Every medical device requires an evaluation of its overall biocompatibility profile prior to its release to market. The overarching standard that covers the framework and guidance on how to approach this is included in ISO 10993-1. While regional vertical-guidance documents may exist (like the FDA guidance document on the application of ISO 10993-1), it should be noted that ISO 10993-1 is the cornerstone standard that is most broadly recognized and accepted around the world, which is critical if you’re intending to market your device in numerous countries or regions.
In 2018, ISO 10993-1 went through a major change. This included a shift of the general concept of biological evaluation from merely a checkbox testing approach to implementing a risk-based strategy where specific biological endpoints of concern for indicated contact type and duration require evaluation (marked with an E in Table A.1 of ISO 10993-1:2018). This does not mean that testing may be omitted willy-nilly but emphasizes that available information should be reviewed and considered to identify what tests should be conducted in addition to what is currently known about the device, its materials, and manufacturing processes to cover the risks posed by the given medical device.
With the revision an additional column was added to Table A.1, which has caused headaches within the medical device industry. This column, requiring physical and/or chemical information, is the only column in Table A.1 that is now marked with an X, meaning it is required for all medical devices regardless of their type and duration of contact. Many manufacturers question whether this means that an extractables study per ISO 10993-18 is required for all devices. This article examines that question in detail to explain why the answer is an emphatic “No.”
Gathering physical and chemical information on a medical device or component is a crucial first step in the biological-evaluation process, which includes material characterization. The extent of physical and/or chemical information required depends on what is known about the material formulation, what nonclinical and clinical safety and toxicological data exist, and the nature and duration of body contact with the medical device. In the writing of the standard it was intended that emphasis should be on the available material information, as well as the type and duration of body contact. For instance, if a medical device uses very common materials, like stainless steel, or some widely used polymers, like polypropylene (PP) or polyethylene (PE) that are used ubiquitously in currently marketed medical devices, then the concern for materials eliciting undesired effects, especially during short-term contact, is considered to be unlikely.
This is, of course, different for novel materials that have no previous experience. Similarly, when the duration of contact becomes longer, like for implantable devices, we need to know more about the material composition and its potential extractables profile to understand the potential risks for this type of use. The same concept of rigor should also be applied to the relevant biological endpoints that need to be covered for the device and are listed in Table A.1. of ISO 10993-1:2018. Based on this, a device that contacts only intact skin would require one set of biological endpoints to be addressed, whereas a device with a more invasive nature should include additional endpoints. As such, the rigor of physical and/or chemical characterization needed for a device should be evaluated for each device on an individual basis.
ISO 10993-1:2018 refers to ISO 10993-18 for material characterization, if deemed necessary. ISO 10993-18 discusses the framework for extractables studies with a chemical analysis approach using various mass spectrometry analysis for extracted organic compounds and elemental analysis. An extractables study provides a comprehensive list of the extractables that should be identified as completely as possible and evaluated for potential toxicity by a toxicologist or trained professional. Extractables studies are complex (reports are often over 100 pages), time consuming (time from initiation to completed analysis can be greater than 3 months), and costly (ranging from $30k to $100k) where very detailed information is obtained. It should also noted that the extractables analysis and toxicological risk assessment are typically used for long-duration systemic toxicity endpoints only, such as carcinogenicity.
Even ISO 10993-18:2020 emphasizes that, “Tests that evaluate systemic effects or endpoints (e.g., systemic toxicity) are more likely to be suitably addressed by chemical characterization than are those tests for local effects (e.g., irritation and implantation effects).” FDA has made it clear that it accepts extractables testing and toxicological risk assessment for systemic toxicities only, namely acute, sub-acute, sub-chronic, chronic, genotoxicity, and carcinogenicity.
Based on this, the chemical characterization study is not considered a value-add for devices that have no systemic exposure (e.g., for intact skin-contacting devices), as the systemic exposure is inhibited by the skin. Similarly, more invasive devices that have only short-term contact to the body during use are required to be evaluated for acute systemic toxicity but (typically) not for longer-term systemic-toxicity effects.
Imagine a surgical instrument that is being used for up to one hour to perform a surgical procedure. When pursuing the chemical characterization, typically either exaggerated conditions (e.g., 50 °C for 72 hours) or exhaustive extraction are utilized in this analysis. Subjecting a device that contacts the body for only one hour would result in a much more extensive set of extractables than actually faced during the clinical use. And taken into consideration that the toxicological analysis of these substances is typically based on very conservative threshold values, such as no observed adverse effect level (NOAEL) from chronic animal studies, the effort put into this does not really address the actual (acute) risks that are pertinent to a limited-contact device.
In essence, you would get a lot of data that you cannot really do anything useful with. It would be like having a haystack but with no needle in it – that is, a lot of work with no clear objective. Indeed, generating all of this data can actually harm a device’s submission to regulators as something needs to be done with all of the data, but nobody knows what to do with it if there aren’t biological endpoints which need to be evaluated.
Thus, for limited-contact devices or devices that have no potential for systemic toxicity, it is much more relevant to address the biological endpoints with means other than chemical characterization. In general, we see the X for physical and/or chemical information as a requirement for the medical device manufacturers to know exactly what materials are going into their device and how their device is manufactured. This is important to know for quality-control purposes and ensure that from lot to lot or batch to batch the device you make is still equivalent with an equivalent biocompatibility profile. This is also important when you are facing some changes to any of these inputs, material changes, supplier changes, manufacturing process changes, changes to the facility, etc. If you know exactly what goes into your device, you know when something is changing, and then you can proactively address these with a risk assessment and, if needed, additional information or data.
If after careful consideration, it is felt that chemistry testing of some sort is really needed to address a perceived regulatory concern, then other less burdensome tests should be considered. For example, the question can be viewed from a cleanliness perspective. Here, the bigger concern comes from the potential manufacturing residuals that could be present on the devices after the production process, such as detergents used in the cleaning process, some potential oil residuals from machining steps, etc. To target these specifically, some higher-level chemistry testing, such as non-volatile residue (NVR) or total organic carbon (TOC) analyses, may be considered instead to demonstrate the overall cleanliness of the device.
Taken together, while the Table A.1 lists physical and/or chemical information as prerequisite information needed for a risk assessment, it does not mean that a full chemical characterization as laid out in ISO 10993-18:2020 needs to be conducted for all medical devices. The following are some points to consider when assessing the need to go down this path are:
- Is my material novel/new formulation?
- What is the intended contact of the device regarding type and duration of exposure? Based on that, are there systemic toxicity endpoints that can and should be covered with extractables studies per ISO 10993-18 or is there a less burdensome alternative option that could be pursued?
In general, common materials and their use within limited-contact devices (or devices with no systemic exposure) should not be tested for ISO 10993-18:2020.