US FDA Biocompatibility Expectations

By Sarah Fitzgerald

Medical device regulators around the world are encouraging coordination and regulatory consistency. From a high level, virtually all medical device regulators take a risk-based approach and require that the benefits of the medical device outweigh the risks before authorization. However, detailed expectations are not yet consistent. The United States (U.S.) Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) has three main areas with expectations that are typically significantly different from those in most other regions of the world. These areas are biocompatibility, reprocessing (cleaning, disinfection, and/or sterilization), and cybersecurity. 

Background on biocompatibility 

Biocompatibility is the ability of a material or overall product not to cause toxic, injurious, or physiological responses to direct or indirect contact with a given object. There are different expectations for medical devices with direct contact (physically contacting body tissue) and for those with indirect contact (fluid or gas passes through the device or component before contacting body tissue). The ISO 10993 series of standards addresses the evaluation of medical devices with direct or indirect contact, whereas the ISO 18562 series is specific to medical device gas pathways. Additional standards for specific medical devices should be considered, such as ISO 7405, specific to dental devices. This article is focused on direct contact biocompatibility under ISO 10993, as that is where Emergo experts generally see the most inconsistency between regulatory expectations. 

Traditionally, biocompatibility has been determined through testing, primarily in animals. The greater contact duration and the more potentially sensitive the tissue types in contact, the more types of testing are generally considered necessary to demonstrate that the device is adequately safe for use. For example, a device that only contacts intact skin for a limited duration is expected to have testing or evaluation conducted for cytotoxicity, irritation, and sensitization. However, a device intended to be implanted for a permanent duration in the bloodstream is expected to undergo testing or evaluation conducted for cytotoxicity, sensitization, irritation or intracutaneous reactivity, acute systemic toxicity, subacute/subchronic toxicity, genotoxicity, material-mediated pyrogenicity, implantation, hemocompatibility, chronic toxicity, and carcinogenicity. Some materials or devices, especially those that are novel and/or resorbed over time, may also require reproductive/developmental toxicity and/or degradation testing. 

ISO 10993-1 helps a company determine what testing to consider for biological risk assessment based on contact type and duration while the other standards in this series provide details on testing and evaluation related to specific aspects of biocompatibility. The table below summarizes the topics of the current ISO 10993 series of standards. Note that it does not provide the full name for these standards. 

Table 1. ISO 10993 Series of Standards Topics

Overview of biocompatibility and regulators 

All regulators consider the risks related to a device not being biocompatible important for a manufacturer to address, and generally rely on ISO 10993-1 to determine which biocompatibility effects need to be addressed for a given device, as described above. 

The ISO 10993 series allows for devices that are considered to have well-established biocompatibility to not require testing. Additionally, several recently updated versions of the standards allow for in vitro rather than in vivo (animal) testing. The ISO 10993-18 standard describing chemical characterization and ISO 10993-17 describing the utilization of a toxicological risk assessment (TRA) of chemical characterization and other data are also intended to be used to evaluate biocompatibility while minimizing in vivo testing. The interpretation on how and when these alternatives to in vivo testing, including in vitro testing and chemical characterization, can be used varies by regulators. 

Biocompatibility and the U.S. FDA versus other regulators

The FDA published an update to its guidance document related to biocompatibility in 2023 and maintains a resource center webpage to help manufacturers understand its perspective on biocompatibility evaluation and testing. Additionally, the FDA maintains a database of recognized standards that specifies if that recognition is partial or complete. 

Well-established biocompatibility

Most regulators accept a literature search demonstrating that the materials in the device have been utilized in other devices or, in some cases, even in general consumer items, and have demonstrated adequate biocompatibility. In some cases, they may also expect chemical characterization and a TRA.  

The FDA is generally considered to have the most restrictive interpretation on determining if biocompatibility is well-established and, therefore if biocompatibility can be justified instead of tested. In general, the FDA considers biocompatibility well established only if a similar device from the same manufacturer, using the same manufacturing and processing methods and used in a similar manner and location in the body, has already been FDA-reviewed and authorized. The FDA explains that manufacturing and processing can alter the physiochemical characteristics of the device, therefore leading to a different biocompatibility response. 

The FDA provides a list of specific materials in Attachment G of its guidance document which, when intended for intact skin contact only, they consider having well-established biocompatibility. 

For all medical devices that are not either very similar to a manufacturer’s own devices or on this specific list of materials that the FDA considers well-established, the FDA expects testing to demonstrate biocompatibility. 

In vitro versus in vivo testing 

Some of the ISO 10993 standards have an option for in vitro testing, including for sensitization (ISO 10993-10) and irritation (ISO 10993-23). In alignment with the principle of the “3Rs” to replace, reduce and/or refine animal use in testing when feasible, where in vitro tests are included in one of the ISO 10993 standards, most other regulators accept this in vitro testing in place of in vivo testing.  

Although the FDA theoretically also abides by the 3Rs, they caveat this by “when feasible” in the guidance document and “where these methods yield equally relevant information to that obtained from in vivo models” in their discussion on partial recognition of these standards in their database. From a practical standpoint, they do not consider the in vitro methods to have been demonstrated as equivalent and so either reject them outright or require a clear demonstration that the two are equivalent, therefore requiring in vivo as well as in vitro testing. 

Chemical characterization and TRAs

Chemical characterization (ISO 10993-18) is generally conducted utilizing chromatographic data derived from an extract of the device with a polar, semi-polar, and non-polar solvent. The results are then analyzed utilizing a TRA (ISO 10993-17). This, either alone or in combination with a literature review demonstrating that a material has well-established biocompatibility as described above, is accepted by many regulators to demonstrate biocompatibility. 

The FDA only partially recognizes these standards and has published a draft guidance document related to chemical characterization. First, it is important to note that the FDA will only consider chemical characterization and a TRA for certain biocompatibility effects (acute, subacute, subchronic and chronic systemic toxicity, genotoxicity, carcinogenicity and reproductive/developmental toxicity) and not for the three most commonly needed tests (cytotoxicity, irritation, and sensitization). Second, it is important to note that the FDA’s expectations, as provided in the draft guidance document, are substantially greater than typical chemical characterization testing. From a practical standpoint, conducting the in vivo testing rather than chemical characterization and TRA, is more likely to be accepted by the FDA. 

Other FDA concerns

The FDA has also expressed concerns related to the biocompatibility testing from several laboratories being unreliable, falsified, or otherwise considered invalid, and therefore has been rejecting some biocompatibility testing even when it seems to have been conducted to FDA expectations. Those concerns have been expressed via FDA news releases, warning letters (including 704332, 705188, 708579), and feedback to specific submissions. The FDA emphasizes that a company should carefully evaluate its test houses as potential suppliers. 

FDA versus other regulator expectations discussion

To summarize, the FDA is generally considered to have the most stringent expectations for testing for biocompatibility. This includes only accepting a justification of well-established biocompatibility in very limited cases, requiring in vivo testing even when other options exist, and only accepting chemical characterization and TRA as a replacement for certain tests and having specific requirements for chemical characterization beyond those described in the relevant ISO standard. Therefore, even if a device has already been authorized by other regulators, the FDA may require significant additional biocompatibility testing to satisfy their requirements. This can be challenging for manufacturers to understand initially and can jeopardize submissions as the FDA only allows a limited time to respond and it may not be practical to conduct certain testing in that timeframe. 

Minimizing risk of FDA not accepting biocompatibility  

There are a few manners to minimize the risk that the FDA will not accept the biocompatibility evaluation and testing provided. 

First, a manufacturer should carefully select and qualify test houses that can provide reliable data. While many test houses are reliable, if a manufacturer has doubts about being able to fully assess these suppliers, they can utilize a company that has been accredited by the FDA per their Accreditation Scheme for Conformity Assessment (ASCA) for biocompatibility testing. FDA guidance documents should be considered in addition to the standards, meaning that in vivo testing should generally be conducted.

Second, if a manufacturer has questions related to the acceptability of their data, even data that has been accepted by other regulators as sufficient to address biocompatibility, they may wish to consider formally reaching out to the FDA via a Q-submission to obtain FDA feedback. It is important to note that a Q-submission is not intended to be a pre-review of a submission, but it is acceptable to summarize evaluation and testing and ask for FDA feedback. 

Concluding remarks  

Biocompatibility is one of the three main areas where the FDA frequently has expectations that do not align with the expectations of other regulators and where even if a device has already been accepted in other regions, additional testing may be necessary. Manufacturers should carefully consider biocompatibility before making a premarket submission to reduce the chance of the submission being rejected by the FDA.