Six steps to assess the situation and determine how to move forward…

Each medical device present or coming on the market needs to have a demonstrated
biocompatibility to protect users from potential biological risks arising from its intended
clinical use.

Therefore, it is required for manufacturers to perform a biological evaluation of
their medical device as outlined in ISO 10993-1:2018 “Biological evaluation of medical devices
– Part 1: Evaluation and testing within a risk management process”. This biological evaluation is
carried out within a risk management process, meaning that relevant existing data is reviewed
and evaluated and, where necessary, additional testing is selected and applied. The ISO 10993-1
guideline identifies several biological endpoints for which the product needs to be evaluated,
either through existing data or testing. One particular endpoint that has to be evaluated for
every medical device, no matter its classification, is cytotoxicity. Due to the highly sensitive
nature of the cytotoxicity test combined with its low cost and short turnaround time, this
endpoint is most often expected to be evaluated through testing, wherein an in vitro cell
culture system is used to evaluate the potential cytotoxic effects of the final finished form of
a medical device. However, it is known that in vitro cytotoxicity testing is a sensitive assay that
can often result in failures. The first reaction to a failing result is often a state of panic. This is
understandable given that it may feel like the complete submission of the medical device is
compromised and that a product will not be approved for commercialization.

ISO 10993-5:2009 “Biological evaluation of medical devices – Part 5: Tests for in vitro
cytotoxicity” provides an apt statement on the assessment of in vitro cytotoxicity results: ‘Any
cytotoxic effect can be of concern. However, it is primarily an indication of potential for in vivo
cytotoxicity and the device cannot necessarily be determined unsuitable for a given clinical
application based solely on cytotoxicity data’. Consequently, any in vitro cytotoxicity failure is
a source of concern that should be investigated to identify whether there is a risk for in vivo
cytotoxicity, but this does not automatically mean a medical device is not biocompatible. Indeed,
provided that a proper biological risk assessment is performed, there are several alternatives to
defend such a result and move towards a successful submission. That being said, figuring out
how to move forward in light of a cytotoxicity failure can be challenging.

This document aims at providing the reader with a step-by-step guide on how to
investigate and assess in vitro cytotoxicity failures in order to determine the appropriate way
forward.

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