ISO 10993-17

ISO 10993-17, the standard published by the International Organisation for Standardisation (ISO) entitled ‘Biological evaluation of medical devices – Part 17: Toxicological risk assessment of components of medical devices”, i.e. “Biological evaluation of medical devices – Part 17: Toxicological risk assessment of components of medical devices”

Regulatorischer Status und Versionshinweis: Der aktuelle Grundtext der Norm ist ISO 10993-17:2023 (zweite Ausgabe) und wurde auf europäischer Ebene als EN ISO 10993-17:2023 angenommen. Diese Ausgabe hat den Geltungsbereich im Vergleich zur ersten Ausgabe aus dem Jahr 2002 deutlich erweitert: Während sich die Ausgabe von 2002 im Wesentlichen auf die Festlegung zulässiger Grenzwerte (allowable limits) für auslaugbare Stoffe konzentrierte, bietet die Fassung von 2023 einen ganzheitlichen Rahmen für die toxikologische Risikobewertung (TRA) aller Komponenten von Medizinprodukten. Der Harmonisierungsstatus im Rahmen der MDR 2017/745 und der Umfang der Anerkennung durch die FDA sollten vor der Einreichung eines Antrags anhand der entsprechenden offiziellen Quellen überprüft werden.

The main purpose of the standard is to provide a toxicological interpretation of the data generated in accordance with ISO 10993-18 (chemical characterisation) and to assess the biological safety of the product within the framework of risk management in accordance with ISO 14971. In other words: whilst ISO 10993-18 answers the question ‘What is present and in what quantities?’, ISO 10993-17 answers the question ‘Are these quantities safe?’.

1. Problem formulation

The starting point for the assessment is the definition of the intended purpose of the medical device, the nature and duration of contact, the patient group (adults, children, vulnerable groups), the route of exposure and the scope of the assessment. This phase establishes the scientific framework for all subsequent steps.

2. Hazard Identification

Identification of product components (polymers, additives, process residues, sterilisation residues, degradation products, substances originating from the packaging, metals)
Review of the available toxicological data and health-based guidelines (HBGV) for each constituent: ADI, TDI, RfD, MRL, OEL, WHO guidelines for drinking water, etc.
Systematic identification of data gaps and uncertainties

3. Hazard characterisation and dose-response relationship

The ingredients are divided into two groups:

Substances with HBGV: Using the existing guideline values, tolerable exposure levels (TE) or allowable limits (AL) are derived, adjusted to reflect exposure from the equipment. This adjustment takes into account the duration of exposure, vulnerable population groups and uncertainty factors.
Ingredients without HBGV: The TTC approach (Threshold of Toxicological Concern) is used used. Specific thresholds (very low exposure levels) apply to the Cramer classification, genotoxic structural alerts and DNA-reactive carcinogens.

Specific endpoints are also taken into account:

Genotoxicity: Structural warning signs and in silico/in vitro data are assessed; for DNA-reactive carcinogens, the TTC approach is applied.
Awareness-raising: In most cases, a qualitative assessment is carried out; the thresholds are limited and, in the context of the equipment, require further justification.
Local effects (irritation/corrosion): Assessment is generally carried out using biological tests (ISO 10993-23); the results are used as supporting data within the TRA.
Reproductive/developmental toxicity and neurotoxicity: The assessment is based on the available data and structural warning signs; a more conservative approach is required for paediatric populations.

4. Exposure Assessment

Calculation of the estimated exposure dose (EED) based on the clinical use of the product: normalisation to body weight (mg/kg/day), contact area, duration and frequency
Conversion of extraction data (ISO 10993-18) to clinical exposure (justification of the differences between the extraction conditions and clinical conditions)
Separate scenarios for different age groups and patient groups
Total exposure (aggregated): exposure to the same substance from multiple sources or via multiple products

5. Risk characterisation

The exposure is compared with the tolerable limit. Common approaches:

Margin of Safety (MOS): the ratio of the TE or AL value to the estimated exposure; an MOS ≥ 1 is generally regarded as acceptable (based on device-specific criteria and regulatory guidelines)
Exposure/TE ratio: If the ratio is < 1, the risk is considered acceptable
Where several components have a similar mechanism of action (MoA), assessment of additivity

6. Uncertainty and Iteration

Assessment of data gaps, analytical uncertainty, interspecific differences and population sensitivity
If the risk is classified as unacceptable, recommendations for the collection of additional data (chemical or biological) or changes to the device design
Updating the assessment throughout the product lifecycle (changes to design, materials, sterilisation or suppliers)

The key parameters reported in the study are:

Scope of the assessment and problem formulation
List of components, concentrations and route of exposure
For each ingredient, HBGV or TTC, and its source
Derived TE/AL values and uncertainty factors
EED calculation and assumptions
MOS or exposure/TE ratio
Assessment of additivity (where applicable)
Uncertainty analysis and data gaps
Result: acceptable / unacceptable and reasons
Recommendations (further tests, design changes, monitoring)

Why is it carried out?

ISO 10993-17 is used for the following scientific and regulatory purposes:

Toxicological interpretation of chemical data: Quantitative assessment of the risk to human health posed by the substances defined in ISO 10993-18
Reduction of biological tests (3Rs): Avoiding unnecessary animal testing through sound chemical and toxicological justification
Integration of risk management: identification, assessment and control of the product’s chemical risks within the framework of ISO 14971
MDR compliance: Provision of the necessary toxicological justification for the biological safety assessment under the EU Medical Devices Regulation (2017/745)
Justification for the need for biological tests: Scientific determination of which endpoints can be covered by chemical data and for which biological tests are required
Materials and process development: Early identification of high-risk components and selection of alternative materials/processes
Sterilisation and degradation products: Risk assessment of EO/ECH, radiolysis products and hydrolytic degradation products
Protection of vulnerable population groups: a conservative assessment for paediatric, neonatal and pregnant patients, and patients with long-term implants
Support with regulatory documentation: Use as a toxicological risk assessment report for applications submitted to the FDA, in accordance with the EU MDR and other regulatory authorities
Approach to the weight of evidence: A contribution to the holistic evaluation of chemical, in vitro and in vivo data within the framework of ISO 10993-1

ISO 10993-17 is an evaluation standard, not a testing standard; it does not generate data itself, but interprets existing data scientifically. The results depend directly on the quality of the chemical characterisation and the scope of the available toxicological data.

As NanoTest, we carry out toxicological risk assessments in accordance with ISO 10993-17 with scientific rigour, drawing on our accredited laboratory facilities and our quality management system.

For information on the processes of problem formulation, the application of HBGV/TTC, TE/AL derivation, exposure assessment, MOS calculation and report generation as part of your toxicological risk assessments in accordance with ISO 10993-17, please feel free to contact NanoTest.

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