Introduction to the Final Guidance
On September 8, 2023, FDA issued the new final guidance “Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”.”
The aim of this guidance document is to provide clarification regarding the use of ISO 10993-1 to prepare PMAs, HDEs, IDE Applications, 510(k) and DeNovo requests for medical devices that come into direct contact or indirect contact with the human body.
This guidance represents FDA’s current thinking about biocompatibility information that should be provided in medical device premarket submissions. Specific updates as discussed below, reflect agency thinking about certain medical devices in contact with intact skin & other minor updates such as revisions to align with current recognized consensus standards.
The guidance breaks down components of ISO 10993-1 into different sections covering a variety of biocompatibility topics and considerations.
Risk Management for Biocompatibility Evaluations
Biological evaluation of a medical device should be conducted within the framework of the risk management process. This process should cover a device risk assessment and lead to identification of potential risks from a biocompatibility perspective. Once risks have been identified, all relevant information (such as literature, clinical or animal study experience, consensus standards or other devices reviewed by FDA) should be reviewed to aid in the identification and mitigation of risks. Using all information in this process, sponsors can clearly summarize conclusions of the risk assessment, discuss relevant information reviewed, and explain what gaps remain. A plan can then be developed to address knowledge gaps through biocompatibility testing or other evaluations to address risks.
This section of the guidance provides attachments & examples to aid understanding of the risk management process.
ISO 10993 – Part 1 and the FDA-Modified Matrix
ISO 10993-1 provides a framework in which to plan biological evaluation of medical devices, and if needed, guidance for selecting tests to evaluate biological response to medical devices. In the latest revision, ISO 10993-1:2018 focuses on minimizing the number of tests performed by giving preference to in-vitro models and to other types of testing where information garnered from these tests will be equally relevant to in vivo testing.
The FDA-Modified Matrix outlines the recommendations for biological effects evaluation based on biocompatibility information to be submitted to support an IDE or marketing application to FDA. This Matrix is considered a framework for the selection of endpoints and should not be considered comprehensive.
The use of ISO 10993-1 and FDA-Modified Matrix can assist sponsors in making evaluations of relevant biocompatibility endpoints and determining if there is a need for additional testing.
General Biocompatibility Testing Considerations
Considerations to be made by the sponsor include the use of medical devices in their final finished form (or representative test article), testing of in situ polymerizing and/or absorbable materials, possibility for biological response resulting from device mechanical failure and unique properties of submicron/nanotechnology components. Recommendations for test article preparation are also discussed within the guidance.
If the risk assessment performed indicates biocompatibility testing is necessary, specific issues should be considered when conducting testing. Considerations should be made for the following testing: cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and degradation assessments. The issues included in this section are specifically areas where deficiencies are frequently identified in submissions.
In understanding the body’s entire exposure to the medical device, all chemical entities contained within the device must be considered. For devices where the patient-contacting portions may contain potentially toxic chemicals, the evaluation of safety should include both chemical risk and the type and duration of exposure. In this guidance, FDA lists out situations in which additional chemistry information may be requested.
Labeling Devices as “-Free”
FDA notes that to communicate with users regarding potential allergenic or toxic compounds, some sponsors have requested to include statements in the device labeling such as “-free”. Use of such terms may give users a false sense of security when using a medical device as with current test methods it may not be possible to reliably assure the absence of the allergen/toxic compound. FDA lists recommendations for alternatives to “-free” and how to incorporate this language into a submission.
The guidance also includes attachments that serve as resources to aid in understanding and use of ISO 10993-1. In this final guidance, Appendix G was updated to specifically cover the FDA's current thinking about the type of biocompatibility information that should be provided in a medical device premarket submission for certain devices in contact with intact skin.
Attachments include the following:
- A- Evaluation Endpoints for Consideration
- B- Device Master Files for Biocompatibility Evaluations
- C- Summary Biocompatibility Documentation
- D- Biocompatibility Evaluation Flow Charts
- E- Content of a Biocompatibility Test Report
- F- Component and Device Documentation Examples
- G- Biocompatibility of Certain Devices in Contact with Intact Skin
- H- Glossary
Call to Action
For those interested in learning more, the FDA is hosting a webinar dedicated to this specific guidance. In this webinar, FDA plans to provide an overview of new guidance attachments, explain changes related to the eSTAR form and answer questions about the final guidance.
Webinar – Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” – Final Guidance
Date: October 12, 2023
Time: 1:00 PM – 2:30 PM ET
Link to FDA Website for more information: https://www.fda.gov/medical-devices/workshops-conferences-medical-devices/webinar-use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1?utm_medium=email&utm_source=govdelivery
Do you have any questions about this standard or the upcoming webinar? MEDIcept has industry experts who can help. Contact us today at firstname.lastname@example.org.
Danielle Short – Associate Medical Device Consultant