Do you know your materials used?
Dealing with extractable unknown substances or substances with missing toxicological data.
Medical devices are often highly complex products that can consist of various materials, such as plastics, metal alloys, ceramics and/or materials of animal origin. For the biological safety assessment it is necessary to investigate the materials, their degradation products and impurities for health based hazards.
Since often the complete composition of the raw materials used are not known, or they may be altered by the manufacturing process (heat, sterilization), extraction tests of the final medical devices are necessary for demonstration of biological safety. ISO standards 10993-18: 2020 and 10993-12:2021 are the basis for extraction conditions and analytical procedures.
The identification of substances by extraction tests
In an initial screening, organic volatile, semi-volatile and non-volatile substances and inorganic elements that can be extracted from the product needs to be identified and toxicologically evaluated. While inorganic elements can be clearly identified by ICP-MS and ICP-OES, the identification of organic molecules is often problematic. Especially in the case of degradation products, colour additives or impurities, toxicological data are often lacking in order to evaluate these substances. How does it work?
Dealing with unidentified substances
First, look at the quantities of unidentified extractable substances. ISO/TS 21726:2019 is an useful tool in this regard. This standard deals with the application of the TTC concept for extractable substances. If the exposure is very low and below the limits specified here, the risk for systemic, genotoxic and carcinogenic effects can be considered negligible and no further identification is necessary. Otherwise, analytical expertise is required. In most cases, these mass spectra are used for identification in screening procedures for organic substances.
These are characteristic of the substances in question. An expert can try to determine the molecular mass as well as important functional groups of the substance from the mass spectra. Based on this information, at least a group assignment can be made followed by potential hazard analysis.
If such an estimation is not possible due to overlap of substances for instance, additional analytical methods (e.g. MaldiTOF, MS/MS coupling) needs to be taken in mind. Based on feedback from FDA, all possible measures has to be taken for identification if the quantity exceeds the analytical evaluation threshold (AET).
Dealing with unknowns
- Application of TTC concept and comparison of exposure with limit values for substances with genotoxic potential.
- If genotoxicity is excluded, comparison with Cramer class III limit (limit for systemic toxicity)
- Identification of molecular weight and functional groups
- Application of further analytical methods
Dealing with identified substances and insufficient toxicological data
If a structure can be assigned to the substance, there are several ways to evaluate this substance toxicologically despite the lack of data. The first possibility is to identify structurally similar substances with existing toxicological data. This is also called read-across. Here, substance databases such as Pubchem or EPA-CompTox Dashboard can help you to identify such substances. A second possibility today is offered by in silico methods (quantitative structure-activity relationship, QSAR) which might help for identification of potential health hazards.
Here, endpoints such as genotoxicity, systemic toxicity, or sensitization can be investigated. If genotoxicity is excluded, substances can be classified into Cramer classes on the basis of their structure, which have significantly higher threshold values compared to potentially genotoxic substances.
Dealing with substances with unknown toxicity potential
- Identification of structurally similar substances
- If genotoxicity is excluded, comparison with Cramer classes (limits for systemic toxicity depending on functional groups)
- In silico characterization (application of quantitative structure-activity relationship, QSAR analysis)
In summary, the toxicological evaluation of unknown substances or substances with insufficient toxicological data is a major challenge for toxicologists. Good cooperation between manufacturer, evaluator, analysts and possibly QSAR specialists is essential to overcome this challenge. If all these methods do not work, further biological tests might become necessary.