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Home - > Testing Services - > How the New FDA Biocompatibility Testing Guidance Could Affect You
How the New FDA Biocompatibility Testing
Guidance Could Affect You
Posted in Testing Services by bmichaels on March 18, 2014
The new ISO 10993 draft guidance document is the most expansive presentation of testing standards for the
medical device industry in more than 18 years.
By Thor Rollins
In April 2013, FDA released draft guidance for industry and FDA administration
staff titled Use of International Standard ISO 10993, Biological Evaluation of Medical Devices Part 1: Evaluation and
Testing. Meant to replace FDAs 1995 G95 document, the new draft guidance document is the most expansive
presentation of testing standards affecting the medical device industry in more than 18 years.
The first part of the article summarizes the new guidance document step by step. The second part discusses how
medical device manufacturers or testing facilities can justify their decisions to perform specific tests or to forego
testing altogether. The third part explains the overall impact of the guidance document on device makers and their
testing partners.
The New GuidanceStep by Step
While the ideas contained in the new guidance
document have appeared in FDA response
letters over the last two years and more, they
have not been presented in summary form until
now. By codifying them in a single document,
FDA has enabled medical device
manufacturers and testing facilities to
reference them in order to perform such tasks
as setting up a test design or evaluating the
impact of a failure. While these ideas are
familiar to many biocompatibility testing
experts, their appearance in the draft guidance
increases their impact.
The ideas in the draft guidance document
cover colorants and other chemical
compounds, test plans, final device approvals,
organ-specific devices, master files, good
laboratory practices for in vivo and in vitro
testing, chronic toxicity and carcinogenicity testing for permanent devices, representative coupon devices, failure
options, sample preparation, prolonged-contact devices, cytotoxicity, hemocompatibility, and implantation criteria.
Colorants and other Chemical Compounds. In a discussion of toxic chemicals, the document specifically addresses
colors and colorantsa topic that was not addressed in the G95 document. Relying on the ISO 10993-17 and ISO
10993-18 chemical characterization standards, the new guidance focuses on safety concerns associated with
chemicals that can leach from medical devices and impact patient safety.
Previously, FDA recognized that color additives are potentially carcinogenic or genotoxic, prompting it to question how
much colorant leaches off of devices, how much it interacts with the body, and how it impacts safety from a
toxicological standpoint. To answer these questions, the agency adopted two different approaches. First, to determine
colorant leachable levels, it requested that companies perform leachables studies that mimic devices actual clinical
use. Second, it limited the scope of leachables studies, focusing instead on the total amount of colorant in the device
and the toxicological effect of releasing all the color at once. While both types of tests have been successful, the new
draft guidance document represents the first time that the question of colorant leaching has been addressed.
The impact of colorants and other chemical compounds on device biocompatibility can be determined by measuring
the quantity of a chemical that leaches from the medical devicea procedure known as extractable leachables
testing. The effects of a chemical on patient safety are determined using a measure known as human daily
exposurethe dose of the chemical per body weight. For male adults, body weight is assumed to be 70 kg, while for
women, children, or infants, it is assumed to be less.
For example, if 0.00023 mg of chloroform leaches off of a device, each kilogram of body weight would be exposed to
0.0000033 mg of chloroform daily. To determine the toxicological effects of this level of chloroform on the body, testing
experts can consult resources such as Toxnet, Toxline, or the Environmental Protection Agency, which contain
no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) for a host of
chemical compounds. By multiplying NOAELs or LOAELs by the human daily level of chloroformand by modifying
factors, depending on the quality and type of data generatedit is possible to calculate the effect of chloroform on the
body.
Containing a wealth of data on chloroform, Toxline indicates that NOAELs for this chemical compound range between
15 and 125 mg per kilogram of body weight. To determine which of these levels is most representative of the medical
device in question, it is necessary to know how the device makes contact with patient, its route of administration, and
its dwell time. In the real-life case of a medical device containing chloroform, the NOAEL of 15 mg/kg was the most
realistic value. Thus, assuming a human daily exposure of 0.0000033 mg/kg, a NOAEL of 15 mg/kg, a safety factor of
100 based on interspecies and intraspecies differentiation, and possible quality of data, the margin of safety is
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45,000. In other words, the device could leach 45,000 times more chloroform than the NOAEL and still be considered
safe.
This type of mathematical research can help medical device manufacturers to justify the chemicals that leach off of a
device. As with chloroform, this method can also be used to determine the toxicological impact of colorants on the
body. In place of chloroform, the colorants CAS number can be entered in the database, providing a good method for
performing risk assessment on devices.
Discussing a Test Plan with FDA.
Biocompatibility tests are so long and expensive
that it is important to discuss them with FDA in
order to be confident that the test plan is correct.
By getting feedback from FDA in advance,
surprises at the back end can be avoided.
FDA Approves Final Devices, Not Individual
Materials. Often, medical device manufacturers
test raw materials for biocompatibility, assuming
that they can apply the results directly to the final
device. While this approach can be successful,
manufacturers must also evaluate the impact of
the production process on the materials. For
example, how do mold-release agents or
sterilization methods such as gamma radiation
affect the biocompatibility of the final device? Just
because a raw material is biocompatible does not
necessarily mean that the device itself will also be biocompatible.
Organ-Specific Devices. The type of testing required to achieve FDA approval for a device also depends on the how
the device will be used. For example, if a device is meant to go into the brain, it must be tested for neurotoxicity. In
most cases, however, medical devices do not target a specific organ.
Master Files: Insufficient Basis for Submissions. Clients say frequently that since all of their materials have master
files, they do not have to perform biocompatibility testing. Indeed, master files can help greatly in risk assessments,
but they cannot replace biocompatibility testing because the same materials may be processed differently in different
medical devices. In addition, materials with master files or the devices from which they are made may not have
undergone sterilization. Thus, before performing risk assessment to determine a devices biocompatibility,
manufacturers must evaluate the impact of their processing methods on the materials they use.
Conti nue to Part 2
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