1. What Is Device Biocompatibility?
2. What Are the FDA and EU/ISO Requirements for Biocompatibility Testing?
3. Do I Need Biocompatibility Data?
4. How Do I Determine Which Tests I Need?
5. Should I Test Device Materials, or Only a Composite of the Finished Device?
6. Is GLP Treatment Required for Biocompatibility Testing?

What Is Device Biocompatibility?

The word biocompatibility refers to the interaction between a medical device and the tissues and physiological systems of the patient treated with the device. An evaluation of biocompatibility is one part of the overall safety assessment of a device. Biocompatibility of devices is investigated using analytical chemistry, in vitro tests, and animal models. The biocompatibility of a device depends on several factors, including:

• the chemical and physical nature of its component materials
• the types of patient tissue that will be exposed to the device
• the duration of that exposure

Of course, the primary purpose of a device biocompatibility assessment is to protect patient safety. Manufacturers will also want to consider corporate regulatory goals and compliance risks in planning a biocompatibility testing program. Inevitably, evaluating the biocompatibility of a device is a risk assessment exercise. There is no risk-free device or device material. The goal of device designers is to minimize risk while maximizing benefit to patients.

What Are the FDA and EU/ISO Requirements for Biocompatibility Testing?

The best starting point for understanding biocompatibility requirements is ISO Standard 10993, Biological Evaluation of Medical Devices. Part 1 of the standard is the Guidance on Selection of Tests, Part 2 covers animal welfare requirements, and Parts 3 through 19 are guidelines for specific test procedures or other testing-related issues (click here for a list of the individual sections of ISO 10993).

Testing strategies that comply with the ISO 10993 family of documents are acceptable in Europe and Asia. In 1995, FDA issued a Blue Book Memorandum G95-1, which replaced the tripartite Guidance (the previous biocompatibility testing standard). FDA has substantially adopted the ISO guideline, although in some areas FDA’s testing requirements go beyond those of ISO.

The specific ISO test procedures vary slightly from the USP procedures historically used for FDA submissions. The ISO procedures tend to be more stringent, so companies planning to register their product in both Europe and the U.S. should follow ISO test methods.  FDA requirements should be verified since additional testing may be needed. Japanese procedures for sample preparation and testing are slightly different from either USP or ISO tests.

Pacific BioLabs highly recommends discussing your proposed biocompatibility testing plan with an FDA reviewer before initiating testing

Do I Need Biocompatibility Data?

Biocompatibility data of one kind or another is almost always required for devices that have significant tissue contact. Refer to the ISO Materials Biocompatibility Matrix, a flow chart from ISO 10993-1, to help determine if your device needs biocompatibility testing.

Most commonly, companies arrange for their own biocompatibility studies. You may be able to reduce the amount of testing you will need on a specific device if you have some or all of the following types of biocompatibility data.

• Data from previous submissions – If data is available from a previous submission, consider the following points as you apply it to your current device. You will need to perform confirmatory testing if there are significant changes in any of these areas:
  • Materials selection
  • Manufacturing processes
  • Chemical composition of materials
  • Nature of patient contact
  • Sterilization methods
• Data from suppliers of materials or components – If vendor data is used, manufacturers should obtain copies of the original study reports. It is important that the laboratory that generated the reports had an experienced staff, a strong track record of cGMP/GLP compliance, and an AAALAC accredited animal science program. Usually manufacturers will want to conduct at least some confirmatory testing of their own (e.g. cytotoxicity and hemocompatibility studies).
• Analytical data – Manufacturers may use analytical data to help demonstrate that a device has a low overall risk or a low risk of producing a given biological effect. Section 18 of ISO Standard 10993, Chemical Characterization of Materials, gives some guidance on this process.
• Clinical data – Clinical data can be used to satisfy some biological effects categories from the ISO 10993-1 test selection matrix. The data may come from clinical trials of the device in question, or from clinical experience with predicate devices or devices containing similar components or materials.

How Do I Determine Which Tests I Need?

The core of the ISO Standard is confirmation of the fitness of the device for its intended use.  The first step in this process is chemical characterization of device components.

Biological testing is probably the most critical step in a biocompatibility evaluation. TheISO materials biocompatibility matrix categorizes devices based on the type and duration of body contact. It also presents a list of potential biological effects. For each device category, certain effects must be considered and addressed in the regulatory submission for that device. ISO 10993-1 does not prescribe a specific battery of tests for any particular medical device. Rather, it provides a framework that can be used to design a biocompatibility testing program.

Device designers should generally consult with an experienced device toxicologist and their clinical investigators to determine how best to meet the requirements of the materials biocompatibility matrix.  For each biological effect category, the rationale for the testing strategy should be documented. This is especially true when a manufacturer decides not to perform testing for an effect specified by the matrix for their category of devices.

Should I Test Device Materials, or Only a Composite of the Finished Device?

As a manufacturer, you should gather safety data on every component and material used in a device. In addition, you should definitely conduct testing on the finished device as specified by ISO 10993-1. Generally, the best approach is to:

• assemble vendor data on candidate materials
• conduct analytical and vitro screening of materials
• conduct confirmatory testing on a composite sample from the finished device.

There is a risk in testing the finished device without developing data on component materials. If an adverse result occurs, it can be difficult to track down the component that is causing the problem. You may end delaying your regulatory submission while you repeat testing on the individual components.

Screening device materials minimizes this risk. The initial chemical characterization should detect leachable materials that could compromise device safety. Inexpensive non-animal studies (such as cytotoxicity and hemocompatibility tests) provide an additional screen for material safety. Material screening tests also help insure that you will not be forced to redesign your device due to biocompatibility test failures. Many manufacturers assemble data on a library of qualified materials used in their products.

Some test procedures do not lend themselves to testing of composite samples. Due to physical limitations, agar overlay or direct contact cytotoxicity tests and implant studies require separate testing of each device component.

For all biocompatibility studies, test samples should be sterilized using the same method as will be used for the finished device.

Is GLP Treatment Required for Biocompatibility Testing?

As a general rule, all biocompatibility testing should be performed in compliance with Good Laboratory Practice (GLP) regulations (FDA or OECD).

GLP regulations apply to biological safety studies conducted in support of regulatory submissions. They govern all phases of testing, including preparation and approval of study protocols, monitoring tests in progress, and issuance of final reports, as well as facility and study management and the role of the Quality Assurance Unit.

GLP treatment is explicitly required for IDE and PMA submissions. FDA reviewers say they strongly prefer GLP treatment for studies supporting 510(k)s.  For European submissions, ISO 10993-1 seems to require GLP treatment, but the wording is somewhat ambiguous. In practice, studies are usually not rejected for lack of GLP treatment.

Manufacturers of device components and materials should have their biocompatibility studies done per GLP so that their clients can use the data in any type of regulatory submission.

Download printable version of our booklet Assessing Biocompatibility – A Guide for Medical Device Manufacturers (PDF).