The Regulatory Team here at Advena UK recently attended a 6 hours’ customised refresher course on Biological Safety and Biocompatibility Testing. We understand it is not always easy interpretating the requirements of EN ISO 10993 series of standards as it is intended for use by professionals, appropriately qualified by training and/or experience.
We have therefore compiled a useful Q&A on biological evaluation to share the knowledge gained during the training to allow others to understand and navigate the complexity of the biological safety assessment process.
Q: What is the purpose of biological evaluation of medical devices and how is it performed?
A: The main aim of a biological evaluation is the protection of humans from potential biological risks arising from the use of medical devices.
It is performed using the ISO 10993-1 standard as a framework to plan and conduct a biological evaluation.
Q: When should a manufacturer evaluate biological safety?
A: The biological safety of a medical device shall be evaluated by the manufacturer over the whole life-cycle of a medical device, starting from concept design to post-market surveillance. For re-usable medical devices, biological safety shall be evaluated for the maximum number of validated processing cycles by the manufacturer.
Regular review and update of biological evaluation documents are required to comply with updated standards and state-of-the-art evidence. Any change in the following could affect the biological safety:
- Change in the source or in the specification of the materials used in the manufacture
- Change in the formulation, processing, primary packaging or sterilization
- Change in the manufacturer’s instructions or expectations concerning storage
- Any evidence that the product can produce adverse biological effects when used in humans
- Any change in the intended use of the product
Q: What is the relationship between EU MDR (EU/2017/745) and biological evaluation documentation?
A: Biological evaluation documentation is one amongst various technical documentation required to be drawn by a manufacturer to prove compliance with applicable general safety and performance requirements.
Q. How is risk management and biological evaluation related?
A. The primary purpose of biological evaluation is to protect patients from biological risks. Biological evaluation is a risk management activity which is to be planned in advance and therefore requires a biological evaluation plan. Simply, planning to conduct testing against all aspects of biocompatibility identified in Annex A of ISO 10993-1 does not meet requirement of ISO 14971. A biological evaluation plan covering all requirement from ISO 10993-1 should be prepared.
Q: What constitutes biological evaluation process?
A: The biological evaluation process includes the following activities:
- Biological Evaluation Plan (BEP)
- Information collection- Toxicology data on relevant component materials/compounds, Information on prior use of relevant component materials/compounds, data from previous biocompatibility tests
- Chemical Characterisation including extractable and leachable data (if required)
- Biocompatibility Testing (if identified from BEP)
- Toxicological Risk Assessment (if required)
- Biological Evaluation Report (BER)
Q: What should be included in the biological evaluation plan?
A: A biological evaluation plan should consist of the following as a minimum, arrangements for:
- Gathering applicable information from published literature (including information sources and search strategies), in house and supplier data etc.
- Conducting the evaluation, including the requirement for any specific technical competencies relevant to the specific medical device application
- Review and approval of the plan
- Approval of any additional testing required
- Final review and approval of the outcomes of the biological risk assessment, including the risk control measures applied and the disclosure of residual risks through means such as product labelling.
Q. Is there a difference in device categorisation provided by EU MDR (EU/2017/745) and ISO 10993-1 and why does this matter?
A. Yes. ISO 10993-1 (section 5) provides categorisation of medical devices for biological evaluation based on the nature and duration of body contact. Terminology and definitions differ to those used in EU MDR (EU/2017/745) Annex VIII as part of the rule-based classification of devices.
Categorisation provided by ISO 10993-1 is important because it affects the biological endpoints that must be considered. The more invasive and longer the duration of body contact leads to increased risk thereby requiring increased endpoints to be evaluated.
Q. What are the various endpoints of biological evaluation and how are they identified?
A. Annex A of ISO 10993-1 contains a table that is generally helpful in identifying endpoints recommended in the biocompatibility evaluation. The endpoints are:
- Physical and/or chemical info
- Cytotoxicity
- Sensitisation
- Irritation or intracutaneous reactivity
- Material mediated pyrogenicity
- Acute systemic toxicity
- Sub acute toxicity
- Sub chronic toxicity
- Chronic toxicity
- Implantation effects
- Hemocompatibility
- Genotoxicity
- Carcinogenicity
- Reproductive/developmental toxicity
- Degradation
Q. Why is physical and chemical characterisation required?
A. Gathering physical and chemical information on the medical device or component is a crucial first step in the biological evaluation and its associated process of material characterisation. Physical and chemical characteristic of a product can have a substantial effect on biological interactions with the medical device and can impact safety.
Physical characterisation is evaluating how physical properties could affect biological response. Example of physical properties include particulates such as nanomaterials, physical form such as geometry, particle size, porosity, surface texture etc.
Chemical characterisation involves assessing the constituent chemicals of the medical device and possible residual process aids or additives used in its manufacture.
Q. What determines the extent of physical and chemical characterisation and which standards should we follow to conduct material characterisation?
A. The extent of physical and/or chemical characterisation required depends on the following:
- what is known about the material formulation
- what non-clinical and clinical safety and toxicological data exists
- the nature and duration of body contact with the medical device
Material characterisation, if performed shall be conducted in accordance with ISO 10993/18. For nanomaterials refer to ISO 10993/22.
Q. Where can I collect information regarding chemical composition?
A. Chemical composition information can be obtained, as indicated in ISO 10993/1 Annex C by conducting a literature review. Other useful data sources include ECHA, PubChem, EFSA, National Toxicology Program.
Q. When is chemical analysis appropriate
A. Chemical analysis is typically required:
- For Long term implantable devices
- To mitigate data gaps (manufacturing process/ raw material data)
- To address systemic toxicity endpoints (Alternative to in vivo studies)
- To justify equivalence
Q. Is testing mandatory to prove compliance with ISO 10993-1 standard?
A. No. The need for testing should be reviewed on a case-by-case basis in the light of existing data, to avoid unnecessary testing. ISO 10993-1:2018 states that animal testing is only justified when existing scientific data and in vitro studies fail to provide adequate information. In vitro irritation test (RhE model) is now recommended in ISO 10993-23:2020. Note: this test is only applicable for devices which contact skin (intact/compromised).
Q. Do I need to re-test my product to comply with a new edition of ISO 10993 series?
A. It depends on the extent of the change. A gap analysis to justify continued validity of studies conducted to previous versions should be performed.
Q. What is a toxicological risk assessment?
A. A toxicological risk assessment document is a comprehensive safety evaluation of a product based on its composition, materials, and intended uses. It includes information such as margin of safety (MoS), tolerable intake (TI), uncertainty factor (UF), no observed adverse effect level (NOAEL), lowest observed adverse effect level (LOAEL), toxicological screening limit (TSL), maximum estimated exposure dose (EEDmax), derived no effect level (DNEL) and acceptable daily intake (ADI).
Toxicological risk assessment is covered in ISO 10993-17. A toxicological risk assessment must be performed by a toxicologist with adequate knowledge and experience.
Q. Are there any additional requirements for devices with novel or leachable materials?
A. Yes. For devices with novel materials, manufacturer should establish/measure the identity and quantity of any novel materials and chemicals present. Similarly, for medical devices that have known or suspected leachable chemical mixtures, potential interactions between the leachables should be considered.
An increasing expectation under EU MDR (EU/2017/745) to include leachable and extractable studies. Additionally, certain endpoints such as acute systemic toxicity, subacute toxicity, subchronic toxicity, chronic toxicity, genotoxicity, carcinogenicity, reproductive/developmental toxicity may be addressed by extractables and/or leachable testing.
If sufficient toxicological data relevant to the expected exposure (quantity, route and frequency) exist, then further extractables and leachable testing need not be required.
Q. Is there a specific standard for biocompatibility evaluation for gas pathway devices?
A. Yes. ISO 18562 is the standard for biocompatibility evaluation of breathing gas pathways in healthcare applications. ISO 10993-1 states ‘For gas pathway device components with only indirect contact, device specific standards should be used to determine the relevant type of biocompatibility evaluations [see ISO 18562 (all parts)]’.
Q: What should be included in the biological evaluation report?
A: A biological evaluation report should contain the following:
- A general description or drawing of the medical device
- Quantitative information on the material composition/formulations and quantitative or qualitative information on physical characteristics for all device components with direct or indirect body contact
- A description of processing conditions that could introduce manufacturing contaminants
- A review of available toxicity and prior use data, relevant to each medical device component with direct or indirect body contact
- Reports from biocompatibility testing
- An assessment of the data
- A statement confirming the risk analysis and risk control measures have been implemented.
How can Advena UK help?
At Advena we have many years of experience helping clients in compiling biological evaluation plan and reports. If your company requires guidance on preparing biological evaluation plan and report, understanding endpoints or need assistance in finding a toxicologist or test laboratory for performing test studies, Advena UK can support you. We are here to guide you on any step of your biological evaluation process.
