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EN ISO 10993-11

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EN ISO 10993-11

EN ISO 10993-11 is a standard published by the International Organisation for Standardisation (ISO) and adopted by the European Committee for Standardisation (CEN), entitled ‘Biological evaluation of medical devices – Part 11: Tests for systemic toxicity”, i.e. “Biological evaluation of medical devices – Part 11: Tests for systemic toxicity”.

Regulatory status and version note: The main text of the standard is ISO 10993-11:2017 (fourth edition) and was adopted at European level as EN ISO 10993-11:2018. The standard has been recognised as a harmonised standard under the EU Medical Devices Regulation (MDR 2017/745). The current consolidated version, any amendments and the scope of recognition by the FDA should be checked against the relevant official sources before submitting an application.

Das Grundprinzip der Norm ist die Bewertung der systemischen toxischen Wirkungen, die nach dem Eindringen von extrahierbaren/löslichen Stoffen aus den Materialien des Medizinprodukts oder aus dem Produkt selbst in den Körper auftreten können. Die Bewertung richtet sich (im Rahmen von ISO 10993-1) nach der Art und Dauer des Kontakts des Produkts und erfolgt nach dem „Weight-of-Evidence“-Ansatz. Nach der Auswertung der chemischen Charakterisierung (ISO 10993-18), des Extrakt- und Auslaugungsprofils, der Materialhistorie und der Literaturdaten werden die erforderlichen Prüfungen ausgewählt; dabei wird unnötiger Tierversuch vermieden.

Systemic toxicity tests are carried out using extracts prepared in accordance with ISO 10993-12, or, where necessary, directly with the medical device or material. The route of administration is selected to reflect the clinical route of administration of the product and the physicochemical properties of the extract; common routes of administration include intravenous (IV), intraperitoneal (IP), oral (tube feeding), dermal and inhalation. Intravenous administration is the most commonly used route for assessing systemic exposure to extracts.

Test categories

1. Acute systemic toxicity

  • Single dose; usually administered intravenously (IV) to mice or rats
  • The observation period is usually 72 hours (up to 7 days in some protocols)
  • Clinical symptoms, body weight and mortality are assessed
  • Relevant OECD references: TG 420, TG 423, TG 425 (oral); for acute inhalation and dermal exposure: TG 403, TG 402

2. Subacute (repeated doses, short-term) systemic toxicity

  • Usually repeated administration over 14–28 days
  • Clinical observation, body weight, feed and water intake, haematology, clinical chemistry, organ weights and histopathology
  • Relevant OECD reference: TG 407 (28-day repeated oral administration)

3. Subchronic systemic toxicity

  • Usually 90 days of repeated administration
  • The endpoints are the same as those in the subacute study; the aim is to determine the NOAEL/LOAEL
  • Related OECD reference: TG 408 (90-day repeated oral administration)

4. Chronic systemic toxicity

  • Administration usually lasting longer than 90 days (e.g. 6–12 months)
  • Is assessed for permanent implants and scenarios involving long-term exposure; however, it is not routinely required for every device
  • Relevant OECD reference: TG 452 (chronic toxicity) – Principles

5. Pyrogenicity due to the material

  • Assessment of the fire-starting potential of appliance extracts
  • The conventional method is the rabbit pyrogen test; alternatively, the validated Monocyte Activation Test (MAT) may be used
  • The determination of bacterial endotoxins (LAL/TAL method) constitutes a separate requirement and is distinct from material-related pyrogenicity; both must be assessed together

The key parameters reported in the study are as follows:

  • Justification for the scope of the assessment and the type of test (acute, subacute, subchronic, chronic, pyrogenicity)
  • Extraction conditions (in accordance with ISO 10993-12: apparatus, temperature, duration, surface-to-volume ratio, concentration)
  • Route of administration, dose/concentration and frequency of administration
  • Test system (type, sex, age, number)
  • Findings from clinical observation and the course over time
  • Body weight, changes in food and water intake
  • Haematology and clinical chemistry parameters
  • Organ weights (absolute/relative) and macroscopic findings
  • Histopathological findings
  • For pyrogenicity: rise in body temperature or MAT results
  • Validity of the positive and negative controls
  • Result: Assessment of systemic toxicity (dose at which an effect was/was not observed) and justification
  • Data on measurement uncertainty and repeatability

What is the purpose of the examination?

EN ISO 10993-11 is carried out for the following scientific and regulatory purposes:

  • Assessment of patient safety: determination of the potential for substances released from the product to enter the systemic circulation and cause toxic effects in the target organs
  • MDR compliance: Provision of the data required for the assessment of biological safety under the EU Medical Devices Regulation (2017/745)
  • Risk management: Assessment and mitigation of the risks associated with systemic exposure, depending on the nature and duration of contact with the medical device
  • Integration into the assessment of extractable and leachable substances: combining the results of chemical characterisation (ISO 10993-18) with the toxicological risk assessment
  • Assessment of pyrogenicity risk: determination of the potential of device extracts to trigger an inflammatory response; assessment of material-related pyrogenicity, independent of endotoxin contamination
  • Materials and Design Development: Early identification of potentially systemically toxic substances and high-risk materials as part of the product development process
  • Weighted evidence and the 3Rs: avoiding unnecessary animal testing by making use of existing data and chemical characterisation; conducting tests only where necessary and with an appropriate design
  • Support with regulatory documentation: for use as part of the biocompatibility dossier in applications to the FDA, in accordance with the EU MDR and other regulatory authorities
  • Approach to evidence weighting: cytotoxicity (ISO 10993-5), genotoxicity (ISO 10993-3), haemocompatibility (ISO 10993-4), implantation (ISO 10993-6), sensitisation (ISO 10993-10) and irritation (ISO 10993-23) – Contribution to the holistic assessment of the medical device

EN ISO 10993-11 does not, on its own, cover the entire biocompatibility profile of the product; local effects, sensitisation, genotoxicity and haemocompatibility are assessed in accordance with separate standards. Furthermore, systemic toxicity tests may not reflect the full extent of clinical exposure; the results should be interpreted in the context of chemical characterisation, other biological tests, product design and clinical data.

As part of our nano-testing services, we carry out systemic toxicity assessments in accordance with EN ISO 10993-11, applying scientific rigour and drawing on our accredited laboratory facilities and quality management system. Our scope of services includes the following:

Development of test strategies and protocols

  • Determination of the scope of assessment in accordance with the type of contact, the duration of contact and the material composition of the medical device
  • Chemical characterisation (ISO 10993-18), assessment of the profile of extractable/leachable substances, the material history and literature data (weighted evidence)
  • Selection and justification of the required test type (acute, subacute, subchronic, chronic, pyrogenicity)
  • Determination of an extraction strategy in accordance with ISO 10993-12 (apparatus, temperature, duration, surface-to-volume ratio, concentration)
  • Selection of the route of administration (intravenous, intraperitoneal, oral, dermal, inhalation) according to the clinical application
  • Planning of species, sex, age, dosage levels and control groups
  • Compliance with requirements relating to ethical approval, animal welfare and the 3Rs principles

For information on test strategies, test types and the choice of routes of administration, extract preparation, sample acceptance criteria, the test schedule and reporting procedures as part of your systemic toxicity and pyrogenicity assessments in accordance with EN ISO 10993-11, please feel free to contact NanoTest.

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