ISO 8536-6:2016
(Main)Infusion equipment for medical use — Part 6: Freeze drying closures for infusion bottles
Infusion equipment for medical use — Part 6: Freeze drying closures for infusion bottles
ISO 8536-6:2016 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.
Matériel de perfusion à usage médical — Partie 6: Bouchons à lyophilisation pour flacons de perfusion
General Information
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Standards Content (Sample)
INTERNATIONAL ISO
STANDARD 8536-6
Third edition
2016-12-01
Infusion equipment for medical use —
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 8536-6:2016(E)
©
ISO 2016
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ISO 8536-6:2016(E)
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ISO 8536-6:2016(E)
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 penetration/sealability . 4
7.2.5 Resistance to ageing . 4
7.2.6 Residual moisture . 4
7.3 Chemical requirements. 4
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
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ISO 8536-6:2016(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.
This third edition cancels and replaces the second edition (ISO 8536-6:2009), which has been technically
revised.
A list of all parts in the ISO 8536 series can be found on the ISO website.
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ISO 8536-6:2016(E)
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.
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.
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INTERNATIONAL STANDARD ISO 8536-6:2016(E)
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 strongly be 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 3302 (all parts), Rubber — Tolerances for products
ISO 7619-1, Rubber, vulcanized or thermoplastic — Determination of indentation hardness — Part 1:
Durometer method (Shore hardness)
ISO 8536-1, Infusion equipment for medical use — Part 1: Infusion glass bottles
ISO 8536-3, Infusion equipment for medical use — Part 3: Aluminium caps for infusion bottles
ISO 8871-1, Elastomeric parts for parenterals and for devices for 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 terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http://www.electropedia.org/
— ISO Online browsing platform: available at http://www.iso.org/obp
3.1
freeze-drying
lyophilization
drying process designed to remove solvents from both aqueous and non-aqueous systems by
sublimation and desorption
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ISO 8536-6:2016(E)
3.2
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.
Dimensions in millimetres
1
2
Key
1 positioning element
2 spacers
NOTE The total height of the freeze drying closure, h , may vary and is subject to mutual agreement between
1
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).
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ISO 8536-6:2016(E)
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
comply with the tolerances specified in Table 1 for the diameter d .
1
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 - 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 7.2.5).
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.
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ISO 8536-6:2016(E)
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 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 special test specimen. Alternatively,
the hardness can be tested on the closures according to ISO 48. If tested according to ISO 48, the
microhardness shall not differ by more than ±5 IRHD from the type sample.
7.2.2 Fragmentation (coring)
When tested for fragmentation in accordance with Annex A, not more than 20 fragments of diameter
equal to or greater than 50 µm per 10 piercings shall be observed.
7.2.3 Spike penet
...
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