ISO 10993-18

ISO 10993-18 is the standard published by the International Organisation for Standardisation (ISO) entitled ‘Biological evaluation of medical devices – Part 18: Chemical characterisation of materials for medical devices within a risk management process’, i.e. ‘Biological evaluation of medical devices – Part 18: Chemical characterisation of materials for medical devices within a risk management process’

Regulatory status and version note: The current base text of the standard is ISO 10993-18:2020 (fourth edition) and has been updated by Amendment 1 (A1:2022). At European level, EN ISO 10993-18:2020+A1:2023 has been adopted. The standard has been recognised as a harmonised standard under the EU Medical Devices Regulation (MDR 2017/745) (Annex ZA); it is also recognised by the FDA. The current consolidated version should be checked against the relevant official sources prior to submission.

The main purpose of the standard is to define the role of chemical characterisation in the assessment of the biological safety of medical devices, as well as how this characterisation fits into the risk management process (ISO 14971). ISO 10993-18 does not replace biological testing, but contributes to the reduction of animal testing (3Rs) by utilising chemical data as part of the ‘weight-of-evidence’ approach.

The key elements of the standard are as follows:

1. Recording of information on materials and equipment

Informationen zu den Herstellungsmaterialien, der Formulierung, dem Herstellungsprozess (Formpressen, Extrudieren, Beschichten usw.), dem Sterilisationsverfahren und der Verpackung des Geräts
Safety data sheets (SDS), certificates and information on composition received from raw material suppliers
Material history, previous data on chemical characterisation and the literature

2. Extraction studies

Zur Bestimmung der Stoffe, die aus dem Medizinprodukt freigesetzt werden können (Extrakte), werden Extraktionsuntersuchungen gemäß ISO 10993-12 durchgeführt. Die Norm definiert drei grundlegende Extraktionsarten:

Extraktion unter simulierten Anwendungsbedingungen (simulated-use extraction): Extraktion unter Bedingungen, die klinische Anwendungsbedingungen nachahmen (z. B. Körpertemperatur, physiologische Lösungsmittel, Kontaktzeit)
Exaggerated extraction: A more comprehensive determination of potentially extractable substances using conditions that are more aggressive than clinical conditions (higher temperature, longer duration, stronger solvents)
Exhaustive extraction: the recovery of as many substances as possible that can be extracted from the material; determination of the material’s ‘worst-case’ profile

3. Analytical characterisation

Various analytical techniques are used to identify and quantify the substances contained in the extracts:

Volatile and semi-volatile organic compounds: GC-MS, GC-FID, headspace GC-MS
Non-volatile organic compounds: HPLC-UV/DAD, LC-MS, LC-MS/MS, LC-HRMS (high-resolution mass spectrometry)
Elemental analysis (metals): ICP-MS, ICP-OES
Ionic compounds: ion chromatography (IC)
Total organic carbon (TOC): Assessment of overall organic pollution
FTIR, NMR: Structural elucidation and confirmation

4. Analytical Evaluation Threshold (AET)

One of the most important concepts in the standard is the Analytical Evaluation Threshold (AET). The AET is a threshold value which, when assessing the extract profile, determines which substances are toxicologically relevant and which can be disregarded. The AET is usually calculated on the basis of the ‘Threshold of Toxicological Concern’ (TTC) approach or substance-specific toxicological data. Substances below the AET can generally be excluded from the toxicological risk assessment.

5. Assessment of leachability

The distinction between the terms ‘extractable’ (extractable) and ‘leachable’ (strong) (actually released during clinical use) is central to the standard. Extraction studies generally determine the profile of extractable substances; however, actual clinical exposure (leachable) may differ from this. The leachable assessment is carried out on the basis of simulated conditions of use or clinical usage data.

6. Toxicological risk assessment

A toxicological risk assessment is carried out for the substances identified in the AET. This assessment covers existing toxicological data, TTC, read-across, structure-activity relationships (SAR/QSAR) and an exposure assessment.
The results are used in the assessment of the product’s biological safety (ISO 10993-1).

7. Relationship with biological tests

Where appropriate, chemical characterisation enables the reduction or replacement of certain biological tests. This applies in particular to cytotoxicity tests (ISO 10993-5) and certain systemic toxicity tests. However, for local tissue effects, sensitisation, genotoxicity and implantation, chemical data alone are generally insufficient and must be evaluated in conjunction with biological tests.

The key parameters reported in the study are as follows:

Information on the device’s materials and manufacture (safety data sheet, certificates, composition)
Type of extraction (simulated use, excessive use, consumption) and extraction conditions (in accordance with ISO 10993-12)
Analytical methods used and limits of detection
AET value and rationale for the calculation
List of identified substances, their concentrations and degree of identification (certain, probable, unknown)
Toxicological data and risk assessment for each substance
Overall assessment of substances below the AET value
Uncertainty assessment for unknown substances
Reasons for the need for biological tests
Data on measurement uncertainty and repeatability

Why is this being done?

ISO 10993-18 is used for the following scientific and regulatory purposes:

Establishing a basis for the biological safety assessment: comprehensive identification and quantification of substances that may be released from the medical device
Reduction of animal testing (3Rs): Avoiding unnecessary animal testing by assessing biological risk on the basis of chemical data; compliance with the MDR and the FDA Modernisation Act 2.0
Integration into the risk management process: assessment and mitigation of the product’s chemical risks in accordance with ISO 14971
MDR compliance: Provision of the chemical data required for the biological safety assessment in accordance with the EU Medical Devices Regulation (2017/745)
Materials and Process Development: Early detection of potentially hazardous substances and production residues during the product development process
Supply chain management: Assessing the purity of raw materials and the impact of changing suppliers
Assessment of sterilisation efficacy: identification of degradation products and residues formed following sterilisation (e.g. EO, gamma, e-beam)
Packaging interaction: Assessment of substances that may migrate from the packaging into the medical device
Support with regulatory documentation: Use as a key component of the biocompatibility dossier for applications to the FDA, in accordance with the EU MDR and other regulatory authorities
Approach to the weight of evidence: contribution to the holistic assessment of the medical device in conjunction with other biological tests (ISO 10993-3, -4, -5, -6, -10, -11, -23) and clinical data

ISO 10993-18 alone does not guarantee the product’s full biological safety profile. Chemical characterisation cannot replace biological testing, particularly for endpoints such as local tissue effects, sensitisation and genotoxicity. The results must be interpreted in conjunction with other biological tests, clinical data and an exposure assessment.

As NanoTest, we carry out chemical characterisation tests in accordance with ISO 10993-18 with scientific rigour, drawing on our accredited laboratory facilities and our quality management system.

For your chemical characterisation studies in accordance with ISO 10993-18, you can contact NanoTest to obtain information on the evaluation of material data, extraction strategies, the selection of analytical methods, AET calculations, toxicological risk assessment and reporting procedures.

Standards