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International
Standard
ISO 18562-1
Second edition
Biocompatibility evaluation
2024-03
of breathing gas pathways in
healthcare applications —
Part 1:
Evaluation and testing within a risk
management process
Évaluation de la biocompatibilité des chemins de gaz respiratoire
utilisés dans le domaine de la santé —
Partie 1: Évaluation et essais au sein d'un processus de gestion du
risque
Reference number
© ISO 2024
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Published in Switzerland
ii
Contents Page
Foreword .iv
Introduction .v
1 Scope . 1
2 Normative references . 2
3 Terms and definitions . 2
4 General principles applying to biocompatibility evaluation of medical devices .11
4.1 General .11
4.2 Type tests .14
4.3 Biocompatibility hazard identification .14
4.4 Extent of risk assessment . . 15
4.5 Biological evaluation plan . 15
4.6 Selection of tests .17
4.7 Subsequent evaluation .18
5 Contamination of breathing gas from gas pathways . 19
5.1 Duration of use .19
5.2 Particulate matter (PM) emissions .19
5.3 Volatile organic substance emissions . 20
5.4 Leachables in condensate . 20
6 Adjustment of exposure dose and inhalation dose for different patient groups .20
6.1 General considerations. 20
6.2 Adjustment for different patient groups . 20
7 Deriving tolerable exposure (TE) for VOS .21
7.1 General process .21
7.2 For medical devices intended for limited exposure use (≤24 h) and prolonged exposure
use (>24 h but <30 d) . 22
7.3 For medical devices intended for long-term exposure (≥30 d) . 23
8 Determining values for leachables in condensate .23
8.1 General . 23
8.2 Adjustments for different patient groups .24
8.3 Exposure dose estimate for condensate .24
9 Risk control .24
10 Benefit-risk analysis .24
11 Biological evaluation report . .25
Annex A (informative) Rationale and guidance .26
Annex B (informative) Reference to the IMDRF essential principles and labelling guidances .28
Annex C (informative) Reference to the essential principles .30
Annex D (informative) Terminology — Alphabetized index of defined terms.31
Bibliography .33
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 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
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 www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 121, Anaesthetic and respiratory equipment,
Subcommittee SC 3, Lung ventilators and related equipment, in collaboration with the European Committee
for Standardization (CEN) Technical Committee CEN/TC 215, Respiratory and anaesthetic equipment, in
accordance with the Agreement on technical cooperation between ISO and CEN (Vienna Agreement).
This second edition cancels and replaces the first edition (ISO 18562-1:2017), which has been technically
revised.
The main changes are as follows:
— added informative mapping annexes to relevant regulatory requirements;
— clarified terms and definitions used in the document;
— expanded the patient groups to include: premature, small child, child, and adolescent;
— introduction of inhalation dose;
— the threshold of toxicological concern is changed;
— expanded the range of volatile organic substances that are tested;
— clarified the appropriate breathing gas volumes to be used in testing for VOS; and
— clarified the appropriate breathing gas volumes to be used in the analysis.
A list of all parts in the ISO 18562 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
This document represents the application of the best-known science, in order to improve patient safety, by
addressing the risk of potentially hazardous substances being conveyed to the patient by the gas stream.
This document is intended to cover the biological evaluation of gas pathways of medical devices within a
risk management process, as part of the overall medical device evaluation and development. This approach
combines the review and evaluation of existing data from all sources with, where necessary, the selection
and application of additional tests.
In general, the ISO 10993 series is intended to cover the biological evaluation of medical devices. However,
the ISO 10993 series does not sufficiently address the biological evaluation of the gas pathways of medical
devices.
Before this document was developed, some authorities having jurisdiction interpreted the ISO 10993-1:2009,
Table A.1 to mean that as materials in the gas pathway form “indirect contact” with the patient, they
should be subjected to tests equivalent to those required for tissue contact parts of medical devices. This
interpretation can lead to tests that are not optimized for evaluation of gas pathways including possible
hazards not being detected.
ISO 10993-1:2018 states that it is not intended to provide a rigid set of test methods as this might result in an
unnecessary constraint on the development and use of novel medical devices. ISO 10993-1:2018 also states
where a particular application warrants it, experts in the product or in the area of application concerned
can choose to establish specific tests and criteria, described in a product-specific vertical standard. This
series of standards is intended to address the specific needs for the evaluation of gas pathways that are not
adequately covered by ISO 10993-1:2018.
This document provides a guide to the development of a biological evaluation plan that minimizes the number
and exposure of test animals by giving preference to chemical constituent testing and in vitro models.
The initial version of this series of standards was intended to cover only the most commonly found
potentially harmful substances. It was felt that it was best to get a functioning document published that
would test for the bulk of the currently known substances of interest. With the use of the TTC (threshold of
toxicological concern) approach, this document has the potential to be used to assess the safety of essentially
any compound released from the gas pathways of respiratory medical devices, with very few exceptions (e.g.
PCBs, dioxins), and not just th
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