The International Organization of Standardization (ISO) is an independent, non-governmental international organization with a membership of 165 national standards bodies. The ISO provides harmonized standards that are used internationally by governmental, non-governmental, and regulatory agencies. The standards (e.g., ISO 10993) are reviewed approximately every 5 years (or as needed) by ISO committee to keep all stakeholders abreast.
The International Organization of Standardization revised the fourth edition of ISO 10993-12 and the guideline ISO 10993-12:2012 was replaced with the fifth edition of ISO 10993-12:2021. The main changes include the harmonization of definitions found in ISO 10993-18 and clarification on extraction process including exhaustive extraction.
Notable addition to sample preparation process outlined in this guideline is that non-patient contacting portions of the medical device should be either physically excluded from extractions or the surface area of the non-patient contact portions should be excluded from the calculation of the extraction ratio. This assessment will require communication between a testing laboratory and the Sponsor.
Another important item addressed in this guideline is the emphasis on devices consisting of components with different duration of tissue exposure. As suggested, the 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, specifically for cytotoxicity tests. Shorter extraction times (i.e., 24 hours) may not be sufficient to obtain extracts that represent chemicals released after longer exposure. Again, more in depth discussion with the Sponsor will be required prior to Protocol development and testing.
Lastly, suggested Reference Material (RM) options (e.g., positive and negative controls) were updated in the new guideline. Laboratories are responsible for selecting an appropriate RMs and qualifying them for appropriate biological responses.
This guideline was created to evaluate a potential risk for irritation responses caused by exposure to medical devices using a step-wise approach. The in vivo irritation studies were previously covered in ISO 10993-10:2010 BIOLOGICAL EVALUATION OF MEDICAL DEVICES — PART 10: TESTS FOR IRRITATION AND SKIN SENSITIZATION and the new guideline separates the assessment of irritation responses from sensitization. The irritation tests outlined in ISO 10993-23 supersede that ones described in ISO 10993-10:2010.
In addition, the testing approaches described in in this new document were harmonized with other testing guidelines including OECD, USP and EP.
For certain devices, a step-wise approach should be considered prior to in vivo tests:
- Chemical characterization (ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15, and ISO 10993-18)
- 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 this new guideline (ISO 10993-23).
- In vivo animal test are appropriate when the test materials cannot be characterized and the risk assessment cannot be obtained by chemical characterization, literature review, or in vitro tests. Implants, external communicating devices, and devices applied to a specific areas (e.g., eye, mucosa, etc) should be evaluated by in vivo test methods.
It is important to note that the Sponsors need to adhere to ISO 10993-1:2018 and FDA expectations: Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”
The adherence to these guidelines should be emphasized for successful submissions to regulatory bodies.