The path to biosafety of medical devices

In this blog post we focus on the biological assessment of medical devices, a crucial process step for ensuring biocompatibility and patient safety. The article walks through the basics of biocompatibility, highlights the requirements of the MDR and explains the important role of the comprehensive series of standards EN ISO 10993, which consists of many parts and deals with different aspects of biological safety. The most important and fundamental part is EN ISO 10993-1, which specifies the general requirements and procedures for biological assessment.

In addition, we provide a detailed insight into the latest changes to the standard as well as the strategic steps for test planning and risk assessment. The article shows what a modern test strategy can look like, taking into account material characterization and alternative methods for reducing animal testing, and provides practical tips for complete documentation in the Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER). Our goal is to provide in-depth knowledge in order to effectively implement the complex requirements of biological assessment while at the same time 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 not to cause negative reactions when in contact with the human body – is a crucial factor in the safety of medical devices. Whether a product comes into direct contact with tissue, blood or other body fluids or has an indirect effect on organs and systems: biological safety must always be guaranteed. Ultimately, the well-being of the patient depends on it. The challenge for manufacturers is to ensure that every material, every substance and every combination of components used does not have any 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 in the body. Safety during repeated use also plays an important role, as some products remain in contact with the human body for long periods of time.

The Medical Devices Regulation (MDR) has formulated strict requirements for this that require manufacturers to carry out comprehensive biological assessments and carefully document them. Annex I, point 10.2, specifies the basic safety and performance requirements that each medical device must meet to ensure safe use. Annex II, point 6.1 also requires complete documentation of the biological assessment as part of the technical documentation.

“The products are designed, manufactured and packaged in such a way that the risks from pollutants and residues for patients - taking into account the intended purpose of the product - as well as for transport, storage and operating personnel are kept as low as possible. Particular attention will be paid to tissues exposed to these pollutants and residues, as well as 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 with regard to 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 EN ISO 10993-1 standard

EN ISO 10993 is the basic standard of a comprehensive series of standards for the biological assessment of medical devices, which consists of many specific parts, each covering different aspects of biocompatibility. The most important and fundamental part of this series of standards is EN ISO 10993-1, which specifies the general requirements and procedures for biological assessment. This standard plays an essential role in the approval process as it provides manufacturers with clear instructions on how to identify, minimize and document potential biological risks. Compliance with EN ISO 10993-1 is therefore often a basic requirement for meeting the safety and performance requirements of the MDR.

The new version of EN ISO 10993-1:2020 introduced some changes and additions to make the assessment even more precise and safer. Particular emphasis was placed on the need for integrated risk management that takes into account not only the chemical composition of the product, but also possible long-term effects and degradation products in the body.

A further, updated version of EN ISO 10993-1 is currently being drafted and brings with it significant innovations that are intended to make the process of biological assessment even more comprehensive and specific. The changes include new wording and more precise definitions intended to ensure more consistent interpretation. An additional section is also introduced that describes specific requirements for the entire life cycle of a product, supporting a more holistic view of biosafety.

The standard itself aims to offer manufacturers a structured biological assessment procedure that covers all relevant aspects of biocompatibility. The area of ​​application includes all medical devices that come into direct or indirect contact with the human body - from skin contact to implantable products to products that enter the bloodstream. The important terms and definitions therefore include central concepts such as biocompatibility , risk analysis and material compatibility , which ensure uniform language and uniform testing standards.

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

3. Biological assessment and testing strategy

The biological evaluation and testing strategy for medical devices is a structured process intended to ensure the safety and biocompatibility of a product throughout its entire life cycle. In EN ISO 10993-1, this systematic procedure for biological assessment is clearly shown in Figure 1.

Figure 1: Systematic procedure for biological assessment (according to Figure 1 from EN ISO 10993-1)

A central aspect of biological assessment is now material characterization in accordance with EN ISO 10993-18. Through the detailed physical-chemical characterization of the materials and their potential degradation products, many risks can be identified and minimized at an early stage. 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 surface of the body,
• Products that come into external contact with the inside of the body
• Implantable medical devices

In addition, the contact is determined:

• Medical devices that only come into contact with the body surface:
  • Intact skin
  • mucous membrane
  • Injured or damaged areas of skin
• Products that come into external contact with the inside of the body
  • 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 determine 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 possible risks from degradation products. A detailed risk analysis can often demonstrate that certain tests are not necessary, thereby avoiding unnecessary animal testing.

Figure 2: Example table from Annex A of EN ISO 10993-1:2020 for medical devices in 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 necessarily have to be processed through testing, like a checklist. EN ISO 10993-1 also allows the use of existing data, such as scientific literature or other validated information, to cover specific endpoints. On this basis, it can be justified why some tests can be omitted if the existing data supports the biosafety evidence. This enables a targeted and resource-saving assessment that still meets all relevant security requirements.

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

4. Documentation and reporting

An essential part of the biological safety assessment of medical devices is careful documentation, which ensures that all assessment and testing processes are recorded in a comprehensible and transparent manner. Two central documents play an important role here: 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 about the intended use and type of physical contact.
• Manufacturing process: Description of the manufacturing process and auxiliary materials used.
• Reusable products: information on cleaning and/or sterilization.
• Physical/chemical information: Existing data to characterize the medical device and the materials it contains.
• Risk assessment: identification of biological endpoints.
• Existing biological safety data: Existing biological tests.
• GAP Analysis: Gap analysis to identify missing information in current security data.
• Test strategy: Selection and justification of the necessary tests, including physical-chemical characterization according to EN ISO 10993-18 (if not yet available).

The Biological Evaluation Report (BER) documents the implementation and results of the evaluation and contains:

• Product description: Details on components, materials and manufacturing processes.
• Intended use and type of contact: Information about the intended use and type of physical contact.
• Manufacturing process: Description of the manufacturing process and auxiliary materials used.
• Reusable products: information on cleaning and/or sterilization.
• Physical/chemical information: Existing data to characterize the medical device and the materials it contains.
• Risk assessment: identification of biological endpoints.
• Material and product characterization: Details of physico-chemical characterization and test results.
• Test results: Description of tests, results and interpretation of in vitro and in vivo tests, including cytotoxicity tests.
• Conclusions: Overall biosafety assessment and recommendations.
• Determine next steps: If additional testing or assessment is required.

5. Conclusion

The biological assessment of medical devices is a complex and multi-layered process that makes a crucial contribution to ensuring patient safety. With the requirements of the MDR and EN ISO 10993-1, manufacturers have a well-founded set of rules at their disposal that enables a structured and risk-based assessment. The material characterization according to EN ISO 10993-18 as well as the clearly defined biological endpoints help to identify risks at an early stage and specifically address them. The systematic approach, supported by precise categorization of contact type and duration, ensures that only necessary and relevant tests are carried out.

A key advantage of the modern approach to biological assessment is the flexibility to incorporate existing data and, if necessary, replace tests with scientifically based reasoning. This not only enables resource-saving but also ethically responsible product evaluation, as the burden on laboratory animals is minimized. The detailed documentation in the BEP and BER ensures that all steps are traceable and compliance with the regulatory requirements is transparently documented. The biological assessment not only creates safety for the patient, but also strengthens trust in medical devices and their responsible development and approval.

6. How we can help you

At medXteam we provide you with comprehensive support in the biological assessment of your medical devices and compliance with regulatory requirements. Thanks to our expertise in the analysis and evaluation of clinical data, we offer you tailor-made solutions for the creation of the Biological Evaluation Plan (BEP) and the Biological Evaluation Report (BER). Our team will help 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 accompany you through the entire process - from material characterization according to EN ISO 10993-18 to the assessment and documentation of all biological risks according to MDR. Our experts are at your side to ensure that your products meet the highest safety standards and meet all regulatory requirements for approval. Let us systematically address the biological risks of your products together and achieve clinically sound, reliable results. Contact us to find out more about how we can help you with your next project.

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