Biocompatibility evaluation of breathing gas pathways in healthcare applications

Insight in Brief

All medical devices need to be evaluated for biocompatibility, especially medical devices that encounter breathing gases. Where the ISO 10993 family is well known in the medical device industry, the ISO 18562 family, being specific for breathing gas pathways and having existed since 2017, is still new or unknown for a lot of manufacturers.

This article summarizes the structure of the ISO 18562 family and its implications on the development of medical devices that come into contact with breathing gases, covering the test strategies. It also discusses the most important parameters of testing such as patient population, contact duration, or the condensate in the breathing gas.

Introduction

Structure of the ISO 18562 family

Before getting into the topic of the evaluation, we must first outline and understand the ISO 18562 structure. ISO 18562 consists of four different parts, where the starting point of the biocompatibility evaluation is ISO 18562-1, which defines the process, planning, and analysis of the test data. For the testing itself, it refers to the following three parts:

ISO 18562-2 for tests for emissions of particulate matter
ISO 18562-3 for tests for emissions of volatile organic compounds (VOCs)
ISO 18562-4 for tests for leachables in condensate

Part 1: Evaluation and testing within a risk management process

Simplified, the process is as follows:

The first step is to evaluate the components in contact with the breathing gas and their materials and the analysis whether enough relevant biocompatibility data is available.
In the next step, the test that is required needs to be defined including the test setup.
The test will be performed.
Once we have the emission data, we can calculate the dosage applied to the patient and assess the risk posed to the patient which is compared to the clinical benefit of the medical device.

When selecting the test to be performed, do not only consider the tests in the parts 2 to 4 of ISO 18562 as there are also other substances that might be of concern and different competent authorities require their evaluation:

SVOCs (Semi-volatile organic compounds) and VVOCs (Very volatile organic compounds)
Ozone where electrostatic or electromechanical parts are active
CO and CO2
Leachables not only in condensate but also anesthetic agents or other substances delivered via the respiratory tract such as inhalation drugs.

When defining the test setup, the manufacturer shall define the duration of use which also defines the time to perform the tests and provides input for the risk evaluation when deriving allowable limits.

To calculate the patient dosage, ISO 18562-1 defines default body weight and breathing volume values to be used for neonates (0.5kg and 0.21m3/d), infants (3.5kg and 2m3/d), pediatric (10kg and 5m3/d) and adult (70kg and 20m3/d) patients.

Part 2: Tests for emissions of particulate matter

The ISO 18562-2 defines test methods to collect particulate matter added to the breathing gas, where either one of the following methods are described and can be used:

One filter method where sufficiently clean input air is ensured. The breathing gas passes this filter which collects the particulate matter. The emitted particulate matter is then measured by weighing the filter.
Two filter methods where sufficiently clean input air is NOT ensured. The breathing gas passes the first filter before entering the medical device and then passes a second filter after the device is under test. The emitted particulate matter is then measured by weighing both filters and subtraction.
Alternatively, a particle counter can be used instead of filters.

The standard defines maximum levels as follows:

less than or equal to 2,5 µm diameter, in excess of 12 µg/m3;
less than or equal to 10 µm diameter, in excess of 150 µg/m3.

Important: The device shall be operated at the maximum clinically relevant flow.

Part 3: Tests for emissions of volatile organic compounds (VOCs)

The ISO 18562-3 defines test methods to collect volatile organic compounds and the TTC limits depending on the exposure time. For the first 24hrs, 360ug/d are allowed, for the subsequent 29d the limit is 120ug/d, and beyond 30 days 40ug/d.

To measure the VOCs (and usually, the same setup is used for VVOCs), the ISO 18562-3 recommends collecting

for continuous flow devices at the breathing volume mentioned above.
For intermittent flow devices in a clinically relevant manner
usually the lowest clinically relevant flow to get the highest VOC concentration.

Having the device set up at the maximum rated ambient temperature, the gas output is sampled at different times according to the test plan. These samples then get analyzed for the total VOC emission and each VOC for its own.

Part 4: Tests for leachables in condensate

Devices where condensate could reach the patient shall also be tested for leachables. To collect the leachable substances, one of the following sampling methods shall be used:

produce and collect condensate under clinically relevant conditions
circulate the water over the surface at a temperature representative of clinical use
perform extraction on the internal gas contact surfaces according to the method of ISO 10993-12

As the first two options are hard to reach and the setup is very complex, most manufacturers and test labs use the extraction methods of ISO 10993-12.

Once the extract is available, the following four tests shall be performed:

Determination of the metal ion content
Perform cytotoxicity tests per ISO 10993-5
Perform sensitization tests per ISO 10993-10
Identify and quantify organic impurities.

Toxicological risk assessment

To close the circle, the last step is back to ISO 18562-1 and perform a toxicological risk assessment. This risk assessment will include all test results and historical data and calculate the dosage the patient will reach. If a device is intended for multiple patient categories, this dosage is calculated for all patient categories. Once these patient doses are known, they can be compared to the maximum exposure data available (or newly generated) to determine the risk posed by the medical device. This is another input for the risk-benefit analysis to be performed for every medical device.

Is ISO 10993 for breathing-gas pathway devices irrelevant?

No, only the breathing gas is evaluated per ISO 18562, all parts of the device that can come into contact with the patient (or user or bystander) also need to be evaluated per ISO 10993.

Summary

Although the ISO 18562 family has existed since 2017, many manufacturers are still unaware of how to implement these regulatory requirements. It is mandatory, that all medical devices are evaluated for biocompatibility and the test lab needs input from the manufacturer.

Do you need support in either creating your biocompatibility evaluation plan, preparing the test setup, or selecting a test laboratory to find a toxicologist who can write your toxicological risk assessment?

Get in contact with our Regulatory Affairs and Quality Management Experts at IMT. We are here to help and support you in your biocompatibility evaluation project.

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