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LEARNINGLEARNING CENTERCENTERASSESSING BIOCOMPATIBILITY: Introduction toASSESSING BIOCOMPATIBILITY: Introduction toBiocompatibility TestingBiocompatibility Testing

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 thetissues and physiological systems of the patient treated with the device. An evaluationof biocompatibility is one part of the overall safety assessment of a device.Biocompatibility of devices is investigated using analytical chemistry, in vitro tests, andanimal models. The biocompatibility of a device depends on several factors, including:

the chemical and physical nature of its component materialsthe types of patient tissue that will be exposed to the devicethe duration of that exposure

Of course, the primary purpose of a device biocompatibility assessment is to protectpatient safety. Manufacturers will also want to consider corporate regulatory goals andcompliance risks in planning a biocompatibility testing program. Inevitably, evaluatingthe biocompatibility of a device is a risk assessment exercise. There is no risk-freedevice or device material. The goal of device designers is to minimize risk whilemaximizing benefit to patients.

What Are the FDA and EU/ISO Requirements for BiocompatibilityTesting?

The best starting point for understanding biocompatibility requirements is ISO Standard10993, Biological Evaluation of Medical Devices. Part 1 of the standard is the Guidanceon Selection of Tests, Part 2 covers animal welfare requirements, and Parts 3 through19 are guidelines for specific test procedures or other testing-related issues (click herefor a list of the individual sections of ISO 10993).

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

The specific ISO test procedures vary slightly from the USP procedures historicallyused for FDA submissions. The ISO procedures tend to be more stringent, socompanies planning to register their product in both Europe and the U.S. should followISO test methods. FDA requirements should be verified since additional testing may beneeded. Japanese procedures for sample preparation and testing are slightly differentfrom either USP or ISO tests.

Pacific BioLabs highly recommends discussing your proposed biocompatibilitytesting 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 thathave significant tissue contact. Refer to the ISO Materials Biocompatibility Matrix, a flowchart from ISO 10993-1, to help determine if your device needs biocompatibility testing.

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

1. 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 needto perform confirmatory testing if there are significant changes in any of theseareas:

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areas:

1. Materials selection 2. Manufacturing processes3. Chemical composition of materials4. Nature of patient contact5. Sterilization methods

2. Data from suppliers of materials or components – If vendor data is used,manufacturers should obtain copies of the original study reports. It is importantthat the laboratory that generated the reports had an experienced staff, a strongtrack record of cGMP/GLP compliance, and an AAALAC accredited animalscience program. Usually manufacturers will want to conduct at least someconfirmatory testing of their own (e.g. cytotoxicity and hemocompatibilitystudies).

3. Analytical data – Manufacturers may use analytical data to help demonstrate thata 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, givessome guidance on this process.

4. Clinical data – Clinical data can be used to satisfy some biological effectscategories from the ISO 10993-1 test selection matrix. The data may come fromclinical trials of the device in question, or from clinical experience with predicatedevices 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 intendeduse. 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 andduration of body contact. It also presents a list of potential biological effects. For eachdevice category, certain effects must be considered and addressed in the regulatorysubmission for that device. ISO 10993-1 does not prescribe a specific battery of testsfor any particular medical device. Rather, it provides a framework that can be used todesign a biocompatibility testing program.

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

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

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

1. assemble vendor data on candidate materials2. conduct analytical and vitro screening of materials3. conduct confirmatory testing on a composite sample from the finished

device.

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

Screening device materials minimizes this risk. The initial chemical characterizationshould detect leachable materials that could compromise device safety. Inexpensivenon-animal studies (such as cytotoxicity a n d hemocompatibility tests) provide anadditional screen for material safety. Material screening tests also help insure that youwill not be forced to redesign your device due to biocompatibility test failures. Manymanufacturers 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 tophysical limitations, agar overlay or direct contact cytotoxicity tests and implant studiesrequire separate testing of each device component.

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

Is GLP Treatment Required for Biocompatibility Testing?

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

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

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

Manufacturers of device components and materials should have their biocompatibilitystudies done per GLP so that their clients can use the data in any type of regulatorysubmission.

Download printable version of our booklet Assessing Biocompatibility - A Guide forMedical Device Manufacturers (PDF).

PBL is FDA registered and ISO 9001:2008 and ISO 13485:2003certified by Intertek.

Our animal science operations are accreditedby AAALAC.

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