Key Essentials of Toxicological Risk Assessment for Medical Device Registration

As the global medical device market continues to expand, ensuring the safety and effectiveness of these specialized products remains a core priority in safeguarding human health. The global medical device regulatory landscape is increasingly shaped by toxicological risk assessment (TRA) principles. 

From a regulatory standpoint, oversight of medical devices was established early. The United States introduced a classification-based management system as early as 1976, while the European Union introduced three medical device directives between 1990 and 1998, later unified under the Medical Device Regulation (MDR) in 2017 to create a standardized regulatory framework across Europe.

Although China’s medical device industry started later, it drew heavily from advanced Western regulatory frameworks to rapidly establish a scientific regulatory system that has evolved in parallel with industry growth. The following legislation demonstrates this progression;

• 1996: Promulgation of the Measures for the Administration of Medical Device Product Registration
• 2000: Issuance of the Regulations on the Supervision and Administration of Medical Devices by the State Council
• 2014: Revision of the Regulations on the Supervision and Administration of Medical Devices
• 2021: Implementation of the newly revised Regulations on the Supervision and Administration of Medical Devices, enforcing the ‘Four Strictest’ regulatory principles 

The necessity of total product life cycle (TPLC) oversight has become a global industry consensus. Before a medical device can enter the clinical trial phase, validating its safety and efficacy through pre-market pathways, such as packaging material testing, biocompatibility evaluation and electrical safety testing, can represent a significant regulatory threshold. 

The ISO 18562 regulatory framework 

The ISO 18562 series mandates a structured risk management approach to biocompatibility evaluations. Because medical devices containing breathing gas pathways interact differently with the human body than non-gas-pathway products, the ISO developed this dedicated set of standards to guide gas pathway biocompatibility assessments. 

For medical devices featuring a breathing gas pathway (e.g. ventilators, anesthesia machines, nebulizers, oxygen therapy masks and breathing circuits), the ISO 18562 series provides a comprehensive evaluation framework covering both physical particulate matter and chemical substances:  

• Part 2 (Particulate matter emissions): addresses the risk of inhalation of solid foreign particles 
• Part 3 (Volatile organic substance emissions): addresses the risk of gaseous chemical inhalation 
• Part 4 (Leachables in condensate): addresses the risk of liquid-mediated substance transfer

TRA under ISO 18562-3 

Following the completion of volatile organic substance (VOS) emissions testing, medical devices must undergo a TRA in accordance with the methodologies and principles outlined in ISO 18562-1 (Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 1: Evaluation and testing within a risk management process). The second edition of this standard, released in March 2024, introduced substantial updates compared with the 2017 first edition, further highlighting the critical role of TRA in biocompatibility evaluations. The updated version provides clearer methodological guidance and introduces several key concepts, including tolerable exposure (TE), inhalation dose and margin of safety (MOS). 

Tolerable exposure (TE) 

Tolerable exposure is defined as the total amount of a specific substance to which a patient can be exposed over a 24-hour period without appreciable hazard to health. This value is derived by multiplying the tolerable intake (TI) by the patient's body weight. Consequently, TE represents a population-specific safe exposure limit, expressed in micrograms per day (μg/day). 

When calculating TE across various exposure durations, the TI value corresponding to that specific timeframe must be selected. For example, if the device contact duration is less than or equal to one day, the acute TI is used to calculate TE. Conversely, if the contact duration is more than 30 days, the long-term exposure TI must be selected to determine the corresponding TE. Standard exposure duration categories include ≤24 hours, >24 hours to 30 days and >30 days, which form the basis for tiered toxicological risk evaluation. 

Inhalation dose 

The inhalation dose refers to the actual mass of a target chemical substance that enters the patient's body via inhalation during the clinical use of a medical device containing a breathing gas pathway. Accurate estimation of the inhalation dose depends not only on reliable analytical chemistry data, but also on scientifically sound assumptions and parameter selection related to clinical use scenarios, patient population demographics and respiratory physiology. ISO 18562-1 establishes distinct respiratory volume parameters tailored to both resting and exertional states, as well as varying patient demographics. Consequently, before calculating the inhalation dose, the intended clinical application and target patient population of the device must be precisely defined. 

Risk characterization criteria 

The MOS serves as the definitive metric for risk characterization in a TRA. It is calculated by dividing the corresponding TE by the estimated inhalation dose, providing a quantitative measure of safety margin.  

The MOS must be evaluated across the defined exposure duration categories (≤24 hours, >24 hours to 30 days, and >30 days). A medical device is considered toxicologically acceptable only when the margin of safety (MOS) exceeds 1 for all identified substances. 

The key reference standards defining the framework, data and methods used to calculate TE and inhalation dose are as follows: 

• ISO 18562‑1:2024 Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 1: Evaluation and testing within a risk management process 
• ISO 18562‑2:2024 Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 2: Tests for emissions of particulate matter 
• ISO 18562‑3:2024 Biocompatibility evaluation of breathing gas pathways in healthcare applications – Part 3: Tests for emissions of volatile organic substances  
• ISO 18562-4:2024 Biocompatibility evaluation of breathing gas pathways in healthcare applications — Part 4: Tests for leachables in condensate   
• GB/T 16886.1 2022 / ISO 10993-1:2018 Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process   

Our solutions 

Leveraging deep technical expertise and staying abreast of dynamic domestic and international regulatory updates, we provide comprehensive technical support for multi-dimensional testing and regulatory filings to fully meet international and domestic submission requirements. 

Our team consists of highly qualified toxicologists with multidisciplinary expertise spanning toxicology, pharmacology, biology, materials science and chemistry. Holding professional credentials widely recognized across global regions, including Diplomate of the American Board of Toxicology (DABT), European Registered Toxicologist (ERT) and UK Registered Toxicologist (UKRT), our team delivers a high level of scientific rigor and supports international regulatory acceptance.  

With extensive project experience, our portfolio encompasses implantable devices, dental materials, medical tubing, complex gas pathway systems (e.g. anesthesia workstations and incubators), drug delivery systems and single use surgical instruments. We have successfully supported numerous clients in securing regulatory registrations across major global jurisdictions, including the US Food and Drug Administration (FDA), the EU MDR and the National Medical Products Administration (NMPA) of China.