Conducting Chemical Characterization/Risk Assessment for FDA Submissions

Biocompatibility evaluation of medical devices has traditionally relied on the results of cell-based and animal-based testing. However, an approach based on chemical analysis of the device has gained increased regulatory acceptance by the U.S. Food and Drug Administration (FDA) as a means to assess some aspects of biocompatibility (biocompatibility endpoints). This approach, known as chemical characterization/risk assessment, involves extraction of the device with various solvents, chemical analysis of compounds extracted from the device (chemical characterization), and a subsequent toxicological risk assessment (TRA) to evaluate potential risk posed by patient exposure to the extracted compounds.

Although chemical characterization/risk assessment has potential advantages over the traditional biocompatibility testing approach (e.g., potentially reduced overall preclinical testing time), manufacturers should realize this approach can be resource-intensive with a subsequent impact on the regulatory budget. Therefore, to provide device safety information in a cost-efficient manner, device manufacturers should understand how the chemical characterization/risk assessment approach fits into a medical device biocompatibility evaluation plan. In particular, it is helpful to understand FDA’s recommendations for using chemical characterization/risk assessment, as it is not needed for every device. It is important to note the information provided in this article is specific to FDA expectations and does not necessarily apply to Europe’s MDR or other non-U.S. regulations.

When to Conduct Chemical Characterization/Risk Assessment
While FDA has not published guidance on how to conduct chemical characterization/risk assessment,¹ it does explain when to use this approach. The 2016 FDA Biocompatibility Guidance² includes language to help manufacturers determine when the chemical characterization/risk assessment approach can be used to address specific biocompatibility endpoints. The guidance remains FDA’s most current formal advisement on evaluating biocompatibility.³

Chemical Characterization/Risk Assessment Biocompatibility Endpoints
Table 1 provides guidance language specifying when chemical characterization/risk assessment may be used to support medical device biocompatibility.

Table 1: Biocompatibility endpoints that may be addressed with chemical characterization/risk assessment.

Section of Guidance	Language	Biocompatibility Endpoints Referenced
VII.	For example, if extractables and/or leachables data demonstrates exposure will be below the derived tolerable intake (TI) for a particular chemical, or the TTC (if a TI cannot be derived), then further toxicological assessment is unnecessary for the evaluation of some biological endpoints (e.g., systemic toxicity, genotoxicity, carcinogenicity).	Subacute/subchronic systemic toxicity
		Chronic systemic toxicity
		Genotoxicity
		Carcinogenicity
III.C.	However, NOAEL/LOAEL values developed to consider reproductive toxicity may be used to assess the potential reproductive toxicity of compounds released from devices that are not in direct contact with reproductive tissues.	Reproductive / developmental toxicity
VI.F.	Genotoxicity testing may be waived if chemical characterization of device extracts and literature references indicate that all components have been adequately tested for genotoxicity.	Genotoxicity

The table shows chemical characterization/risk assessment can potentially be used to address biocompatibility endpoints such as subacute/subchronic systemic toxicity, chronic systemic toxicity, genotoxicity, carcinogenicity, and reproductive/developmental toxicity in a device’s biological safety evaluation. Using the chemical characterization/risk assessment approach to address these endpoints is consistent with MCRA’s recent experience in discussing regulatory submissions with FDA.

The chemical characterization/risk assessment approach is not recommended for assessing other biocompatibility endpoints that should be considered in evaluating biological safety. These endpoints include cytotoxicity, sensitization, irritation, hemocompatibility, material-mediated pyrogenicity, and implantation. While the toxicology community is making progress in extrapolating irritation and sensitization thresholds from toxicological data, these approaches have not yet been accepted by FDA.

To Test or Not to Test
Common Scenarios
Chemical characterization/risk assessment is a powerful methodology for addressing select biocompatibility endpoints. Therefore, it makes sense to conduct chemical characterization/risk assessment when these particular endpoints must be addressed in an FDA submission. Two common examples include submitting a first-time FDA application for a new permanent implant, and submitting a manufacturing or design change to a legally marketed implant device, in which the change could impact biocompatibility.

In both situations, chemical characterization/risk assessment serves as only part of the biocompatibility evaluation. FDA does not typically accept characterization/risk assessment to assess cytotoxicity, sensitization, irritation, hemocompatibility, pyrogenicity, and implantation biocompatibility endpoints. Those endpoints must be addressed with either biological testing or scientific rationale.

Addressing Positive Biological Testing Results
Chemical characterization/risk assessment also can help explain positive results from biological testing. Biological tests are an important tool in biocompatibility evaluation, as they can identify whether the subject device can potentially produce an adverse biological response. However, some biological tests are optimized for high sensitivity; therefore, a positive result does not necessarily indicate a clinically relevant patient safety concern. With a positive biological test result, chemical characterization can identify the source of the positive result and quantitate the amount of chemical source in the device. Subsequently, a TRA can then be used to estimate patient risk based on toxicological information specific to the identity and quantity of the compound of concern. The guidance describes this approach in Section VI.F.:

In the event of a positive result, we recommend further investigation⁴ to identify the source of the genotoxin. We recommend this information be used to help evaluate the overall benefit-risk of the device using a TRA with respect to carcinogenicity.

Recommended Situations for Chemical Characterization/Risk Assessment
In general, the biocompatibility endpoints addressable through chemical characterization/risk assessment may alternatively be addressed with biological testing. But the guidance identifies several exceptions in which chemical characterization and TRA are recommended in conjunction with, or in place of, biological testing for these endpoints. These situations are summarized in Table 2.

Table 2: Situations in which chemical characterization and TRA are recommended in conjunction with, or in place of, biological testing, per FDA guidance.

Section	Language	Device properties	How to apply chemical characterization and TRA*
VII.	For some devices including chemicals with known toxicities (e.g., drugs or biologics used in combination products), it may not be possible to mitigate the toxicological risks with traditional biocompatibility testing conducted on the medical device in its final finished form. For example, genotoxicity, carcinogenicity, and developmental toxicity endpoints may be better assessed through chemical characterization and a review of the literature. Therefore, in these particular situations, data from chemical characterization and toxicology information from the literature may be necessary to support the risk assessment.	Combination product devices containing drugs, biologics, or other chemicals with known toxicities	Conduct chemical characterization and TRA instead of biological testing to address the endpoint for which the device is expected to be positive
VII.	For some devices manufactured from materials that change over time (e.g., combination products, or in-situ absorbable or degradable materials), it may not be appropriate to only use the biocompatibility information from the as-manufactured device to predict the toxicity of the device over its implant life. Therefore, data from chemical characterization and toxicology information from the literature may be necessary to support the risk assessment.	Absorbable or degradable products	Conduct chemical characterization and TRA in addition to biological testing
VII.	For devices made from novel materials never before used in a legally U.S.-marketed medical device, toxicology information (i.e., data from the literature, additional biocompatibility testing of the final device, or toxicity testing of the chemicals of concern) may be necessary so a complete toxicity assessment of the new materials can be conducted	Novel materials	Conduct chemical characterization and TRA in addition to biological testing

*This approach is limited to addressing the following endpoints: subacute/subchronic systemic toxicity, chronic systemic toxicity, genotoxicity, carcinogenicity, and/or reproductive/developmental toxicity.

Establishing Toxicological Equivalence via Chemical Characterization/Risk Assessment
In some cases, the chemical characterization/risk assessment approach can be used to establish the toxicological equivalence of two devices. For example, the extractables and leachables profile of a medical device that is the subject of a new regulatory submission can be compared to that of a currently marketed device to determine if both products are toxicologically equivalent. Historically, comparative chemical characterization has been used to show the biocompatibility of a device is the same or no worse than that of a marketed reference device; however, today this approach is rarely successful. While using this approach to compare device biocompatibility is theoretically possible, the extractable and leachable profiles of two different devices are almost always different, with neither being considered a clear worst case.⁵ Thus, it is difficult to use this approach to leverage biocompatibility data from a reference device to support the subject product. Consequently, the chemical characterization/risk assessment of the subject device must stand on its own, and would serve as only part of the biocompatibility evaluation for the device. This means FDA would likely request biological testing or rationale to address cytotoxicity, sensitization, irritation, acute systemic toxicity, material-mediated pyrogenicity, implantation, and hemocompatibility (if applicable).

Conclusion
The medical device industry continues to await FDA’s guidance on how to conduct chemical characterization/risk assessment.₁ In the meantime, device manufacturers can still benefit from the clear paradigm FDA has provided on when to use chemical characterization/risk assessment as part of a biocompatibility evaluation. By following FDA’s 2016 Biocompatibility Guidance, manufacturers pursuing the U.S. market can make efficient resource decisions by conducting a device’s chemical characterization/risk assessment only when truly necessary. 

Acknowledgement: The concept for this article comes in part from the presentation given by Ron Brown, principal toxicologist at Risk Science Consortium LLC last fall.⁶

References

1. To date, the FDA has not published comprehensive guidance on their technical expectations for chemical characterization methods, and FDA has not recognized an external consensus standard on chemical characterization. This includes the latest revision for the international standard for chemical characterization, ISO 10993-18:2020, which FDA helped to revise but has not yet formally recognized.
2. US Food and Drug Administration (2016) “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process’”. Available at www.fda.gov/media/85865/download
3. A new revision of the international standard for biocompatibility (ISO 10993-1) has published in 2018. However, FDA has not recognized the overarching table in the standard that advises on when to evaluate physio/chemical properties. Therefore, the 2016 Guidance continues to serve as the primary reference for FDA’s expectations on when to conduct chemical characterization/risk assessment.
4. Note: Further investigation appears to refer to chemical characterization since the next recommended step is a TRA.
5. One exception is when the proposed device is nearly identical to the referenced device, such as in the case where the proposed device is the referenced device with the implementation of a minor design or manufacturing change.
6. Brown, R. Exploring Biocompatibility vs. Chemical Assessment in E&L Study Design. Podium Presentation, PharmaED Extractables and Leachables West Coast Meeting. 18 Nov 2019.

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Robert A. Allen, Ph.D., is a senior associate in regulatory affairs at MCRA LLC. Rob’s role at MCRA involves developing medical device regulatory strategies and submissions for FDA and international regulatory agencies. Rob also develops biocompatibility evaluation strategies including biological testing and rationales to support new device applications or modifications. Prior to MCRA, Rob worked as a lead reviewer and biocompatibility reviewer at FDA’s Center for Devices and Radiological Health, Office of Device Evaluation, Division of Cardiovascular Devices. Rob completed his Ph.D. in bioengineering at the University of Pittsburgh.