Biological evaluation of medical devices – Part 12: Sample preparation and reference materials

We all are aware that the 2021 version of the ISO 10993-12 has been released and there is anxiety amongst the medical device professionals and manufacturers regarding the new additions in the amendment. Since this standard has repealed the 2012 version of ISO 10993-12, medical device manufacturers are keen to know if they are meeting the requirements set out in the amendment. However, we can say that the standard is only modified a little and this might give a sigh of relief to the readers. Let’s now move to the next section wherein we shall be discussing the changes made to the 2021 version of ISO 10993-12.

What is new in the ISO 10993-12:2021? 

A broad view of the definitions along with an extended focus on Biological Testing

The update to the ISO 10993-12 version focuses on clarification of the definitions along with a more detailed explanation of sample preparation recommendations for biological testing. The standard now clearly states that it mentions the requirements for sample preparation recommendations for biological testing only as compared to the previous version that emphasized both biological testing and clinical testing.

New Sample Preparation Requirements

Here are a few sample preparation requirements that are added in ISO 10993-12:2021:

  1. Extraction of limited contact Medical Devices for cytotoxicity can be conducted at 37 ± 1) °C for (24 ± 2) hours.
  2. The extraction period of prolonged/long-term devices extended from 24 hours to 72 hours since 24 hours is considered insufficient for an extract to provide the effect of chemicals released beyond 24 hours of use. However, if there is sufficient data available to prove that the chemical release beyond 2 hours is the same as that of below 24 hours, then 72 hours of extraction period is not required.
  3. Non-patient contacting portions of the medical device shall now be physically excluded from the extractions or the surface area of the non-patient contacting portions shall be excluded from extraction-ratio calculations.

Additional guidance on Absorbable materials

ISO 10993-12:2021 cross-refers to additional guidance (ISO/TS-37137-1) for extraction and handling of devices containing absorbable materials. The guidance document clearly states some additional requirements when testing these devices. For example, the temperature, pH value, and osmolarity during extractions, etc.

Updates on Reference Material (RM)

The new guideline updates options on the Reference Material (Positive and negative controls). Now Laboratories can choose the RM based on their convenience and qualify the RM for biological purposes.

In summary, the changes to the new version are not exhaustive, however, a consultation with the regulatory body is always required prior to conducting the biological testing in order to ensure that the testings are acceptable by the regulatory body, as they will be the ones reviewing the test reports during the auditor during a regulatory submission review.

Concerned about where to begin?

Elexes team is here to help you. We have done a number of gap assessments between old and new versions of standards and advised companies on what action items must be taken to address the gaps and stay abreast with the latest applicable requirements. Feel free to contact us via email at or call +1 650-503-6615 for further details.

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Elexes Team

Elexes medical consulting is one of the leading regulatory & compliance consultant for several industries: Medical device, Pharmaceuticals, Cosmetics, Food, and Biologics.

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