Global Regulatory Pulse

FDA Finalizes Biocompatibility Guidance for Medical Devices

In Consulting, FDA, Regulatory by Kristy Katzenmeyer-Pleuss and Don Pohl

On June 16, 2016, FDA issued the 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 guidance will supersede FDA’s Blue Book Memorandum #G95-1 “Use of International Standard ISO-10993, ‘Biological Evaluation of Medical Devices Part 1: Evaluation and Testing,’” (dated May 1, 1995) starting on September 14, 2016. The draft version of the guidance was released on April 23, 2013; this blog will highlight the updates in the final guidance compared to the draft.

The final guidance, which is now 65 pages compared to the 38 pages in the draft, is applicable to 510(k), Premarket Approval (PMA), de novo, Humanitarian Device Exemption (HDE) and Investigational Device Exemption (IDE) submissions. The guidance now has a new section on risk management and emphasizes a risk management approach with benefit-risk analysis for the biological evaluation of medical devices. The process starts with a risk assessment of the device to identify potential risks, determine data available to mitigate risks, and finally, the interpretation of the data collected to confirm if all risks have been adequately addressed.

Recommendations related to the use of color additives in medical devices were removed from the draft guidance and are intended to be issued in a separate guidance. For additional information related to FDA’s color additive policy for medical devices, see NAMSA’s March 2016 blog. It also appears that FDA has removed references to gas pathway contacting devices in their final guidance.

The final guidance now has a consolidated, single table with testing recommendations as opposed to the draft that had two separate tables for initial and supplemental tests for consideration. In addition, material-mediated pyrogenicity was added as a biological endpoint to consider in the consolidated table. Carcinogenicity testing was also added as an additional biological effect to be considered for surface devices with permanent contact with breached or compromised surfaces.

Similar to the draft guidance, FDA provides general biocompatibility testing recommendations as well as test-specific recommendations for cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and degradation testing. In general, the use of chemical characterization is highlighted more throughout the guidance and there is a new section titled “Chemical Assessment”. Serial dilutions of extracts are suggested for inherently cytotoxic materials tested for cytotoxicity. For sensitization testing, the Buehler method is now mentioned for topical devices in contact with skin. The hemocompatibility testing section related to complement activation no longer recommends testing for C3a. For genotoxicity, the final guidance now explicitly states that testing “may be waived if chemical characterization of device extracts and literature references indicate that all components have been adequately tested for genotoxicity”. In addition, in vivo genotoxicity testing is now marked as “optional”, but should be considered for devices that contain novel materials. It is also stated that in vivo genotoxicity testing should not be used as a method to rule out a positive result from in vitro genotoxicity testing. The use of structure activity relationship (SAR) modeling is now explicitly suggested when experimental data is not available for the carcinogenicity potential of a material.

There are also several new attachments to the final guidance, including recommendations on how to provide summary biocompatibility information in your submission as well as the recommended contents of a biocompatibility test report. Detailed recommendations for the information to include in Device Master Files, which are frequently used by material suppliers to allow FDA access trade secret or confidential information on a material used in the manufacture of a medical device, are now provided in Attachment B.

The final guidance also now includes a glossary of key definitions relevant to biocompatibility assessments. The glossary now defines a novel material as a “material that has not previously been used in any legally US-marketed medical device”, which differs slightly from the definition used throughout the draft guidance (i.e., a material that has not previously been used in a marketed medical device with the same type and duration of contact). Throughout the guidance, specific delineations are made for devices that use novel materials.

FDA will host a webinar on July 21, 2016, from 1-2:30pm ET to further discuss the final guidance with industry.

You may also check out NAMSA’s recorded webinar on this guidance, originally hosted on June 21, 2016.


Kristy Katzenmeyer-Pleuss, Ph.D, is a former FDA medical device reviewer and currently a Senior Medical Research Manager, Regulatory at NAMSA. She holds a Ph.D. in Bioengineering from the University of Washington and a B.S. in Chemical Engineering from the University of Wisconsin-Madison. Her experience includes developing high-level regulatory strategy and policy, facilitating communications and meetings with regulatory agencies, and drafting premarket submissions and deficiency responses. Kristy has experience with a variety of medical device types and combination products, including general and plastic surgery, wound care, dermatologic, cardiovascular, orthopedic, neural, ophthalmic, ENT, dental, respiratory, infection control, general hospital, digital health, etc. She is also a subject matter expert in biocompatibility and reprocessing (reusable and reprocessed single-use devices).

Don Pohl is currently the Manager of Biological Safety & Validation at NAMSA. He holds a Bachelor’s degree from Ohio State University. Don has over 20 years of experience in the pre-clinical evaluation of medical devices for biological safety. During his career, he has held a variety of positions ranging from laboratory supervision/management, GLP Study Director, Technical Specialist for Laboratory Information Management System, Technical Specialist and project manager for Biological safety and biological risk assessment consultation. He has specific expertise in the evaluation process outlined in ISO 10993-1 as well as the expectations of the USFDA and other countries in their interpretation of the biological safety evaluation of medical devices.