The biological evaluation of medical devices is the structured demonstration that the materials of a product and the substances that can be released from them do not cause unacceptable biological risks under the intended conditions of use. It is conducted as a process within risk management and documented in a dedicated report known in English as the Biological Evaluation Report, abbreviated BER. The basis is the general safety and performance requirements of Annex I of Regulation (EU) 2017/745 and the ISO 10993 series of standards. Biological evaluation is not a testing program, but a reasoned evaluation chain: review the data situation, identify gaps, perform only the tests that are actually required, and classify the results toxicologically.
Legal Basis in the Regulation
Annex I Section 10 of Regulation (EU) 2017/745 requires that products be designed and manufactured such that the properties of the materials used and their interaction with tissues, cells, and body fluids correspond to the intended purposes; toxicity, flammability, and the release and uptake of substances are explicitly mentioned. Section 10.4 sets out specific requirements for carcinogenic, mutagenic, reprotoxic, and endocrine-disrupting substances. Annex II Section 6.1(b) explicitly lists biocompatibility, including the identification of all materials in direct or indirect contact with patients or users, as part of the preclinical data and requires test design, protocols, analytical methods, and results. If new tests are waived, this decision must be explicitly justified under Annex II, for example with tests on identical materials from a legally marketed predecessor product.
Normative Basis of the ISO 10993 Series
ISO 10993-1:2018 describes the general principles of biological evaluation within a risk management process and categorizes products by type of body contact in Section 5.2 and by contact duration in Section 5.3 into limited, prolonged, and permanent contact. From this categorization, the endpoint table in Annex A derives which biological endpoints are to be considered, such as cytotoxicity, sensitization, irritation, systemic toxicity, genotoxicity, implantation behavior, or hemocompatibility. The other parts of the series provide the methods: Part 18 for chemical characterization, Part 17 for toxicological risk assessment of constituents, Part 12 for sample preparation, Part 10 for sensitization testing and Part 23 for irritation testing, Parts 9 and 15 for degradation products. Several of these parts are listed as harmonized standards to the Regulation in Implementing Decision (EU) 2021/1182 as amended; Part 1 itself is not listed there, which does not limit its application as state of the art but removes the presumption of conformity.
Evaluation Plan and Data Gap Analysis
The starting point is a biological evaluation plan that defines the intended purpose, type and duration of contact, list of materials, manufacturing steps including sterilization, and the endpoints to be considered. The report then compiles the material and process characterization, the evaluation of existing data from literature, predecessor products, and supplier documentation, the data gap analysis derived from this, the tests performed, and their evaluation.
Toxicological Evaluation and Report Conclusion
The core is the toxicological risk assessment: releasable substances are quantified, compared with tolerable intake levels, and assessed in relation to clinical exposure. The report concludes with an explicit conclusion on biological safety and is the responsibility of a professionally qualified person, typically with toxicological training. Changes to materials, suppliers, cleaning, or sterilization procedures trigger a re-evaluation.
Distinction from Clinical Evaluation and Risk Management
Biological evaluation is a preclinical evaluation of materials and releases; it does not make statements about the clinical benefit or performance of the product. This task is fulfilled by the Clinical Evaluation Report, which integrates clinical data and the benefit-risk conclusion and uses the biological evaluation only as an input. Likewise, it is not a substitute for risk management for medical devices, but provides it with the biological hazards, evaluations, and residual risk statements. The related term biocompatibility of medical devices refers to the property to be evaluated, whereas biological evaluation refers to the procedure by which this property is demonstrated. Both reports are independent components of the technical documentation and are reviewed separately in audits.
Relevance for clinical trials
Before the start of a clinical investigation, the biological safety of the investigational device must be demonstrated preclinically. Annex XV of Regulation (EU) 2017/745 requires information on the preclinical evaluation for the application for authorization, and the investigator’s brochure relies on the results of the biological evaluation when describing residual risks, contraindications, and warnings. Ethics committees and competent authorities regularly assess whether the endpoint selection matches the planned type and duration of contact and whether data gaps are plausibly justified.
If a material, supplier, or sterilization procedure is changed during the study, it must be assessed whether a substantial modification exists and whether the biological evaluation must be updated. Full-service CROs such as Mediconomics support manufacturers and sponsors in structuring the preclinical data situation before submission and keeping the biological evaluation consistent with the investigation plan, investigator’s brochure, and technical documentation.
Frequently Asked Questions (FAQ)
Must separate biocompatibility tests be performed for each product?
No. ISO 10993-1 requires first the evaluation of existing data. Tests are only required for the remaining data gaps; a waiver must be justified in writing according to Annex II of the Regulation.
How often must the report be updated?
On an event-driven basis. Triggers include changes to materials, suppliers, manufacturing, cleaning, or sterilization processes, new toxicological findings, and results from post-market surveillance.
Is a supplier certificate on material quality sufficient?
No. Material certificates demonstrate the identity and purity of the starting material, not the biological safety of the finished, processed, and sterilized product. The product in its final state is always evaluated.
Regulatory References
- Regulation (EU) 2017/745, Annex I Sections 10 and 10.4
- Regulation (EU) 2017/745, Annex II Section 6.1(b)
- ISO 10993-1:2018, Sections 5.2 and 5.3 and Annex A
- ISO 10993-12, -17, -18, and -23 on sample preparation, toxicological risk assessment, chemical characterization, and irritation testing
- Implementing Decision (EU) 2021/1182 as amended, list of harmonized standards to the MDR
