Chemical characterisation of medical devices: understanding the ISO 10993-18 and ISO 10993-12 standards

ISO 10993-18: Chemical characterisation at the heart of biological risk assessment

ISO 10993-18:2020 defines the requirements and methods for identifying extractable and leachable substances present in a medical device. It is the starting point for the toxicological assessment process, providing the chemical profile of materials that will be in direct or indirect contact with the patient.

The main objective is to anticipate the risks associated with exposure to chemical substances, which may come from the components of the device (metals, polymers, ceramics, adhesives, colouring agents or other additives), or from the manufacturing processes or sterilisation processes in their initial state or after storage. These substances are extracted using solvents under conditions simulating clinical use, then identified and quantified using analytical techniques such as GC-MS, LC-MS or ICP-MS.

The results obtained are then used to:              

• Determine the potential toxicity of substances via risk analysis (ISO 10993-17)
• Decide whether additional biological tests are necessary or can be avoided
• Support regulatory dossiers submitted to the authorities (EMA, FDA, MDR, etc.)

The methodological approach to chemical characterisation

The first step, once the data on the composition and manufacturing processes of the device have been provided, is to define the extraction and analytical conditions, in line with its end use (replicates, standards, TEA).

ISO 10993-12: Standardisation of samples and test conditions

ISO 10993-12:2021 completes this process by defining the requirements for the preparation of samples used in biological tests, including those required by ISO 10993-18.

In particular, it specifies:

• Methods for cutting, cleaning and packaging samples
• Surface volumes to be extracted depending on the type of contact (skin, mucous membrane, implant, etc.)
• Standardised solvents and extraction times
• Sterilisation conditions, where applicable

This standardisation is crucial to ensure the reproducibility and comparability of test results, particularly when it comes to demonstrating the biocompatibility of a material in the face of international regulatory requirements.

ISO 10993-18: Determination of chemical profiles of materials: extractables and leachables 

ISO 10993-18, which deals with the methodology for assessing extractables and leachables, provides detailed guidance on how to carry out tests to determine which chemical substances can be extracted or released from materials used in medical devices. This methodology is crucial for assessing the potential for migration of chemical substances from the material and their impact on patient safety.

Sampling and testing conditions:

• Materials to be tested
• Extraction solvents:
  • Biological solvents 
  • Organic solvents
  • Temperature and humidity conditions 

Extraction test:

• Time and temperature 
• Solvent/sample ratio
• Chemical analysis: After extraction, the solvents are analysed to identify and quantify the chemicals present. This may include analysis by:
  • Gas chromatography / Mass spectrometry (GC-MS) / Semi-volatile substances
  • High-performance liquid chromatography-MS / non-volatile substances
  • Inductively coupled plasma mass spectrometry (ICP-MS) or OES 
  • Other options to be considered:
    • GC-MS Head Space - volatile substances
    • Ion chromatography - small cations and anions

Analysis of results:

After the extraction and release tests, the results are analysed to identify the chemical substances released and quantify them using material databases. The aim is to determine whether these substances are present in concentrations likely to pose a health risk.

The concentrations obtained are compared with safety thresholds, which can be determined from toxicological databases or regulatory references.

A strategic and regulatory approach

The use of ISO standards 10993-18 and 10993-12 is not limited to a compliance requirement. It is part of a strategic approach to risk management, making it possible to:

• Anticipate potential points of non-compliance
• Reduce in vivo testing by using reliable chemical data
• Speed up the certification process and time-to-market

Our expertise for your compliance

At Applus+ Laboratories, we support you at every stage of the biological evaluation of your medical devices. Our laboratories have the most advanced analytical equipment and recognised expertise in chemical characterisation to ISO 10993-18, as well as in sample preparation to ISO 10993-12.

We can help you:

• Develop a test strategy tailored to your device
• Carry out the chemical analyses, interpret the results and prepare the final report for your regulatory submissions
• Optimise your development times by avoiding unnecessary testing