In 2018, the International Organization for Standardization (ISO) published 10993-1, an updated framework for assessing biological safety in medical devices. The standard requires a biological evaluation of each medical device as part of a risk management process. ISO 10993-1 focuses heavily on categorizing medical devices based on the nature and duration of anticipated contact with human tissue and existing data sets to support biological safety. Alongside revisions to ISO 10993-1, revisions to ISO 10993-18 in 2020 and anticipated changes to ISO 10993-17 will contribute to evolving expectations for biological evaluations.
ISO verbiage specifically states that 10993-1 wasn’t written as a rigid set of test methods with pass/fail criteria. Instead, appropriately trained professionals must consider chemical characterization, toxicological risk assessment, and biocompatibility results for sufficient evidence to evaluate each device’s potential risk to patients.
Researchers expect the new version of ISO 10993-17 to be published soon, as it was under development at the time of publication. The standard promises to expand guidance on conducting toxicological risk assessments (TRAs). It aims to establish whether the potential toxicological risks of chemicals extracted from a medical device are without appreciable harm to health. Preparing for ISO 10993-17 requires an understanding of the revised ISO 10993-18.
Preparing manufacturers for the update
In 2020, ISO published a revision to 10993-18 to provide more direction on chemical characterization, following the release of the most recent version of ISO 10993-1. ISO 10993-1:2018 introduced physical and/or chemical characterization as a crucial first step in any biological evaluation and risk assessment process. While a medical device’s chemical, toxicological, physical, electrical, morphological, and mechanical properties will determine its fit for use, each property represents another variable that can add to overall risk. That’s why a robust approach to chemical characterization is paramount to regulatory success and, ultimately, patient safety.
The analytical evaluation threshold (AET) is one of the most notable elements introduced with ISO 10993-18. It’s based on the dose-based threshold (DBT), lab extraction volume, and number of devices used in the extraction. The AET considers patient population, contact duration, and the number of devices intended for use; it sets the baseline at which chemicals should be identified and reported. During submission, regulators will expect to see rationale for how the AET was set and whether the chemistry report met those expectations. The standard requires all compounds at or above the AET to be identified. Many devices also now require the concentration of extracts to meet the AET.
Identifying and quantifying the universe of chemicals at or above the AET results from collaboration between manufacturers, chemists, and material scientists. Manufacturers are responsible for ensuring their product reflects the most current data and regulatory requirements, and their partnership with scientists helps ensure product safety and integrity. Inaccuracies or oversights may undermine a medical device’s submission package, so fully understanding the data contained in the finalized risk assessment is crucial.
When conducting extractables and leachables (E/L) testing, chemists will usually unearth compounds they anticipated, as well as compounds they didn’t expect. Any compounds chemists find – expected or not – provide the basis for device risk assessment. The TRA will determine if the compounds in a device render it safe or show potential for risk (i.e., equivocal results).
Proactive planning prior to E/L testing ensures chemists, toxicologists, and manufacturers align on the study design and reinforces the importance of their partnership and collaboration. Device manufacturers supply all information on materials, packaging, manufacturing environment, and labeling. Toxicologists determine the target DBT and potential toxicological risks, and chemists ensure their methods are sensitive and selective enough to meet TRA requirements.
Better tools, better results
Revisions to ISO 10993-17 promise new mechanisms to support the efforts of manufacturers and laboratories. Companies that prioritize chemical characterization and TRAs may be able to address some biological endpoints through chemical characterization and TRAs instead of conducting biocompatibility testing. TRAs can address endpoints, including systemic toxicity (acute, subacute/subchronic, and chronic), carcinogenicity, genotoxicity, and reproductive and developmental toxicity.
Toxicological risk assessments involve two critical concepts – hazard and exposure. To properly evaluate risk, it’s essential to understand which chemicals may be extracted (i.e., the hazard) and at what levels (i.e., the worst-case exposure). Other important considerations are the nature and duration of contact, as well as patient population.
Once chemists finish identifying and quantifying the chemical constituents at or above the AET, toxicologists can estimate exposure dose and derive tolerable intake (TI) levels or appropriate threshold of toxicological concern (TTC) values, when indicated. TI and TTC are based on available toxicity data, and in the absence of that data, in silico modeling can support the selection of the TTC per ISO/TS 21726:2019.
Dividing the TI/TTC by the maximum exposure dose allows toxicologists to derive a margin of safety (MOS). The MOS is a tool that toxicologists use, along with expert judgment, to evaluate the toxicological risk.
Concepts that may be useful for toxicological risk assessment:
1. Toxicological screening limit – Prioritization of screening data for toxicological risk assessment reduces the total number of chemicals that require further evaluation. Recently, the concept of a toxicological screening limit was introduced to evaluate screening data derived from medical device extracts. It identifies chemicals that are without appreciable toxicological risk. Toxicological screening limits are different for short-term and long-term exposure and may help remove chemicals of low toxicological concern, based on the duration of exposure.
2. Estimation of exposure dose – Often, chemicals release at higher levels of exposure initially and taper off through time. The released kinetics of extractable chemicals should be factored into worse-case daily exposure. Guidance on calculating exposure doses based on known or assumed release kinetics will help toxicologists better understand short- and long-term risks, as well as determine when additional release kinetics information is needed.
3. Evaluating the MOS – An MOS =1 may need further investigation, but an MOS >1 often supports acceptable toxicological risk. Since this measure doesn’t provide a full perspective of toxicological risk, experts must consider other factors. For example, suppose a critical adverse health effect is associated with high potency and severity of a chemical; a patient could have greater possibility of adverse health effects, even though the MOS is >1. Furthermore, if the critical adverse health effect is more relevant for a particular patient population or clinical scenario, it may require additional scrutiny. This situation highlights the importance of expert judgment and an experienced toxicologist evaluating the MOS.
The current version of ISO 10993-17 only provides information on establishing allowable limits for chemicals, while the revised version is expected to provide more comprehensive requirements and guidance to conduct toxicological risk assessments. Working with a laboratory partner that understands the complexities and nuances of the updated ISO 10993-17 can help ensure a smoother regulatory submission process.
A final note
ISO 10993-1 redefined biological evaluations and risk assessments for all medical devices. ISO 10993-18 highlighted the importance of materials characterization and introduced the AET. Soon, a revised ISO 10993-17 will establish state-of-the-art methods for evaluating risks associated with medical device chemical constituents.
The medical device regulatory landscape is evolving and will for the foreseeable future. In fact, medical devices with biological risk assessments conducted as recently as 2020 are likely outdated and may require reevaluation. An experienced laboratory testing partner can review past and future submission packages, ensure collaboration between various research groups, and pave the way for regulatory success.
About the authors: Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec specializing in extractables and leachables studies. Dr. Sherry Parker is WuXi AppTec’s senior director of regulatory toxicology, has more than 20 years of toxicology and medical device experience, and is an expert in biological evaluation of medical devices and combination products.