A Risk-Based Approach for Biocompatibility

by | Aug 6, 2019 | Cleanroom News, Cleanroom Standards

Biocompatibility and ISO 10993

A Risk-Based Approach for Biocompatibility and ISO 10993:2018-1

We address ISO 10993 compliance and the risk-based approach for biocompatibility assessments

Continuing our conversation on the EU Medical Device Regulations1 and changes in regulatory environment, we turn to biocompatibility assessments and the updated ISO 10993 (ISO 10993:2018‑1) released in August 2018.2. The updated standard highlights that particular attention will be focused on the device materials used, rationale for biocompatibility tests performed, the compatibility of these materials with biological tissues, and the impact of the manufacturing processes on the material properties. Under MDR review, medical devices will be held to a greater level of analysis on the biological evaluation. Increased oversight will be focused on the rationale for tests performed and support with clinical evidence.

But to understand the changes in regulatory expectations, it is beneficial to start with a discussion of biocompatibility expectations under the Medical Device Directives.3 MDD had requirements for materials used in medical devices and focused on toxicity, flammability, and biocompatibility. From the manufacturer perspective, there was flexibility in the data that could be provided to support these elements of safety.

A Risk-Based Approach to Biocompatibility

Now, the European Commission has adopted a risk-based approach and intends to review chemical characterization, microbiological testing, biocompatibility, and toxicity for devices. This is coupled with expert-level reviews by the Notified Bodies to assess the full picture of the biological evaluation. In other words, determination of appropriate materials, risks, and required tests are left up to the manufacturer and review by the notified body. The ISO 10993 2018 revision is a starting point for biological evaluation of medical devices within a risk management process and defines biocompatibility as “the ability of a device or material to perform with the appropriate host response in a specific application.” A risk-based approach for biocompatibility should then focus on the risks of the materials and how those materials and the device as a whole interacts with the body and are detailed in Annex B. It is recommended to perform a literature review of the specific materials and manufacturing processes to understand risks and identify gaps, detailed in Annex C. To that end, the biocompatibility evaluation should begin by identifying the:

  • Intended use environment of the device
  • Risks and potential adverse reactions of the device, of the materials, or from interactions the device has with the body
  • Degree to which these risks can be mitigated

A review of data available for the device and review of literature on the device and similar devices serves to identify risks that remain to be addressed and often the solutions for how to address these issues.

Biocompatibility Gap Assessments

To complete the biocompatibility gap assessment, walk through the process shown below for a medical device. Begin by gathering information to fully understand the materials, often performed via chemical characterization. Next perform an initial risk assessment or rely on risk management documentation to identify risks to the patient and user, including the cumulative sum of duration of use and frequency of use they will have to the device. Can this information be used as support in the biocompatibility assessment? If new data sets are needed to address the gaps, use all information obtained to provide a rationale for the tests that will be or have been performed. Since the primary goal of ISO-10993 is protection of humans, any gaps that remain will need to be addressed. The secondary goal of ISO-10993 is to ensure animal welfare. To that end, the rationale should address the number and exposure of the test animals.

Gap Assessment Strategy for Biocompatibility Evaluation




Biological Risk Assessment Endpoints

Biocompatibility tests help determine whether a device performs as intended without causing any adverse or harmful effects for patients or users, and mitigate any biological risks posed by the device. Testing should be performed on the final medical device, representative samples from the final device, or materials processed in the same manner as the final device (including sterilization, if needed). Also, ensure data is provided for endpoints specific to your device and that endpoints are up-to-date for any new or revised standards for your device. The medical device categories and endpoints for biological risk assessments from ISO 10993:2018-1 Annex A are shown below.

Medical Device Categorization and Endpoints for Biological Risk Assessment

Nature of Body Contact The nature of body contact describes the device category such as a surface medical device, an externally communicating device, or an implanted device
Tissue Contact

The nature of body contact is further divided by the type of tissue the device comes into contact with:

  • Surface medical device: intact skin, mucosal membrane, breached or compromised surface
  • Externally communicated device: blood path, indirect; tissue, bone, or dentin; and circulating blood
  • Implanted device: tissue, bone; blood
Contact Duration

The contact duration is divided into 3 categories and include:

  • ≤24 hours of contact
  • >24 hours to 30 days of contact
  • >30 days of contact

However, it is the cumulative sum of exposure that is most important for the assessment and this includes the cumulative sum of contact and the frequency of contact

Endpoints of Biological Evaluation

Endpoints to address in biological evaluation include:

  • Chemical and physical
  • Cytotoxicity
  • Sensitization
  • Irritation or intracutaneous reactivity
  • Material-mediated pyrogenicity
  • Genotoxicity
  • Carcinogenicity
  • Toxicity including acute systemic, subacute, subchronic, and chronic
  • Implantation effects
  • Hemocompatibility
  • Reproductive/developmental toxicity
  • Degradation


In conclusion, the interpretation of the biological risk assessment should be complied as the overall biological evaluation. This should include the 1) strategy and planned content for the biological evaluation, 2) criteria for determining the acceptability of the materials for the intended purpose, congruent with the risk management plan, 3) adequacy of the material characterization, 4) rationale for tests, 5) interpretation of existing data (including literature evaluation), 6) results of testing, 7) whether there is a need for additional data (provide details as necessary), and 8) the overall biological safety conclusions. When a design change occurs, the biocompatibility evaluation should be revisited. Scope of the re‑evaluation should be appropriate to the nature of the change and focus on the specific materials changed, nature and use of the medical device, and potential interactions. To bring the biological risk assessment information full circle, the information above should also be incorporated into design documentation, risk management file, and validation and verification with a statement confirming that risk analysis and risk controls have been completed.

Precision Environments works hard to meet your needs and we understand that changes in medical device regulations poses challenges for manufacturers and testing facilities alike. Call today to talk with our team of experts about how our modular cleanrooms are easily modified and provide configurations to meet your current business needs to support biocompatibility testing while enabling flexibility for your future.


  1. European Union Medical Device Regulations: Regulation 2017/745 of the European Parliament and of the Council of 05 April 2017 on Medical Devices Amending Directive 2011/83/EC, Regulation No 178/2002, and Regulation No 1223/2009, and repealing Council Directives 90/385/EEC and 93/42/EEC.
  2. ISO 10993:2018-1 Biological Evaluation of Medical Devices—Part 1: Evaluation and Testing Within A Risk Management Process, August 2018.
  3. Medical Device Directive 93/42/EEC Regarding Medical Devices (1993), Directive 90/385/EEC Regarding Active Implantable Medical Device (1990), and Directive 98/79/EC Regarding In Vitro Diagnostic Medical Devices (1998).

Where to go next?

Contact us for an assessment of your cleanroom and procedures with the goal of ensuring that bioburden and sterility requirements are met. We also offer turnkey medical device cleanroom design and construction services to provide the perfect levels of cleanliness for the manufacturing of medical devices and support the sterile packaging processes of these devices for your continued success!

Biocompatibility and ISO 10993-1

ISO 10993-1:2018

Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process

ISO 10993 specifies:

  • the general principles governing the biological evaluation of medical devices within a risk management process;
  • the general categorization of medical devices based on the nature and duration of their contact with the body;
  • the evaluation of existing relevant data from all sources;
  • the identification of gaps in the available data set on the basis of a risk analysis;
  • the identification of additional data sets necessary to analyse the biological safety of the medical device;
  • the assessment of the biological safety of the medical device.

The ISO 10993 document applies to evaluation of materials and medical devices that are expected to have direct or indirect contact with:

  • the patient’s body during intended use;
  • the user’s body, if the medical device is intended for protection (e.g., surgical gloves, masks and others).

ISO 10993 is applicable to biological evaluation of all types of medical devices including active, non-active, implantable and non-implantable medical devices. The document also gives guidelines for the assessment of biological hazards arising from:

  • risks, such as changes to the medical device over time, as a part of the overall biological safety assessment;
  • breakage of a medical device or medical device component which exposes body tissue to new or novel materials.

Other parts of ISO 10993 cover specific aspects of biological assessments and related tests. Device-specific or product standards address mechanical testing. This document excludes hazards related to bacteria, moulds, yeasts, viruses, transmissible spongiform encephalopathy (TSE) agents and other pathogens.

Learn more at the International Organization for Standardization website:



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