ISO 8536-6:2009
(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 8536-6:2009 specifies the shape, dimensions, material, performance requirements and labelling for the type of closure for infusion bottles, as described in ISO 8536-1, which are 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 ISO 8536-6:2009 are intended for single use only.
Matériel de perfusion à usage médical — Partie 6: Bouchons à lyophilisation pour flacons de perfusion
General Information
Relations
Standards Content (Sample)
INTERNATIONAL ISO
STANDARD 8536-6
Second edition
2009-11-15
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 8536-6:2009(E)
©
ISO 2009
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ISO 8536-6:2009(E)
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ii © ISO 2009 – All rights reserved
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ISO 8536-6:2009(E)
Contents Page
Foreword .iv
Introduction.v
1 Scope.1
2 Normative references.1
3 Terms and definitions .2
4 Shape and dimensions .2
5 Designation .3
6 Material .4
7 Requirements.4
7.1 General .4
7.2 Physical requirements .4
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.11
Annex E (informative) Determination of residual moisture .12
Bibliography.15
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ISO 8536-6:2009(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 8536-6 was prepared by Technical Committee ISO/TC 76, Transfusion, infusion and injection equipment
for medical and pharmaceutical use.
This second edition cancels and replaces the first edition (ISO 8536-6:1995), which has been technically
revised in order to align this part of ISO 8536 with ISO 8871-1, ISO 8871-4 and ISO 8871-5.
ISO 8536 consists of the following parts, under the general title Infusion equipment for medical use:
⎯ Part 1: Infusion glass bottles
⎯ Part 2: Closures for infusion bottles
⎯ Part 3: Aluminium caps for infusion bottles
⎯ Part 4: Infusion sets for single use, gravity feed
⎯ Part 5: Burette infusion sets for single use, gravity feed
⎯ Part 6: Freeze drying closures for infusion bottles
⎯ Part 7: Caps made of aluminium-plastics combinations for infusion bottles
⎯ Part 8: Infusion equipment for use with pressure infusion apparatus
⎯ Part 9: Fluid lines for use with pressure infusion equipment
⎯ Part 10: Accessories for fluid lines for use with pressure infusion equipment
⎯ Part 11: Infusion filters for use with pressure infusion equipment
⎯ Part 12: Check valves
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ISO 8536-6:2009(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 part of ISO 8536 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, e.g., ISO 15378 or GMP Guidelines as published by the European
Community and the United States of America.
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INTERNATIONAL STANDARD ISO 8536-6:2009(E)
Infusion equipment for medical use —
Part 6:
Freeze drying closures for infusion bottles
1 Scope
This part of ISO 8536 specifies the shape, dimensions, material, performance requirements and labelling for
the type of closure for infusion bottles, as described in ISO 8536-1, which are 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 part of ISO 8536 are intended for single use only.
NOTE The potency, purity, stability and safety of a medicinal product during its manufacture and storage can be
strongly 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 48, Rubber, vulcanized or thermoplastic — Determination of hardness (hardness between 10 IRHD and
100 IRHD)
ISO 3302-1, Rubber — Tolerances for products — Part 1: Dimensional tolerances
ISO 3302-2, Rubber — Tolerances for products — Part 2: Geometrical tolerances
ISO 7619-1, Rubber, vulcanized or thermoplastic — Determination of 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
ISO 8871-5:2005, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 5:
Functional requirements and testing
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ISO 8536-6:2009(E)
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1
freeze drying
lyophilization
drying process designed to remove solvents from both aqueous and non-aqueous systems by sublimation and
desorption
3.2
freeze drying closure
closure that 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
1
manufacturer and user.
Figure 1 — Example to illustrate a freeze drying closure design
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ISO 8536-6:2009(E)
Table 1 — Dimensions of freeze drying closures
Dimensions in millimetres
a
Nominal size d h h h
d
1 2 3 4
2
±0,2 ±0,3 min. min.
±0,1
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 3302-1 and
ISO 3302-2.
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 slightly conical shape, it shall be 0,8 mm maximum 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 The freeze drying closure shall be designed and manufactured in such a way that the removal of the
reconstituted product with a hypodermic needle can be visually controlled in order to minimize the amount of
residual product.
4.9 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 so that under regular
processing conditions they do not fall off or become distorted.
4.10 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 part of ISO 8536 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 part of ISO 8536 is designated as follows:
Freeze drying closure ISO 8536-6 - 32
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ISO 8536-6:2009(E)
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 has to 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 7.2.7).
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 that 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 upon 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 closures 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.
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 ten piercings shall be observed.
7.2.3 Spike penetration force
When tested for penetrability in accordance with Annex B, the force needed to penetrate the closure shall not
exceed 80 N, and the average value shall be less than 75 N. No closure shall be pushed into the bottle during
piercing.
7.2.4 Spike penetration/sealability
When tested in accordance with Annex C, compl
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