The ISO 18562 series of standards was initially released in 2017 to help address the specific needs for the evaluation of gas pathways of medical devices that were not adequately covered by ISO 10993-1. In March 2024, a revised ISO 18562 series of standards was released and includes several additions and changes. We will highlight some of these major changes and the impact on manufacturers.
The Scope of each standard provides a listing of example gas pathway devices. Notably, medical respiratory personal protective equipment (PPE) is now included. Although not explicitly stated, it is assumed that this refers to items such as surgical masks and surgical N95 respirators. The inclusion of medical respiratory PPE, along with references to multiple supporting publications, highlights the importance of volatile organic substances (VOS) and/or particulate matter that could have harmful effects when inhaled.
New Terms and Patient Population Standards
Several new terms have been introduced within the standards, including “infrequent use” and “total exposure period”. Considering the vague definitions of these terms, there could be significant ramifications to device manufacturers. Based on the provided definitions, devices that were previously categorized as having limited or prolonged durations of patient contact could be bumped into longer term categories, which will alter the amount of testing required. As an example of total exposure period, if a device is used once a month for 5 minutes per treatment for a total of 12 months, the device would be considered to have 365 days of patient exposure (long-term). If, however, data can be provided to support that the device has infrequent use (“…used at different treatment occasions at intervals that are expected to be long relative to the elimination time of any leachable harmful substance from the patient’s body”), then the device could be categorized based on a single treatment. From a practical perspective, proving that a device has infrequent use will be challenging, especially if unidentified chemicals or chemicals with limited toxicokinetics data are detected.
The standards also include an emphasis on the effects of aging/life cycle of the device, which is in alignment with ISO 10993-1. At this point, it is unclear if the expectation to address aging and life cycle of the device will be through testing, clinical history or a combination of both.
The updated ISO 18562 standards have expanded the suggested patient populations.
| Previous Version (2017) | Revised Version (2024) |
| Neonates (0.5 kg) | Premature neonates (0.5 kg) |
| Infants (3.5 kg) | Infants (3.5 kg) |
| Pediatrics (10 kg) | Small children (10 kg) |
| Adults (70 kg) | Children (20 kg) |
| – | Adolescents (32 kg) |
| – | Adults (60 kg) |
Additionally, default daily breathing volumes for the expanded patient populations is presented in the standard. The default daily breathing volume (now specified as “resting”) is substantially lower for adults and slightly higher in the other patient populations compared to the previous version of the standard. For devices that may be used during periods of exercise, maximum exercise ventilation also needs to be considered.
Expanded Testing Requirements
As outlined in ISO 18562-3:2024, testing of volatile organic substances (VOS) has been expanded to include targeted compounds based on the materials of construction and manufacturing process(es) of the device. This underscores the importance of preparing an evaluation plan prior to beginning testing. During sampling, targeted compounds below 1 µg/m3 and non-targeted compounds below 2 µg/m3 do not need to be reported or toxicologically assessed. Furthermore, updated threshold of toxicological concern (TTC) values are included in the revised ISO 18562 series of standards for VOS detected. For devices having limited or prolonged duration exposures, the TTC limit is 120 µg/day (based on ICH M7:2023) and “shall not be scaled according to body mass.” For devices having long-term exposure, the TTC limit is 2 µg/m3; based on the reduced default daily breathing volume, in adults, the long-term TTC value (when converted to units of µg/day) will be lower.
Another notable change in ISO 18562-4:2024 is the emphasis on exposure dose estimate for leachables, based on the condensate volume reaching the patient. It can no longer be assumed that a default volume 1 ml of condensate will reach the patient–note that this assumption was not recognized by the US Food and Drug Administration (FDA). It is now expected that the quantity of condensate that forms in the device be measured, experimentally. It goes on state that, in situations where ≤ 0.1 ml of condensate forms in 24 hours, under worst-case conditions, no further extractables testing is required. Obtaining the condensate volume can be especially helpful with assessing extractables/leachables data sets, as the worst-case exposure dose based on extraction volumes (from testing) is usually an extreme exaggeration.
In the past, when toxicologically evaluating leachables data, it was common practice to assume that all detected chemicals have patient exposure via the lungs. ISO 18562-4:2024 now clarifies that devices connected to the patient by a tube into the trachea have exposure via inhalation (lungs), whereas devices connected via mask or tube into the nose have exposure via ingestion (condensate is swallowed, orally). This clarification will help some devices during the toxicological evaluation process, as uncertainty for route of exposure differences when deriving tolerable intake values will not be needed (i.e., an oral point of departure being used for an oral exposure scenario). Additionally, updated TTC values are included in the revised ISO 18562 series of standards for leachable chemicals detected in condensate, which are based on the values derived in ICH M7:2023 and “shall not be scaled according to body mass”.
From a biocompatibility perspective, the prior version of ISO 18562-4 indicated that the endpoints of cytotoxicity and sensitization need to be addressed. The revised version adds irritation and while this is a change, irritation testing of gas pathway devices has been something that the US FDA routinely requests.
Final Considerations
While not technically a change to the ISO 18562 series of standards, the concept of Tolerable Exposure (TE) has been retained. As such, the toxicologists are now in a very interesting predicament for their evaluations; should TE be used to align with ISO 18562 or should Tolerable Intake (TI) be used to align with ISO 10993-17:2023? Essentially, whichever approach is chosen, it feels like we are walking into an inevitable deficiency. Now, mathematically, it doesn’t really make any difference whether TE or TI is used, as long as the risk assessor is mindful of their units. However, it will be interesting to see which approach regulatory reviewers will prefer.
At this point, the US FDA has yet to release their extent of recognition for the ISO 18562 series of standards. Therefore, there is some level of uncertainty if a biological risk assessment written in alignment with the 2024 version will be fully accepted by the Agency. However, from our perspective and experience, it seems likely the US FDA will recognize most of the standards. Based on our prior experience, the US FDA has requested extraction vehicles in addition to purified water be used in leachables testing, we shall see if the US FDA will continue with this expectation, or if they will recognize what is included in the standard.
How Can NAMSA Help?
NAMSA has a dedicated team of toxicologists and consultants available to work with you to interpret and follow these updated standards. Our experts can help with toxicological risk assessments, perform risk characterization and assess for biological hazards while also meeting the test requirements of various global marketplaces. Contact us today to learn more.
Phillip Smiraldo, PhD, DABT
Phillip holds a PhD in Molecular and Cellular Biology from the University of Toledo Medical Center (formerly Medical College of Ohio) and a BS in Biology from Bowling Green State University (summa cum laude; with minors in Chemistry and Italian Language). He was a Postdoctoral Fellow at the University of Texas Southwestern Medical Center (awarded two grants to support his research), authored several articles that were published in peer-reviewed journals (regarding his research of DNA repair in mammalian cells), and authored a book chapter appearing in Telomerases: Chemistry, Biology, and Clinical Applications, and has provided several oral presentations. Dr. Smiraldo's timeless experience in the medical device industry encompasses toxicology, biological safety and preclinical study design, as well as extensive preparation of biological and toxicological risk assessments for submission in countries complying with EU and US FDA regulations. Prior to his current position as Toxicologist, he was a Medical Research Scientist and Study Director (NAMSA), overseeing special/custom preclinical functional studies, preclinical safety studies and simulated-use chemistry studies. Before joining NAMSA, Dr. Smiraldo was a Staff Toxicologist at WIL Research (approximately 2.5 years), where he was a Study Director of preclinical safety studies for pharmaceutical- and chemical-based products.
Cayla Ruch, PhD, DABT
Dr. Ruch is a Board Certified Toxicologist with over 6 years of experience in the medical device industry. She was previously a Study Director responsible for conducting safety and efficacy preclinical studies and studies in compliance with the ISO 10993 standards, and a Project Manager for the Biological Safety Team. Dr. Ruch received her PhD in Nutritional Biochemistry from the University of Minnesota – Twin Cities, with a research focus on high fat diet induced cognitive decline. In 2023, she received her Diplomate of the American Board of Toxicology (DABT) certification. Dr. Ruch is an active member of the Society of Toxicology.