The International Organization of Standardization (ISO) is an independent organization that develops harmonized standards for use by governmental and non-governmental regulatory agencies. ISO Standard 10993 governs safety testing of medical devices and device materials.
In January 2021, ISO updated the 10993-12 guideline on sample preparation and reference materials and created a new guideline 10993-23 covering irritation testing procedures. Adherence to all sections of ISO 10993 is critical for successful submissions to regulatory bodies.
The main changes to ISO 10993-12 include the harmonization of definitions with those found in ISO 10993-18 (chemical characterization of device materials) and clarification on extraction procedures including exhaustive extraction.
The most notable change to the sample preparation process is that non-patient contacting portions of the medical device should now either be physically excluded from extractions, or the surface area of the non-patient contact portions should be excluded from the calculation
of the extraction ratio.
Another important change is the emphasis on devices consisting of components with different duration of tissue exposure. Components with different tissue exposure should be extracted and tested separately. For devices with tissue exposure longer than 24 hours, extraction times of 72 hours are recommended, including specifically for cytotoxicity tests. Shorter extraction times (e.g., 24 hours) may not be sufficient to obtain extracts that include chemicals released after longer exposure.
Lastly, the new guideline updates options for Reference Material (RM) (e.g., positive and negative controls). Laboratories are responsible for selecting appropriate RMs and qualifying them for applicable biological responses.
These changes will require more in-depth discussion between Sponsors and testing laboratories prior to protocol development and testing.
This new guideline presents a stepwise approach for evaluating the risk for irritation responses caused by exposure to medical devices. Previously, in vivo irritation studies were covered in ISO 10993-10, which also covers sensitization testing procedures. Tests outlined in the new section supersede those described in ISO 10993-10.
In addition, the new document harmonizes testing approaches with those described in guidelines from OECD, USP and EP.
For many devices, a stepwise evaluation of irritation potential should be conducted prior
to in vivo tests:
- Chemical characterization (ISO 10993 – sections 9, 13, 14, 15, and 18)
- Literature review including an evaluation of chemical and physical properties to evaluate for irritant properties
- In vitro alternative tests using a validated RhE assay. This assay is described in detail in the new ISO 10993-23.
- In vivo animal testing is appropriate when the test materials cannot be characterized and the risk assessment cannot be completed using data from chemical characterization, literature review, or in vitro
- Implants, external communicating devices, and devices applied to a specific area
(e.g., eye, mucosa, etc.) should be evaluated by in vivo test methods.
It is important to note that FDA and international regulators expect Sponsors to adhere to ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” when performing safety evaluations of new devices and device materials.