ISO 10993-18: Medical Device Extractables Leachables Testing Using Chemical Characterization

The official title: ISO 10993-18:2020: “Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process”

There are generally three critical elements evaluating biological risks; 1) complete chemical information/chemical characterization, 2) toxicological risk assessment, and 3) biocompatibility testing. Chemical characterization is the starting point that feeds into toxicological risk assessments, as the combination of these two steps often addresses several biocompatibility endpoints. Biocompatibility testing should be used to help meet the necessary endpoints that cannot or could not be addressed in the chemistry and risk assessment.

Part 18, provides guidance on chemical characterization testing requirements and exposure dose estimation, ultimately helping the chemist gather the information necessary to design a study that will be appropriate for the toxicological risk assessment. Regulatory bodies in the US and EU have incrementally interpreted, adopted, and implemented ISO 10993-18:2020. While the FDA stopped short of full recognition, it does expect manufacturers submitting products for use in the U.S. to address the requirements of the standard. MDR has accepted the standard as “state of the art” and generally holds manufacturers to it.

The best way to meet expectations is to stay current with regulatory updates. Our technical and regulatory experts serve as active participants and hold leadership positions within international regulatory standards committees. This allows us to better anticipate regulatory changes ahead of the published standards and guidance and track regulatory trends. We guide our clients’ test plans based on our industry knowledge, regulatory collaboration, and the extensive number of products we have assisted through product clearance.

Chemical characterization, also referred to as materials characterization, should be designed with the nature and duration of clinical exposure in mind. Chemical information can be a paper-based review of all materials or chemical data can be generated in a screen for all potential extractables/leachables or a targeted study focusing on a single compound of concern. However, extractables/leachables (E/L) testing is often necessary due to the risk of impurities in the raw materials and hazardous chemicals being introduced into the medical device during routine activity such as manufacturing, sterilization, and storage.

Chemical characterization of a medical device is the first step in the biological evaluation process, which means you should care about ISO 10993-18 early on in the preclinical testing process. But it must be completed on the finished medical device as part of the regulatory submission package. This gives chemists and toxicologists the full picture, including manufacturing and sterilization methods that might impact the extractables profile of the product.

Chemical characterization should be considered a journey, not a check-box exercise.

For many medical devices, exhaustive and exaggerated extractions are recommended by ISO 10993-18:2020 and are expected by regulators.

Extractables study designs challenge devices under extreme conditions to maximize the extraction of chemicals from the devices and provide information for estimating potential hazards. Exhaustive extraction studies involve extracting devices in solvents with ranges of polarity and repeating the extractions until the amount of extractable material in subsequent extractions is less than 10 percent by gravimetric analysis of that detected in the initial extractions. The intent of extractables studies is to determine the cumulative amounts of each chemical that could potentially extract from devices over time. Exaggerated extractions may be the appropriate method to maximize extractable chemicals that could be released from limited and some prolonged duration devices. Exaggerated extractions also use aggressive solvents and elevated temperatures to yield extractions.

Leachables/simulated-use study designs may be conducted to evaluate the potential for chemicals to extract or leach from devices under clinically relevant conditions. These studies incorporate the actual clinical matrix (leachable study) or a solvent that simulates the environment of clinical use (simulated-use studies).

Because TRAs based on exhaustive extractions often require additional chemical characterization studies (e.g., leachables or simulated-use) to further refine exposure assessments and mitigate risk, it may be helpful from a timeline perspective to conduct both studies concurrently. Otherwise, the studies can be conducted sequentially with the understanding that longer timelines may be necessary to conduct a complete toxicological assessment of the device.

This process of chemical identification is laborious and requires investment in equipment, expert personnel, and the time commitment to complete identification.

Yes. Instrument redundancy is available at both sites for all key analytical platforms to ensure there is ample capacity to reduce turnaround times. This also allows our clients to conduct their programs seamlessly at either of the two global sites. Expedited testing options are available at both sites to give clients the option to receive their testing results sooner if there is a need.

NAMSA has made significant improvements in reducing the “unknowns” identified during non volatile testing of extracts. Unknowns are less than 1% for all peaks. NAMSA has extensive experience in interpretation and identification of analytes with significant investments made in training and external tools to enhance our interpretation confidence. The lab has established an extensive library covering a wide range of compounds spanning a range of medical devices.

NAMSA has extensive experience working with regulatory bodies have have several team members who previously worked at the US FDA. We will work closely with you after your program is complete to answer questions after submission of data to a regulatory body. This includes joining you in direct discussions with regulatory authorities.

In 2024, the US FDA unveiled a Chemicals List for Analytical Performance (CLAP) dataset designed to help assist chemistry labs in ensuring the robustness of chemical characterization methods used to assess the biocompatibility of medical devices. The CLAP data set was specific to semi-volatile organic compound (SVOC) extractables data. NAMSA has evaluated FDA CLAP dataset and determined that there is a significant overlap of recommended compounds between CLAP and our internal database. We have been working on building our internal RRF database for all techniques over the past 5 years with chemical compounds covering a variety of chemicals.