The path to biosafety of medical devices

In this blog post, we focus on the biological evaluation of medical devices, a crucial step in ensuring biocompatibility and patient safety. The post guides you through the fundamentals of biocompatibility, highlights the requirements of the MDR, and explains the significant role of the comprehensive EN ISO 10993 series of standards, which comprises many parts and addresses various aspects of biological safety. The most important and fundamental part is EN ISO 10993-1, which specifies the general requirements and procedures for biological evaluation.

Furthermore, we offer a detailed insight into the latest changes to the standard as well as the strategic steps for test planning and risk assessment. This article demonstrates what a modern test strategy can look like, taking into account material characterization and alternative methods for reducing animal testing, and provides practical guidance on complete documentation in the Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER). Our aim is to impart sound knowledge to effectively implement the complex requirements of biological evaluation while simultaneously ensuring the highest safety standards for medical devices.

Underlying regulations

EU Regulation 2017/745 (MDR)

EN ISO 10993-1

1 Introduction

Biocompatibility—the ability of a material to avoid adverse reactions when in contact with the human body—is a crucial factor for the safety of medical devices. Whether a product comes into direct contact with tissue, blood, or other bodily fluids, or acts indirectly on organs and systems, biological safety must always be guaranteed. Ultimately, the patient's well-being depends on it. The challenge for manufacturers is to ensure that every material, substance, and combination of components used has no undesirable effects on the human organism. This includes not only direct physical interactions but also chemical interactions that can arise from degradation products or changes within the body. Safety during repeated use is also important, as some products remain in contact with the human body for extended periods.

The Medical Device Regulation (MDR) sets out strict requirements for this, obligating manufacturers to conduct comprehensive biological assessments and document them carefully. Annex I, section 10.2, specifies the essential safety and performance requirements that every medical device must meet to ensure safe use. Annex II, section 6.1, further requires complete documentation of the biological assessment as part of the technical documentation.

"The products are designed, manufactured and packaged in such a way as to minimize the risks to patients from harmful substances and residues, taking into account the intended purpose of the product, as well as to transport, storage and handling personnel. Particular attention is paid to tissues exposed to these harmful substances and residues, as well as to the duration and frequency of exposure." (MDR Annex I, paragraph 10.2)

“Detailed information on the test setup, complete test or study protocols, methods of data analysis, in addition to data summaries and test results, in particular regarding the biocompatibility of the product, including the identification of all materials in direct or indirect contact with the patient or user […].” (MDR Annex II, paragraph 6.1)

2. The standard EN ISO 10993-1

EN ISO 10993 is the basic standard in a comprehensive series of standards for the biological evaluation of medical devices. This series comprises many specific parts, each covering different aspects of biocompatibility. The most important and fundamental part of this series is EN ISO 10993-1, which defines the general requirements and procedures for biological evaluation. This standard plays a crucial role in the approval process, as it provides manufacturers with clear guidelines on how to identify, minimize, and document potential biological risks. Compliance with EN ISO 10993-1 is therefore often a prerequisite for meeting the safety and performance requirements of the MDR (Medical Device Regulation).

The new version of EN ISO 10993-1:2020 introduces several changes and additions to make the assessment even more precise and reliable. Particular emphasis is placed on the need for integrated risk management that considers not only the chemical composition of the product, but also potential long-term effects and degradation products in the body.

A further, updated version of EN ISO 10993-1 is currently in draft form and introduces significant innovations designed to make the biological assessment process even more comprehensive and specific. These changes include new wording and more precise definitions intended to ensure more consistent interpretation. In addition, a new section is being introduced that describes specific requirements for the entire life cycle of a product, thus supporting a more holistic approach to biological safety.

The standard itself aims to provide manufacturers with a structured procedure for biological assessment that covers all relevant aspects of biocompatibility. Its scope encompasses all medical devices that come into direct or indirect contact with the human body – from skin contact and implantable products to products that enter the bloodstream. Key terms and definitions therefore include central concepts such as biocompatibility , risk analysis , and material compatibility , ensuring a common language and uniform testing standards.

The fundamental principles of EN ISO 10993-1 are based on a risk-based approach: First, the product design is analyzed to assess potential contact with the body and the material composition. Then, depending on the risk profile, specific biological tests are defined – from cytotoxicity and sensitization to long-term tests. This structured approach helps manufacturers to systematically identify and minimize all biological risks in order to ensure product safety throughout its entire life cycle.

3. Biological assessment and testing strategy

The biological evaluation and testing strategy for medical devices is a structured process designed to ensure the safety and biocompatibility of a product throughout its entire life cycle. This systematic approach to biological evaluation is clearly illustrated in Figure 1 of EN ISO 10993-1.

Figure 1: Systematic approach to biological evaluation (According to Figure 1 from EN ISO 10993-1)

A key aspect of biological assessment is now material characterization according to EN ISO 10993-18. Detailed physicochemical characterization of materials and their potential degradation products allows many risks to be identified and minimized early on. This reduces the need for extensive in vivo testing and supports the use of alternative testing methods.

Annex A of EN ISO 10993-1 describes specific biological endpoints that must be evaluated depending on the type and application of the medical device. The product is first assigned to a category:

• Medical devices that only come into contact with the body surface,
• Products that come into external contact with the body's interior
• Implantable medical devices

Furthermore, the contact will be determined:

• Medical devices that only come into contact with the body surface:
  • Intact skin
  • Mucosa
  • Injured or damaged skin areas
• Products that come into external contact with the body's interior
  • Blood vessel system, indirectly
  • Tissue/Bone/Dentin
  • Circulating blood
• Implantable medical devices
  • Tissue/bone
  • blood

and the contact duration is defined, which is divided into levels A (≤24 h), B (>24 h to 30 d) and C (>30 d).

This detailed categorization helps to define a specific testing strategy for each product. The choice of tests depends not only on the type of contact but also on the expected long-term effects and the potential risks posed by degradation products. A comprehensive risk analysis can often demonstrate that certain tests are unnecessary, thus avoiding unnecessary animal testing.

Figure 2: Example table from Annex A of EN ISO 10993-1:2020 for medical devices that come into contact with the body surface

These endpoints must be evaluated in detail in the Biological Evaluation Report (BER). However, this does not mean that all endpoints must necessarily be tested like a checklist. EN ISO 10993-1 also allows the use of existing data, such as scientific literature or other validated information, to cover certain endpoints. This provides a basis for justifying why some tests can be omitted, provided the available data support the biological safety assessment. This enables a targeted and resource-efficient evaluation that still meets all relevant safety requirements.

This enables a flexible assessment that meets both safety requirements and ethical considerations by minimizing animal testing as much as possible. The integration of alternative testing methods, such as in vitro procedures and computer-based simulations, is an essential component of modern biological assessment.

4. Documentation and reporting

A crucial component of the biological safety assessment of medical devices is meticulous documentation, ensuring that all assessment and testing processes are recorded in a traceable and transparent manner. Two key documents play a vital role in this: the Biological Evaluation Plan (BEP) and the Biological Evaluation Report (BER).

The Biological Evaluation Plan (BEP) defines the strategy for the biological evaluation of the product:

• Product description: Details on components, materials and manufacturing processes.
• Intended use and type of contact: Information on the intended use and type of physical contact.
• Manufacturing process: Description of the manufacturing process and the auxiliary materials used.
• Reusable products: Information on cleaning and/or sterilization.
• Physical/chemical information: Existing data for characterizing the medical device and the materials it contains.
• Risk assessment: Identification of biological endpoints.
• Existing biological safety data: Existing biological tests.
• GAP analysis: A gap analysis to identify missing information in current security data.
• Test strategy: Selection and justification of the necessary tests, including physicochemical characterization according to EN ISO 10993-18 (if not already available).

The Biological Evaluation Report (BER) documents the execution and results of the evaluation and includes:

• Product description: Details on components, materials and manufacturing processes.
• Intended use and type of contact: Information on the intended use and type of physical contact.
• Manufacturing process: Description of the manufacturing process and the auxiliary materials used.
• Reusable products: Information on cleaning and/or sterilization.
• Physical/chemical information: Existing data for characterizing the medical device and the materials it contains.
• Risk assessment: Identification of biological endpoints.
• Material and product characterization: Details of the physicochemical characterization and test results.
• Test results: Description of the tests, results and interpretation of in vitro and in vivo tests, including cytotoxicity tests.
• Conclusions: Overall assessment of biological safety and recommendations.
• Determining further steps: If additional tests or assessments are required.

5. Conclusion

The biological evaluation of medical devices is a complex and multifaceted process that plays a crucial role in ensuring patient safety. The requirements of the MDR and EN ISO 10993-1 provide manufacturers with a sound regulatory framework that enables a structured and risk-based assessment. Material characterization according to EN ISO 10993-18, along with clearly defined biological endpoints, helps to identify risks early and address them effectively. The systematic approach, supported by precise categorization of contact type and duration, ensures that only necessary and relevant tests are performed.

A key advantage of the modern approach to biological evaluation lies in its flexibility to incorporate existing data and, where necessary, replace tests with scientifically sound arguments. This enables not only resource-efficient but also ethically responsible product evaluation, as the burden on laboratory animals is minimized. Detailed documentation in the BEP and BER ensures that all steps are traceable and compliance with regulatory requirements is transparently documented. Thus, biological evaluation not only provides safety for patients but also strengthens trust in medical devices and their responsible development and approval.

6. How we can help you

At medXteam, we provide comprehensive support for the biological evaluation of your medical devices and compliance with regulatory requirements. Thanks to our expertise in the analysis and evaluation of clinical data, we offer tailored solutions for creating the Biological Evaluation Plan (BEP) and the Biological Evaluation Report (BER). Our team helps you develop an effective testing strategy that covers all relevant biological endpoints while maximizing the use of clinical data and scientific literature to avoid unnecessary testing.

We guide you through the entire process – from material characterization according to EN ISO 10993-18 to the assessment and documentation of all biological risks in accordance with the MDR. Our experts are at your side to ensure that your products meet the highest safety standards and fulfill all regulatory requirements for approval. Let's work together to systematically address the biological risks of your products and achieve clinically sound, reliable results. Contact us to learn more about how we can support you in your next project.

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