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EN ISO 10993-10

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EN ISO 10993-10:2023

EN ISO 10993-10:2023 is the European version of the standard ‘Biological evaluation of medical devices – Part 10: Tests for skin sensitisation’, i.e. ‘Biological evaluation of medical devices – Part 10: Tests for skin sensitisation’. The base text ISO 10993-10:2021 (fourth edition) has been adopted unchanged as EN ISO 10993-10:2023. The scope of the standard defines procedures for assessing the potential of medical devices and their components to cause skin sensitisation (delayed hypersensitivity)[reference:1].

Changes to the regulatory status and scope: Whilst the 2010 version of the standard covered both irritation and skin sensitisation tests, the 2021 version focuses exclusively on skin sensitisation. Irritation tests have been transferred to the ISO 10993-23:2021 standard[reference:2][reference:3]. However, the 2010 version continues to be used as a historical reference point in some regulatory contexts and when assessing existing documentation[reference:4]. EN ISO 10993-10:2023 has been recognised as a harmonised standard under the EU Medical Devices Regulation (MDR 2017/745).

The basic principle of the standard is to assess whether chemicals released from materials or extracts of medical devices cause a delayed hypersensitivity reaction following skin contact. For methods of extract preparation, reference is made to ISO 10993-12[reference:6]. The assessment is carried out as part of a tiered approach (tiered testing strategy); following chemical characterisation and the evaluation of the available data, suitable biological tests are selected[reference:7].

The main test methods used within the scope of the standard are as follows:

In vivo methods (compulsory/main methods)

  • Guinea Pig Maximisation Test (GPMT): an adjuvant-based method (Freund’s Complete Adjuvant); considered to be the most sensitive guinea pig test[reference:8]. It comprises induction and challenge phases via intradermal and topical application.
  • Buehler test (closed-patch test): induction and provocation without an adjuvant, using an occlusive plaster; it is less sensitive than the GPMT, but does not require the use of an adjuvant[Reference:9].
  • Murine local lymph node assay (LLNA): An alternative in vivo method based on topical application to the mouse ear and the measurement of lymph node cell proliferation [Reference: 10]. Validated in accordance with OECD TG 429.

In vitro alternatives (Annex C – for information)

Appendix C of the standard lists the in vitro methods for skin sensitisation validated under OECD Guideline TG 442 [Reference:11]. These methods include RhE-based tests (Reconstructed Human Epidermis), h-CLAT, LuSens, SENS-IS, EpiSensA and GARDskin [Reference:12] [Reference:13]. However, a significant limitation is that these methods have not been fully validated for extracts from medical devices and cannot fully replace in vivo tests in marketing authorisation applications [reference:14][reference:15].

The key parameters reported in the study are as follows:

  • Test method used (GPMT, Buehler, LLNA or in vitro) and the rationale for its selection
  • Conditions for the preparation of the test substance/extract (in accordance with ISO 10993-12)
  • Usage, dosage/concentrations and excipient (vehicle)
  • Conditions of the induction and challenge phases
  • Skin reaction scores following the challenge (erythema, oedema)
  • Number/percentage of animals that responded
  • For the LLNA: Stimulation Index (SI)
  • For in vitro tests: cell viability and biomarker levels
  • Validity of the positive and negative controls
  • Result: Assessment and justification: ‘sensitising / non-sensitising’
  • Data on measurement uncertainty and repeatability

Why is the test carried out?

EN ISO 10993-10 is carried out for the following scientific and regulatory purposes:

  • Assessment of the safety of medical devices: Determination of the potential of product materials or their extracts to cause skin sensitisation (contact allergy) in patients
  • MDR compliance: Provision of the data required for the biological safety assessment under the EU Medical Devices Regulation (2017/745)
  • Risk management: Assessment and mitigation of the sensitisation risk associated with the parts of the product that come into contact with the patient and the user
  • Material selection and development: Early identification of potentially sensitising materials and evaluation of alternatives as part of the product development process
  • 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
  • Animal welfare (3Rs): Use of in vitro alternatives and a tiered approach wherever possible; support for regulatory trends towards reducing animal testing in accordance with the MDR and the FDA Modernisation Act 2.0[reference:17]
  • Approach to assessing the weight of evidence: Contribution to the holistic assessment of the product in conjunction with data on chemical characterisation (ISO 10993-18), cytotoxicity (ISO 10993-5), irritation (ISO 10993-23) and other biocompatibility data

EN ISO 10993-10 does not, on its own, cover the entire biocompatibility profile of the product. The results must be interpreted in conjunction with chemical characterisation, other biological tests and clinical data. As regulatory acceptance of in vitro alternatives for extracts from medical devices has so far been limited, in vivo data may be required in critical cases.

As part of our nano-testing services, we carry out skin sensitisation assessments in accordance with EN ISO 10993-10, utilising our accredited laboratory facilities and quality management system, and applying scientific rigour. Our scope of services includes the following:

Drawing up the test strategy and protocol

  • Establishment of a multi-stage testing strategy based on the nature of the contact, the duration of contact and the material composition of the product
  • Evaluation of the available chemical characterisation (ISO 10993-18) and toxicological data
  • Selection and justification of the appropriate test method (GPMT, Buehler, LLNA or in vitro)
  • Establishment of a strategy for extract preparation in accordance with ISO 10993-12 (polar/non-polar solvents, temperature, duration)[reference:18]
  • Planning of positive and negative controls; compliance with ethical and regulatory requirements

Please feel free to contact Nano-Test for information on test strategies, choice of methods, extract preparation, sample acceptance criteria, test schedules and reporting procedures in connection with your skin sensitisation assessments in accordance with EN ISO 10993-10.

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