Biological
evaluation of
medical devices 2Part 3: Tests for
10993Biocomp
03/16/2012 AAMI ANSI ISO
117
genotoxicity,
3:2003/(R)2009
carcinogenicity,
and reproductive
toxicity
Recognition List Number: 028 Publication Date: 03/16/2012
Part B: SUPPLEMENTARY INFORMATION
Recognition Number 2-117: AAMI / ANSI / ISO 10993-3:2003/(R)2009, Biological
evaluation of medical devices - Part 3: Tests for genotoxicity, carcinogenicity, and
reproductive toxicity. (Biocompatibility)
Date of Standard: 2003.
Addresses of Standards Organizations:
Association for the Advancement of Medical Instrumentation (AAMI)
4301 North Fairfax Drive
Suite 301
Arlington, VA 22203
American National Standards Institute (ANSI)
25 West 43rd Street
4th Floor
New York, NY 10036
International Organization for Standardization (ISO)*
1, Rue de Varembe
Case Postale 56
CH 1211 Geneva 20, 0
SWITZERLAND
CDRH Office and Division Associated with Recognized Standards:
OFFICE OF DEVICE EVALUATION (ODE)
Devices Affected:
All permanent surface devices that contact mucosal membrane and breached or
compromised surfaces
Permanent external communicating devices that contact blood path indirectly
Prolonged and permanent external communicating devices that contact
tissue/bone/dentin
All external communicating devices that contact the circulating blood
All prolonged and permanent contact implant devices
Processes Affected:
510(k), PMA, IDE, PDP, HDE
Type of Standard:
Horizontal
Extent of Recognition:
The genetic toxicity test battery for medical devices should include at least three
assays: a test for gene mutation in bacteria, an in vitro test with cytogenetic
evaluation of chromosomal damage with mammalian cells or an in vitro mouse
lymphoma tk assay, and an in vivo test for chromosomal damage using rodent
hematopoietic cells. Due to the diversity of medical devices, it is recognized that not
all tests identified will be necessary or practical for any given device. It is
indispensable for testing that each device be considered on its own merits:
additional tests not indicated in the table may be necessary. Additionally, tests are
suggestions and other comparable tests can be substituted for suggested tests with
accompanying scientific justification.
For devices with polymeric component(s), the test material should be prepared using
an exaggerated sample extraction method. The standard recommends only two
assays.
Additionally, an assessment of risk in the standard includes only a partial list that
should be considered. FDA recommends including the following factors when
determining if carcinogenicity testing is warranted:
1. total duration of exposure,
2. exposure route,
3. extent of localized (at the site of implantation) and systemic exposure,
4. patient population,
5. device's indication for use,
6. cause of concern (e.g., structure-activity relationship, previous demonstration in
the product class),
7. device's physical characteristics (e.g, device size, pore size, surface continuity,
surface condition, device thickness),
8. metabolites of the device material
9. biologic components, and
10. genotoxicity results
Complete standard, except as follows:
Clause 2 - The OECD references should be modified to reflect medical device
conditions for example, maximum tolerated dose testing may not be attainable or
practical for device extracts.
Clause 4.1 Exclude the following: ?Testing for genotoxicity, however, is not necessary
for medical devices, and components thereof, made only from materials known to
show no genotoxicity. Testing for genotoxicity is indicated where a review of the
composition of the materials reveals the possible presence in the final medical
device of compounds that might interact with genetic material, or when the chemical
composition of the medical device is unknown. In such circumstances, the genotoxic
potential of suspect chemical components should be assessed, bearing in mind the
potential for synergy, in preference to carrying out genotoxicity tests on the material
or medical device as a whole. When the genotoxicity of a medical device has to be
experimentally assessed, a series of in vitro tests shall be used. This series shall
include either two tests if 4.2.1.2 is performed, which uses the mouse lymphoma
assay incorporating colony number and size determination, or three tests if 4.2.1.1 is
performed. When tests are performed, at least two tests, investigating different
endpoints, shall use mammalian cells.?
Clause 4.2.2 Exclude this clause
Clause 4.2.4 Exclude this clause
Clause 4.2.5 Exclude this clause
Clause 4.3.1 - For devices with cumulative contact duration greater than 30 days and
involve the testing of polymeric or porous device materials, the extract (when
applicable) should be prepared using an exhaustive method.
Clause 4.3.2 - In addition to the finished device (ready-to-use state), testing may be
warranted for additional device states such as, wear debris generated from
implanted device or intermediate reaction states for in situ polymerizing devices.
Clause 4.3.3 Exclude this clause
Clause 5.1 Carcinogenicity testing may be recommended for new materials and old
materials with new intended uses, patient populations or treatment sites.
Clause 5.2.1 FDA interprets significant and adequate human-use history to mean the
medical device, which undergoes a similar manufacturing process, is used to treat a
similar patient population, with a similar intended use at a similar treatment site.
Clause 5.3 Exclude this clause
Clause 5.4.2 Exclude this clause
Note: For in situ polymerizing materials, there may be additional sample preparation
requirements, so the review division should be contacted prior to conducting these
studies. For materials with submicron components, there may be additional sample
preparation and/or test conduct requirements, so the FDA should be contacted prior
to conducting these studies.
Related CFR Citations and Product Codes:
Relevant Guidance:
There is no relevant guidance developed at this time.