FDA Biocompatibility – New Risk Based Guidance on ISO 10993

FDA Biocompatibility - New Risk Based Guidance on ISO 10993 Brandwood:Biomedical Global Medical Device and IVD Regulatory Services

Maybe a quieter life for these little fellows?The long awaited refresh of US FDA’s biocompatibility guidance has finally arrived.  This is a quantum leap from the old G95-1 Blue Book Memo.  The guidance is firmly rooted in a risk based approach, and provides  detailed advice on all aspects of biological safety evaluation.  The controversial modified Table from ISO 10993 still remains, however parallel activities in ISO may see the new version of ISO 10993 coming into close alignment with FDA’s view.

Firstly – this is a very different guidance document from the now superseded General Program Memorandum G95-1.  This guidance is  a substantial work, running to 65 pages there’s a lot to absorb here.  The guidance tackles the overall risk management approach which is embodied in the 2009 version of ISO 10993.  It also introduces some more recent elements of other parts of ISO 10993 such as Thresholds of Toxicological Concern (ISO 10993-17).

The approach to biocompatibility testing has for too long been characterised as an exercise in box ticking: simply consult the table in ISO 10993 part one, determine which endpoints are checked off in the table,  do those tests and move on.  The problem with that approach is twofold:

  1. there’s often plenty of information available to support safety without the need for testing – so it’s both wasteful and (in the case of animal testing) unethical to do the testing.
  2. There’s precious little thought involved in such approaches: aspects of safety which are not covered in the generic advice may be missed – e.g. should you be considering a modified test regime because of specific features of your device such as contact with a particular organ or tissue type?

In summary both bad economics and bad science.

The 2009 revision of ISO 10993-1, plus the related ISO TR 15499 technical report on implementing an evaluation program in context of ISO 14971 risk management attempted to change all that.   ISO Technical Committee 194 is currently working on a new draft of ISO 10993-1 which will include the entire content of TR 15499 in an informative Annex.   The Part 1 standard has already been updated to make it very clear that all those crosses in boxes in the evaluation table simply identify safety endpoints that must be considered.  They do not necessarily require that testing be conducted.  Application of thought and expertise is required to determine the most appropriate course of action.

FDA’s table in this updated guidance still differs from that in the standard – with FDA expecting consideration of a wider range of endpoints for given exposures.  However it’s worth noting that the standard itself is currently under revision.  Although it’s still some way to go before the next edition is finalised, FDA has had a very active role in the drafting process and it’s likely that there’ll be a deal of convergence when the next revision is published.

The other key consideration in a properly conducted biological evaluation is first knowing the device.  That means using chemistry first and then only doing biology later if there are gaps that chemistry can’t address.  What does this mean in practice?  Well, understand the materials of the device.  What is the formulation?  What additives are present such as colorants, antioxidants?  What other substances may be added during processing – are there contaminants such as catalysts, extrusion waxes, mold release agents, sterilant residues?  Does processing change the material properties – what about the effects of radiation sterilisation, or the application of heat?  All of these are questions of materials characterisation and chemistry.  Often it’s possible to get a complete characterisation of the material and establish that there are no extractable substances of toxicological concern – in which case there’s no need to do biological testing.

FDA’s new guidance recognises this and steps through how to take such an approach in some detail.  There’s still a fair bit of inbuilt conservatism, and there should surely be no surprise in that, but overall the approach is quite clear:

  • First: know your device – understand the materials and chemistry well.
  • Understand the device usage and what that means for the biological endpoints to be considered then…
  • Consider them!  Your submission should address each and every endpoint of relevance and either provide testing data or materials chemistry plus review of toxicology literature to establish that the finished device is safe – or provide a valid justification why the specific endpoint is not applicable to your particular device.

Overall – The agency is to be congratulated on such a detailed and considered document.  It’s a valuable addition to guidance alongside the entire family of ISO 10993 standards and the ISO TR 15499 Technical report.

Useful Links:

The FDA Guidance

Other articles on biocompatibility

ISO website – ISO 10993 parts.

ISO TR 15499 guidance on risk based assessment framework


Help button-Quick Call-Brandwood BiomedicalNeed help on biocompatibility?  We can support you with expert reports and arrangement of chemical or biological testing.  Brandwood Biomedical Founder and Principal Consultant Arthur Brandwood is a Biomaterials Scientist who has participated in ISO 10993 standards development for over 20 years.  Call us now to discuss how we can help.

Contact us, drop us an Email help@brandwoodbiomedical.com or call  1 888-271-5063 (US toll free) ♦ 400-842 7017 (Beijing – toll free) ♦ +61 2 9906 2984 (Sydney).


Workshop on Biocompatibility
Chengdu China 10-13 October

Several of the Senior Experts of the ISO drafting committee for the ISO 10993 series will be in China for the China International Medical Devices Regulatory Forum (CIMDR) in Chengdu 10-13 September.  Join them for a full day workshop on biological evaluation and the application of ISO 10993.

See www.cimdr.com for registration details.

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