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03b BiocompatibilityTesting

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BIOCOMPATIBILITY TESTING AT SGS
For over thirty years, SGS has conducted biocompatibility testing for the medical device and pharmaceutical
industries. Our facility in NJ includes a 10,000 square foot vivarium which is registered and inspected by the
USDA and US FDA. With ISO 9001 certified operations, SGS is certain to meet your quality and regulatory
requirements.
Our experienced staff can help you design a cost-effective safety test program for your product. We provide
next-day quotes on most biocompatibility testing projects. And we are dedicated to providing you with clear,
well-written reports and prompt, personalized service. Please call Business Development at (888) 747 8782
to discuss your testing requirements, or visit our website at www.us.sgs.com/lifescience.
SGS’s testing capabilities for medical device companies include the following:
Biocompatibility Tests
! Cytotoxicity
! Sensitization
! Irritation
! Genotoxicity
! Implantation
! Hemocompatibility
! Subchronic Toxicity
! Systemic Toxicity
! Biological Indicator Tests
! Environmental Monitoring
! Bacterial Endotoxin (LAL)
! Cleaning, Disinfection,
and Sterilization Validation
! Accelerated Aging and
Expiration
! Sterilant Residues
! AA, IR, GC, HPLC
! Total Organic Carbon (TOC)
! Organic Solvent Residues
QA/QC Testing
! Bioburden
! AAMI/ISO Dose Audits
Validation Support
! AAMI/ISO Sterilization Validation
! Reusable Device
! Package Integrity Testing
Extractable Material Characterization
! USP Physiochemical Tests
– Plastics or Elastomeric Closures
United States Pharmacopeia (USP) – an independent, not-for-profifit, nongovernmental organization
to improve global health through public standards and related programs.
SGS Life Science Services
ASSESSING BIOCOMPATIBILITY
A GUIDE FOR MEDICAL DEVICE MANUFACTURERS
TABLE OF CONTENTS
Biocompatibility Testing at SGS.......................................................................................................................................................................................1
Introduction to Biocompatibility Testing.....................................................................................................................................................................3
What is Device Biocompatibility?.................................................................................................................................................................................3
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?...................................................................................................................................................................4
Should I Test Device Materials, or only a Composite of the Finished Device? ...........................................................................................................5
Is GLP Treatment Required for Biocompatibility Testing?...........................................................................................................................................5
The Biocompatibility Planning Tool.............................................................................................................................................................................6
All About Extracts.............................................................................................................................................................................................................7
Sample Preparation .........................................................................................................................................................................................................8
Formulas for Surface Area Calculation ............................................................................................................................................................................8
ISO 10993 - Listing of Individual Parts.............................................................................................................................................................................9
Device Categories – Definitions & Examples.................................................................................................................................................................10
Non-Contact Devices .....................................................................................................................................................................................................10
ISO Materials Biocompatibility Matrix........................................................................................................................................................................11
Test Turnaround Time and Sample Requirements...................................................................................................................................................12
Biological Test Methods .................................................................................................................................................................................................13
Cytotoxicity (Tissue Culture)......................................................................................................................................................................................13
Sensitization Assays..................................................................................................................................................................................................13
Irritation Tests ............................................................................................................................................................................................................14
Acute Systemic Toxicity.............................................................................................................................................................................................14
Subchronic Toxicity....................................................................................................................................................................................................14
Genotoxicity ...............................................................................................................................................................................................................15
Implantation Tests .....................................................................................................................................................................................................15
Hemocompatibility .....................................................................................................................................................................................................16
Carcinogenesis Bioassay ..........................................................................................................................................................................................17
Reproductive and Developmental Toxicity ................................................................................................................................................................17
Pharmacokinetics ......................................................................................................................................................................................................17
Preclinical Safety Testing ..........................................................................................................................................................................................18
Histopathology Services ............................................................................................................................................................................................18
Analytical Testing of Biomaterials ..................................................................................................................................................................................19
Material Characterization ...............................................................................................................................................................................................20
SGS’s Commitment to Excellence .................................................................................................................................................................................21
Quality Systems.........................................................................................................................................................................................................21
cGMP Compliance.....................................................................................................................................................................................................21
GLP Compliance........................................................................................................................................................................................................21
Accreditations ............................................................................................................................................................................................................22
References.....................................................................................................................................................................................................................22
Contact Information........................................................................................................................................................................................................22
REQUEST FOR TESTING – Please photocopy the form at the end of this booklet when submitting samples
for testing.
To view this booklet online, go to www.us.sgs.com/publications_us
Rev. 1.1, 05-07
Page 2
Assessing Biocompatibility
INTRODUCTION TO BIOCOMPATIBILITY TESTING
By: SGS Life Science Services
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.
While in use, substances may leach off of a medical device into adjacent tissue. Some leachables or
extractables are not biologically safe. Many of the various biocompatibility tests include sample preparation
steps designed to rinse the leachables and extractables form the device. The extract is then tested. The
actual device material may be used in some other tests.
Of course, the primary purpose of a device biocompatibility assessment is to protect patient safety.
Manufacturers should consider both corporate regulatory goals and compliance risks and potential future
product liability exposure in planning a biocompatibility testing program. Ultimately, 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. (A list of the individual sections of ISO 10993 can be found on page 9.)
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, in which it substantially adopted the ISO guideline.
However, 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 both USP and ISO tests.
SGS highly recommends discussing your proposed biocompatibility testing plan with an FDA
reviewer before initiating testing
The FDA G95-1 has been replaced by "Use of International Standard ISO-10993,
‘Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing.’”
Page 3
SGS Life Science Services
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 chart from ISO 10993-1 (page 11) 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.
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 need to perform confirmatory testing if there are
significant changes in any of these areas.
a.
b.
c.
d.
e.
Materials selection
Manufacturing processes
Chemical composition of materials
Nature of patient contact
Sterilization methods
cGMP - current good manufacturing practice
GLP - good laboratory practice
2. 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 and a strong track record of cGMP/GLP compliance. Usually manufacturers should
perform some confirmatory testing of their own (e.g. cytotoxicity and hemocompatibility studies) to
support vendor data. Note that molding, fabrication, gluing, welding, assembly and sterilization can
affect the biocompatibility of a medical device.
3. 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.
(See also pages 19 -20.)
4. 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 suitability of device material for its intended application.
The first step in this process is chemical characterization of device components. See page 19 for specifics of
such a program.
Biological testing is probably the most critical step in a biocompatibility evaluation. The ISO materials
biocompatibility matrix (page 11) 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.
Page 4
Assessing Biocompatibility
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:
1. assemble vendor data on candidate materials
2. conduct analytical and vitro screening of materials
3. 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 up
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.
Page 5
SGS Life Science Services
THE BIOCOMPATIBILITY PLANNING TOOL
Device companies spend a tremendous amount of time, money and energy developing and implementing
biocompatibility testing programs. We have developed this 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 page references to get more detail on
each specific topic. For information on materials characterization and analytical testing of devices, see page
19-20.
Testing
Testing
Test Planning
THE BIOCOMPATIBILITY PLANNING TOOL
What is the device category and body
contact duration?
Device category definitions and examples of devices that
fall into each category are given on page 10.
See page 10 for definitions of the three device duration
categories.
What biocompatibility data is already
available?
Alternative sources for biocomp data are presented on
page 4.
How do I select tests from the
Biocompatibility Matrix?
Refer to the Materials Biocompatibility Matrix on page 11
to determine which biological test categories and
procedures are appropriate for your device.
Pages 13-18 discuss specific test procedures.
How do I decide on extracting media
and conditions?
More information on extracts and sample preparation is
found on pages 7 and 8.
Page 8 shows formulas used to calculate the surface area
of your device.
How do I determine test sample
requirements?
See page 12 for sample requirements for each test. Or,
contact SGS for a price quote which will specify sample
requirements for each test procedure.
Should the studies be performed
following Good Laboratory
Procedures (GLP) regulations?
GLP treatment is required for certain types of regulatory
submissions. More information can be found on page 5.
How do I determine testing costs?
Please call Business Development at (888) 747 8782.
How do I initiate testing?
Sign and return the quote acceptance form, complete and
submit the Request for Testing form on pages 23-24, and
send sterilized samples to SGS.
Page 6
Assessing Biocompatibility
ALL ABOUT EXTRACTS
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 substances. 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 at the bottom of this
page 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, SGS 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)
Dimethyl sulfoxide (DMSO) is an
organosulfur compound with the
formula (CH3)2SO.
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)
Page 7
SGS Life Science Services
SAMPLE PREPARATION
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 SGS, 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 table on page 12 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
Device Shape
Formula
Square or Rectangle
A=LxW
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
Solid Cylinder (including ends)
A = (OD x π x L) + (2 π r2)
Triangle
A = (b x h)/2
Sphere
A=4xπr
Trapezoid
A = (h x [p + q])/2
Circular Ring
4 π2Rrrc
2
Legend
A = surface area
OD = outer diameter
W = width
RR = ring radius (circular ring)
X, Y = longest and shortest distances through the center of an ellipse
h = height
p, q = length of the parallel sides of a trapezoid
ro = ½ OD
ID = inner diameter
L = length
R = radius
rc = cross section radius (circular ring)
π = 3.14
b = base length
n = number of sides of a polygon
ri = ½ ID
Page 8
Assessing Biocompatibility
ISO 10993 - BIOLOGICAL EVALUATION OF MEDICAL DEVICES
LISTING OF INDIVIDUAL PARTS
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)
* ANSI/AAMI (The United States ISO Member Body) is considering a version of this document for use in the U.S.
Page 9
SGS Life Science Services
DEVICE CATEGORIES – DEFINITIONS & EXAMPLES
Device Categories
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
External
Communicatin
g Device
Examples
Devices that contact breached or otherwise compromised
external body surfaces. Examples include ulcer, burn and
granulation tissue dressings or healing devices and
occlusive patches.
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.
Devices principally contacting bone. Examples include
orthopedic pins, plates, replacement joints, bone
prostheses, cements and intraosseous devices.
Tissue/bone
Implant Device
Blood
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.
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 DEVICES
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.
Page 10
***
Intrauterine
Device (IU):
birth control
Assessing Biocompatibility
***
ISO MATERIALS BIOCOMPATIBILITY MATRIX
Biological Effect
A
Skin
B
C
Surface
Device
A
Mucosal Membrane
B
C
Breached or
Compromised
Surface
A
B
C
A
Blood Path, Indirect
B
C
External
Communicating
Device
A
Tissue/Bone/Dentin"
B
C
A
Circulating Blood
B
C
A
Tissue/Bone
B
C
Implant Device
A
Blood
B
C
!
!
!
!
!
!
!
!
!
!
!
F
!
!
!
!
!
!
!
!
!
!
!
!
F
F
F
!
F
!
F
F
F
F
F
F
F
!
!
!
!
F
F
!
!
F
!
!
!
!
!
!
F
!
!
!
!
!
!
!
!
!
!
!
!
!
F
!
!
!
!
!
F#
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
F
!
!
!
!
!
!
!
!
!
!
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
Note
"
Tissue includes tissue fluids and subcutaneous spaces
F = Additional Tests which may be required
by FDA for US submissions
Note
#
For all devices used in extracorporeal circuits
Note
!
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.
Page 11
Biodegradation!
!
Carcinogenicity
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
Hemocompatibility
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
!
Implantation
Contact
Genotoxicity
(> 30 days)
Category
Sensitization
C - Permanent
Cytotoxicity
B - Prolonged
(24 hours-30 days)
Subacute and Subchronic Toxicity
(< 24 hours)
Systemic Toxicity (acute)
A - Limited
Irritation or Intracutaneous Reactivity
Nature of Body Contact
Chronic Toxicity
Supplementary
Evaluation Tests
Initial Evaluation Tests
Reproductive/Developmental!
Medical Device Categorization by
Contact Duration
SGS Life Science Services
***
TEST TURNAROUND TIME AND SAMPLE REQUIREMENTS
SAMPLE AMOUNT
REQUIREMENT
TEST NAME
Surface Area (cm2)
Cytotoxicity
USP Agar Overlay
USP MEM Elution
USP Direct Contact
ISO Agar Overlay
ISO MEM Elution
ISO Direct Contact
1 cm2 x 2 pieces
1 cm2 x 2 pieces
#
60
1 cm2 x 3 pieces
1 cm2 x 3 pieces
60#
Sensitization
Maximization Test
Closed Patch Test
240
1 in2 x 130 pieces
Irritation
USP Intracutaneous Test
ISO Intracutaneous Test
ISO Dermal Irritation
FHSA Primary Skin Irritation
ISO Ocular Irritation
FHSA Primary Eye Irritation
Mucous Membrane Irritation
60
#
60
60#
NA
60#
NA
#
60
USP Systemic Injection Test
#
Systemic Toxicity
Subchronic
(14 – 180 Days)
Genotoxicity
Implantation
Hemocompatibility
Chronic
Carcinogenesis
Analytical Tests
Weight (gram or mL)
TURN AROUND
(in weeks)
2
2–3
16
60-80
8
8–9
#
#
4
4
10
10
10
10
Varies
Varies
4
3
4
55
2-3
6–7
Varies
Varies
Varies
#
8
6
#
8
8
11
12
NA
3 devices
120#
3 devices
4
6
NA
NA
3
7 – 28
54
3–4
2
2
2
2
240
150#
#
10
10
4-6
4-6
60#
4
4-6
2
4-7
Inquire
Inquire
Inquire
2
2
Inquire
60
10 devices/540
2
cm
12 devices
12 devices
Material Mediated Pyrogen Test
Intraperitoneal Test
Intravenous Test
Implant Tests
Other Procedures
Ames Test
"
$
Varies
120
Mouse Micronucleus Assay
Chromosomal Aberration Test
120
120#
Implantation Test
Acute 7 Day
Subchronic 14 – 180 Day
Chronic > 180 Day
– Histopathology
Hemolysis – Direct Contact (duplicate)
Hemolysis – Direct Contact (triplicate)
Hemolysis – Sample Extract (duplicate)
Hemolysis – Sample Extract (triplicate)
In Vitro Platelet Aggregation Assay
In Vitro Hemocompatibility Assay
Partial Thromboplastin Time (PTT),
Prothrombin Time (PT)
Complement Activation
Long Term Implant
Lifetime Toxicity
Lifetime Toxicity
USP Physicochemical Tests
Infrared Scan
Other Procedures
12 strips 1 x 10 mm
NA
120#
Inquire
Inquire
Inquire
720
5 cm x 1 cm (min.)
Inquire
NA
NA
3
3–4
3–4
" - Sample requirements based on surface area calculations. The weight of the device may be used if the surface area cannot be calculated.
# - Double these amounts for materials < 0.5 mm in thickness
! - Depends on duration of implant
$ - 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
Page 12
Assessing Biocompatibility
BIOLOGICAL TEST METHODS
The following pages describe some of the specific procedures recommended for biocompatibility testing.
This listing does not imply that all procedures are necessary for any given device, nor does it indicate that
these are the only available tests.
CYTOTOXICITY (TISSUE CULTURE)
Cell culture assays are used to assess the biocompatibility of a material or extract through the use of isolated
cells in vitro. These techniques are useful in evaluating the toxicity or irritancy potential of materials and
chemicals. They provide an excellent way to screen materials prior to in vivo tests.
There are three cytotoxicity tests commonly used for medical devices. The Direct Contact procedure is
recommended for low density materials, such as contact lens polymers. In this method, a piece of test
material is placed directly onto cells growing on culture medium. The cells are then incubated. During
incubation, leachable chemicals in the test material can diffuse into the culture medium and contact the cell
layer. Reactivity of the test sample is indicated by malformation, degeneration and lysis of cells around the
test material.
The Agar Diffusion assay is appropriate for high density materials, such as elastomeric closures. In this
method, a thin layer of nutrient-supplemented agar is placed over the cultured cells. The test material (or an
extract of the test material dried on filter paper) is placed on top of the agar layer, and the cells are
incubated. A zone of malformed, degenerative or lysed cells under and around the test material indicates
cytotoxicity.
The MEM Elution assay uses different extracting media and extraction conditions to test devices according
to actual use conditions or to exaggerate those conditions. Extracts can be titrated to yield a semiquantitative measurement of cytotoxicity. After preparation, the extracts are transferred onto a layer of cells
and incubated. Following incubation, the cells are examined microscopically for malformation, degeneration
and lysis of the cells. (See page 7 for more information on the selection of extracting media and conditions.)
At least one type of cytotoxicity test should be performed on each component of any device.
Eagle's minimal essential medium (MEM) is a synthetic cell culture medium developed
SENSITIZATION ASSAYS by Harry Eagle in 1955/1959 that can be used to maintain cells in tissue culture.
Sensitization studies help to determine whether a material contains chemicals that cause adverse local or
systemic effects after repeated or prolonged exposure. These allergic or hypersensitivity reactions involve
immunologic mechanisms. Studies to determine sensitization potential may be performed using either
specific chemicals from the test material, the test material itself, or most often, extracts of the test material.
The Materials Biocompatibility Matrix recommends sensitization testing for all classes of medical devices.
The Guinea Pig Maximization Test (Magnusson-Kligman Method) is recommended for devices that will have
externally communicating or internal contact with the body or body fluids. In this study, the test material is
mixed with complete Freund’s adjuvant (CFA) to enhance the skin sensitization response.
The Closed Patch Test involves multiple topical doses and is recommended for devices that will contact only
unbroken skin.
Page 13
SGS Life Science Services
IRRITATION TESTS
These tests estimate the local irritation potential of devices, materials or extracts, using sites such as skin or
mucous membranes, usually in an animal model. The route of exposure (skin, eye, mucosa) and duration of
contact should be analogous to the anticipated clinical use of the device, but it is often prudent to exceed
predicted exposure conditions somewhat to establish a margin of safety for patients.
In the Intracutaneous Test, extracts of the test material and blanks are injected intradermally. The injection
sites are scored for erythema and edema (redness and swelling). This procedure is recommended for
devices that will have externally communicating or internal contact with the body or body fluids. It reliably
detects the potential for local irritation due to chemicals that may be extracted from a biomaterial.
The Primary Skin Irritation test should be considered for topical devices that have external contact with intact
or breached skin. In this procedure, the test material or an extract is applied directly to intact and abraded
sites on the skin of a rabbit. After a 24-hour exposure, the material is removed and the sites are scored for
erythema and edema.
Mucous Membrane Irritation Tests are recommended for devices that will have externally communicating
contact with intact natural channels or tissues. These studies often use extracts rather than the material
itself. Some common procedures include vaginal and eye irritation studies. (See page 7 for more
information on extracts.)
ACUTE SYSTEMIC TOXICITY
By using extracts of the device or device material, the Acute Systemic Toxicity test detects leachables that
produce systemic (as opposed to local) toxic effects. The extracts of the test material and negative control
blanks are injected into mice (intravenously or intraperitoneally, depending on the extracting media). The
mice are observed for toxic signs just after injection and at four other time points. The Materials
Biocompatibility Matrix recommends this test for all blood contact devices. It may also be appropriate for any
other device that contacts internal tissues.
induced fever
The Material Mediated Pyrogen test evaluates the potential of a material to cause a pyrogenic response, or
fever, when introduced into the blood. Lot release testing for pyrogenicity is done in vitro using the bacterial
endotoxin (LAL) test. It must be validated for each device or material. However, for assessing
biocompatibility, the rabbit pyrogen test is preferred. The rabbit test, in addition to detecting bacterial
endotoxins, is sensitive to material-mediated pyrogens that may be found in test materials or extracts.
SUBCHRONIC TOXICITY
Tests for subchronic toxicity are used to determine potentially harmful effects from longer-term or multiple
exposures to test materials and/or extracts during a period of up to 10% of the total lifespan of the test
animal (e.g. up to 90 days in rats). Actual use conditions of a medical device need to be taken into account
when selecting an animal model for subchronic toxicity. Appropriate animal models are determined on a
case-by-case basis.
Subchronic tests are required for all permanent devices and should be considered for those with prolonged
contact with internal tissues.
Page 14
Assessing Biocompatibility
GENOTOXICITY
Genotoxicity evaluations use a set of in vitro and in vivo tests to detect mutagens, substances that can
directly or indirectly induce genetic damage directly through a variety of mechanisms. This damage can
occur in either somatic or germline cells, increasing the risk of cancer or inheritable defects. A strong
correlation exists between mutagenicity and carcinogenicity.
Genotoxic effects fall into one of three categories: point mutations along a strand of DNA, damage to the
overall structure of the DNA, or damage to the structure of the chromosome (which contains the DNA). A
variety of tests have been developed to determine if damage has occurred at any of these levels. These
assays complement one another and are performed as a battery.
The most common test for mutagenicity, the Ames test, detects point mutations by employing several strains
of the bacteria Salmonella typhimurium, which have been selected for their sensitivity to mutagens. The
Mouse Lymphoma and the HGPRT assays are common procedures using mammalian cells to detect point
mutations. The Mouse Lymphoma assay is also able to detect clastogenic lesions in genes (chromosome
damage). Assays for DNA damage and repair include both in vitro and in vivo Unscheduled DNA Synthesis
(UDS). Cytogenetic assays allow direct observation of chromosome damage. There are both in vitro and in
vivo methods, including the Chromosomal Aberration and the Mouse Micronucleus assays.
ISO 10993-1 specifies an assessment of genotoxic potential for permanent devices and for those with
prolonged contact (>24 hours) with internal tissues and blood. Extracorporeal devices with limited contact
(<24 hours) may require a genotoxicity evaluation. Generally, devices with long-tem exposure require an
Ames test and two in vivo methods, usually the Chromosomal Aberration and Mouse Micronucleus tests.
Devices with less critical body contact may be able to be tested using only the Ames test.
When selecting a battery of genotoxicity tests, you should consider the requirements of the specific
regulatory agency where your submission will be made. Because of the high cost of genotoxicity testing,
SGS strongly recommends that you consult your FDA reviewer before you authorize testing.
IMPLANTATION TESTS
Implant studies are used to determine the biocompatibility of medical devices or biomaterials that directly
contact living tissue other than skin (e.g. sutures, surgical ligating clips, implantable devices, etc.). These
tests can evaluate devices, which, in clinical use, are intended to be implanted for either short-term or longterm periods. Implantation techniques may be used to evaluate both absorbable and non-absorbable
materials. To provide a reasonable assessment of safety, the implant study should closely approximate the
intended clinical use.
The dynamics of biochemical exchange and cellular and immunologic responses may be assessed in
implantation studies, especially through the use of histopathology. Histopathological analysis of implant sites
greatly increases the amount of information obtained from these studies.
Page 15
SGS Life Science Services
The complement system is a part of the immune system that enhances the ability of
antibodies and phagocytic cells to clear microbes and damaged cells from an organism,
promotes inflflammation, and attacks the pathogen's cell membrane.
HEMOCOMPATIBILITY
Materials used in blood contacting devices (e.g. intravenous catheters, hemodialysis sets, blood transfusion
sets, vascular prostheses) must be assessed for blood compatibility to establish their safety. In practice, all
materials are to some degree incompatible with blood because they can either disrupt the blood cells
(hemolysis) or activate the coagulation pathways (thrombogenicity) and/or the complement system.
The hemolysis assay is recommended for all devices or device materials except those which contact only
intact skin or mucous membranes. This test measures the damage to red blood cells when they are
exposed to materials or their extracts, and compares it to positive and negative controls.
DEVICES OR COMPONENTS WHICH CONTACT CIRCULATING BLOOD AND THE
CATEGORIES OF APPROPRIATE TESTING — EXTERNAL COMMUNICATING DEVICES
System
Complement
Hematology
Platelets
Thrombosis
Device Examples
Coagulation
Test Category
a
Atherectomy devices
x
Blood monitors
a
x
Blood storage and administration equipment,
Blood collection devices, Extension sets
x
a
x
x
x
x
x
Extracorporeal membrane oxygenator systems
Haemodialysis/haemofiltration equipment,
Percutaneous circulatory support devices
x
x
Catheters, guidewires, intravascular endoscopes,
Intravascular ultrasound, laser systems,
Retrograde coronary perfusion catheters.
x
x
x
a
x
a
Cell savers
x
x
x
Devices for absorption of specific substances from blood
x
x
x
x
Donor and therapeutic apheresis equipment
x
x
x
x
a
Hemolysis testing only
Page 16
Assessing Biocompatibility
DEVICES OR COMPONENTS WHICH CONTACT CIRCULATING BLOOD AND THE
CATEGORIES OF APPROPRIATE TESTING — IMPLANT DEVICES
Annuloplasty rings, mechanical heart valves
x
Intra-aortic balloon pumps
x
Total artificial hearts, ventricular-assist devices
x
System
a
x
x
x
x
x
x
a
Embolization devices
x
a
Endovascular grafts
x
x
Implantable defibrillators and cardioverters
x
x
Pacemaker leads
x
x
a
x
a
a
Leukocyte removal filter
x
x
Prosthetic (synthetic) vascular grafts and patches,
including arteriovenous shunts
x
x
Stents
x
x
Tissue heart valves
x
x
Tissue vascular grafts and patches,
including arteriovenous shunts
x
x
Vena cava filters
x
x
a
Complement
Hematology
Platelets
Thrombosis
Device examples
Coagulation
Test Category
a
a
a
a
a
Hemolysis testing only
CARCINOGENESIS BIOASSAY
These assays are used to determine the tumorigenic potential of test materials and/or extracts from either a
single or multiple exposures, over a period consisting of the total lifespan of the test system (e.g. two years
for rat, 18 months for mouse, or seven years for dog).
Carcinogenicity testing of devices is expensive, highly problematic, and controversial. Manufacturers can
almost always negotiate an alternative to full scale carcinogenicity testing of their devices.
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
These studies evaluate the potential effects of test materials and/or extracts on fertility, reproductive function,
and prenatal and early postnatal development. They are often required for devices with permanent contact
with internal tissues.
PHARMACOKINETICS
Pharmacokinetic or ADME (Absorption/Distribution/Metabolism/Excretion) studies are used to investigate the
metabolic processes of absorption, distribution, biotransformation, and elimination of toxic leachables and
potential degradation products from test materials and/or extracts. They are especially appropriate for
bioabsorbable materials or for drug/device combinations. Our toxicology team is happy to work with you in
setting up the appropriate PK or ADME study for your product.
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SGS Life Science Services
PRECLINICAL SAFETY TESTING
The objectives of preclinical safety studies are to define pharmacological and toxicological effects not only
prior to initiation of human studies but throughout clinical development. Both in vitro and in vivo studies can
contribute to this characterization.
HISTOPATHOLOGY SERVICES
Implant studies are often the most direct evaluation of device biocompatibility. The test material is placed in
direct contact with living tissue. After an appropriate period, the implant site is recovered and examined
microscopically for tissue reaction. The histopathologist can detect and describe many types of tissue and
immune system reactions.
Similarly, in subchronic and chronic studies, various organs and tissues are harvested at necropsy and
evaluated microscopically for toxic effects. Many of these studies also call for clinical chemistry analysis of
specimens or serum samples form the test animals.
Page 18
Assessing Biocompatibility
MATERIALS CHARACTERIZATION AND ANALYTICAL TESTING OF BIOMATERIALS
Analytical procedures provide the initial means for investigating the biocompatibility of medical device
materials. Knowledge of device materials and their propensity for releasing leachable matter will help
manufacturers assess the risks of in vivo reactivity and preclude subsequent toxicology problems with
finished devices.
Increasingly, FDA has been asking for analytical characterization of device materials and potential
leachables per ISO 10993-17 and 10993-18. Many firms also use analytical procedures for routine QC of
raw materials or finished products.
The degree of chemical characterization required should reflect the nature and duration of the clinical
exposure and should be determined be based on the data necessary to evaluate the biological safety of the
device. It will also depend on the nature of the materials used, e.g. liquids, gels, polymers, metals,
ceramics, composites or biologically sourced material.
The following strategy is suggested as a sound program for chemical characterization of a device material:
1. Determine the qualitative composition of each device component or material. This information should be
available from the material vendor, or it can be determined through laboratory testing. The list of
constituents should include
a. the identity of the matrix (i.e. the major component such as the specific polymer, alloy, or metal)
b. all plasticizers, colorants, anti-oxidants, fillers, etc. deliberately added during fabrication of the
material
c. impurities such as unreacted monomers and oligomers
d. manufacturing materials such as solvent residues, slip agents, and lubricants.
2. Estimate the potential for patient exposure for each item on the material constituent list. Use literature
searches of toxicological databases to assess the likelihood of tissue reactivity. For potentially toxic
constituents, design and conduct laboratory studies to determine the extractable levels of those
constituents. Use exaggerated conditions of time and temperature, and consider appropriate detection
limits. Additional studies may be needed to assess levels of extractables released in actual use
conditions.
3. Data generated from this characterization process can be used to create a material data file. The
information can then be used as a reference for continued testing of device materials to ensure
consistency of future production lots. This may in turn reduce the need for routine biological testing.
Additional uses of analytical characterization data might include:
1. Use in an assessment of the overall biological safety of a medical device.
2. Measurement of the level of any leachable substance in a medical device in order to allow the
assessment of compliance with the allowable limit derived for that substance from health based risk
assessment.
3. Judging equivalence of a proposed material to a clinically established material.
4. Judging equivalence of a final device to a prototype device to check the relevance of data on the latter to
be used to support the assessment of the former.
5. Screening of potential new materials for suitability in a medical device for a proposed clinical application.
Page 19
SGS Life Science Services
TRADITIONAL EXTRACTABLE MATERIAL CHARACTERIZATION
•
USP Physicochemical Tests – Plastics
•
USP Physicochemical Test Panel for Elastomeric Closures for Injections
•
USP Polyethylene Containers Tests – Heavy Metals and Non-volatile Residues
•
Indirect Food Additives and Polymers Extractables (21CFR Part 177)
•
Sterilant Residues – Ethylene Oxide, Ethylene Chlorohydrin, Ethylene Glycol
TESTS PROCEDURES FOR EXTRACTABLE MATERIAL
•
UV/Visible Spectroscopy
•
Gas Chromatography
•
Liquid Chromatography
•
Infrared Spectroscopy (IR)
•
Mass Spectrometry
•
Residual Solvents
•
Atomic Absorption Spectroscopy (AAS)
•
Inductively-coupled Plasma Spectroscopy (ICP)
BULK MATERIAL CHARACTERIZATION
•
Infrared Spectroscopy Analysis for Identity and Estimation of Gross Composition
o
Reflectance Spectroscopy
o
Transmission Spectroscopy
•
Atomic Absorption Spectroscopy (AAS)
•
Inductively-coupled Plasma Spectroscopy (ICP)
•
Thermal Analysis
SURFACE CHARACTERIZATION
•
IR Reflectance Spectroscopy
•
Scanning Electron Microscopy (SEM)
•
Energy-dispersive X-ray Analysis (EDX)
Page 20
Assessing Biocompatibility
SGS’S COMMITMENT TO EXCELLENCE
Since 1878, quality testing services and client satisfaction have been our primary objectives in serving
industry. During this period, SGS staff has increased to over 43,000 dedicated professionals. Operating 16
laboratories worldwide, SGS Life Science Services represents the largest network for GMP/GLP-compliant
quality control testing, with unmatched geographic coverage serving local as well as global companies.
With the addition of Northview Laboratories, SGS now has facilities in Northbrook, IL, Fairfield, NJ, and
Mississauga, ON, expanding our ability to offer high quality analytical services to the pharmaceutical and
medical device industry in North America. Our success grows from our commitment to the highest level of
quality in all of our operations.
QUALITY SYSTEMS
It is our commitment to:
•
Measure our regulatory compliance by ensuring we meet or exceed all regulatory requirements and to
ensure our core quality systems are operating properly.
•
SGS Life Science Services business is regulatory science. We use FDA current Good Manufacturing
Practice (cGMP) regulations as our baseline level of compliance. When requested by the client, we
adhere to Good Laboratory Practice (GLP) regulations. We also comply with the requirements of ISO
9001-2000 and for animal sciences, USDA. At SGS, the core quality systems are:
%
%
%
%
%
%
%
%
Documentation Procedures
Standard Operation Procedures (SOPs)
Training Systems and Documents
Equipment Validation, Calibration, and Preventive Maintenance
Vendor Qualification and Monitoring
Quality Audits – Internal, Client, and Regulatory
Quality Objective Monitoring and Trending
Management Review Meetings
cGMP COMPLIANCE
SGS and all of its medical device and pharmaceutical clients are required to operate in accordance with
cGMP (current Good Manufacturing Practices) regulations. SGS is committed to perform all testing in
accordance with our understanding of the cGMPs. A comprehensive body of standard operating procedures
covers all aspects of our laboratory operations. We are routinely inspected by the FDA and auditors from
many of our clients.
SGS does not assume any responsibility for the appropriateness and/or regulatory acceptance of any client's
testing program. It is the responsibility of each client to assess the testing and test validation requirements
of their products and quality control systems. Our staff will endeavor to alert clients of testing programs that
may need further consideration to determine conformance to cGMPs.
GLP COMPLIANCE
For most biocompatibility submissions, the FDA and EPA require that testing be performed in accordance
with GLP (Good Laboratory Practice) regulations. It is the client's responsibility to determine when GLP
treatment is required and to inform SGS in writing of this requirement at the time of sample submission.
SGS will perform testing in accordance with GLPs when requested by the client. (There is an additional
charge for GLP treatment.)
Page 21
SGS Life Science Services
ACCREDITATIONS
SGS has been ISO 9001 certified by the British Standards Institute and by National Quality Association. FDA
registration numbers for SGS's facilities are available upon request. Please contact us if you need
additional information. Our staff would be pleased to have you visit and audit our laboratories at your
convenience.
REFERENCES
AAMI Standards and Recommended Practices, Volume 4: Biological Evaluation of Medical Devices, which
includes AAMI/ANSI/ISO Standard 10993. (Annex B of 10993-1 is an extensive bibliography of U.S. and
international reference documents.)
ASTM F-748-98, Practice for Selecting Generic Biological Test Methods for Materials and Devices
Biocompatibility Testing and Management, Nancy J. Stark; Clinical Design Group, Chicago, 1994
ISO Standard 10993, Biological Evaluation of Medical Devices - Parts 1 – 20
Guidelines for the Intraarticular Prosthetic Knee Ligament (FDA)
PTCA Catheter System Testing Guideline (FDA)
Safety Evaluation of Medical Devices, Shayne Cox Gad; Marcel Dekker, Inc., New York, 2002
USP <1031>, The Biocompatibility of Materials Used In Drug Containers, Medical Devices, and Implants
CONTACT INFORMATION
Business Development
(888) 747 8782
SGS Life Science Services
75 Passaic Avenue
Fairfield, NJ 07004
(973) 244 2435
SGS Canada, Inc.
(905) 890 4880
310 Brunel Road
Mississauga, ON L4Z 2C2, CAN
SGS Northview Laboratories (847) 564-8181
1880 Holste Road
Northbrook, IL 60062
www.us.sgs.com/lifescience
Page 22
REQUEST FOR TESTING: BIOCOMPATIBILITY, page 1 of 2
REPORT TO:
INVOICE TO:
____________________________
____________________________
PHONE NO. __________________
____________________________
____________________________
FAX NO. _____________________
____________________________
____________________________
P.O. NO._____________________
____________________________
____________________________
QUOTE NO. __________________
____________________________
____________________________
EMAIL _____________________________________________________
SEND LAB REPORT BY (Test fees include delivery by email, fax or mail. 2nd & 3rd means are $6 additional. FedEx and UPS at additional cost):
ˆ Email
ˆ Fax
ˆ Mail
ˆ FedEx – Acct. No. _______________
ˆ UPS – Acct. No.________________
ˆ Report cc to: ___________________
SAMPLE IDENTIFICATION (Please use the exact wording as desired on final report): _________________________________
__________________________________________________________________________________________
NO. OF SAMPLES _______________
SPLWT/VOL. ____________________
SAMPLE CODE _________________
LOT NO.________________________
EXP. DATE______________________
SPECIAL HANDLING:___________________________________________________________________________________
TYPE OF HAZARD: _________________________________________________
ˆ HAZARDOUS
ˆ NOT HAZARDOUS
Please include MSDS if samples are hazardous.
List parts of test article to be tested: ________________________________________________________________________
Final intended use/application of test article: _________________________________________________________________
STABILITY TESTING:
ˆ N/A
STERILITY TESTING:
CAN SAMPLE BE CUT?
UNUSED SAMPLES:
EXTRACTION CONDITIONS
ˆ
50°C for 72 hours
ˆ
ˆ
ˆ
ˆ
ˆ
ˆ
Completed
non-sterile
YES
discard
121°C for 1 hour
37°C for 72 hours
ˆ
ˆ
ˆ
ˆ
ˆ
ˆ
To be completed by sponsor
sterile, method ________________
NO
return to sponsor
70°C for 24 hours
other____________________________
2
SURFACE AREA IN cm , if known _____________________________________________
THICKNESS IN mm , if known _________________________________________________
SURFACE AREA CALC. COMPLETED BY:
ˆ Sponsor
ˆ
ˆ
To Be Completed by SGS
via CAD (technical) Drawing
ˆ Consultant
ˆ other____________________________
ISO 10993-12:2002(E) 10.3.2 The standard surface area can be used to determine the volume of extract needed. This area
includes the combined area of both sides of the sample and excludes indeterminate surfaces irregularities. When the surface
area cannot be determined due to the configuration of the sample, a mass/volume of extracting fluid shall be used.
Unusually complex surface area calculations that are to be performed by SGS will incur additional charges.
Extraction of large samples may incur additional media charges.
Should these tests be performed according
to GLP regulations?
ˆ
YES
ˆ
NO
Most biocompatibility studies should be performed according to GLP regulations.
It is the responsibility of the test sponsor to request GLP treatment. There is an additional charge for GLP treatment.
Date results of all tests needed:_____________________________________________
SPECIAL INSTRUCTIONS: ____________________________________________________________________
__________________________________________________________________________________________
Please continue on page 2
REQUEST FOR TESTING: BIOCOMPATIBILITY, page 2 of 2
TESTS REQUIRED: (continued from page 1)
ˆ ISO
ˆ USP
Please specify method:
ˆ Agar Diffusion
ˆ MEM Elution (extract test)
ˆ Direct Contact
All cytotoxicity samples will be extracted and/or incubated at 37°C for 24 hours in MEM, unless otherwise specified by sponsor.
ˆ Other extraction and/or incubation period: ______________________________________
ˆ Other media:______________________
CYTOTOXICITY: ISO 10993-5
SENSITIZATION: ISO 10993-10
ˆ Murine Local Lymph Node Assay (LLNA)
ˆ Maximization Test (ISO)
Please select extraction media:
ˆ Saline
ˆ DMSO
Please select extraction media:
ˆ Saline
ˆ Other____________________________
ˆ Acetone in Olive Oil
ˆ Other____________________________
ˆ Vegetable Oil
ˆ Closed Patch Test (ISO)
IRRITATION: ISO 10993-10
ˆ ISO Intracutaneous
ˆ ISO Primary Eye
ˆ ISO Primary Skin
Please select extraction media:
ˆ Vegetable Oil
ˆ FHSA Primary Eye
ˆ FHSA Primary Skin
ˆ Vaginal
ˆ Penile
Mucous Membrane Test:
SYTEMIC: ISO 10993-11
ˆ USP Systemic Toxicity Test
Please select extraction media:
ˆ Vegetable Oil
ˆ Material Mediated Pyrogen Test (Saline Extract Only)
SUBACUTE: ISO 10993-11
ˆ Repeated Dose Toxicity Study
Duration:
ˆ 14 days
Please select route of administration:
ˆ Dermal
ˆ Intraperitoneal
SUBCHRONIC/CHRONIC: ISO 10993-11
Duration: _________________ days
ˆ Repeated Dose Toxicity Study
Please select route of administration:
ˆ Oral
ˆ Intravenous
GENOTOXICITY: ISO 10993-3
ˆ Ames Test
ˆ Mouse Lymphoma
ˆ Chromosomal Aberration
ˆ Mouse Micronucleaus
IMPLANTATION: ISO 10993-6
ˆ ISO
(Histopathology is included in all ISO
implantation studies.)
Please select extraction media:
ˆ Saline
ˆ PEG 400
ˆ USP
Subacute
Subchronic
Chronic
Duration –
Duration –
Duration –
HEMOCOMPATIBLITY: ISO 10993-4
ˆ Hemolysis - ISO (triplicate)
ˆ Direct Contact
ˆ Sample Extract
ˆ Hemolysis - USP (duplicate)
ˆ Prothrombin Time (PT)
ˆ Partial Thromboplastin Time (PTT)
ˆ Platelet Aggregation
ˆ Platelet Count
ˆ In vivo thrombogenicity (device must be tubular in nature)
ˆ
ˆ
ˆ
ˆ
ˆ
ˆ
ˆ
USP Intracutaneous
Saline
Other____________________________
Other guideline ____________________
Other guideline ____________________
Rectal
Hamster Cheek Pouch
ˆ Saline
ˆ Other____________________________
ˆ
ˆ
ˆ
ˆ
28 days
Oral
Intravenous
Other____________________________
ˆ Dermal
ˆ Intraperitoneal
ˆ Other____________________________
ˆ DMSO
ˆ Other____________________________
ˆ
ˆ
ˆ
ˆ
Histopathology
7 days
ˆ 14 days
60 days ˆ 90 days
180 days ˆ 365 days
ˆ 30 days
ˆ Complement Activation
ˆ Platelet Activation
ˆ Other___________________________
OTHER TESTS/SPECIAL INSTRUCTIONS: _______________________________________________________
__________________________________________________________________________________________
TESTING AUTHORIZED BY:___________________________________
Form No. RFA 08-2.2©
(please sign)
DATE:_______________________
Provläsningsexemplar / Preview
APPENDIX
ISO 10993-1 Excerpt
INTERNATIONAL
STANDARD
ISO
10993-1
This is only the table of contents. The full
PDF of ISO 10993-1 can be purchased from
the ISO website for US$158:
https://www.iso.org/standard/68936.html
Fifth edition
2018-08
Corrected version
2018-10
Biological evaluation of medical
devices —
Part 1:
Evaluation and testing within a risk
management process
Évaluation biologique des dispositifs médicaux —
Partie 1: Évaluation et essais au sein d'un processus de gestion du
risque
Reference number
ISO 10993-1:2018(E)
© ISO 2018
Provläsningsexemplar / Preview
ISO 10993-1:2018(E)

COPYRIGHT PROTECTED DOCUMENT
© ISO 2018
All rights reserved. Unless otherwise specified, or required in the context of its implementation, no part of this publication may
be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting
on the internet or an intranet, without prior written permission. Permission can be requested from either ISO at the address
below or ISO’s member body in the country of the requester.
ISO copyright office
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Phone: +41 22 749 01 11
Fax: +41 22 749 09 47
Email: [email protected]
Website: www.iso.org
Published in Switzerland
ii

© ISO 2018 – All rights reserved
Provläsningsexemplar / Preview
ISO 10993-1:2018(E)

Contents
Page
Foreword......................................................................................................................................................................................................................................... iv
Introduction................................................................................................................................................................................................................................. vi
1
2
3
4
5
6
7
Scope.................................................................................................................................................................................................................................. 1
Normative references...................................................................................................................................................................................... 1
Terms and definitions...................................................................................................................................................................................... 2
General principles applying to biological evaluation of medical devices.................................................. 5
Categorization of medical devices....................................................................................................................................................... 9
5.1
General............................................................................................................................................................................................................ 9
5.2
Categorization by nature of body contact......................................................................................................................... 9
5.2.1
Non-contacting medical devices......................................................................................................................... 9
5.2.2
Surface-contacting medical devices.............................................................................................................. 10
5.2.3
Externally communicating medical devices........................................................................................... 10
5.2.4
Implant medical devices.......................................................................................................................................... 11
5.3
Categorization by duration of contact.............................................................................................................................. 11
5.3.1
Contact duration categories................................................................................................................................. 11
5.3.2
Transitory-contacting medical devices...................................................................................................... 11
5.3.3
Medical devices with multiple contact duration categories..................................................... 11
Biological evaluation process...............................................................................................................................................................12
6.1
Physical and chemical information for biological risk analysis.................................................................. 12
6.2
Gap analysis and selection of biological endpoints for assessment........................................................ 12
6.3
Biological testing................................................................................................................................................................................. 13
6.3.1
General................................................................................................................................................................................... 13
6.3.2
Testing for evaluation................................................................................................................................................ 14
Interpretation of biological evaluation data and overall biological risk assessment................18
Annex A (informative) Endpoints to be addressed in a biological risk assessment.........................................20
Annex B (informative) Guidance on the conduct of biological evaluation within a risk
management process.....................................................................................................................................................................................25
Annex C (informative) Suggested procedure for literature review....................................................................................38
Bibliography.............................................................................................................................................................................................................................. 40
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Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www​.iso​.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www​.iso​.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation on the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to the
World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT) see the following
URL: www​.iso​.org/iso/foreword​.html.
This document was prepared by Technical Committee ISO/TC 194, Biological and clinical evaluation of
medical devices.
This fifth edition cancels and replaces the fourth edition (ISO 10993-1:2009), which has been technically
revised. It also incorporates the Technical Corrigendum ISO 10993-1:2009/Cor.1:2010.
The main changes compared to the previous edition are as follows:
a)
revised Annex A “Endpoints to be addressed in a biological risk assessment” with new columns for
“physical and/or chemical information” and “material mediated pyrogenicity” as well as columns
for “chronic toxicity,” “carcinogenicity,” “reproductive/developmental toxicity,” and “degradation”
which now indicates “endpoints” to be considered with “E” (instead of “tests” to be conducted with
an “X”);
b) replaced Annex B “Guidance on the risk management process” with “Guidance on the conduct of
biological evaluation within a risk management process” (formerly ISO TR 15499);
c)
additional definitions for terms used throughout the ISO 10993 series of standards;
e)
additional information on the evaluation of nanomaterials, and absorbable materials;
d) additional information on the evaluation of “Non-contacting medical devices” and new information
on the evaluation of “Transitory-contacting medical devices”;
f)
additional reference to ISO 18562 (all parts) for “Biocompatibility evaluation of breathing gas
pathways in healthcare applications”;
g) significant editing changes throughout the document;
A list of all parts in the ISO 10993 series can be found on the ISO website.
This corrected version of ISO 10993-1:2018 incorporates the following correction.
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—In Table A.1, 6th column, “Sensitization” has been added as a table heading.
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Introduction
The primary aim of this document is the protection of humans from potential biological risks arising
from the use of medical devices. It is compiled from numerous International and national standards
and guidelines concerning the biological evaluation of medical devices. It is intended to describe the
biological evaluation of medical devices within a risk management process, as part of the overall
evaluation and development of each medical device. This approach combines the review and evaluation
of existing data from all sources with, where necessary, the selection and application of additional tests,
thus enabling a full evaluation to be made of the biological responses to each medical device, relevant
to its safety in use. The term “medical device” is wide-ranging and, at one extreme, consists of a single
material, which can exist in more than one physical form, and at the other extreme, of a medical device
consisting of numerous components made of more than one material.
This document addresses the determination of the biological response to medical devices, mostly in a
general way, rather than in a specific device-type situation. Thus, for a complete biological evaluation, it
classifies medical devices according to the nature and duration of their anticipated contact with human
tissues when in use and indicates, in a matrix, the biological endpoints that are thought to be relevant in
the consideration of each medical device category. See also 3.14, Note 1 to entry.
The range of biological hazards is wide and complex. The biological response to a constituent material
alone cannot be considered in isolation from the overall medical device design. Thus, in designing a
medical device, the choice of the best material with respect to its biocompatibility might result in a
less functional medical device, biocompatibility being only one of a number of characteristics to be
considered in making that choice. Where a material is intended to interact with tissue in order to
perform its function, the biological evaluation needs to address this.
Biological responses that are regarded as adverse, caused by a material in one application, might not be
regarded as such in a different situation. Biological testing is based upon, among other things, in vitro
and ex vivo test methods and upon animal models, so that the anticipated behaviour when a medical
device is used in humans can be judged only with caution, as it cannot be unequivocally concluded
that the same biological response will also occur in this species. In addition, differences in the manner
of response to the same material among individuals indicate that some patients can have adverse
reactions, even to well-established materials.
The primary role of this document is to serve as a framework in which to plan a biological evaluation. A
secondary role is to utilize scientific advances in our understanding of basic mechanisms, to minimize
the number and exposure of test animals by giving preference to in vitro models and to chemical,
physical, morphological, and topographical characterization testing, in situations where these methods
yield equally relevant information to that obtained from in vivo models.
It is not intended that this document provide a rigid set of test methods, including pass/fail criteria,
as this might result in either an unnecessary constraint on the development and use of novel medical
devices, or a false sense of security in the general use of medical devices. Where a particular application
warrants it, experts in the product or in the area of application concerned can choose to establish
specific tests and criteria, described in a product-specific vertical standard.
ISO 10993 series is intended for use by professionals, appropriately qualified by training and experience,
who are able to interpret its requirements and judge the outcome of the evaluation for each medical
device, taking into consideration all the factors relevant to the medical device, its intended use and the
current knowledge of the medical device provided by review of the scientific literature and previous
clinical experience.
Informative Annex A contains a table that is generally helpful in identifying endpoints recommended
in the biocompatibility evaluation of medical devices, according to their category of body contact and
duration of clinical exposure. Informative Annex B contains guidance for the application of the risk
management process to medical devices which encompasses biological evaluation.
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INTERNATIONAL STANDARD
ISO 10993-1:2018(E)
Biological evaluation of medical devices —
Part 1:
Evaluation and testing within a risk management process
1 Scope
This document specifies:
— the general principles governing the biological evaluation of medical devices within a risk
management process;
— the general categorization of medical devices based on the nature and duration of their contact with
the body;
— the evaluation of existing relevant data from all sources;
— the identification of gaps in the available data set on the basis of a risk analysis;
— the identification of additional data sets necessary to analyse the biological safety of the medical
device;
— the assessment of the biological safety of the medical device.
This document applies to evaluation of materials and medical devices that are expected to have direct
or indirect contact with:
— the patient's body during intended use;
— the user’s body, if the medical device is intended for protection (e.g., surgical gloves, masks and
others).
This document is applicable to biological evaluation of all types of medical devices including active,
non-active, implantable and non-implantable medical devices.
This document also gives guidelines for the assessment of biological hazards arising from:
— risks, such as changes to the medical device over time, as a part of the overall biological safety
assessment;
— breakage of a medical device or medical device component which exposes body tissue to new or
novel materials.
Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Devicespecific or product standards address mechanical testing.
This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform
encephalopathy (TSE) agents and other pathogens.
2
Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-2:2006, Biological evaluation of medical devices — Part 2: Animal welfare requirements
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ISO 10993-3, Biological evaluation of medical devices — Part 3: Tests for genotoxicity, carcinogenicity and
reproductive toxicity
ISO 10993-4, Biological evaluation of medical devices — Part 4: Selection of tests for interactions with blood
ISO 10993-5, Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
ISO 10993-6, Biological evaluation of medical devices — Part 6: Tests for local effects after implantation
ISO 10993-7, Biological evaluation of medical devices — Part 7: Ethylene oxide sterilization residuals
ISO 10993-9, Biological evaluation of medical devices — Part 9: Framework for identification and
quantification of potential degradation products
ISO 10993-10, Biological evaluation of medical devices — Part 10: Tests for irritation and skin sensitization
ISO 10993-11:2017, Biological evaluation of medical devices — Part 11: Tests for systemic toxicity
ISO 10993-12, Biological evaluation of medical devices — Part 12: Sample preparation and reference
materials
ISO 10993-13, Biological evaluation of medical devices — Part 13: Identification and quantification of
degradation products from polymeric medical devices
ISO 10993-14, Biological evaluation of medical devices — Part 14: Identification and quantification of
degradation products from ceramics
ISO 10993-15, Biological evaluation of medical devices — Part 15: Identification and quantification of
degradation products from metals and alloys
ISO 10993-16, Biological evaluation of medical devices — Part 16: Toxicokinetic study design for
degradation products and leachables
ISO 10993-17, Biological evaluation of medical devices — Part 17: Establishment of allowable limits for
leachable substances
ISO 10993-18, Biological evaluation of medical devices — Part 18: Chemical characterization of materials
ISO/TS 10993-20, Biological evaluation of medical devices — Part 20: Principles and methods for
immunotoxicology testing of medical devices
ISO 14971:2007, Medical devices — Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
ISO and IEC maintain terminological databases for use in standardization at the following addresses:
— IEC Electropedia: available at http:​//www​.electropedia​.org/
— ISO Online browsing platform: available at https:​//www​.iso​.org/obp
3.1
biocompatibility
ability of a medical device (3.14) or material (3.12) to perform with an appropriate host response in a
specific application
3.2
biological risk
combination of the probability of harm to health occurring as a result of adverse reactions associated
with medical device (3.14) or material (3.12) interactions, and the severity of that harm
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3.3
biological safety
freedom from unacceptable biological risk (3.2) in the context of the intended use
3.4
chemical constituent
any synthetic or natural substance that is used in a process for manufacturing materials (3.12) and/
or medical devices (3.14), including the base material(s), additives (antioxidants, UV stabilizers, color
additives, dyes, etc.), and processing aids (solvents, lubricants, antifoaming agents, etc.)
3.5
data set
information, such as physical and/or chemical characterization, toxicity data, etc. from a variety of
sources necessary to characterize the biological response to a medical device
3.6
direct contact
medical device (3.14) or medical device component that comes into physical contact with body tissue
3.7
externally communicating medical device
medical device (3.14) or medical device component that is partially or wholly located outside the body
but has either direct or indirect contact with the internal body fluids and/or tissues
3.8
final product
medical device (3.14) or medical device component that has been subjected to all manufacturing
processes for the “to be marketed” medical device including packaging and if applicable, sterilization
3.9
geometry
device configuration
shape and relative arrangement of the parts of the medical device (3.14)
3.10
implant
medical device (3.14) which is intended to be totally introduced into the human body or to replace an
epithelial surface or the surface of the eye by means of clinical intervention and which is intended to
remain in place after the procedure
3.11
indirect contact
medical device (3.14) or medical device component through which a fluid or gas passes, prior to the fluid
or gas coming into physical contact with body tissue (in this case the medical device or medical device
component itself does not physically contact body tissue)
3.12
material
synthetic or natural polymer, metal or alloy, ceramic, or composite, including tissue rendered nonviable, used as a medical device (3.14) or any part thereof
3.13
material characterization
broad and general process of collecting existing information about a material’s chemistry, structure
and other properties, and if appropriate, new data, to facilitate the evaluation of these properties
3.14
medical device
any instrument, apparatus, implement, machine, appliance, implant, reagent for in vitro use, software,
material (3.12) or other similar or related article, intended by the manufacturer to be used, alone or in
combination, for human beings, for one or more of the specific medical purpose(s) of:
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— diagnosis, prevention, monitoring, treatment or alleviation of disease;
— diagnosis, monitoring, treatment, alleviation of or compensation for an injury;
— investigation, replacement, modification, or support of the anatomy or of a physiological process;
— supporting or sustaining life;
— control of conception;
— disinfection of medical devices;
— providing information by means of in vitro examination of specimens derived from the human body;
and does not achieve its primary intended action by pharmacological, immunological or metabolic
means, in or on the human body, but which may be assisted in its intended function by such means.
Medical devices include dental devices.
Note 1 to entry: Products which may be considered to be medical devices in some jurisdictions but not in others
include:
—
disinfection substances;
—
devices incorporating animal and/or human tissues;
—
—
aids for persons with disabilities;
devices for in vitro fertilization or assisted reproduction technologies;
[SOURCE: GHTF/SG1/N071:​2012, 5.1 modified to clarify that dental devices are included]
3.15
nanomaterial
material (3.12) with any external dimension in the nanoscale or having internal structure or surface
structure in the nanoscale
[SOURCE: ISO/TR 10993-22:2017, 3. 7, modified — Notes to entry have been deleted.]
3.16
non-contacting
indicates that the medical device (3.14) or medical device component has neither direct nor indirect
contact with body tissues
3.17
physical and chemical information
knowledge regarding formulation, manufacturing processes, geometric and physical properties and
type of body contact and clinical use that is used to determine whether any additional biological or
material characterization testing is needed
3.18
risk analysis
systematic use of available information to identify hazards and to estimate the risk
[SOURCE: ISO 14971:2007, 2.17, modified— The Note has been deleted.]
3.19
risk assessment
overall process comprising a risk analysis (3.18) and a risk evaluation (3.20)
[SOURCE: ISO 14971:2007, 2.18]
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3.20
risk evaluation
process of comparing the estimated risk against given risk criteria to determine the acceptability of
the risk
[SOURCE: ISO 14971:2007, 2.21]
3.21
risk management
systematic application of management policies, procedures and practices to the tasks of analysing,
evaluating, controlling and monitoring risk
[SOURCE: ISO 14971:2007, 2.22]
3.22
toxic
capable of causing an adverse biological response
3.23
toxicological hazard
potential for a chemical substance or material (3.12) to cause an adverse biological reaction, taking into
account the nature of the reaction and the dose required to elicit it
3.24
toxicological risk
probability of a specified degree of an adverse reaction occurring in response to a specified level of
exposure
3.25
toxicological threshold
limit, such as a tolerable intake (TI), tolerable exposure (TE), allowable limit (AL) value, or Threshold
of Toxicological Concern (TTC) below which adverse effects are not expected for relevant biological
endpoints
3.26
transitory contact
medical device (3.14) or medical device component that has a very brief duration of contact with
body tissue
4 General principles applying to biological evaluation of medical devices
4.1 The biological evaluation of any material or medical device intended for use in humans shall form
part of a structured biological evaluation plan within a risk management process in accordance with
ISO 14971:2007, Annex I, as given in Figure 1 of this document. This risk management process involves
identification of biological hazards, estimation of the associated biological risks, and determination of
their acceptability. Annex B provides guidance on this process. The biological evaluation shall be planned,
carried out, and documented by knowledgeable and experienced professionals.
The risk management plan should identify aspects of the biological evaluation requiring specific
technical competencies and shall identify the person(s) responsible for the biological evaluation.
The evaluation shall include documented, informed consideration of advantages/disadvantages and
relevance of:
a)
medical device configuration (e.g. size, geometry, surface properties) and a listing of a medical
device’s materials of construction (qualitative) and where necessary, the proportion and amount
(mass) of each material in the medical device (quantitative);
b) the physical and chemical characteristics of the various materials of construction and their
composition;
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