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.

Outsourcing testing to a specialized lab comes with a number of benefits, including access to experts to identify all the compounds and more visibility into regulatory requirements.

You are the expert in your medical device, but identifying compounds (expected and unexpected) requires an entirely different set of skills and knowledge. When you outsource to the right lab, you gain access to experts who are capable of complex elucidation to identify compounds and you have access to their chemical database.

Although commercially available libraries to help identify chemicals exist for gas chromatography, the LC-MS method does not have a commercially available library. Partnering with a lab dedicated to complete chemical characterization with no unknowns alleviates some of the burden of identification.

Specialized labs often have visibility into types of products, regulations, new standards, and questions or requests that may come from regulatory agencies. This visibility will help you address Additional Information (AIs) requests quickly. Also, the ability to anticipate questions helps with the initial design of studies to proactively address potential concerns.