How to Create a Complete Biological Evaluation Report (BER) That Meets Regulatory Expectations

A Biological Evaluation Report (BER) is a cornerstone document in the biological risk assessment process for medical devices. It integrates chemical characterization, toxicological risk assessment, biological testing results, and historical data to present a scientifically justified evaluation of the device’s biological safety. Under the European Medical Device Regulation (MDR 2017/745) and ISO 10993-1:2023, the preparation of a complete and scientifically sound BER is not merely a regulatory formality — it is critical to demonstrating patient safety and device efficacy.

This article outlines the critical elements, structure, and best practices for producing a BER that aligns with global regulatory expectations.

 

1. Purpose and Role of the BER

The BER serves as a comprehensive risk assessment demonstrating that a device is safe for its intended use regarding biological hazards. It is not a summary of tests but a critical evaluation combining all relevant biological safety information. Its preparation requires scientific reasoning, an understanding of toxicological principles, and a risk-based mindset consistent with ISO 14971 for medical device risk management.

Regulatory bodies such as the European Notified Bodies, U.S. Food and Drug Administration (FDA), and other international agencies expect the BER to provide clear evidence that biological risks are identified, evaluated, and appropriately mitigated.

 

2. Structure of a Complete BER

While each BER must be tailored to the specific device and its use, certain core components must be systematically addressed:

2.1 Device Description and Intended Use

A clear and detailed description of the device, including its design, intended purpose, patient contact type (surface, external communicating, or implant), and duration of exposure (limited, prolonged, or permanent), is essential. The intended clinical application directly informs the biological endpoints to be assessed.

2.2 Material Composition

Every material in the device that comes into direct or indirect contact with the body must be listed. Chemical compositions must be described in as much detail as possible, including additives, process residues, coatings, and manufacturing aids.

If full chemical information is unavailable (e.g., proprietary materials), a documented effort to obtain the information should be included, and alternative strategies such as chemical characterization testing must be undertaken.

2.3 Review of Existing Data

An exhaustive search for existing biocompatibility and chemical data is essential. Sources include:

• Previous testing reports
• Supplier material data sheets
• Published scientific literature
• Regulatory databases (e.g., FDA 510(k) summaries)

Existing information must be critically assessed for relevance. Factors such as material similarity, manufacturing changes, and sterilization methods must be considered to determine if the historical data remains valid.

2.4 Chemical Characterization and Toxicological Risk Assessment

Chemical characterization per ISO 10993-18:2020 is fundamental. Extractables and leachables studies should be performed under clinically relevant conditions to identify all potential chemical constituents.

Subsequently, a toxicological risk assessment (TRA) evaluates whether detected substances pose unacceptable risks to patients. This involves:

• Comparing exposure levels to established toxicological thresholds (e.g., Tolerable Intake (TI) values)
• Considering cumulative exposure based on device usage patterns
• Addressing potential risks from unknown or unquantifiable substances

The TRA must follow the principles of ISO 10993-17:2023, ensuring that any calculated Margin of Safety (MoS) is adequate.

2.5 Biological Testing Results

Where historical data and chemical characterization are insufficient to address all biological endpoints (as outlined in ISO 10993-1 Annex A), targeted biological testing must be performed. Common tests include:

• Cytotoxicity (ISO 10993-5)
• Sensitization (ISO 10993-10)
• Irritation or intracutaneous reactivity (ISO 10993-10)
• Systemic toxicity (ISO 10993-11)
• Genotoxicity, implantation, hemocompatibility where necessary

Testing methodologies must be clearly described, including:

• Test article preparation
• Methodological standards followed
• Acceptance criteria and results interpretation

Negative, equivocal, or unexpected results must be discussed critically, not merely reported.

2.6 Gap Analysis

A transparent analysis must identify any limitations in available data or testing results. For any data gaps, scientific rationales must be provided explaining why additional testing is not necessary, or a plan for future data collection must be proposed.

Common scientifically acceptable justifications include:

• Established biocompatibility of identical materials
• Chemical characterization showing no risk-relevant leachables
• Low-risk patient contact type and exposure duration

2.7 Overall Biological Risk Conclusion

The BER must culminate in a risk-benefit conclusion that:

• Integrates all evidence
• Demonstrates that residual biological risks are acceptable
• Connects to the device’s overall risk management documentation per ISO 14971

This final assessment must be coherent, scientifically defendable, and free of contradictions.

 

3. Best Practices for Preparing a BER

Preparing a regulatory-ready BER requires scientific rigor and strategic planning:

• Start Early: Biological risk evaluations should begin during device design to allow timely adjustments.

• Use a Multidisciplinary Team: Toxicologists, material scientists, and clinical experts should collaborate.

• Focus on Scientific Justification: Regulators value logical, evidence-based arguments more than exhaustive testing.

• Document Every Decision: Rationales for testing decisions, data acceptance, and risk conclusions must be transparent.

• Stay Updated: ISO 10993 standards are living documents. Use the latest versions (e.g., ISO 10993-1:2023, ISO 10993-18:2020, ISO 10993-17:2023).

4. Common Challenges and How to Avoid Them

4.1 Over-Reliance on Supplier Declarations

Certificates of biocompatibility from material suppliers are often insufficient unless they precisely match the device’s processing and sterilization methods. Always perform an independent risk assessment.

4.2 Incomplete Chemical Characterization

Inadequate extractables and leachables studies lead to regulatory delays. Ensure that worst-case scenarios are covered, including sterilization and clinical use conditions.

4.3 Misinterpretation of Testing Results

Simply passing a cytotoxicity test does not guarantee overall biocompatibility. Interpretation must consider clinical relevance, consistency across endpoints, and chemical profile.

 

Conclusion

A well-prepared Biological Evaluation Report is an indispensable tool for demonstrating that a medical device is biologically safe for its intended use. It must be scientifically robust, fully documented, and tailored to the specific risks of the device. With the evolving regulatory landscape in Europe under MDR and the global harmonization of ISO 10993 series standards, manufacturers cannot afford to treat the BER as a mere formality.
A strategic, risk-based approach to the BER not only ensures compliance but also strengthens the scientific integrity and marketability of the device.

 

About the Author: Dr. Damian Matak

Dr. Damian Matak – an expert in medical device biocompatibility testing, serving as the CEO of ISO 17025-accredited and GLP-certified laboratories, including EBI – European Biomedical Institute and NABI – North American Biomedical Institute. As a member of the Polish Society of Toxicology and the I Local Ethical Committee, Dr. Matak contributes significantly to advancing safety standards in the biomedical field.