Key Components of a Biological Evaluation Plan (BEP)

A Biological Evaluation Plan (BEP) consists of a planned and structured document within a risk management process that assesses the biological risks posed to the patients on whom a device is intended to be used.

The BEP provides a comprehensive description of the medical device of interest, including the different variants of the devices covered by the evaluation. The important points to be mentioned and considered in the BEP include:

• Which market is targeted (regulatory context): Appropriate regulatory guidance and/or requirements (e.g., FDA biocompatibility guidance for the US market) should be considered depending on the market.
• The clinical intended use of the device: Includes the target population and the cumulated worst-case exposure (contact) of the device with the patient’s body. These points will determine the categorization of the device in accordance with ISO 10993-1, as well as other relevant guidelines. This will define the list of minimum biocompatibility endpoints applicable to the device and to be addressed in the BEP.
• The composition of the device: The exhaustive list of raw materials used in the construction of the device, as well as the raw material(s) supplier(s) will be described. In the BEP, the type of contact with the patient will be discussed (direct, indirect, no contact).
• The manufacturing process (including packaging and sterilization) of the device: The use of any processing agents contacting the device during the manufacturing process will be assessed.
• Previously conducted biocompatibility testing: The availability of biocompatibility testing (biological and/or chemical characterization) conducted on the device already.
• The availability of clinical data: Clinical studies and/or post-market surveillance data, when the device is already commercialized.

All the points listed above will impact the strategy elaborated in the BEP to evaluate the safety of the device. It is emphasized that simply planning to conduct testing against all of the aspects of biocompatibility identified in Annex A (ISO 10993-1) does not meet the requirements of ISO 14971 or ISO 10993-1. As mentioned in ISO 10993-1:2018 Clause 4.1, the biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals.

The BEP document will follow the rules of the risk management process per ISO 14971:2019, i.e., risk analysis, risk evaluation, risk control, and re-assessment of the risks following any changes. These points are further discussed.

Risk Analysis

The goal of this step is to provide predictive evidence of potential hazards to the patients using the device. This risk analysis will focus on potential risks related to the raw materials with patient contact, and manufacturing process.

Material characterization of the medical device or component is a crucial first step in the biological evaluation. For each patient-contacting raw material, documentation related to the raw material (e.g., Safety Data Sheet, Regulatory compliance statement, etc.) will be gathered and discussed in the BEP. A literature review on patient-contacting raw materials is also conducted to identify any documented known toxicological hazards of raw materials. If there is material information suggesting that one or more constituents with known toxicities are present in a medical device at potentially harmful levels, the biological evaluation must consider the associated risk, regardless of the categorization of the medical device.

The manufacturing process may also introduce harmful manufacturing residues on the device surface that will contact the patient’s body fluids during clinical use. Hence, any manufacturing additives, processing aids, or other potential contaminants, such as sterilant residues, will be reviewed to evaluate the possibility of the presence of toxic residues from the manufacturing process. Packaging materials that directly or indirectly contact the medical device should also be considered.

Risk Evaluation

The risk evaluation must consider all relevant information collected on the medical device, including chemical and physical data, preclinical tests, clinical studies, post-market experience, and any other pertinent data.

A gap analysis of these data will determine whether the available information is sufficient to demonstrate the device’s biological safety.

When biocompatibility testing already exists on the device, the gap assessment will focus on the following points:

• If changes have been implemented to the device since the completed testing
• If the test method follows the current or previous version of the ISO standards
• If the test results are still valid against the current version of the ISO standards

Any differences will have to be discussed to evaluate if the completed studies remain valid to support the biocompatibility profile of the device under evaluation.

Risk Control

Risk control is the process of identifying and implementing measures to reduce risks. Testing may be required to obtain reliable estimates of biological risks and to complete the biological evaluation if existing data are insufficient to demonstrate the device’s biological safety.

When applicable, the BEP will detail the elaborated testing strategy, including the choice of the test procedures. If several variants of the device exist, the representative device for testing should be discussed in the BEP. Representative device(s) should be selected in order to maximize the amount of leachables/extractables that may be generated by the raw materials and the manufacturing process (e.g., worst-case scenario).

Justifications for either conducting or waiving biocompatibility tests should be discussed in the BEP.

After all information has been obtained in accordance with the BEP and any biological risk control measures have been implemented and verified, the manufacturer shall prepare a comprehensive Biological Evaluation Report (BER). If the risk is not estimated to be negligible, it shall be treated as a residual risk, and the manufacturer should conduct a benefit-risk assessment (ISO 14971).

Re-Assessment of Risks

The biological risk assessment of a device shall be re-evaluated if any of the changes described in Clause 4.9 of ISO 10993-1:2018 occur. This includes changes in materials (source or specification), changes in the formulation, processing, primary packaging or sterilization, changes in storage instructions, changes in the intended use, and any evidence that the product can produce adverse biological effects when used in humans.

The biological risks associated with a change should be identified, evaluated, assessed, and controlled.