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Medical Devices

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Use of International Standard ISO-10993, 'Biological Evaluation of Medical Devices Part 1: Evaluation and Testing' (Replaces #G87-1 #8294) (blue book memo)(Text Only)

This guidance was written prior to the February 27, 1997 implementation of FDA’s Good Guidance Practices, GGP’s. It does not create or confer rights for or on any person and does not operate to bind FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or both. This guidance will be updated in the next revision to include the standard elements of GGP’s.

NOTE:  This memo was distributed with Blue Book Memorandum #G95-1, 
entitled Use of International Standard ISO-10993, "Biological 
Evaluation of Medical Devices Part 1:  Evaluation and Testing" and 
relates to implementation of #G95-1.

May 1, 1995

Director, Office of Device Evaluation (ODE)
                                                                      
Required Biocompatibility Training and Toxicology Profiles for 
Evaluation of Medical Devices

Division Directors, ODE 

The new blue book memorandum #G95-1 entitled "Use of International 
Standard ISO-10993, "Biological Evaluation of Medical Devices Part-1: 
Evaluation and Testing," includes an FDA-modified matrix that 
designates the type of testing needed for various medical devices 
(copy attached).  It also includes a flow chart entitled 
"Biocompatibility Flow Chart for the Selection of Toxicity Tests for 
510(k)s."  The guidance will be effective for all submissions that 
will be received on or after July 1, 1995.  The former guidance, #G87-
1 entitled "Tripartite Biocompatibility Guidance," may continue to be 
applied until a final decision is reached on each submission received 
prior to July 1, 1995.  Sponsors may, however, choose to follow this 
new memorandum immediately.  In addition, questions presented to staff 
by submitters regarding this change in biocompatibility testing should 
be discussed with you to determine the most appropriate resolution of 
the issues. 

To implement the new blue book policy, it is essential that we train 
all our reviewers in the proper use of the ISO-10993 with modified 
matrix.  I have asked Dr. Raju Kammula to arrange training sessions to 
train all reviewers in ODE.  

Through CDRH Staff College he will be scheduling several training 
sessions to discuss the differences between the Tripartite and ISO 
guidances and how to use the new bluebook guidance with modified ISO 
matrix.  These training sessions will be conducted in May and June.  
Please advise all reviewers in your division to attend a training 
session so that they will be fully informed and knowledgeable on how 
to use the ISO standard before July 1, 1995.  

I have also asked Raju Kammula to coordinate the development of 
toxicology profiles for devices in prolonged and permanent contact 
categories and devices with a significantly large volume of 
submissions.  Each division must identify the appropriate devices and 
develop these profiles.  Please provide the name of at least one 
individual to work with Raju Kammula to develop these profiles.     


Attachment

cc:  D. Bruce Burlington M.D.

   

General Program Memorandum - #G95-1
         
May 1, 1995
         
Director, Office of Device Evaluation (ODE)
         
         
Use of International Standard ISO-10993, "Biological Evaluation of 
Medical Devices Part 1: Evaluation and Testing"
         
ODE Reviewing Staff
         
         
Purpose
        
The purpose of this memo is to replace, after July 1, 1995, the use of 
ODE General Program Memorandum G87-1, entitled "Tripartite 
Biocompatibility Guidance", dated April 24, 1987 with Part-1 of the ISO 
standard "Biological Evaluation of Medical Devices", which includes an 
FDA-modified matrix.   
         
Background
         
Biological evaluation of medical devices is performed to determine the 
potential toxicity resulting from contact of the component materials of 
the device with the body.  The device materials should not, either 
directly or through the release of their material constituents: 
(i) produce adverse local or systemic effects; (ii) be carcinogenic; 
or, (iii) produce adverse reproductive and developmental effects.  
Therefore, evaluation of any new device intended for human use requires 
data from systematic testing to ensure that the benefits provided by 
the final product will exceed any potential risks produced by device 
materials.
         
When selecting the appropriate tests for biological evaluation of a 
medical device, one must consider the chemical characteristics of 
device materials and the nature, degree, frequency and duration of its 
exposure to the body.  In general, the tests include: acute, sub-
chronic and chronic toxicity; irritation to skin, eyes and mucosal 
surfaces; sensitization; hemocompatibility; genotoxicity; 
carcinogenicity; and, effects on reproduction including developmental 
effects.  However, depending on varying characteristics and intended 
uses of devices as well as the nature of contact, these general tests 
may not be sufficient to demonstrate the safety of some specialized 
devices.  Additional tests for specific target organ toxicity, such as 
neurotoxicity and immunotoxicity may be necessary for some devices.  
For example, a neurological device with direct contact with brain 
parenchyma and cerebrospinal fluid (CSF) may require an animal implant 
test to evaluate its effects on the brain parenchyma, susceptibility to 
seizure, and effects on the functional mechanism of choroid plexus and 
arachnoid villi to secrete and absorb (CSF).  The specific clinical 
application and the materials used in the manufacture of the new device 
determines which tests are appropriate.  

Some devices are made of materials that have been well characterized 
chemically and physically in the published literature and have a long 
history of safe use.  For the purposes of demonstrating the substantial 
equivalence of such devices to other marketed products, it may not be 
necessary to conduct all the tests suggested in the FDA matrix of this 
guidance.  FDA reviewers are advised to use their scientific judgement 
in determining which tests are required for the demonstration of 
substantial equivalence under section 510(k).  In such situations, the 
manufacturer must document the use of a particular material in a 
legally marketed predicate device or a legally marketed device with 
comparable patient exposure.  
         
International Guidance and Standards
         
In 1986, FDA, Health and Welfare Canada, and Health and Social Services 
UK issued the Tripartite Biocompatibility Guidance for Medical Devices.  
This Guidance has been used by FDA reviewers, as well as by 
manufacturers of medical devices, in selecting appropriate tests to 
evaluate the adverse biological responses to medical devices.  Since 
that time, the International Standards Organization (ISO), in an effort 
to harmonize biocompatibility testing, developed a standard for 
biological evaluation of medical devices (ISO 10993).  The scope of 
this 12-part standard is to evaluate the effects of medical device 
materials on the body.  The first part of this standard "Biological 
Evaluation of Medical Devices: Part 1: Evaluation and Testing", 
provides guidance for selecting the tests to evaluate the biological 
response to medical devices.  Most of the other parts of the ISO 
standard deal with appropriate methods to conduct the biological tests 
suggested in Part 1 of the standard. 
         
ISO 10993, Part 1, and the FDA-modified Matrix
         
The ISO Standard, Part 1, uses an approach to test selection that is 
very similar to the currently-used Tripartite Guidance, including the 
same seven principles.  It also uses a tabular format (matrix) for 
laying out the test requirements based on the various factors discussed 
above.  The matrix consist of two tables.  See Attachment A, Table 1 - 
Initial Evaluation Tests for Consideration, and Attachment B, Table 2 - 
Supplementary Evaluation Tests for Consideration.  Attachment C is a 
biocompatibility flow chart for the selection of toxicity tests for 
510(k)s.  It may be applicable to some PMAs also but not all PMAs.  In 
addition, FDA is in the process of preparing toxicology profiles for 
specific devices.  These profiles will assist in determining 
appropriate toxicology tests for these devices.  
         
To harmonize biological response testing with the requirements of other 
countries, FDA will apply the ISO standard, Part 1, in the review 
process in lieu of the Tripartite Biocompatibility Guidance.
         
FDA notes that the ISO standard acknowledges certain kinds of 
discrepancies.  It states "due to diversity of medical devices, it is 
recognized that not all tests identified in a category will be 
necessary and practical for any given device.  It is indispensable for 
testing that each device shall be considered on its own mertis:  
additional tests not indicated in the table may be necessary."  In 
keeping with this inherent flexibility of the ISO standard, FDA has 
made several modifications to the testing required by ISO 10993-Part 1.  
These modifications are required for the category of surface devices 
permanently contacting mucosal membranes (e.g., IUDs).  The ISO 
standard would not require acute, sub-chronic, chronic toxicity and 
implantation tests.  Also, for externally communicating devices, 
tissue/bone/dentin with prolonged and permanent contact (e.g., dental 
cements, filling materials etc.), the ISO standard does not require 
irritation, systemic toxicity, acute, sub-chronic and chronic toxicity 
tests.  Therefore, FDA has included these types of tests in the matrix.  
         
Although several tests were added to the matrix, reviewers should note 
that some tests are commonly requested while other tests are to be 
considered and only asked for on a case-by-case basis.  Thus, the 
modified matrix is only a framework for the selection of tests and not 
a checklist of every required test.  Reviewers should avoid 
proscriptive interpretation of the matrix.  If a reviewer is uncertain 
about the applicability of a specific type of test for a specific 
device, the reviewer should consult toxicologists in ODE.
            
FDA expects that manufacturers will consider performing the additional 
tests for certain categories of devices suggested in the FDA-modified 
matrix.  This does not mean that all the tests suggested in the 
modified matrix are essential and relevant for all devices.  In 
addition, device manufacturers are advised to consider tests to detect 
chemical components of device materials which may be pyrogenic.  We 
believe that ISO 10993, Part 1, and appropriate consideration of the 
additional tests suggested by knowledgeable individuals will generate 
adequate biological data to meet FDA's requirements.  Reviewers in the 
Office of Device Evaluation will accept data developed according to the 
ISO-10993, Part 1, with the matrix as modified and presented in this 
memorandum (#G95-1).  
         
Manufacturers are advised to initiate discussions with the appropriate  
review division in the Office of Device Evaluation, CDRH, prior to the 
initiation of expensive, long-term testing of any new device materials 
to ensure that the proper testing will be conducted.  We also recognize 
that an ISO standard is a document that undergoes periodic review and 
is subject to revision.  ODE will notify manufacturers of any future 
revisions to the ISO standard referenced here that affect this 
document's requirements and expectations.  
         
Effective Date:  This Guidance is effective for all submissions that 
will be received on or after July 1, 1995.  The former guidance, G87-1 
entitled "Tripartite Biocompatibility Guidance," may continue to be 
applied until a final decision is reached on each submission received 
prior to July 1, 1995.  Sponsors may, however, choose to follow this 
new memorandum immediately.  After this transition period for 
submissions covered by the Tripartite Biocompatibility Guidance, G87-1 
will be recinded and replaced by this guidance.
        
         
         
                       Susan Alpert, Ph.D., M.D.

Attachment A

Table 1 - Initial Evaluation Tests for Consideration

Attachment B

Table 2 -Supplementary Evaluation Tests for Consideration

Attachment C

Biocompatibility Flow Chart for the Selection of Toxicity Tests fopr 510(k)s