Strict new requirements for evaluating medical device safety highlight the importance of comprehensive chemical characterization.
Medical device biological safety evaluations involve a stepwise process that ensures the risks of adverse reactions associated with use of a medical device are reduced as much as practically possible. Chemical characterization has always played a role in the biological safety evaluation process, but with the release of International Organization for Standardization (ISO) 10993-18:2020, the requirements for documenting information about the chemical constituents that reside in or on a medical device are more rigorous than ever.
Chemical characterization is required for all new medical devices, but it can also be a useful tool to address some of the changes specified in ISO 10993-1, Section 4.9 that trigger a new biological risk assessment for existing devices.”
Chemical characterization is required for all new medical devices, but it can also be a useful tool to address some of the changes specified in ISO 10993-1, Section 4.9 that trigger a new biological risk assessment for existing devices, including the following:
Additionally, a recent uptick in chemical characterization has been driven by the European Union’s Medical Device Regulation (MDR), which requires medical devices marketed in Europe to be compliant with the latest version of ISO 10993- 18:2020 and has resulted in longer than average timelines for testing.
Chemical characterization is accomplished first through information gathering on the materials of construction and the manufacturing, packaging, and sterilization processes. This information must be documented in a Biological Safety Evaluation in accordance with ISO 10993-1 (ISO, 2018). Often, information gathering is insufficient to fully characterize potential health risks associated with the device, so testing is required. Device manufacturers are then faced with the question of what kind of chemical characterization testing should be conducted. New Developments in Medical Device Chemical Characterization “Chemical characterization is required for all new medical devices, but it can also be a useful tool to address some of the changes specified in ISO 10993-1, Section 4.9 that trigger a new biological risk assessment for existing devices.” To answer this question, one must consider several factors that influence the device’s extractable profile, including the compatibility of the solvent(s) with the device’s materials of construction (ideally the solvent will extract all constituents without degrading the device materials) and the duration and temperature of the extraction. While ISO 10993-18 provides some guidance to these questions, the standard allows for various options, and all selections must be justified. For example, study parameters for devices with a limited duration (e.g., devices with less than 24 hours of use) will differ from study parameters for devices with prolonged patient contact duration (e.g., devices with 24 hours up to 30 days of cumulative use) and long-term devices (> 30 days) (ISO, 2020). Seeking out an experienced partner to help guide the selection of chemical characterization parameters and their justification up front can save time and money and avoid the selection of parameters that are inappropriate for the device or regulatory body.
Among the most important choices when initiating chemical characterization testing is selecting the solvent, or solvents, to use in the extraction. The first consideration when selecting a solvent is the purpose of the extraction. Under exhaustive conditions, typically, harsh solvents that are polar (e.g., water), semi-polar (e.g., methanol), and non-polar (e.g., hexane) in nature are selected to extract as many chemical constituents as possible, as expediently as possible. While non-polar solvents such as hexane have no clinically relevant basis, they excel at extracting chemicals such as machining oils from metallic implants in an analytically expedient manner to determine the worst-case patient exposure. Similarly, exaggerated extractions use one or two solvents to create a profile of constituents that represents an overestimation of potential patient exposure (see Figure).
Conversely, in simulated-use extractions, solvents are selected to represent as closely as possible the fluid(s) the device contacts under clinical conditions. However, ISO 10993-18 does not provide a comprehensive list of simulated-use solvents; rather, each simulated use solvent requires a justification relating the solvent’s extractive power to the physiological conditions of the device (ISO, 2020). This is especially important for devices reviewed by the United States Food and Drug Administration (US FDA). The extra effort is worth it – where exhaustive and exaggerated extractions overestimate exposure, the benefit of a simulated-use study is a clinically relevant exposure estimate.
In addition to the quantity of chemical constituent release, the rate at which the constituents are released from the device is equally as critical. Exhaustive and exaggerated extractions typically release high levels of constituents quickly, resulting in over-estimation of assumed daily patient exposure (see Figure). Simulated-use studies can be designed to provide information on both the quantity and the rate of constituent release and are described in the forthcoming ISO 10993-17 as “release kinetics studies.” Release kinetics studies allow for a refinement of the exposure estimate by providing a daily release quantity and, therefore, information on the short-term and long-term toxicological risks associated with the device. For example, a release kinetics study could show a trend of decreasing concentrations of extractables released every day until a certain time point (e.g., 30 days) when exhaustion has been achieved and no more extractables are released from the device (see Figure). In this example, the release kinetics data support adjusting the daily lifetime exposure identified in the exhaustive extraction to a short-term daily exposure lasting only 30 days, simplifying the toxicological risk assessment.
Chemical characterization is an extensive process that can take months or even a year or more for long-term devices. Manufacturers should be prepared for multiple sets of extractions, be willing to ask for guidance on the selection of critical chemical characterization parameters, and ensure justifications are appropriately documented.
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International Organization for Standardization (ISO). 2018. “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process (Fifth Edition).” ISO 10993-1: 2018. 48p., October.
International Organization for Standardization (ISO). 2020. “ISO 10993-18:2020: Biological evaluation of medical devices – Part 18: Chemical characterization of medical device materials within a risk management process (Second Edition).” ISO 10993-18: 2020 (E). 74p.