ISO 18562 standard series – Biocompatibility evaluation of breathing gas pathways in healthcare applications

ISO 18562 standard series – Biocompatibility evaluation of breathing gas pathways in healthcare applications

Determining and assessing the biocompatibility of medical devices and their component materials is of great importance for ensuring product safety. Any negative impact on patients in their environment should be avoided. The ISO 18562 series of standards addresses the risk of transmission of potentially hazardous substances to the patient via the gas pathway.

The biological evaluation of medical devices is regulated by the international series of standards ISO 10993 – “Biological evaluation of medical devices”. It currently consists of 18 individual standards as well as specific technical reports and additional guidelines. A new edition of ISO 10993-1 “Evaluation and testing as part of a risk management process” was published in October 2018.

The series of standards and its differentiation from ISO 10993

ISO 10993 describes methods for simulating direct contact between the human body and the medical device or contact with substances that can be released by (body) fluids. However, the biological evaluation of breathing gas pathways in medical devices is not adequately addressed in this series of standards. In the introduction of ISO 18562, it is pointed out that in the past, the interpretation of ISO 10993-1 by the authorities constituted that materials in the airways are in indirect contact with the patient. Accordingly, the products should be subjected to tests that are comparable to tests for medical devices that come into contact with tissue. This interpretation can lead to potential hazards not being recognised or tests being carried out with doubtful benefits. The purpose of the ISO 18562 standard series is to enable an appropriate biological assessment of medical devices by considering additional specific requirements for breathing gas pathways. The documents include guidance for the development of an evaluation plan that minimises the number and exposure of test animals by, among other things, testing the chemical components and favouring in vitro models.

The series of standards consists of the following four individual standards:

At ISO level, the series of standards was first published in 2017 and the latest revision was published in March 2024.

As a biological test needs to be both well planned and sensibly tested, we, as a service provider in supporting the planning on the manufacturer’s side, spoke to the Hohenstein Medical test laboratory in Bönnigheim about carrying out the tests in accordance with the ISO 18562 standard series. Hohenstein has many years of expertise in testing the biocompatibility of medical devices as an accredited test laboratory.

Hohenstein is a testing laboratory for textiles, how did you start with testing breathing gas pathways?

With the Hohenstein Medical sub-brand, we have also been testing non-textile products for many years. In addition, sub-components of devices such as filters are often fibre-based, so it’s not too far away. The ISO 18562 series of standards is very complex, and not just in terms of the number of tests and evaluation procedures. In particular, the prior project planning plays a major role here, as each test must be adapted to the individual medical device or component material and many factors, such as the volume flow for ventilators or inhalation devices, play a major role.

Manufacturers are therefore advised to select a test laboratory for tests in accordance with ISO 18562 that:

• offers individualised study planning and support,
• offers all parts of ISO 18562 from a single source and at a single location,
• does not have excessively long waiting and testing times.

Hohenstein Medical is one of the few testing laboratories that offers a full range of tests in accordance with ISO 18562. Detailed study planning in direct consultation with the client is absolutely essential for this test, which ultimately saves time and therefore money for the customer. Testing in accordance with ISO 18562 closes a gap in the field of biocompatibility and will become increasingly important in the coming years. The Hohenstein Medical team supports customers from the planning stage to the test report.

What tests does the ISO 18562 standard series cover?

The principle of the series of standards is that all materials or medical devices, parts and accessories for use on patients must be assessed for biocompatibility. This does not necessarily mean that everything has to be tested. Depending on the composition, manufacture or application, a review may lead to the conclusion that no additional testing is required. The evaluation of the medical device must include the following points:

• The composition with the physical and chemical properties of the components over the expected lifetime of the medical device.
• Data on human exposure.
• Safety data on the product, its components, degradation products and metabolites.

Testing is recommended if it is not possible to determine which components can dissolve in the gas flow or in condensates of the medical device.

The first of the four sub-standards ISO 18562-1 describes how the evaluation of biocompatibility should be planned, carried out, documented and assessed. The test selection is described as well as the definition of threshold values. The other parts of the series of standards (ISO 18562-2, ISO 18562-3 and ISO 18562-4) describe the process for the test procedures to be used for emissions and leachable substances.

In addition to the hazardous agents mentioned, other substances may be added to the breathing gas pathway that are not covered by this series of standards. However, the standard already indicates that authorities may also require the manufacturer to assess the biocompatibility risk posed by ozone, nitrogen oxides, carbon monoxide and carbon dioxide.

How does ISO 18562 testing work?

The test for the emission of particles is described in the second part of the series of standards ” Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 2: Tests for emissions of particulate matter”. All air-conducting and/or air-producing parts of medical devices are scrutinised and detached particles are captured using filters in accordance with the standard. Alternatively, particle emissions can be measured using a particle counter, which measures all particles released from the device or material in the air flow. The standard specifies threshold values that must not be exceeded.

The third part of the series of standards deals with testing for emissions of volatile organic compounds (VOCs). For this purpose, the medical device to be tested is operated according to the manufacturer’s specifications, usually with ultra-pure air, at an individually defined temperature, humidity and volume flow. The air escaping from the medical device is collected and tested for VOCs. The identity and quantity of each compound released is provided for toxicological risk assessment as described in ISO 18562-1.

In the new version of the standard, which was published in March 2024, VVOCs (very volatile organic compounds) and SVOCs (semi-volatile organic compounds) are also relevant for risk assessment in addition to VOCs. Hohenstein already offers analyses of these compounds.

The last part of ISO 18562 “Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 4: Tests for leachables in condensates” deals with condensates that can occur in gas-conducting medical devices and their component materials as a result of respiration. These condensates can dissolve substances from the materials, which are subsequently absorbed by the patient via the respiratory tract. In some cases, different substances are extracted from the materials than it would be the case if they were airborne. The condensate test is divided into different biological and chemical sub-tests in the standard:

• Cytotoxicity according to DIN EN ISO 10993-5
• Sensitisation according to DIN EN ISO 10993-10
• Irritation according to DIN EN ISO 10993-23
• Organic residues and
• Heavy metal analysis

The tests already known from the ISO 10993 series of standards are adapted to the objectives of ISO 18562, e.g. through the choice of extraction media and threshold values.

What are the changes between the 2017 and 2024 version?

The ISO 18562 standard series was published for the first time in 2017. Although not yet as established as the ISO 10993-1 series, it represents another important building block for the biological evaluation of medical devices. However, anyone who has already carried out tests according to the ISO 18562 series 2017 may now be asking themselves what changes have been made to the 2024 edition. These can be summarised as follows:

Several new terms have been introduced in the updated standard and threshold values have been moved. The various patient populations have been revised and defined more precisely, including data for body weights and standard breathing volumes. Due to the new terms and definitions, devices and accessories that previously fell under the category of limited and prolonged exposure may now fall under the definition of long-term exposure, so the testing requirements may also change. Various changes deal with toxicological risk assessment, primarily the definition of TTC values and the introduction of the inhalation dose. Life cycle analysis is also coming more into focus. However, it is not yet clear whether this will be analysed with the help of tests or on the basis of clinical data.

In addition to the familiar medical devices that come into contact with patients via the respiratory tract and previously had to be assessed using ISO 18562, personal protective equipment (respiratory masks) now also falls within the scope of the standard. Particle testing in accordance with ISO 18562-2 now only has to consider particles from a size of 0.25 µm (previously: 0.2 µm). The respective thresold values for particle release remain the same.

The term “VOS” was introduced as a generic term for all volatile organic substances. The intended testing according to ISO 18562-3 now includes very volatile (VVOC), volatile (VOC) and semi-volatile (SVOC) organic compounds (previously: VVOC and SVOC only if specifically requested by the authority). In addition, the terms oral uptake and chemicals exposed via the lungs have been defined more precisely in 18562-4, which provides more clarity for toxicological assessment. The testing of the condensate according to ISO 18562-4 has also been aligned with the chemical characterisation according to ISO 10993-18, for example by mentioning the Analytical Evaluation Threshold (AET). The maximum condensate volume that can reach the patient should now be determined. A further endpoint, the irritation test, has been added for the condensate tests in question. This test can be performed in accordance with DIN EN ISO 10993-23.

Most of the changes to the ISO 18562 series of standards from 2024 have a direct impact on the Biological Evaluation Plan (BEP) and once again demonstrate its importance for a high-quality biocompatibility assessment.

The implementation of the biological evaluation of medical devices is a multi-part process consisting of various components. This usually includes material characterisation, literature research and, under certain circumstances, application-related testing. We will be happy to plan and develop together with you how you can combine all these aspects efficiently and effectively. Contact seleon Consulting and our partners at Hohenstein Medical.

Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.