ISO 10993 Biocompatibility Testing for Medical Devices When Is It Required

ISO 10993 Biocompatibility Testing for Medical Devices: When Is It Required?

Biocompatibility testing is not a standard checklist of laboratory tests that every medical device must complete.

The correct starting point is a biological evaluation.

For medical devices that come into direct or indirect contact with the human body, the manufacturer needs to evaluate whether the materials, manufacturing processes, residues, degradation products and finished device could create unacceptable biological risks during the intended conditions of use.

As at 24 April 2025, ISO 10993-1:2018, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process, remained the principal edition establishing this framework.

For South African regulatory purposes, SAHPRA’s technical-dossier framework contains a dedicated Biocompatibility and Toxicology Evaluation section. SAHPRA expects information on patient-contacting materials, tests and standards applied, protocols, results and a scientific explanation of why particular studies were performed or omitted.

The practical question is therefore not simply whether the device needs biocompatibility testing. It is what biological risks need to be evaluated for the finished device and what evidence is necessary to demonstrate that those risks are acceptable.

What is biocompatibility?

Biocompatibility concerns whether a medical device can perform its intended function without creating unacceptable biological effects when it interacts with the patient or user.

The assessment can consider materials, additives, coatings, adhesives, processing aids, manufacturing residues, sterilisation residues, degradation products, leachable substances, surface characteristics and the intended nature and duration of body contact.

The same raw material can create a different biological risk depending on how it is processed and used.

Biocompatibility should therefore be evaluated in the context of the finished medical device and its intended clinical use.

What is ISO 10993?

ISO 10993 is a family of international standards addressing the biological evaluation of medical devices.

As at April 2025, the central standard was ISO 10993-1:2018, which provides the framework for evaluating biological safety within a risk-management process.

The wider ISO 10993 family covers areas including interactions with blood, cytotoxicity, sensitisation, systemic toxicity, chemical characterisation, toxicological risk assessment, irritation and degradation.

Not every part applies to every device. The biological evaluation determines which evidence is relevant.

Is ISO 10993 required in South Africa?

SAHPRA expects appropriate evidence supporting the biological safety of medical devices where biological interaction is relevant.

The Authority’s technical-dossier framework contains a specific Biocompatibility and Toxicology Evaluation section.

Applicants are expected to identify patient-contacting materials, relevant tests and standards, protocols, results and the rationale supporting the studies performed or omitted.

This is a risk-based approach rather than an automatic requirement to perform every biological test available.

Biological evaluation is not the same as biological testing

A biological evaluation is the overall process of reviewing evidence and determining whether biological risks are acceptable.

Biocompatibility testing is one possible source of evidence within that process.

Other evidence can include material specifications, chemical characterisation, toxicological information, previous testing, scientific literature, clinical experience and relevant post-market information.

The objective is to address the relevant biological endpoints adequately rather than maximise the number of laboratory tests.

When does a medical device need a biocompatibility assessment?

Biological evaluation is particularly relevant where a medical device or component has direct or indirect contact with the patient or user.

This can include contact with intact skin, mucous membranes, compromised surfaces, tissue, bone, dentine, circulating blood or internal tissues.

Indirect contact should also be considered where substances or fluids pass through a component before reaching the patient.

The actual exposure pathway should therefore be assessed.

Devices without patient contact

A device with no direct or indirect patient contact may not require the same conventional ISO 10993 assessment as a patient-contacting device.

The conclusion should nevertheless be documented.

The manufacturer should confirm whether any component contacts the patient, transfers substances to the patient or creates another biologically relevant exposure.

Where a biological evidence category is not applicable, an appropriate scientific justification should be retained.

How the type of body contact affects the assessment

ISO 10993-1 categorises devices according to the nature of body contact.

Common categories include surface-contacting devices, externally communicating devices and implant devices.

The specific tissue contacted also matters.

An intact-skin device presents different biological questions from a blood-contacting catheter or long-term implant.

The contact category should therefore be defined before the manufacturer determines which biological endpoints require evaluation.

Why contact duration matters

Under the ISO 10993-1 framework applicable at this article’s publication date, exposure was commonly categorised as:

  • limited: up to 24 hours;
  • prolonged: more than 24 hours and up to 30 days; and
  • long-term or permanent: more than 30 days.

Longer contact can increase the relevance of additional biological endpoints.

Repeated use and cumulative exposure should also be considered where relevant.

Which biological endpoints may need to be considered?

Potential biological endpoints can include cytotoxicity, sensitisation, irritation, systemic toxicity, material-mediated pyrogenicity, genotoxicity, carcinogenicity, reproductive toxicity, implantation effects, haemocompatibility and degradation-related effects.

This is not a universal test list.

Individual endpoints may be addressed through existing evidence, chemical characterisation, toxicological assessment, testing or a justified conclusion that the endpoint is not applicable.

Cytotoxicity

ISO 10993-5 addresses in vitro cytotoxicity testing.

Cytotoxicity assessment examines whether substances associated with the device adversely affect mammalian cells.

It is commonly considered for patient-contacting devices but remains one element of the overall biological evaluation.

A successful cytotoxicity test does not, by itself, establish complete biocompatibility.

Sensitisation

ISO 10993-10:2021 addresses skin sensitisation.

Sensitisation concerns the potential for device materials or released substances to trigger an immune-mediated allergic response following exposure.

Changes in materials, adhesives, coatings, colourants and processing chemicals should therefore be assessed for their potential effect on the existing biological evidence.

Irritation

ISO 10993-23:2021 addresses testing for irritation.

Irritation assessment considers the potential for local inflammatory responses resulting from contact with the device, its materials or extracts.

The selected evidence should reflect the anatomical site and actual clinical exposure.

Systemic toxicity

ISO 10993-11:2017 addresses evaluation of potential adverse systemic reactions associated with medical device materials.

The biological evaluation should consider whether chemicals released from the device could enter the body and produce systemic effects.

Chemical characterisation and toxicological assessment can therefore be important in determining whether additional systemic-toxicity evidence is needed.

Haemocompatibility

ISO 10993-4:2017 addresses interactions between medical devices and blood.

Blood-contacting devices may require consideration of thrombosis, coagulation, platelet effects, haemolysis, complement activation and other relevant interactions.

The biological evaluation should reflect the device’s actual relationship with circulating blood.

Genotoxicity, carcinogenicity and reproductive toxicity

Certain devices may require consideration of genotoxicity, carcinogenicity or reproductive and developmental toxicity depending on their materials and exposure profile.

Relevant factors include contact duration, chemical constituents, patient population, exposure level and available toxicological evidence.

These endpoints should be selected through biological risk assessment rather than added automatically to every test programme.

Implantation and tissue response

Implanted devices can create prolonged interaction with tissue.

The manufacturer may need to assess inflammation, local tissue response, degradation, material stability and other effects associated with the implant environment.

The anatomical location and duration of implantation are fundamental to determining the appropriate evidence.

Chemical characterisation

ISO 10993-18:2020 provides a framework for chemical characterisation of medical-device materials within a risk-management process.

Chemical characterisation can address the materials of construction, chemical constituents, substances introduced during manufacturing, extractables, leachables and relevant degradation products.

This information can identify potential biological hazards and guide decisions on whether additional testing is necessary.

Toxicological risk assessment

ISO 10993-17:2023 addresses toxicological risk assessment of medical-device constituents.

The assessment considers whether patient exposure to identified substances is associated with appreciable harm.

Relevant factors can include the chemical identity, toxicological profile, exposure amount, route of exposure and duration.

The presence of a chemical therefore needs to be considered together with the patient’s likely exposure.

Can existing data replace new biocompatibility testing?

Potentially, yes.

Existing evidence may support the biological evaluation where it is sufficiently applicable to the proposed finished device.

Relevant evidence can include previous testing, established material data, chemical characterisation, toxicological information, scientific literature, previous device generations and clinical or post-market experience.

The manufacturer should demonstrate why that evidence is relevant rather than relying on a general statement that the material has been used before.

Why testing the raw material alone may not be enough

The finished device may contain substances or characteristics that are not represented by the original raw-material specification.

Manufacturing can introduce adhesives, lubricants, processing aids, cleaning residues, coatings, inks or other substances.

Heat, radiation and sterilisation can also affect material chemistry.

A raw-material certificate can therefore support the biological evaluation without necessarily establishing biological safety of the complete finished product.

Why the final finished device matters

SAHPRA’s technical-dossier guidance states that biocompatibility testing should be conducted on samples representative of the finished device and the sterilised device where the product is supplied sterile.

The test article should therefore adequately represent the commercial formulation, processing, coatings, adhesives, colourants and other characteristics capable of influencing biological safety.

Where an earlier configuration was tested, the manufacturer should justify why the evidence remains applicable.

Sterilisation and biocompatibility

Sterilisation can influence biological safety through material changes or residual substances.

The manufacturer should therefore consider whether the selected sterilisation process affects the biological characteristics of the finished device.

SAHPRA’s technical-dossier framework addresses sterilisation validation separately while also requiring biocompatibility evidence to represent the sterilised product where appropriate.

A sterile product is not automatically a biologically compatible product.

Product changes and repeat testing

Not every change requires repetition of every previous biocompatibility test.

Changes should nevertheless trigger reassessment of the biological evaluation.

Relevant changes can include material suppliers, formulations, adhesives, colourants, coatings, manufacturing processes, cleaning, sterilisation, intended use, anatomical contact and contact duration.

Where existing evidence remains applicable, the rationale should be documented. Where it does not, additional characterisation or testing may be necessary.

How ISO 10993 connects with ISO 14971

ISO 10993-1 approaches biological evaluation within a wider risk-management process.

The manufacturer identifies biological hazards, evaluates potential exposure and harm, establishes controls, generates appropriate evidence and evaluates the remaining biological risk.

The biological evaluation should therefore interact directly with the device’s overall risk-management file.

See ISO 14971 Risk Management for Medical Devices: Practical Requirements.

What SAHPRA expects in technical documentation

SAHPRA’s technical-dossier framework expects the Biocompatibility and Toxicology Evaluation to identify patient-contacting materials and explain the studies, standards, protocols, data and results supporting biological safety.

The applicant should also explain why particular studies were selected or omitted and why the total evidence is sufficient.

Where testing is not applicable, an appropriate rationale should be provided.

Test articles should represent the final finished device and, where relevant, the sterilised device.

Verion Medical’s technical documentation and labelling services support manufacturers in organising this evidence for South African regulatory readiness.

Common biocompatibility mistakes

Common mistakes include treating ISO 10993 as a universal testing checklist, sending a product for testing before determining the biological evaluation strategy and testing only the raw material rather than the finished device.

Other weaknesses include overlooking sterilisation effects, ignoring indirect patient contact, failing to consider cumulative exposure, performing unnecessary testing without reviewing existing evidence and failing to justify omitted endpoints.

Manufacturers should also avoid maintaining individual laboratory reports without an overall biological evaluation linking the evidence to the device and its risks.

A practical biological evaluation process

Start by defining the device and intended purpose.

Identify materials and components with direct or indirect patient or user contact.

Determine the nature, duration and frequency of exposure.

Review the materials, manufacturing process and sterilisation method.

Gather existing biological, chemical, toxicological, clinical and post-market evidence.

Identify the relevant biological endpoints and determine which are already adequately addressed.

Use chemical characterisation and toxicological assessment where appropriate.

Commission additional biological testing only where evidence gaps remain.

Ensure test articles represent the finished product and sterilised configuration where relevant.

Document the overall biological-safety conclusion within the risk-management process and maintain the evaluation through subsequent device and process changes.

Key regulatory and standards references

  • ISO 10993-1:2018, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process
  • ISO 10993-4:2017, Selection of tests for interactions with blood
  • ISO 10993-5:2009, Tests for in vitro cytotoxicity
  • ISO 10993-10:2021, Tests for skin sensitization
  • ISO 10993-11:2017, Tests for systemic toxicity
  • ISO 10993-17:2023, Toxicological risk assessment of medical device constituents
  • ISO 10993-18:2020 and Amendment 1:2022, Chemical characterization of medical device materials within a risk management process
  • ISO 10993-23:2021, Tests for irritation
  • SAHPRA draft SAHPGL-MD-10, Registration of a Non-IVD Medical Device – Technical Dossier
  • SAHPRA Essential Principles of Safety and Performance
  • ISO 14971:2019, Medical devices – Application of risk management to medical devices

As at 24 April 2025, ISO 10993-1:2018 remained the applicable edition. Later revisions are intentionally outside the historical scope of this article.

How Verion Medical supports biocompatibility and technical documentation

Verion Medical supports medical device manufacturers in determining what biological-safety evidence is needed for South African regulatory readiness.

Our technical documentation and labelling services can support review of patient-contacting materials, existing biocompatibility evidence, test reports, chemical-characterisation information, biological evaluation documentation and technical-file gaps.

Where biological safety needs to be integrated into the manufacturer’s wider risk-management framework, our ISO 13485 and Quality Management Systems services can support risk-management, design-control and change-control processes.

Our medical device classification services can also support confirmation of the South African classification and intended-purpose framework on which the wider technical documentation depends.

Our broader medical device regulatory affairs services support manufacturers preparing products for the South African market and assessing whether existing international evidence can support local regulatory requirements.

The objective is not to commission every possible ISO 10993 test. It is to establish a scientifically justified biological evaluation showing that the relevant biological risks have been identified, adequately addressed and supported by appropriate evidence.

If your organisation needs to determine which ISO 10993 assessments or tests are appropriate for a medical device intended for South Africa, contact Verion Medical for a technical documentation and biocompatibility gap assessment.