ISO 18562 – Biocompatibility evaluation
Breathing gas pathways in healthcare applications
What have we discovered after three years of biocompatibility testing of breathing components? ISO 18562, published in 2017, has become the industry standard for testing the biocompatibility of breathing components. They published it one year before the current version of ISO 10993-1, the general reference for medical device biocompatibility testing. Examples of breathing components (such as endotracheal tubes) are listed as mucosal membrane contact in ISO 10993, while ISO 18562 adds particulate and gas testing to ISO 10993.
ISO 18562 has four components: general principles, evaluation of particle emission, evaluation of volatile gas emission, and evaluation of liquid bourn leachables in condensate. This document provides an in-depth breakdown of these four components of the standard.
ISO 18562-1 Biocompatibility Evaluation and testing within a risk management process
They discuss the applied principles of testing and toxicological risk assessment in this section of the standard. According to the scope, ISO 18562-1 covers devices that deliver breathed air or other materials into the respiratory tract. We should also consider ISO 10993 if the outside of the device contacts the patient. We should include data that may already be available in the risk analysis, in accordance with ISO 10993-18.
ISO 18562-1 states that we can test (without subsequent changes) a representative device, manufactured in the same manner as the final product. If a risk analysis reveals the toxicological hazard is the same, then the Biological Evaluation Plan should be created to determine which testing (if any) is necessary. If processing, materials, handling, or purpose change, a re-evaluation is required.
Toxicological Risk Assessment
Clause 6 explains how to calculate the VOC dosage supplied to a patient during use. They divide it into five categories, each of which is related to breathing volumes:
- Short term use – use the actual gas flow in.
- Neonate – default inspired volume 0.21m³ per day (according to ISO 10562-1).
- Infant – default inspired volume 2.0m³ per.
- Paediatric – default inspired volume 5.0m³ per.
- Adult – default inspired volume 20m³ per.
From the µg per litre value measured by the test laboratory, these volumes can be used to compute the inspired dose supplied. This clause, together with clause 7, investigates the toxicological concerns caused by any VOCs or leachates discovered in the patient’s environment. We should evaluate materials based on individual toxicity data, according to the statement. We can use typical ‘Thresholds of Toxicological Concern’ based on patient mass and contact time if no inhalation toxicity data is available. If the volume of condensate entering a patient is unknown, we can allow a volume of 1ml per day to be used in the computations.
Sample Numbers
It does not specify the number of samples that we should analyse in the standard. Traditional biocompatibility testing follows ISO 10993-12, which establishes sample requirements based on surface area (or mass) rather than the number of goods utilised. This is true for ISO 18562 section four, the leachables. Particles and vapours, on the other hand, have no such direction.
We can easily test multiple samples of ‘mass manufactured’ components for short-term use. We can restrict the availability of samples for long-term use ventilators, and testing can take a long time (up to 30 days). To make matters worse, samples may be large, making additional VOC samples expensive to examine. To avoid cross contamination, we must keep each test unit in its own temperature-controlled test chamber for the duration of the sampling.
It is permissible to employ representative samples. A preproduction sample for a sophisticated product, such as a ventilator, is an example of this. We usually evaluate smaller components in their final state, as well as from their packaging.
Up to now, we’ve only examined single-use components with a sample size of three and a single ventilator sample. We anticipate there will be pressure to increase these figures.
ISO 18562-2 Biocompatibility Evaluation of breathing gas pathways, particulate emission
ISO 18562-2 gives a choice of test methods for capturing particles. We can do gravimetrically this by filtering the air on a 0.2 µm filter and counting all particles emitted over 24 hours, above this size. The second method is a particle counter, which syphons off a small part of the airflow.
We usually perform the test at the maximum flow rate. This creates a worst-case scenario by dislodging particles. A syphoning expansion chamber is possible.
Both methods have their strengths and weaknesses. Because numerous filters can be used to improve airflow, the filtration method lends itself well to longer-term and higher-flow monitoring. The problem is that accurate measurements of minuscule particle masses are difficult to come by. We also capture all particles larger than 0.2 microns using this method. ISO 18562-2 specifies methods for quantifying particles with diameters ranging from 0.2 to 10 microns, but it also implies that we should consider other sizes in a risk assessment. While a single 20-micron particle may dominate many 0.2-micron particles, detecting its presence is beneficial.
Particle counting syphons out a fraction of the airflow, so it’s hard to get a representative sample. Furthermore, many laboratories previously provided counters with a minimum particle size of 0.25 microns, which are now being misused. The counters aren’t designed to be used continuously, so careful selection is essential to collect a 24-hour reading.
We can add an expansion chamber to the system if exceptionally high flow rates for a short period are necessary. This can also be used to imitate a cough or sudden breath.
We must take measures in both ways to reduce and subtract the background particle count. We should carry the test out using an air supply filtered at 0.1 micron or less, and should be very dry.
ISO 18562-3 Biocompatibility Evaluation of breathing gas pathways, VOC emissions
We usually do testing for volatile organic compound emissions at the device’s minimal flow rate, to give time for released vapours to diffuse into the airflow. It’s also frequently done at a high temperature to promote volatization. VOCs are compounds that turn into gases when heated below 260 degrees Fahrenheit.
The toxicologist usually performs the test at the product’s minimum recommended flow rate to provide gases enough time to disperse into the airflow at their highest concentration. Then they make the short-term devices measurements after 30 minutes, 60 minutes and 24 hours. They include 30 and 60 minute results to assess emission decay.
They take the same measurements after 30 minutes, 60 minutes, and 24 hours for long-term devices. After the first 48 hours, they collected readings every 3 days (up to 30 days) until the emissions fell below 40g per day. We can collect the emitted VOCs in various ways. ISO 18562-3 focuses primarily on thermal desorption (TD) systems. Activated carbon filters are one option. ISO 16000-6 standard is a guideline.
Thermal desorption samples have a little airflow, like particle counting. Sensitivity decreases. Since complete gas mixing is probable, capture should be homogeneous. The toxicologist then analyses the captured gases. Complex release and recapture procedures may be required to record low boiling point gases at this stage of the test.
ISO 16000-6 and ISO 18562-3 have little in common, besides the gas absorption process.
In the environmental standard, they sample outside gas, while they sample internal gas for biocompatibility. Test temperatures vary. They should test the breathing component at the device’s maximum recommended temperature. This evaluates worst-case VOC emission.
After absorption, the gas is then desorbed and analysed using gas chromatography mass spectrometry (GC-MS). This method is extremely sensitive, detecting ppb levels or less.
A toxicologist assesses risk based on chemical analysis results. Medical Engineering Technologies’ testing includes positive and negative controls. The positive control is a mixture of 12 possible VOCs. These controls determine system efficiency, LOD, and LQ (LOQ).
Inorganic Gases
Limits on the abundance of some very low boiling point inorganic gases are included in several environmental regulations for respired air. Irritants can be produced when certain of these gases react with VOCs. In the United States, carbon dioxide, carbon monoxide, and ozone concentrations must all be measured.
ISO 18562-4 Biocompatibility evaluation of breathing gas pathway, Tests for leachables in condensate
Only if there is a liquid passage from the gas pathway into the patient does ISO 18562-4 apply. If there is two-way breathing, condensates from exhaled air can enter into the patient, this can happen. The other circumstance is If water is added into the system by nebulization or humidification. Chemical and biological testing are essential in these situations (ISO 18562 does not allow chemical analysis to replace the biological testing, in contrast to ISO 10993-1: 2020). For chemical analysis, the sample requirement follows ISO 10993-12, with aqueous only extract. Some nebulised medications may contain aliphatic compounds. The biological testing will cover this situation.
Chemical testing includes analysis for metals and organic compounds. Obtaining test samples for a face mask or filters is pretty simple. However, it can get complicated with large devices, just like the other tests (VOCs and particles). Many ventilators and diagnostic devices require a sampling technique. Because the gas channel is being tested, extracting from the device’s interior surfaces without cutting or disassembly is desirable.
We should observe the typical requirements of ISO 10993 for devices with extensive patient contact (for example, tracheal tubes), according to the introduction to ISO 18562-4.
They normally perform chemical analysis of organic and inorganic materials once the extracts are accessible. Ionisation is used to detect inorganics (metals), which is followed by spectral or mass measurements in an electric field. Chromatographic separation and mass spectroscopy analysis are used to detect organic compounds (primarily carbon-based materials).
Negative controls (samples where the solvent has gone through all the same processes, but there is no product present) and positive controls (negative samples ‘spiked’ with known levels of suspected contaminants) are used to control and quantify the chemical analysis.
Cytotoxicity and sensitisation studies are part of biological testing. They carry these out in accordance with GLP guidelines.
CLIN-r+ top tips on being compliant:
There is a requirement for the biocompatibility assessment of a huge array of medical and drug delivery devices to go beyond ISO 10993 and include consideration of particles and volatile materials that a patient can inspire. This assessment can be carried out by examining existing data, but frequently requires testing of each specific product. Particle testing is relatively straightforward. The VOC testing can be complicated in execution and analysis. The devices range from simple tubes to complicated diagnostic devices, in which a patient sits inside while breathing through a measurement system, which introduces various gases into the airflow.
Incubators and other patient housing devices are also covered. The chemical testing will certainly reveal many unexpected elements that must be investigated by a toxicologist.
In terms of ISO 18562-1, ISO 18562-2, ISO 18562-3, and ISO 18562-4, there are currently no specific requirements for examining the interaction between medications and their delivery mechanism.
We can express the data gathered and the toxicity in various ways, which can sometimes be perplexing. Although the requirements for leachate testing for fluid that can enter the respiratory system have improved, they can also be difficult to meet. If you have any questions or need professional assistance, CLIN-r+ has a wealth of experience in biocompatibility evaluation. Get in touch!
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