ISO 10993-1: 2018 is the 5th edition of the biocompatibility standard for evaluation of medical devices. The new version replaces the 2009 version of the standard.
Historically, biological safety evaluations for medical devices were comprised of an investigation into biocompatibility tests required to meet regulatory obligations.
However, since 2009, the emphasis on a risk management process and characterization of materials continues to shift biological safety standard. Medical device manufacturers can no longer simply contract with a test lab; review and accept a recommended product evaluation plan.
The company shall begin to think about how the biological safety assessment of a medical device will have to be conducted long before any biological tests are performed.
With the release of ISO 10993-1:2018 in August 2018, there is a continued focus in biological safety planning and implementation processes, as well as the characterization of materials.
Once again, medical device manufacturers are being asked to go beyond the simple process of identifying a set list of biocompatibility tests when evaluating a device’s biological safety.
In this sense the company is inclined to carefully evaluate and select materials already in the design phase.
It is therefore advisable to implement a systematic risk-based approach that takes into account the aspects of biological safety in defining the choices regarding the constituent material parts of the device and the related production processes.
TS Quality & Engineering thanks to its experience in the sector and its team of experts can support you both:
- in the planning phase, outlining a specific Biological Evaluation Plan;
- in the execution of a specific Biological Evaluation Risk Assessment;
- in the identification of the tests necessary to confirm the biocompatibility of the medical device;
- in issuing the summary document, the Biological Evaluation Summary Report.
Contact us at firstname.lastname@example.org for more details.
Overview of changes
The 5th edition includes a foreword that explains the changes from the 4th edition. The 5th edition replaces the 4th edition (i.e., ISO 10993-1-2009), and it incorporates the correction that was made in 2010. The most significant changes from the previous edition are:
- revision of Annex A “Endpoints to be addressed in a biological risk assessment”. While Table A1 in the previous version of the Standard was often used by manufacturers as a simple checklist for biological tests to be performed during the biological evaluation process, the 2018 version focuses on additional aspects of biocompatibility. Table A.1 was expanded with the addition of six new columns:
- “physical and/or chemical information”
- “material mediated pyrogenicity”
- “chronic toxicity”
- “reproductive/developmental toxicity”
In addition, instead of tests to be conducted being identified with an “X,” the updated table now identifies endpoints to be considered with “E.”. The following text is reported: “E means endpoints to be evaluated in the risk assessment (either through the use of existing data, additional endpoint-specific testing, or a rationale for why assessment of the endpoint does not require an additional data set). If a medical device is manufactured from novel materials, not previously used in medical device applications, and no toxicology data exists in the literature, additional endpoints beyond those marked “E” in this table should be considered. For particular medical devices, there is a possibility that it will be appropriate to include additional or fewer endpoints than indicated”. Essentially, endpoints must be evaluated if possible through data or evaluations available otherwise by performing specific tests.
The only column containing an “X” is the column for physical and/or chemical information. This information is identified as a prerequisite for a risk assessment
- The new Annex A is now 5 pages in length.
- The 3-pages that were Annex B, “Guidance on the risk management process,” has been completely replaced with 13-pages from ISO TR 15499-2016, “Guidance on the conduct of biological evaluation within a risk management process.”
- Twenty-one (21) new definitions for terms were added to the 5th edition–including “3.9 geometry device configuration,” “3.15 nanomaterial,” “3.16 non-contacting,” “3.17 physical and chemical information,” “3.25 toxicological threshold” and “3.26 transitory contact.”
- Additional information on the evaluation of non-contacting medical devices and transitory-contacting medical devices was added.
- Expansion of the standard to include evaluation of nanomaterials and absorbable materials. This includes addition of section B.4.3.3 in Annex B for guidance on pH and osmolality compensation for absorbable materials.
- An additional reference to ISO 18562-1, -2, -3 and -4, for “Biocompatibility evaluation of breathing gas pathways in healthcare applications,” was added as well. However, the four standards in the ISO 18562 series should be purchased if you are conducting a biocompatibility evaluation for a device of this type (e.g., respiratory gas humidifiers).
- Annex C is almost identical to the previous version. The only change was the addition of “Preference may be given to GLP over non-GLP data,” to clause C.2.3.
Correspondence with FDA Guidance on Use of ISO 10993-1: 2018
Table A.1 in Annex A is quite similar to Table A.1 in the FDA guidance and the columns of Table A.1 match except the column for “physical and/or chemical information.” Although, the FDA guidance does not have a column in the table indicating that physical and chemical characterization is required as a prerequisite for the risk assessment, it is very clear from the language in the guidance that information about the physical and chemical characteristics of the device “should be provided in sufficient detail for FDA to make an independent assessment during our review and arrive at the same conclusion.” The FDA guidance also requires information about the surface properties of the finished device. The FDA guidance does not, however, include guidance on pH and osmolality compensation for absorbable materials. The FDA guidance also does not include a reference to the ISO 18562 series of standards, but the FDA product classification database was updated in June to include reference to the ISO 18562 series of standards when they were added to the database of recognized standards.
Correspondence with the European Directive and EU MDR
The 4th edition of the EN version has Table ZA.1 explaining the correlation between the standard and the European Directive. Specifically, Clauses 4, 5, 6 and 7 of the European Standard correspond to Annex I, Essential Requirements 7.1, 7.2 and 7.5 in the MDD. In the new Regulation (EU) 2017/745, these clauses correspond with Annex I, Essential Requirements 10.1, 10.2 and 10.4. Therefore, you should expect the European version of ISO 10993-1-2018 to include a table similar to Table ZA.1, but you should also anticipate that your evaluation of biological risks will need to be updated and additional testing may be required in order to remain compliant for any devices that are CE Marked.
Changes to the biological evaluation process
As in the previous version of the biocompatibility standard, Figure 1 is a decision tree that follows the biological evaluation process outlined in the standard. At first glance, the updated Figure 1 appears to be essentially unchanged. However, even though the updated figure has exactly the same shape and the same number of elements, there are subtle changes. For example, the potential effects of geometry is emphasized in the ISO 10993-1-2018. The more significant change in the process is at the end. Where it used to say, “Testing and/or justification for omitting suggested tests,” the updated figure now includes a reference to Annex A under those words. Where it used to say, “Perform Biological Evaluation,” the updated figure now says, “Perform Toxicological Risk Assessment (Annex B)”.
Annex B is where the most visible changes are found in the ISO 10993-1-2018. For example, in the previous version of the biocompatibility standard, there was a reference to creating a prospective, biological evaluation plan as part of the risk management plan. In the 5th edition, clause B.2.2 outlines the Biological Evaluation Plan–which is sometimes referred to by its acronym of “BEP” by third-party testing labs.
In addition, clause B.4 provides guidance for biological evaluation. This guidance is directly copied from ISO/TR 10993-22, but it answers the frequently asked question of “how do you perform a biological evaluation.” The basic steps of the biological evaluation, which have not changed, are:
- Material characterization (B.4.1)
- Collection of existing data (B.4.2)
- Device testing considerations (B.4.3)
- Biological safety assessment (B.4.4)
However, the guidance provides details for each step, as well as general guidance on when changes may require re-evaluation of biological safety, GLPs and biocompatibility evaluation documentation. In general, the focus of ISO 10993-1-2018 is now on the evaluation of toxicological data in Annex B, rather than passing a few required tests that were previously identified in Table A.1.
Will ISO 10993-1-2018 Require you to Retest for Biocompatibility?
In general, I do not expect that the changes to ISO 10993-1-2018 will require extensive retesting for your company. However, you can expect a significant amount of rewriting of your biological evaluation report to be required. Now you will need to more fully characterize the physical and chemical characteristics of your device, and you will need to provide a more comprehensive biological safety assessment–including an evaluation of toxicological data for each chemical including in the formulation of your device. It’s possible that you may even identify certain chemicals in the material formulation that prevent you from using a material–even though the material may have passed all biocompatibility tests in the past.