How the New FDA Guidance on Biocompatibility Affects Medical Device Manufacturers

Biocompatibility is an essential aspect of the medical device industry. Biocompatibility testing ensures that devices do not contain materials or substances that could be harmful to patients during initial use or over the course of time. Biocompatibility tests can be used to detect many possible negative side effects of a product on patient. These may include effects on cells and physiological systems, tissue irritation and inflammation, immunological and allergic reactions and the possibility of cellular mutations leading to cancer. Email:marketing@medicilon.com.cn Web:www.medicilon.com

In June 1906, President Theodore Roosevelt signed into law the Food and Drug Act, which addressed "adulterated" products. Adulterated includes the addition of fillers of reduced "quality or strength;" coloring to conceal "damage or inferiority;" formulation with additives "injurious to health;" or the use of "filthy, decomposed, or putrid" substances in a product. It took until 1995 for FDA to release an official guidance specific to medical device regulation.

This document, known as the “blue book,” was the basis of biocompatibility testing regulation for decades. FDA published a draft guidance document on the “Use of International Standard ISO 10993-1 ‘Biological evaluation of medical devices—Part 1: Evaluation and testing within a risk management process’” in April 2013, and this draft marked the first updated direction regarding biocompatibility from FDA. A final version was issued in June of this year, which was officially adopted as the replacement for the G95 Bluebook memorandum on September 14, 2016.

During the three years that the document circulated as a draft, it doubled in length providing great insight into FDA’s regulatory expectations and the agency’s interpretation of the ISO 10993-1 guidelines in general. FDA guidance document on the use of ISO 10993-1 outlines the testing approach necessary to bring a medical device to market. Medical device manufacturers need to consider FDA’s interpretation of the ISO 10993-1 standard.

This guidance document can be divided into three areas: current thinking, new trends, and justification information. Current thinking references statements or thought processes that are recent trends from FDA as seen in feedback from medical device submissions. New themes are areas of updated insight or clarification of approaches to be taken. Justification information provides alternatives to the standard in vitro/in vivo biocompatibility tests in addressing specific biological endpoints.

Current Thinking

The guidance reflects the current trends that have been considered and adopted by FDA.

FDA expands what constitutes “contact” with a medical device to apply to practitioners. Prior to this document, FDA previously only considered biocompatibility testing for “contact” with patients. The risks devices pose to the practitioner need to be identified and assessed based on how the contact occurs without personal protective equipment (PPE). Handles and other parts of devices should be assessed based on how a practitioner would come into contact without wearing PPE; i.e. if the handle of a device will never be touched with a bare hand, then biocompatibility testing would not need to take place. The guidance does address PPE, however, and specifically states that “masks or gloves intended for protective purposes by clinical practitioners should be assessed for biocompatibility.”

The guidance expands upon patient “contact” to include indirect tissue contact through a fluid or gas path. However, if there is no contact to the patient (or practitioner), then no testing is needed. This applies in particular to electronic components that support medical device equipment, but have no contact.

The guidance now accounts for specific device types. Many device types have existing parallel standards with specific information or risks to address based on use, and these standards supersede ISO 10993-1. Recognized Consensus Standards can be checked for acceptance on the FDA website.

There is a new 10-page section, “Section III. Risk Management for Biocompatibility Evaluations.” Risk is not a new term when considering biological evaluations, but, the approach was not always clear. A large part of risk identification starts with materials and processes in medical device manufacturing. Materials can be supplied with documentation to support their biocompatibility which ensures that what is going into the device is safe, but processes including washing, rinses, anodization/passivation, and sterilization (to name a few) also impact the final medical device. FDA “does not clear or approve individual materials that are used in the fabrication of medical devices.” Testing for biocompatibility considerations should be performed on the device in its final and finished form. Once the risks have been identified, mitigation through testing and/or literature research occurs. The selection of tests to be performed should be based on history of materials, patient contact, and device-specific guidance (if available).

The guidance document now includes very specific language regarding many of the biological endpoints that are addressed through the ISO 10993 standard series. There are a few current trends that were expected interpretations of the applicable standard, but now these expectations are written rather than implied. Hemolysis testing can be performed either directly or indirectly, based on contact of the device. The guidance document clarifies that devices “having direct contact with circulating blood” should go through hemolysis, complement, and thrombogenicity testing regardless of contact time.

An entire new section on Chemical Assessment was added in the final version of the guidance document. Although the section is new, the practice is not. FDA outlines when a chemical assessment may be a useful part of a Biological Safety Evaluation:

Novel material not used previously in a legally marketed device in the U.S.

New material or process used to modify the material formulation

To mitigate risks of genotoxicity, carcinogenicity, and reproductive toxicity

To address device material changes that occur over time

To address any unexpected findings in the biocompatibility testing panel performed to determine if further mitigation is necessary

There is new emphasis on the requirement to address chronic toxicity and carcinogenicity. These test methods can take more time and be more expensive, but chemistry with a toxicological evaluation can be a useful tool to mitigate that cost and turn-around time.