Characterization of extractables and leachables (E&L) by ISO 10993-18 is one of the first medical device biocompatibility assessment steps and is generally required for all new devices to ensure compliance with the EU Medical Device Regulation (MDR). E&L testing can also be used to ensure that raw materials are safe and suitable for use in medical devices.
MDR requirements for E&L testing
The MDR obligates manufacturers to ensure the biological safety of their devices when they come into contact with the human body. As a part of this process, E&L testing is used to check that the medical device does not release harmful substances that are hazardous to health during its use. The released chemicals can be categorized into two groups:
Extractables refer to the chemicals released from a medical device or material when extracted in laboratory conditions.
Leachables refer to the chemicals released from a medical device or material during clinical use.
The ISO 10993-18 standard was added to the list of EU MDR harmonized standards in March 2024, which means that devices compliant with ISO 10993-18 are now presumed to conform with the relevant parts of the MDR.
Preparation for E&L testing
The selection of extractables and leachables testing methods and conditions depends on the medical device characteristics, such as materials, configurations, composition, body contact site, and duration of use. These details should be documented in the Biological Evaluation Plan (BEP), which assesses the risks inherent to a medical device in a structured manner and recommends testing to address these risks. To ensure that all risks related to extracted and leached chemicals are evaluated appropriately, the BEP should preferably be in place before E&L testing is commenced.
Choosing extraction conditions and parameters
The extraction conditions in E&L testing are designed to simulate the worst-case leachables profile, representing the maximum potential chemical release from the medical device under clinical use. This includes all chemicals present in the device, such as contaminants, degradation products, processing aids, and additives.
The typical extraction conditions for medical devices in different contact duration categories are listed below:
Limited contact devices (< 24h) – Simulated use conditions
Prolonged contact devices (24h - 30d) – Exhaustive conditions
Long-term contact devices (>30d) – Exhaustive conditions
Alternatively, exaggerated conditions can be used for all contact categories.
In addition, an extraction temperature and time need to be selected according to the guidelines provided in ISO 10993-12. Temperature and time selection depend on the characteristics of the medical device and its clinical use, but for example, 37 °C and 72 h are some of the typically used parameters for an E&L study.
Solvent selection should account for the medical device’s material composition to avoid significant swelling or disintegration of the device. Typically, at least two solvents with different polarities are required to extract substances with different solubilities. Commonly used solvents include water (polar), saline (polar), ethanol (semi-polar), isopropanol (semi-polar), and hexane (non-polar).
Choosing analytical methods
Once extraction has been performed, the extracts are analyzed using different analytical methods for comprehensive screening of volatile (VOC), semi-volatile (SVOC), and non-volatile (NVOC) organic compounds, inorganic elements, and anionic compounds. Some commonly used methods to fulfill MDR requirements are listed below:
VOCs – Headspace-gas chromatography (HS-GC)
SVOCs – Gas chromatography-mass spectrometry (GC-MS)
NVOCs – Liquid chromatography-mass spectrometry (LC-MS)
Inorganic elements – Inductively coupled plasma-mass spectrometry (ICP-MS)
Anionic compounds – Ion chromatography (IC)
Evaluation of E&L results
The evaluation of medical device extractables starts with the establishment of an Analytical Evaluation Threshold (AET). The AET corresponds to the individual medical device and is dependent on the intended use of the device. Its purpose is to set a concentration limit to pinpoint the potential risk compounds from the analytical raw data. The following information is required to calculate the correct AET:
Medical device contact category (limited, prolonged, or long-term)
Duration of the body contact
Number of devices a user would be exposed to in a day
Any chemicals found in concentrations exceeding the AET will require further evaluation, i.e. a Toxicological Risk Assessment (TRA). If chemicals do not exceed the AET, further evaluation is not needed. Together, E&L testing and the TRA can help manufacturers determine which toxicological tests are required for the medical device.
Measurlabs’ solutions for E&L testing
Measurlabs provides a comprehensive selection of extractables and leachables testing and additional toxicology and biocompatibility testing services to fulfill MDR requirements. We also offer the preparation of a Biological Evaluation Plan and Biological Evaluation Report (BER). Don’t hesitate to contact us through the form below to request a quote or ask for more information.