Introduction
When developing a medical device, it is paramount to ensure that it is safe for contact with the human body. One critical element of this safety assessment is biocompatibility testing—the evaluation of how materials interact with biological systems. Whether a device touches the skin for minutes or is implanted for years, it must not cause harm.
This article explores the fundamentals of biocompatibility, regulatory expectations, standards, and best practices for testing medical devices.
What is biocompatibility?
Biocompatibility refers to the ability of a material to perform with an appropriate host response in a specific situation. In simple terms, it means that the materials in a medical device should not trigger harmful reactions when they come into contact with the body.
Reactions that biocompatibility testing seeks to avoid include:
- Toxicity (harm to cells or tissues)
- Irritation or sensitisation (local inflammation or allergic responses)
- Systemic effects (harm that affects the whole body)
- Chronic inflammation
- Carcinogenicity (cancer-causing potential)
- Genotoxicity (damage to genetic material)
- Reproductive or developmental toxicity
Why is biocompatibility testing important?
Biocompatibility testing is essential for:
- Patient safety: Preventing adverse reactions and long-term harm.
- Risk management: Identifying and mitigating potential hazards associated with device materials.
- Regulatory approval: Demonstrating compliance with safety requirements under various regulations.
Even if well-known, established materials are used, their biological effects can change once they’re incorporated into a device and combined with manufacturing processes like moulding, coating, or sterilisation. Testing verifies that the final device is safe as it will be used.
What devices need biocompatibility testing?
Virtually all medical devices that contact the human body, even indirectly, require some form of biocompatibility evaluation. This includes:
- External communicating devices (e.g. surgical instruments, catheters)
- Surface devices (e.g. electrodes, wound dressings)
- Implants (e.g. orthopaedic implants, heart valves)
The level of testing depends on:
- Type of body contact (e.g. skin, blood, bone, mucosal membrane)
- Duration of contact:
- Limited (≤24 hours)
- Prolonged (>24 hours to 30 days)
- Long-term (>30 days)
Regulatory expectations for biocompatibility studies
The gold standard for biocompatibility assessment is the ISO 10993 series: Biological evaluation of medical devices. This is a multi-part standard that covers various tests and evaluations. Some of the most relevant parts include:
- ISO 10993-1:2018 Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management process. This provides the overall framework and helps manufacturers determine necessary testing based on the device’s type and contact duration.
- ISO 10993-5:2009 Biological evaluation of medical devices: Part 5: Tests for in vitro cytotoxicity
- ISO 10993-10:2021 Biological evaluation of medical devices: Part 10: Tests for skin sensitisation
- ISO 10993-11:2017 Biological evaluation of medical devices: Part 11: Tests for systemic toxicity
- ISO 10993-17:2023 Biological evaluation of medical devices: Part 17: Toxicological risk assessment of medical device constituents
- ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterisation of medical device materials within a risk management process
Many regulators expect biocompatibility assessments to follow the ISO 10993 series.
Under the Medical Device Regulation (EU 2017/745 - MDR) General Safety and Performance Requirements (GSPRs) (Annex I), manufacturers must demonstrate that devices:
- Are designed and manufactured to minimise risk of biological harm (GSPR 10)
- Have materials compatible with human tissues
The ISO 10993 series is the recognised approach for showing compliance.
The FDA expects biocompatibility evaluations to follow the ISO 10993 series standards, but also provides its own guidance:
- FDA guidance: Use of International Standard ISO 10993-1
- Emphasis on a risk-based approach and chemical characterisation
- Clear expectations for when and how testing should be conducted
Health Canada
Health Canada expects biocompatibility evaluations to follow the ISO 10993 series, as outlined in the Health Canada recognised standards list.
Australia Therapeutic Goods Administration (TGA)
The TGA requires evidence that medical devices meet the Essential Principles, and references ISO 10993 for biological safety assessments:
U.K. Medicines and Healthcare products Regulatory Agency (MHRA)
The UK Medical Devices Regulations 2002 (as amended) require that devices be biocompatible, and the MHRA recognises ISO 10993 as the applicable standard series.
Biocompatibility evaluation process
Before jumping into lab testing, manufacturers should perform a chemical characterisation of the device materials (ISO 10993-18). This involves:
- Identifying all materials and components
- Analysing potential leachables or extractables (chemicals that could migrate out of the device during use)
- Understanding how manufacturing processes and sterilisation may alter material properties
This step often highlights potential concerns or identifies areas where testing can be minimised by applying a risk-based approach.
ISO 10993-1 requires manufacturers to assess risk before testing. This involves:
- Reviewing material safety data
- Considering prior use of the material in similar devices
- Evaluating existing literature and historical data
- Deciding which biological endpoints (e.g. cytotoxicity, sensitisation) require testing
Some tests may be unnecessary if materials are well-characterised and have a long history of safe use in comparable applications.
If testing is required, manufacturers typically conduct:
- Cytotoxicity tests (ISO 10993-5): Measures the device’s potential to damage or kill cells.
- Sensitisation and irritation tests (ISO 10993-10): Assesses the risk of allergic or irritant reactions.
- Systemic toxicity tests (ISO 10993-11): Evaluates potential harmful effects on the whole body.
- Hemocompatibility tests (ISO 10993-4): Required for devices contacting blood, checking for risks like clotting or haemolysis.
- Genotoxicity, carcinogenicity, reproductive toxicity tests (ISO 10993-3, -6, -7): Needed for certain implantable or prolonged-contact devices.
These tests are typically performed by accredited laboratories under Good Laboratory Practices (GLP).
Challenges in biocompatibility testing
While the principles of biocompatibility testing are straightforward, manufacturers often face challenges, including:
Complex material formulations
Modern medical devices often consist of multiple materials and layers, including base materials, adhesives, coatings, inks, colourants, and surface treatments. Each component may interact with the body differently, and its combined effects can be difficult to predict. For example, an otherwise well-characterised polymer could be coated with an antimicrobial agent, a lubricant, or a decorative ink — all of which introduce new chemical constituents that may leach out during use.
Evaluating the biocompatibility of such complex formulations requires careful chemical characterisation to identify extractables and leachables from each component and their potential interactions. It also increases the complexity of test design because the biological response must reflect the device as it will actually be used, not just its individual parts.
Combination products
Devices that combine medical devices with drugs or biologics are considered combination products (or substance-based products). These products introduce additional complexities because the device material and the active pharmaceutical ingredient (API) must be evaluated together for biocompatibility.
The potential for drug-material interactions, new degradation products, or synergistic toxicities means that testing must address not just the device and drug separately but also their combined use. Regulatory authorities typically expect a more detailed risk assessment and testing that reflects worst-case exposure scenarios for both the device and drug components.
Novel materials
The push for innovation has led to the development of new biomaterials such as bioresorbable polymers, nanomaterials, and hybrid materials designed for specialised functions. While these novel materials may offer unique benefits, they often lack a history of safe clinical use.
As a result, manufacturers must rely heavily on extensive testing to establish safety profiles. Without existing data to draw on, both the scope and depth of biocompatibility testing usually increase. Sometimes, novel materials may require additional or customised test methods beyond the standard ISO 10993 battery to address unique concerns, such as degradation products or nanoscale behaviour.
Sterilisation effects
Sterilisation is essential for ensuring the microbiological safety of medical devices, but it can have unintended effects on material properties. Certain processes, such as gamma irradiation, ethylene oxide (EtO) sterilisation, or electron beam exposure, may alter the chemical structure of polymers, coatings, or adhesives. These changes can lead to the formation of new chemical species (e.g. free radicals, degradation byproducts) that could leach out during use.
Because of this, manufacturers must often perform post-sterilisation biocompatibility testing or chemical characterisation to confirm that the sterilisation process has not introduced new risks. In some cases, ageing studies are also required to assess the impact of sterilisation on the device’s shelf life.
Animal welfare concerns
There is increasing regulatory and societal pressure to reduce, refine, and replace animal testing where possible. Traditional biocompatibility studies often relied heavily on animal models, but today there is a strong shift toward alternative approaches.
Chemical characterisation techniques are becoming more sophisticated, allowing for better risk assessments without biological testing. in vitro test systems (such as 3D tissue models, cell cultures, or organ-on-chip technologies) are being developed and refined to provide equivalent or superior insights without the ethical and logistical challenges of animal studies. Regulators generally encourage manufacturers to justify animal use and to apply a risk-based approach that relies on material data, chemical analysis, and literature evidence wherever possible before resorting to in vivo tests. This shift requires manufacturers to stay current with evolving science and regulatory guidance on acceptable non-animal testing strategies while ensuring that their risk assessments remain robust and defensible.
Best practices for biocompatibility testing
- Plan early: Don’t leave biocompatibility to the end of development. Early material selection and risk assessment can save significant time, costs, and rework. Considering biocompatibility from the outset helps avoid last-minute surprises that could delay regulatory approval or require design changes. This proactive approach also allows manufacturers to identify safer, well-characterised materials that may reduce the need for extensive testing.
- Use a risk-based approach: Testing is only part of the picture. By leveraging comprehensive material data, published literature, and thorough chemical characterisation, manufacturers can often justify reduced or alternative testing strategies, helping to minimise unnecessary animal studies. Integrated risk management ensures that biocompatibility is assessed in the broader context of device safety alongside usability engineering, mechanical integrity, and other essential performance criteria.
- Consider worst-case scenarios: Biocompatibility doesn’t end with the initial design. Manufacturers should evaluate how sterilisation processes, device ageing, environmental exposure, and mechanical wear could affect the chemical and biological properties of the device over its entire life cycle. Planning for these factors from the beginning helps ensure that devices remain safe and compliant throughout their intended use.
- Keep detailed records: Regulators expect clear, traceable documentation of biocompatibility evaluation. This includes the rationale for selecting specific tests (or choosing not to test), the methods and standards applied, and the results obtained. Well-organised records make regulatory reviews smoother, help defend decisions during audits, and provide valuable data for future device iterations.
- Partner with accredited labs: Biocompatibility testing should be conducted by laboratories with proven expertise in medical device evaluations and compliance with Good Laboratory Practice (GLP). Working with experienced, accredited partners ensures that testing is reliable, scientifically sound, and acceptable to regulators. It also reduces the risk of delays or rejections due to inadequate or poorly documented test results.
Conclusion
Biocompatibility testing plays a vital role in ensuring the safety of medical devices and protecting patients. By adopting a thoughtful, risk-based approach, manufacturers can meet regulatory expectations, reduce unnecessary testing, and bring safe, effective devices to market.
Resources
European Union: MDR/IVDR
Under the Medical Device Regulation (EU 2017/745 - MDR) General Safety and Performance Requirements (GSPRs) (Annex I), manufacturers must demonstrate that devices:
- Are designed and manufactured to minimise risk of biological harm (GSPR 10)
- Have materials compatible with human tissues
The ISO 10993 series is the recognised approach for showing compliance.
U.S.A Food and Drug Administration
The FDA expects biocompatibility evaluations to follow the ISO 10993 series standards, but also provides its own guidance:
- FDA guidance: Use of International Standard ISO 10993-1
- Emphasis on a risk-based approach and chemical characterisation
- Clear expectations for when and how testing should be conducted
Health Canada
Health Canada expects biocompatibility evaluations to follow the ISO 10993 series, as outlined in the Health Canada recognised standards list.
Australia Therapeutic Goods Administration (TGA)
The TGA requires evidence that medical devices meet the Essential Principles, and references ISO 10993 for biological safety assessments:
U.K. Medicines and Healthcare products Regulatory Agency (MHRA)
The UK Medical Devices Regulations 2002 (as amended) require that devices be biocompatible, and the MHRA recognises ISO 10993 as the applicable standard series.
International Standards
- ISO 10993 series: Biological evaluation of medical devices. This is a multi-part standard that covers various tests and evaluations. Some of the most relevant parts include:
- ISO 10993-1:2018 Biological evaluation of medical devices: Part 1: Evaluation and testing within a risk management process. This provides the overall framework and helps manufacturers determine necessary testing based on the device’s type and contact duration.
- ISO 10993-5:2009 Biological evaluation of medical devices: Part 5: Tests for in vitro cytotoxicity
- ISO 10993-10:2021 Biological evaluation of medical devices: Part 10: Tests for skin sensitisation
- ISO 10993-11:2017 Biological evaluation of medical devices: Part 11: Tests for systemic toxicity
- ISO 10993-17:2023 Biological evaluation of medical devices: Part 17: Toxicological risk assessment of medical device constituents
- ISO 10993-18:2020 Biological evaluation of medical devices — Part 18: Chemical characterisation of medical device materials within a risk management process
Acceptance Criteria: The predefined standards and specifications that a device must meet during testing and evaluation to be deemed suitable for its intended use and to comply with regulatory requirements.
Biocompatibility: The ability of a material to perform with an appropriate host response when applied as intended.
Carcinogenicity: The potential of a material or substance to induce or promote cancer development in exposed tissues.
CE Marking: A certification mark that indicates conformity with health, safety, and environmental protection standards for products sold within the European Economic Area (EEA).
Change Control: The systematic process of managing and documenting modifications to a device or its manufacturing process to ensure that all changes are assessed, approved, implemented, and tracked in compliance with regulatory standards and quality management systems.
Chronic Inflammation: A prolonged and persistent immune response to a material or device, which can lead to tissue damage or failure of the implant over time.
Chemical Characterisation: Identifying and analysing the chemical composition and properties of materials used in a medical device, including any substances that could leach out during use. Also see Chemical Characterisation.
Classification: The process of categorising devices into different classes based on their intended use, level of risk to patients and users, and regulatory controls necessary to ensure safety and effectiveness.
Combination Products: Medical devices that are combined with a drug, biologic, or both, creating a product that integrates multiple regulatory requirements.
Compliance: Adherence to regulations, standards, and guidelines set forth by regulatory authorities.
Conformity Assessment: A process used to determine whether a product, service, system, or entity meets specified standards, regulations, or requirements.
Developmental Toxicity: The potential of a material or substance to harm fertility, embryonic development, or offspring health. Also see Reproductive Toxicity.
Extractables: Chemicals that can migrate out of a medical device under conditions of use or during testing, potentially posing risks to patients. Also see Leachables.
Genotoxicity: A material’s ability to damage DNA or other genetic material, which can lead to mutations or cancer.
Good Laboratory Practices (GLP): A set of quality standards that govern the conduct, documentation, and reporting of non-clinical laboratory studies to ensure data integrity and regulatory compliance.
Harm: Physical injury or damage to the health of people or damage to property or the environment.
Harmonisation: The process of aligning standards, requirements, and procedures across different jurisdictions to ensure consistent safety and efficacy evaluations and market access for medical devices.
Hazard: A potential source of harm.
Hazardous Situation: Circumstances in which people, property, or the environment are exposed to one or more hazards.
Instructions for Use (IFU): The document provided by the manufacturer that includes essential information on a medical device’s intended purpose, proper handling, operation, maintenance, and safety precautions for users.
Intended purpose: The use for which a medical device is intended according to the information provided by the manufacturer on the labelling, in the instructions for use (IFU), or in promotional materials. This may also be referred to as the Intended Use in some jurisdictions. Also see Indication of Use.
International Medical Device Regulators Forum (IMDRF): A global regulatory collaboration focused on harmonising medical device regulations to facilitate patient access to safe and effective devices. This organisation was formerly the Global Harmonization Task Force (GHTF).
in vitro Diagnostics (IVD): Medical tests conducted on samples taken from the human body, such as blood or tissue, to detect diseases, conditions, or infections outside the body.
Irritation: A material’s ability to provoke local inflammation or trigger allergic immune responses after contact with the body. Also see Sensitisation.
ISO 13485: An international standard that specifies requirements for a quality management system (QMS) specific to the medical devices industry.
Labelling: The label on a medical device and all descriptive and informational literature associated with the device. Also see Instructions for Use (IFU)
Leachables: Chemicals that can migrate out of a medical device under conditions of use or during testing, potentially posing risks to patients. Also see Extractables.
Maintenance: Regular, planned actions taken to ensure that the devices remain in optimal working condition, including inspection, calibration, cleaning, and repair. Also see Preventative Maintenance and Corrective Maintenance.
Manufacturer: A legal entity that designs, produces, assembles, or labels a medical device with the intention of placing it on the market.
Material Characterisation: Identifying and analysing the chemical composition and properties of materials used in a medical device, including any substances that could leach out during use. Also see Chemical Characterisation.
Quality Management System (QMS): A formalised system that documents the structure, responsibilities, and procedures required to achieve effective quality management.
Regulation: The rules, laws, standards, and requirements set by regulatory authorities to ensure the safety, efficacy, and quality of devices intended for medical use.
Regulatory Authority: An official body overseeing and enforcing laws, regulations, and standards within a specific industry or sector to ensure compliance and protect public interests. Also known as a Regulatory Authority. Also see Competent Authority and Notified Body.
Regulatory Submission: The formal process of submitting documentation and data to regulatory authorities for review and approval to market or sell the device within a specific jurisdiction.
Residual Risk: The risk remaining after risk control measures have been taken.
Reproductive Toxicity: The potential of a material or substance to harm fertility, embryonic development, or offspring health. Also see Developmental Toxicity.
Risk: The combination of the probability of occurrence of harm and the severity of that harm.
Risk Analysis: The systematic use of available information to identify hazards and to estimate the risk.
Risk Assessment: The overall process comprising risk analysis and risk evaluation.
Risk Communication: The exchange of information about risks between decision-makers and other stakeholders.
Risk Control: The process by which decisions are made, and measures are implemented to reduce or maintain risks within specified levels. It is also known as Risk Mitigation.
Risk Evaluation: The process of comparing the estimated risk against given risk criteria to determine the acceptability of the risk.
Risk Management (RM): The systematic application of management policies, procedures, and practices to the tasks of analysing, evaluating, controlling, and monitoring risk.
Risk Management File (RMF): A compilation of all documents and records generated during the risk management process.
Safety: The condition of being protected from or unlikely to cause danger, risk, or injury.
Sensitisation: A material’s ability to provoke local inflammation or trigger allergic immune responses after contact with the body. Also see Irritation.
Standard: A document that provides guidance, requirements, or specifications established by regulatory bodies, industry organisations, or international consensus groups.
Supply Chain: Activities, processes, and entities involved in the sourcing, manufacturing, distribution, and logistics management of these devices from suppliers to end-users.
Systemic Effects: Occur when harmful substances from a device enter the bloodstream or tissues, causing adverse reactions throughout the body rather than at the contact site.
Technical Documentation: All documents that demonstrate the design, manufacture, and performance of the device, essential for ensuring compliance with regulatory requirements. This is also known as the Technical File.
Toxicity: The potential of a material or substance to cause damage or death to cells, tissues, or organs upon exposure.
User: Any individual who operates or interacts with a medical device, including healthcare professionals, patients, and caregivers.