation teams performing acceptance and performance testing
• Regulatory and procurement specialists specifying packaging for parenteral medicinal products
• Contract manufacturers and sterile‑fill/finish sites applying cGMP practices

Benefits:

• Reduces risk of coring, leakage and moisture‑related degradation
• Standardises dimensions and tests for interchangeability and regulatory compliance
• Supports robust lyophilization workflows and product shelf‑life assurance

Related standards

• ISO 8536-1, ISO 8536-3, ISO 8536-7 (infusion bottle caps and combinations)
• ISO 8871‑1, ISO 8871‑4 (elastomeric parts - extractables/biological)
• ISO 48‑4 (hardness), ISO 3302 (tolerances), ISO 2230 (rubber storage), GMP guidelines / ISO 15378 (cGMP for primary packaging)

Keywords: ISO 8536-6:2025, freeze drying closures, lyophilization closures, infusion bottles, elastomeric closures, residual moisture, spike penetration, fragmentation, medical infusion equipment.

Standards Content (Sample)

International
Standard
ISO 8536-6
Fourth edition
Infusion equipment for medical use —
2025-03
Part 6:
Freeze drying closures for
infusion bottles
Matériel de perfusion à usage médical —
Partie 6: Bouchons à lyophilisation pour flacons de perfusion
Reference number
© ISO 2025
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: [phone]
Email: [e-mail]
Website: www.iso.org
Published in Switzerland
ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 1
3 Terms and definitions . 1
4 Shape and dimensions . 2
5 Designation . 3
6 Material. 3
7 Requirements . 4
7.1 General .4
7.2 Physical requirements .4
7.2.1 Hardness .4
7.2.2 Fragmentation (coring) .4
7.2.3 Spike penetration force .4
7.2.4 Spike retention/sealability .4
7.2.5 Resistance to ageing .4
7.2.6 Residual moisture .5
7.3 Chemical requirements . .5
7.4 Biological requirements .5
8 Labelling . 5
Annex A (normative) Determination of fragments . 6
Annex B (normative) Determination of spike penetration force . 8
Annex C (normative) Spike retention/sealability . 10
Annex D (normative) Closure piercing device .12
Annex E (informative) Determination of residual moisture .13
Bibliography .16

iii
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 document should be noted. This document was drafted in accordance with the editorial rules of the
ISO/IEC Directives, Part 2 (see http://www.iso.org/directives).
ISO draws attention to the possibility that the implementation of this document may involve the use of (a)
patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent
rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a)
patent(s) which may be required to implement this document. However, implementers are cautioned that
this may not represent the latest information, which may be obtained from the patent database available at
http://www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.
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
http://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 fourth edition cancels and replaces the third edition (ISO 8536-6:2016), which has been technically
revised.
The main changes are as follows:
[1]
— reference to has been removed:
— reference to ISO 8536-7 has been added;
— information regarding fragment size and sterilization step have been clarified.
A list of all parts in the ISO 8536 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.

iv
Introduction
Freeze drying closures are put on the top of infusion bottles after filling, leaving sufficient openings for the
sublimation process and vacuum. At the end of the drying process, they can be fully inserted into the glass
container by hydraulic or mechanical means in the vacuum chamber.
Freeze drying closures can pick up water during shipping, storage, washing and steam sterilization cycles,
which is difficult to remove in a subsequent drying cycle. As a consequence, the freeze drying closures are
usually loaded with residual moisture. Depending upon the mass of the freeze-dried product and the degree
of its sensitivity to water, the residual moisture in the rubber material can spoil the freeze-dried preparation
during storage.
These specific process requirements have been addressed in this document by specifying relevant
requirements for freeze drying closures including a test method on determination of residual moisture.
Primary packaging components made of elastomeric materials are an integral part of medicinal products
and thus the principles of current Good Manufacturing Practices (cGMP) apply to the manufacturing of these
components.
[2]
Principles of cGMP are described in, for example, ISO 15378 or GMP Guidelines as published by the
European Community and the United States of America.

v
International Standard ISO 8536-6:2025(en)
Infusion equipment for medical use —
Part 6:
Freeze drying closures for infusion bottles
1 Scope
This document specifies the shape, dimensions, material, performance requirements and labelling for the
type of closure for infusion bottles, as described in ISO 8536-1, that is used in connection with the freeze-
drying (or lyophilization) of drugs and biological materials.
The dimensional requirements are not applicable to barrier-coated closures.
Closures specified in this document are intended for single use only.
NOTE The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be
strongly affected by the nature and performance of the primary packaging.
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 48-4, Rubber, vulcanized or thermoplastic — Determination of hardness — Part 4: Indentation hardness by
durometer method (Shore hardness)
ISO 3302 (all parts), Rubber — Tolerances for products
ISO 8536-1, Infusion equipment for medical use — Part 1: Infusion glass bottles
ISO 8536-3, Infusion equipment for medical use — Part 3: Aluminium caps for infusion bottles
ISO 8536-7, Infusion equipment for medical use — Part 7: Caps made of aluminium-plastics combinations for
infusion bottles
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
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at http:// www .iso .org/ obp
— IEC Electropedia: available at http:// www .electropedia .org/

3.1
fragmentation
formation of elastomeric particles that are generated when the disc or other elastomeric components that
forms part of the primary container closure is pierced by a needle, spike or other access device for filling or
delivery
Note 1 to entry: Coring is one mechanism to generate fragments.
[3]
[SOURCE: ISO 11608-3:2022 , 3.4, modified — changed "disc coring" to "coring".]
3.2
freeze-drying
lyophilization
drying process designed to remove solvents from both aqueous and non-aqueous systems by sublimation
and desorption
3.3
freeze drying closure
closure which enables the drying of a frozen pharmaceutical preparation in a vacuum chamber
4 Shape and dimensions
4.1 The dimensions of freeze drying closures shall be as given in Table 1. Figure 1 illustrates the general
design of a freeze drying closure.
Key
1 positioning element
2 spacers
NOTE The total height of the freeze drying closure, h , can vary and is subject to mutual agreement between
manufacturer and user.
Figure 1 — Example to illustrate a freeze drying closure design

Table 1 — Dimensions of freeze drying closures
Dimensions in millimetres
a
Nominal d d h h h
1 2 2 3 4
size ±0,3 ±0,2 ±0,3 min. min.
32 30,8 23,6 4,0 4 3,7
28 27,1 19,6 3,4 4 2,2
a The value of d is applied in that area which is defined by h .
2 3
4.2 If not otherwise specified, general dimensional tolerances shall be in accordance with
ISO 3302 (all parts).
4.3 If spacers are located on the top of the flange, they shall not interfere with the marks for the injection
site. The height of the spacers shall not exceed 0,3 mm.
On the top surface, there may be marks or indentations.
4.4 If the flange of the closure has a slight conical shape, the conicity shall be 0,8 mm max. in relation
to the diameter in order to facilitate production. The tolerances of the trimming edge of the flange shall
conform with the tolerances specified in Table 1 for the diameter d .
4.5 The plug part shall provide slits, channels or other appropriate means in conjunction with protruding
or positioning elements at the outer diameter, which enable insertion in a drying (halfway) position during
the sublimation process.
4.6 The design of the positioning elements to hold the freeze drying closure firmly in the sublimation
position should not compromise the full insertion of the closure.
4.7 The design of the flange part in conjunction with the plug design shall permit both the reconstitution
of the freeze-dried product with the appropriate solvent and the removal of the dissolved product by means
of a piercing device.
4.8 When freeze drying closures are put in place for the lyophilization process and the container is
exposed to transport processes, they should exhibit sufficient shock and vibration resistance that under
regular processing conditions they do not fall off nor become distorted.
4.9 All edges of the closure may be rounded.
5 Designation
A freeze drying closure for infusion bottles can be designated by the words “freeze drying closure” followed
by the number of this document followed by the nominal size.
EXAMPLE A freeze drying closure for infusion bottles of nominal size 32 complying with the requirements laid
down in this document is designated as follows:
Freeze drying closure ISO 8536-6:2025 - 32
6 Material
The elastomeric material used shall meet the requirements specified in Clause 7.
The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at
(121 ± 2) °C for 30 min without exceeding the specified limits and without the impairment of its performance
characteristics under the conditions of normal use. In case of other sterilization methods, e.g. irradiation,
the suitability of the material shall be evaluated.

With regard to the special requirement for low residual moisture, the drying process shall be included in the
evaluation of the material's performance characteristics (see also 7.2.6).
Closures shall be made from the elastomeric formulation originally tested and approved by the end-user.
The closure manufacturer shall ensure the conformance of each delivery with the type sample and the
compliance with previously agreed functional and compendium requirements.
NOTE It is current practice to prefer elastomeric materials which use straight or halogenated butyl rubbers
as a base polymer, since this class of materials exhibits an excellent barrier function against water vapour and gas
permeation.
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 closures on receipt by the user.
7.2 Physical requirements
7.2.1 Hardness
The hardness agreed between the manufacturer and user shall not differ from the nominal value by more
than ±5 International Rubber Hardness Degrees (IRHD, for highly elastic rubber comparable to Shore A)
when tested in accordance with ISO 48-4 on a special test specimen.
7.2.2 Fragmentation (coring)
When tested for fragmentation in accordance with Annex A, not more than 20 fragments per 10 piercings
shall be observed.
7.2.3 Spike penetration force
When tested for pene
...