Narrative of New ISO 10993-1 Standard – Part 1: “Evaluation and testing within a risk management process”

By Laurence Lister, Department Head, Biocompatibility Services

The big topic in biocompatibility this year is the release of the much anticipated final version of, “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process'”, from the FDA.  The draft was issued in April of 2013 and this final document was released June 16, 2016, although many of had our hands on a copy on the 15^th.  It went into effect on September 14, 2016.  If you memorized the draft version, scrub your mind.  The final version is substantially different.  This final version lays out a pathway to adhere to the intent of ISO 10993-1 in which forethought and consideration and a strategic approach to manufacturing and evaluating a medical device, through a risk management process.  It is intended to try to get away from the check box mentality that exists in many people conducting biocompatibility.  Examples are given in which an actual biocompatibility test need not be conducted and how to justify how or why they are not to be conducted.  The fact remains that the biological effect category still needs to be addressed in one fashion or another.  These justifications are not going to be easy.  It is not acceptable to simply say that a material has been historically used.  It has to have been historically used by Your company, in a similar device for a similar indication.

For someone new to the scene, and this FDA guidance is available for free on the internet, they may get a head of themselves very easily.  It gives the testing matrix of ISO 10993-1 as modified by the FDA.  It even discusses each testing/biological effect category with study specific considerations.  What else is there?  There are the subsequent chapters of 10993.

The document states that FDA recognizes the ISO standards undergo periodic review and revision.   The document specifies that complete test reports should be provided for all tests performed because the ISO 10993 standards have many options, and sometimes do not include pass/fail criteria.   A declaration of conformity is not sufficient for FDA to draw a conclusion of substantial equivalence to a predicate device and therefore to support the declaration, a copy of the study test report should also be provided.

Where are the ISO standards in this periodic review and revision FDA is talking about?  The stage of an of the ISO 10993 series standards can be found on the ISO.org website.  Two standards are listed as published.  All of them have been published.  But, being listed as published (code 60.60), indicates that it will be a while before any modifications to these documents will hit public view.  These two documents are ISO 10993-12 and ISO 10993-3.  The chapters on sample prep and genotoxicity, carcinogenicity and reproductive toxicity, respectively.  ISO 10993-3 has been supplemented in 2015 with a technical report in 2015.  ISO 10993-2 the chapter on Animal welfare just completed a review cycle (Code 90.60).  Chapters 9, 15, 18, 19, and 20, the chapters dealing with degradation products, degradation products from metals or alloys, chemical characterization, physico-chemical, morphological and topographical characterization, and immunotoxicity, respectively have been approved to start as a new review process (code 10.99).  The voting has closed on ISO 10993-5 and 11 which are the chapters on In Vitro Cytotoxicity and Systemic toxicity, respectively.  The international standard has been confirmed for chapters ISO 10993-10, 13, 14, and 17 which provide guidance for irritation and sensitization, degradation products of ceramics, degradation of polymeric devices, and limits on leachables, respectively (code 90.93).  The chapter on ethylene oxide sterilization residuals, ISO 10993-7 has been registered as a new project with the committee (code 20.00).  Toxicokinetic study design and tests for interactions with blood, ISO 10993-16 and 4, respectively have been approved for final draft (code 40.99).  ISO 10993-6 which deals with local effects after implantation is in final draft and has a target publication date of December 5, 2016.  This new iteration provides more guidance on how to conduct some different kinds of implants.  It should not invalidate previous implant studies, as the changes are not of that nature.  And the chapter that everybody is always talking about, ISO 10993-1, Evaluation and testing within a risk management process, has been reviewed and voted on by the committee.

ISO 10993 series of documents are the parent documents, and as FDA stated are subject to periodic review and revision.  This is done by an international committee which consists of experts put forth by the member body of a nation’s standards institute.  In the USA it is ANSI in the UK it is BSI and in Germany it is DIN.  These national bodies have their own review cycle in which they reaffirm, reaffirm with modifications or reject the ISO 10993 series of documents published at that time in their review cycle.  It is important to understand that these are separate, yet similar or identical documents.  The latest version of an ISO 10993 document is the document published by the International Organization for Standardization and not the readopted version by a member body such as ANSI, BSI or DIN.

Toxikon has been involved in the conduct of biocompatibility evaluations from the very onset of the industry.  We actively participate in the national and international working groups and committees for the development of these standards.  It is a lot to know.  Don’t distract your projects by trying to keep all this information straight. Please come to us for advice and options on how to proceed with biocompatibility evaluations.