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Tripartite Biocompatibility Guidance April 24, 1987 (G87-1)

General Program Memorandum #G87-1

April 24, 1987


Tripartite Biocompatibility Guidance

[NOTE:  THE ORIGINAL ATTACHMENT II, DEVICE CATEGORIES AND SUGGESTED  
BIOLOGICAL TESTING, IS NOT INCLUDED AT THIS TIME.]

Purpose

A copy of the Tripartite Biocompatibility Guidance for Medical 
Devices, dated September 1986, is attached.  The purpose of this 
guidance is to establish an approach for the evaluation of the 
toxicity of medical devices.  This guidance is intended to assist 
manufacturers and government health authorities to anticipate the 
information needed for such evaluation.  ODE is in the process of 
developing further guidance that expands on the Tripartite 
guidance as it applies to the review of submissions made to ODE.

Background

The Tripartite Subcommittee for Medical Devices is comprised of 
the senior officials of the medical device authorities of the 
United States, the United Kingdom, and Canada.  During its 
September 1984 meeting, the Subcommittee decided that development 
of a common approach to toxicity testing would be highly 
desirable.  The Subcommittee established the Toxicology Subgroup 
to work this goal.  The guidance document produced by the 
subgroup, Tripartite Biocompatibility Guidance for Medical 
Devices, has been distributed to each of the three countries with 
the common understanding that it would be circulated in the 
respective national communities for comment and use "as 
appropriate."  Our Center's Toxicology Committee will be asked to 
circulate the guidance among appropriate scientific and industry 
groups for informal comment.  In the interim, ODE will utilize 
this guidance.

Scope and Application of the Guidance

The Tripartite guidance enunciates fundamental principles for 
toxicity evaluation of medical devices and provides a rational 
framework for their application.  The application of these 
principles envisions the assignment of  a given medical device to 
a category defined by (1) the nature of contact of the device 
with the body (e.g., external, externally communicating, or 
internal contact), (2) the time of contact (e.g., transient, 
short-term, or long-term), and (3) generic material(s) of device 
manufacture (e.g., polymers).  The Tripartite guidance contains a 
table of suggested tests related to the nature and duration of 
contact for safety evaluation of medical devices made of 
polymers.  Until such time that the Tripartite Subcommittee or 
ODE develops additional tables of suggested tests for device 
materials other than polymers, ODE divisions should use their
judgment in adapting the present table to the other materials
(e.g., metals, ceramics, biologicals).  ODE reviewers should 
expect the submitter of any IDE or PMA to have considered the 
relevance and importance of each of the tests suggested for the 
respective device category, and either to submit the data or to 
present a sound argument why the information is not needed for 
the evaluation.  In a similar manner, reviewers should consider 
the suggested tests for their relevance in the determination of 
substantial equivalence for 510(k) submissions, and require and 
review data when deemed appropriate.

Effective Date:  This memorandum is effective immediately.

Attachment I



                                                   ATTACHMENT I


         TRIPARTITE BIOCOMPATIBILITY GUIDANCE FOR MEDICAL DEVICES

                                Prepared by Toxicology
                                Sub-group of the
                                Tripartite Sub-Committee
                                on Medical Devices
                                September 1986


                          TABLE OF CONTENTS

         1.  Introduction

         2.  Device Categories:  Definitions and Examples

         3.  Biological Tests

         4.  Device Categories and Suggested Biological Tests


    TRIPARTITE BIOCOMPATIBILITY GUIDANCE FOR MEDICAL DEVICES

I.  INTRODUCTION

The purpose of the Tripartite Biocompatibility Guidance is
to offer an approach relevant to Canada, United Kingdom and the United 
States for the evaluation of the toxicity of medical devices.  This 
guidance is intended to assist manufacturers and government health 
authorities to anticipate information needed for such evaluation, but 
would not be considered as legal requirements.  However, all three 
countries may impose legal requirements for specific testing for a 
medical product depending upon its regulatory status; e.g., in the 
United States and Canada, absorbable and biodegradable implant 
materials are treated as medical devices, where as in the United 
Kingdom these materials are treated as drugs.  More specific guidance 
and requirements would be requested by the health authorities of the 
individual governments.  The Tripartite guidance is the outcome of 
lengthy discussions by the members of Toxicology Subgroup of the 
Tripartite Subcommittee on Medical Devices and is based on the 
following fundamental toxicity evaluation principles:

1.  The selection of material(s) to be used in device manufacture and 
    its toxicological evaluation should initially take into account 
    full characterization of the material, for example, formulation, 
    known and suspected impurities and processing.

2.  The material(s) of manufacture, the final product and possible 
    leachable chemicals or degradation products should be considered 
    for their relevance to the overall toxicological evaluation of the 
    device.

3.  Tests to be utilized in the toxicological evaluation should take 
    into account the bioavailability of the bioactive material, i.e., 
    nature, degree, frequency, duration and conditions of exposure of 
    the device to the body.  This principle may lead to the 
    categorization of devices which would facilitate the selection of 
    appropriate tests.

    Note:  A further aspect in deciding on categories of devices
           could by the generic nature of the materials of
           manufacture.

4.  Any in vitro or in vivo experiments or tests must be conducted 
    according to recognized good laboratory practices followed by 
    evaluation by competent informed persons.

5.  Full experimental data, complete to the extent that an independent 
    conclusion could be made, should be available to the reviewing 
    authority, if required.

6.  Any change in chemical composition, manufacturing process, 
    physical configuration or intended use of the device must be 
    evaluated with respect to possible changes in toxicological 
    effects and the need for additional toxicity testing.

7.  The toxicological evaluation performed in accordance with this 
    guidance should be considered in conjunction with other 
    information from other non-clinical tests, clinical studies and 
    post-market experiences for an overall safety assessment.

II. DEVICE CATEGORIES - Definitions and Examples

    A.  Non-Contact Devices

        Devices that do not contact the patient's body directly or 
        indirectly; examples include in vitro diagnostic devices.     

    B.  External Devices

            1.  Intact surfaces

                Devices that contact intact external body surfaces 
                only; examples include electrodes, external prostheses 
                and monitors of various types.

            2.  Breached or compromised surfaces

                Devices that contact breached or otherwise compromised 
                external body surfaces; examples include ulcer, burn 
                and granulation tissue dressings or healing devices 
                and occlusive patches.

    C.  Externally Communicating Devices

        1.  Intact natural channels

            Devices communicating with intact natural channels; 
            examples include contact lenses, urinary catheters, 
            intravaginal and intraintestinal devices 
            (sigmoidoscopes, colonoscopes, stomach tubes, 
            gastroscopes), endotracheal tubes, and bronchoscopes.

        2.  Blood path, indirect

            Devices that contact the blood path at one point and serve
            as a conduit for fluid entry into the vascular system;
            examples include solution administration sets, extension
            sets, transfer sets, and blood administration sets.

        3.  Blood path, direct

            Devices that contact recirculating blood; examples include
            intravenous catheters, temporary pacemaker electrodes,
            oxygenators, extracorporeal oxygenator tubing and
            accessories, and dialyzers, dialysis tubing and
            accessories.

    D.  Internal Devices

        1.  Bone

            Devices principally contacting bone; examples include 
            orthopedic pins, plates, replacement joints, bone 
            prostheses and cements.

        2.  Tissue and tissue fluid

            Devices principally contacting tissue and tissue fluid or 
            mucus membranes where contact is prolonged; examples 
            include pacemakers, drug supply devices, neuromuscular 
            sensors and stimulators, replacement tendons, breast 
            implants, cerebrospinal fluid drains, artificial larynx, 
            vas deferens valves, ligation clips, tubal occlusion 
            devices for female sterilization, and intrauterine 
            devices.

        3.  Blood

            Devices principally contacting blood; examples including 
            permanent pacemaker electrodes, artificial arteriovenous 
            fistulae, heart valves, vascular grafts, blood monitors, 
            internal drug delivery catheters, and ventricular assist 
            pumps.

III.  BIOLOGICAL TESTS*

        Sensitization Assay

        Estimates the potential for sensitization of a test material
        and/or the extracts of a material using in an animal and/or 
        human.

        Irritation Tests

        Estimate the irritation and sensitization potential of test 
        materials and their extracts, using appropriate site or 
        implant tissue such as skin and mucous membrane in an animal 
        model and/or human.

        Cytotoxicity

        With the use of cell culture techniques, this test determines 
        the lysis of cells (cell death), the inhibition of cell 
        growth, and other toxic effects on cells caused by test 
        materials and/or extracts from the materials.

        Acute Systemic Toxicity

        Estimates the harmful effects of either single or multiple 
        exposure to test materials and/or extracts, in an animal 
        model, during a period of less than 24 hours.

        Hemocompatibility

        Evaluates any effects of blood contacting materials on 
        hemolysis, thrombosis, plasma proteins, enzymes, and the 
        formed elements using an animal model.

        Pyrogenicity - Material Mediated

        Evaluates the material mediated pyrogenicity of test material 
        and/or extracts.

        Hemolysis

        Determines the degree of red blood cell lysis and the 
        separation of hemoglobin caused by test materials and/or 
        extracts from the material in vitro.

        Implantation Tests

        Evaluate the local toxic effects on living tissue, at both the 
        gross level and microscopic level, to a sample material that 
        is surgically implanted into appropriate animal implant site 
        or tissue e.g. muscle, bone,; for 7 - 90 days.     

        Mutagenicity (Genotoxicity)

        The application of mammalian or non-mammalian cell culture 
        techniques for the determination of gene mutations, changes in 
        chromosome structure and number, and other DNA or gene 
        toxicities caused by test materials and/or extracts from 
        materials.

        Sub-Chronic Toxicity

        The determination of harmful effects from multiple exposures 
        to test materials and/or extracts during a period of one day 
        to less than 10% of the total life of the test animal (e.g., 
        up to 90 days in rats).
 
        Chronic Toxicity

        The determination of harmful effects from multiple exposures 
        to test materials and/or extracts during a period of 10% to 
        the total life of the test animal (e.g., over 90 days in 
        rats).

        Carcinogenesis Bioassay

        The determination of the tumorogenic potential of test 
        materials and/or extracts from either a single or multiple 
        exposures, over a period of the total life (e.g., 2 years for 
        rat, 18 months for mouse or 7 years for dog).

        Pharmacokinetics

        To determine the metabolic processes of absorption, 
        distribution, biotransformation, and elimination of toxic 
        leachables and degradation products of test materials and/or 
        extracts.

        Reproductive and Developmental Toxicity

        The evaluation of the potential effects of test materials 
        and/or extracts on fertility, reproductive function, and 
        prenatal and early postnatal development.

        *The tests for leachables, such as contaminants, additives 
         monomers, and degradation products must be conducted by 
         choosing appropriate solvent systems that will yield a 
         maximal extraction of leachable materials to conduct 
         biocompatibility testing.

         The effects of sterilization on device materials and 
         potential leachables, as well as, toxic by-products as a 
         consequence of sterilization should be considered.  
         Therefore, testing should be performed on the final 
         sterilized product or representative samples of the final 
         sterilized product.

Updated 5/21/1996

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