ASSESSING BIOCOMPATIBILITY: Biocompatibility Planning Tool (BioPT)

Intro to Biocompatibility Testing | Test Planning (BioPT) | Biological Test Methods | Analytical Testing Of Biomaterials

Device companies spend a tremendous amount of time, money and energy developing and implementing biocompatibility testing programs. Pacific BioLabs has developed the BioPT (Biocompatibility Planning Tool) to guide you through the basic concepts of device testing and to help manufacturers select testing procedures to comply with current regulatory requirements.

The chart below gives you an overview of the process. Follow the links to get more detail on each specific topic. Click here for information on materials characterization & analytical testing of devices.

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• All About Extracts
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    Medical device biocompatibility problems are most often caused by toxins that leach out of the device into the surrounding tissues or body fluids. So in the laboratory, extracts of device materials are often used in assessing biocompatibility. These extracts are generally prepared using exaggerated conditions of time and temperature to allow a margin of safety over normal physiological conditions.

    Analytical extraction studies allow the chemist to identify and quantitate specific leachable moieties. This data can in turn help the device toxicologist or risk assessor determine the worst case scenario for patient exposure and the risk to patient health.

    Extracts are also used in many of the biological tests specified by ISO 10993. Table 1 lists the most commonly used extracting media. For most devices, only saline and vegetable oil extracts are needed. 

    Extracts are selected on the basis of the biological environment in which the test material is to be used. A saline (SCI) extract approximates the aqueous, hydrophilic fluids in the body. It also permits the use of extreme temperatures in preparing the extracts, thus simulating certain sterilization conditions.

    Tissue culture media may even more closely approximate aqueous body fluids, but cannot be used for high temperature extractions. Vegetable oils are non-polar, hydrophobic solvents and simulate the lipid fluids in the body. For technical reasons, DMSO extracts are often used in certain genotoxicity and sensitization tests. Two other common extracting media – Alcohol in SCI and PEG – should be used only if they approximate the solvent properties of drugs or other materials that will contact the device during its normal use.

    Extraction conditions (temperature and time) should be at least as extreme as any conditions the device or material will encounter during sterilization or clinical use. Generally, you will want to choose the highest extraction temperature that does not melt or fuse the material or cause chemical changes. To provide some margin of safety for use conditions, Pacific BioLabs recommends an extraction condition of at least 50°C for 72 hours. For devices that are susceptible to heat, an extraction condition of 37°C for 72 hours may be acceptable. Table 2 lists common extraction conditions.
    
    

    TABLE 1: Extracting Media Sodium Chloride for Injection, USP (SCI) Vegetable Oil 1:20 Alcohol in SCI Polyethylene Glycol 400 (PEG) DMSO Clinically Relevant Solvents

    TABLE 2:  Extraction Conditions 37°C for 24 hours 37°C for 72 hours 50°C for 72 hours 70°C for 24 hours 121°C for 1 hour Other Conditions (justification required)

    
    
    
• Sample Preparation
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    The simplest method for determining the surface area of a device is usually to use the CAD program from the design engineering group. Typically the surface area can be calculated with a just a few keystrokes. Alternatively, you can calculate the surface area using the equations below. Or you can submit a sample device and/or an engineering drawing to Pacific BioLabs, and our staff will perform the calculations.

    Typically, the standard surface area of your device is used to determine the volume of extract needed for each test performed. This area includes the combined area of both sides of the device but excludes indeterminate surface irregularities. If the surface area cannot be determined due to the configuration of the device, a mass/volume of extracting fluid can be used. In either case, the device is cut into small pieces before extraction to enhance exposure to the extracting media. In some cases, it is not appropriate to cut the device; such devices are tested intact.

    The Test Turnaround Time and Sample Requirements table lists the amount of sample required for many procedures. Generally, we recommend using the ratio of sample to extracting media specified in ISO 19993-12 (i.e. either 6 cm²/mL or 3 cm²/mL, depending on the thickness of the test material). For some types of materials, the ratio used for USP Elastomeric Closures for Injections (1.25 cm² per mL) is preferred.

• Formulas For Surface Area Calculation
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    Device Shape Formula Square or Rectangle A = L x W Hollow Cylinder A = (ID + OD) π x L Disk A (one side) = π r² Ellipse A = (π x X x Y)/4 Regular Polygon A = (b x h x n)/2

    Device Shape Formula Solid Cylinder (including ends) A = (OD x π x L) + (2 π r²) Triangle A = (b x h)/2 Sphere A = 4 x π r² Trapezoid A = (h x [p + q])/2 Circular Ring 4 π²Rrrc

    
    Legend

    A = surface area		ID = inner diameter>
    OD = outer diameter		L = length
    W = width		R = radius
    RR = ring radius (circular ring)		rc = cross section radius (circular ring)
    X, Y = longest and shortest distances through the center of an ellipse		π = 3.14
    h = height		b = base length
    p, q = length of the parallel sides of a trapezoid		n = number of sides of a polygon
    r0 = ½ OD		ri = ½ ID

    
    
• ISO 10993 - Biological Evaluation Of Medical Devices: Listing Of Individual Parts
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    Part  Topic 1 Evaluation and Testing 2 Animal Welfare Requirements 3 Tests for Genotoxicty, Carcinogenicity, and Reproductive Toxicity 4 Selection of Tests for Interactions with Blood 5 Tests for Cytotoxicity – In Vitro Methods 6 Tests for Local Effects after Implantation 7 Ethylene Oxide Sterilization Residuals 8 Selection and Qualification of Reference Materials for Biological Test 9 Framework for Identification & Quantification of Potential Degradation Products 10 Test for Irritation and Sensitization 11 Test for Systemic Toxicity 12 Sample Preparation and Reference Materials 13 Identification and Quantification of Degradation Products from Polymers 14 Identification and Quantification of Degradation Products from Ceramics 15 Identification and Quantification of Degradation Products from Coated and Uncoated Metals and Alloys 16 Toxicokinetic Study Design for Degradation Products and Leachables 17 Establishment of Allowable Limits for Leachable Substances 18 Chemical Characterization of Materials* 19 Physicochemical, Mechanical and Morphological Characterization (Draft) 20 Principles and Methods for Immunotoxicology Testing of Medical Devices (Draft)

    
    * = The United States ISO Member Body, ANSI/AAMI, is considering a version of this document for use in the U.S. 
    

• Device Categories – Definitions & Examples
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    Device Categories Examples Surface Device Skin Devices that contact intact skin surfaces only. Examples include electrodes, external prostheses, fixation tapes, compression bandages and monitors of various types. Mucous membrane Devices communicating with intact mucosal membranes. Examples include contact lenses, urinary catheters, intravaginal and intraintestinal devices (stomach tubes, sigmoidoscopes, colonoscopes, gastroscopes), endotracheal tubes, bronchoscopes, dental prostheses, orthodontic devices and IUD’s. 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. External Communicating Device Blood path indirect Devices that contact the blood path at one point and serve as a conduit for entry into the vascular system. Examples include solution administration sets, extension sets, transfer sets, and blood administration sets. Tissue/bone/dentin communicating Devices communicating with tissue, bone, and pulp/dentin system. Examples include laparoscopes, arthroscopes, draining systems, dental cements, dental filling materials and skin staples.  This category also includes devices which contact internal tissues (rather than blood contact devices).  Examples include many surgical instruments and accessories.  Circulating blood Devices that contact circulating blood. Examples include intravascular catheters, temporary pacemaker electrodes, oxygenators, extracorporeal oxygenator tubing and accessories, hemoadsorbents and immunoabsorbents. Implant Device Tissue/bone Devices principally contacting bone. Examples include orthopedic pins, plates, replacement joints, bone prostheses, cements and intraosseous devices. Devices principally contacting tissue and tissues fluid. Examples include pacemakers, drug supply devices, neuromuscular sensors and stimulators, replacement tendons, breast implants, artificial larynxes, subperiosteal implants and ligation clips. Blood Devices principally contacting blood. Examples include pacemaker electrodes, artificial arteriovenous fistulae, heart valves, vascular grafts and stents, internal drug delivery catheters, and ventricular assist devices. Non-Contact Device n/a These are devices that do not contact the patient's body directly or indirectly. Examples include in vitro diagnostic devices. Regulatory agencies rarely require biocompatibility testing for such devices.

  
  
• ISO Materials Biocompatibility Matrix
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    This table is only a framework for the development of an assessment program for your device and is not a checklist.
    • = ISO Evaluation Tests for Consideration  F = Additional Tests which may be required  for US submissions		Note1  Tissue includes tissue fluids and subcutaneous spaces Note2  For all devices used in extracorporeal circuits Note3  Depends on specific nature of the device and its component materials
    Consult with the FDA before performing any biocompatibility testing if you are submitting an IDE or you have a device/drug combination.

  
  
• Test Turnaround Time And Sample Requirements
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    REQUIREMENT TEST NAME SAMPLE AMOUNT(1) TURN AROUND (in weeks) Surface Area (cm2) Weight (gram or mL) Cytotoxicity USP Agar Overlay 1 cm² x 2 pieces 2 2 – 3 USP MEM Elution 1 cm² x 2 pieces USP Direct Contact 60(2) ISO Agar Overlay 1 cm² x 3 pieces ISO MEM Elution 1 cm² x 3 pieces ISO Direct Contact 60(2) Sensitization Murine Local Lymph Node Assay (LLNA) 120 cm² 8 5 Maximization Test 240(2) 16 8 Closed Patch Test 1 in2 x 130 pieces 60-80 8 – 9 Irritation USP Intracutaneous Test 60(2) 4 3 ISO Intracutaneous Test 60(2) 4 ISO Dermal Irritation 60(2) 10 3 – 4 FHSA Primary Skin Irritation NA 10 ISO Ocular Irritation 60(2)‚ 10 3 – 4 FHSA Primary Eye Irritation NA 10 Mucous Membrane Irritation 60(2) Varies Varies Systemic Toxicity USP Systemic Injection Test 60(2) 4 3 Material Mediated Pyrogen Test 10 devices/540 cm² 4 2 - 3 Subchronic (14 – 180 Days) Intraperitoneal Test 12 devices 55 6 – 7 Intravenous Test Implant Tests 12 devices (4)   Varies Other Procedures Varies Varies Varies Genotoxicity Ames Test 120(2) 8 6 Mouse Lymphoma Assay 900(2) 60 13 – 15 Mouse Micronucleus Assay 120(2) 8 11 Chromosomal Aberration Test 120(2) 8 12 Implantation Implantation Test Acute 7 Day Subchronic 14 – 180 Day Chronic > 180 Day 12 strips 1 x 10 mm   3 7 – 28 54 – Histopathology NA 3 – 4 Hemocompatibility Hemolysis – Direct Contact (duplicate) NA 4 2 Hemolysis – Direct Contact (triplicate) 3 devices 6 2 Hemolysis – Sample Extract (duplicate) 120(2) NA 2 Hemolysis – Sample Extract (triplicate) 3 devices NA 2 In Vivo Thrombogenicity 6 – 2 ½ “ long pieces 10 - 12 In Vitro Platelet Aggregation Assay 240(2) 10 4 - 6 In Vitro Hemocompatibility Assay 150(2) 10 4 - 6 Partial Thromboplastin Time (PTT), Prothrombin Time (PT) 60(2) 4 4 - 6 Complement Activation 120(2) 2 4 - 7 Chronic Long Term Implant Inquire Inquire Lifetime Toxicity Inquire Inquire Carcinogenesis Lifetime Toxicity Inquire Inquire Analytical Tests USP Physicochemical Tests 720 NA 2 Infrared Scan 5 cm x 1 cm (min.) NA 2 Other Procedures Inquire Inquire

    
    (1) - Sample requirements based on surface area calculations. The weight of the device may be used if the surface area cannot be calculated.
    (2) - Double these amounts for materials < 0.5 mm in thickness.
    (3) - Depends on duration of implant.
    (4) - 15 strips per time point, each strip 1 mm x 10 mm, sample should be supplied by Sponsor in specified size, separately packaged and sterilized, ends should be smooth and rounded.