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Dec 23, 2014

Navigating the New FDA Draft Guidance on ISO 10993: Biological Evaluation of Medical Devices

FDA issued a new draft guidance in 2013 on 
the biological evaluation of medical devices.
by Cheryl Wagoner
Principal Consultant/Owner
Wagoner Consulting LLC

As part of FDA’s efforts to harmonize their requirements with those around the world, it has issued a number of guidance documents to help explain the agency’s position, especially in cases where FDA has some variance with a given international standard.  The current FDA guidance regarding biological evaluation of medical devices, Blue Book Memo #G95-1, was issued July 1, 1995 and replaced the FDA Tripartite Biocompatibility Guidance #G87-1 (April 24, 1987).  On April 23, 2013, FDA issued a new draft guidance entitled “Use of the International Standard ISO-10993 BiologicalEvaluation of Medical Devices Part 1: Evaluation and Testing”.  This guidance has much in common with the current Blue Book Memo, but expands the details in a number of areas especially regarding the test matrix and the level of detail regarding each test.

ISO 10993-1 and the obsolete Tripartite document rely upon seven basic principles which are preserved in the new guidance.
  • Material selection should take into account full characterization for all materials used to manufacture the device.
  • Materials, final product and possible leachable or degradation products should be considered for relevance to the overall toxicological evaluation.
  • Tests should take into consideration the bioavailability of the material.
  • Good Laboratory Practices (GLP) should be used or scientific justification to support validity if not
  • Full data is to be submitted unless conducted according to recognized standard.
  • Any change should be evaluated for possible change in toxicological effects and possibly the need for additional testing
  • Toxicological evaluation should be considered with other non-clinical, clinical, or post-market experience for overall safety assessment.

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As part of harmonization efforts, FDA agreed to apply ISO 10993-1 instead of Tripartite though FDA has made modifications to the testing required.  The draft FDA guidance contains two matrices instead of one. 
  • Table 1:  Initial Evaluation Tests for Consideration includes the same matrix as ISO10993-1 plus additional recommended tests.
  • Table 2:  Supplementary Evaluation Tests for Consideration.  This table was part of the 2009 version of ISO 10993-1 but has been removed from the current version.  Table 2 includes chronic toxicity and carcinogenicity as well as biodegradation and reproductive and developmental toxicity.

FDA’s position is that certain tests should be considered for a broader set of devices/patient exposure than ISO 10993-1 specifies.  These tests include:
  • Acute systemic toxicity
  • Subchronic toxicity
  • Implantation
  • Irritation
  • Genotoxicity
  • Pyrogenicity

One of the first steps to determining which tests may be appropriate is to categorize based upon the nature of body contact ranging from surface device to implant device.  Once the category is determined, one next determines the type of contact and the duration of contact.  For example, some surgical instruments may be categorized as external communicating devices with limited (≤24 hours) circulating blood contact. 

Because of the room for interpretation that is inherent in this guidance and due to the time- consuming and expensive nature of some of the recommended testing, I advise you to contact FDA if there is any question about the category into which a particular device may belong.  It is also important to keep in mind that not all tests in the matrix may be relevant for all devices.  The modified matrix should be considered as a guideline and not a checklist.  It is possible that some tests suggested by the matrix are inappropriate for a given device.  It is also possible that additional tests that are not suggested by the matrix may be appropriate for a given device.

Besides the differences in the matrices, the draft guidance provides additional detail over and beyond ISO 10993-1 regarding test-specific considerations in order to assist manufacturers as well as FDA reviewers.  The guidance also presents FDA’s position regarding labeling as “free.”  The position is that statements such as “latex-free,” “DEHP-free,” etc. should be revised  to state “Not made with natural rubber latex” or “not made with DEHP” in order to avoid a potential lack of accuracy.

In summary, the draft guidance generally follows ISO 10993-1 but it is not identical. 
  • One should use the guidance together with ISO 10993-1. 
  • The FDA recommendations are more comprehensive than the standard. 
  • As with all draft guidances, it should be considered to represent the agency’s current thinking on this topic.
  • Don’t assume the material does or does not have to be tested.
  • Consider using a reputable lab with the expertise to help determine which tests may be appropriate.
  • If in doubt, call FDA for clarification and/or agreement on which testing and by what methods may be appropriate.


Cheryl Wagoner has 20 years of experience in quality assurance and regulatory affairs. She currently is the principal consultant/owner of Wagoner Consulting LLC, where she provides consulting services to medical device and pharmaceutical companies.  Previously, she has held various positions in quality, regulatory, clinical and compliance fields in the medical device, biologics, and pharmaceutical industries.

Cheryl is a member of Regulatory Affairs Professionals (RAPS).  She completed the RAPS Executive Development Program at the Kellogg School of Management. 

Cheryl can be reached at:
910-386-9019



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