Fall 2022

Medical Device Safety Assessment Overview

By Joel M. Cohen, Sc.D., DABT

Over the past decade, growth in the >$400 billion medical device industry can be attributed to a number of factors, including the rapid growth of the elderly population and advancements in biomedical technology. For example, medtech miniaturization has improved accessibility to remote areas of the body and increased options for minimally invasive surgery; it has also enhanced the feasibility and utility of portable and wearable medical devices. While the COVID-19 pandemic introduced significant supply chain challenges and temporarily decreased demand for devices related to elective or non-emergency procedures, the industry at large experienced increased global demand for medical supplies, ranging from in vitro diagnostic tests and respiratory care devices to ventilators and surgical masks.

The World Health Organization (WHO) estimates there are roughly 2 million different kinds of medical devices available today on the global market. In the US, a medical device is defined by the US Food and Drug Administration (US FDA) as any health or biomedical technology that is “intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease.” This broad definition covers everything from relatively low-risk products, such as bandages and surgical masks, to high-risk pacemakers and orthopedic implants.

The World Health Organization (WHO) estimates there are roughly 2 million different kinds of medical devices available today on the global market.”

All medical devices require an assessment of potential risks prior to market approval. The specific biological safety endpoints required for evaluation are based on the nature and duration of the device’s contact with the human body, as detailed in the International Organization for Standardization (ISO) 10993 series of standards. These international standards also note that systemic toxicity, genotoxicity, carcinogenicity, and developmental toxicity endpoints may be addressed via toxicological risk assessment of the chemical components of the device, including an evaluation of extractable and leachable (E&L) chemical constituents. Recent regulatory updates and revisions to standards have increased the requirements for chemical characterization studies. ISO 10993-18, for example, was revised in 2020 and formally introduced several new concepts to medical device E&L testing. Study designs should be tailored to the specific device under test. Reference standards used for extractable identification and semiquantitation should be selected based on the device materials of construction and manufacturing flow (i.e., the chemicals you might expect to see released from the device). An analytical evaluation threshold (AET) should be calculated based on the patient population, duration of contact, and worst case number of devices used concurrently. Any extractable compounds detected above the AET are then submitted for toxicological risk assessment, while those below the AET are considered to pose negligible risk to patients.

Low AETs often challenge the sensitivity of analytical instruments, requiring limits of quantitation in the low microgram or even nanogram range. Aggressive extraction conditions designed to achieve “exhaustion” (i.e., the maximum concentration of extractable chemicals that could be released without degrading the device) can yield hundreds and sometimes thousands of chemicals above the AET that require toxicological evaluation. A large percentage of these low-level extractables often lack complete toxicological data packages. Risk assessments for such “no-data” chemicals often require multiple lines of evidence, including in silico toxicology predictions, thresholds of toxicological concern (TTCs), and safety data for similarly structured compounds (i.e., read-across).

Steps in Extactables and Leachables Study

Notably, there is currently a lack of recognized standards or guidance for conducting a read-across assessment on medical device extractables. Still, a framework for best practices for read-across assessments of medical device extractables can be adapted based on the principles of Good Read-Across Practice (GRAP) (Ball et al., 2016; Cohen et al., 2018) and guidance established for other industries/regulatory contexts (e.g., ECHA, 2017; OECD, 2015). Adopting best practices from these established frameworks, read-across assessments should document similarities between target and analogue compounds related to chemical structure, physicochemical properties, toxicity/biological reactivity, and toxicokinetic and metabolic profiles. Transparent documentation of strengths, limitations, and uncertainties in a read-across assessment can better characterize uncertainty and confidence in the overall risk assessment and also aid in the development of scientifically defensible and health-protective conclusions.

If tolerable risk cannot be justified, all is not lost. Additional chemistry testing to confirm the identity and concentration of chemicals driving potential risks can improve confidence in the exposure assessment. Release kinetics studies (described in more detail later in this issue) can offer an even more refined exposure estimate for comparison against chemical-specific allowable limits. In such situations, cross disciplinary dialogue between device engineers, analytical chemists, and toxicologists can lead to creative and scientifically justified approaches for assessing potential risks to patients from medical devices.