How to Conduct Biological Evaluations for Medical Devices Using ISO 10993

Understanding Biological Evaluation of Medical Devices

Biological evaluation of medical devices is initiated within a structured risk management framework as outlined by ISO 10993^[2]. This process is essential for identifying and assessing biological hazards and the associated risks^[2].

How to Comply with ISO 10993 for Medical Device Biological Evaluation

Complying with ISO 10993 for the biological evaluation of medical devices is crucial for ensuring patient safety and meeting regulatory requirements. The U.S. Food and Drug Administration (FDA) has issued guidance on the use of International Standard ISO 10993-1 for biological evaluation of medical devices, which is applicable to various types of applications, including Premarket Applications (PMAs), Humanitarian Device Exemptions (HDEs), Investigational Device Applications (IDEs), Premarket Notifications (510(k)s), and De Novo requests for medical devices that come into direct or indirect contact with the human body^[1]. The purpose of this guidance is to help determine the potential for an unacceptable adverse biological response resulting from contact of the component materials of the device with the body, and it provides clarification and updated information on the use of International Standard ISO 10993-1 to support applications to the FDA^[1].

The U.S. Food and Drug Administration (FDA) and other competent authorities evaluate medical devices that come into direct or indirect contact with the human body for the potential for an unacceptable adverse biological response^[1]. 

The biocompatibility assessment is based on several factors, including the nature of contact, type of contact, frequency and duration of contact, and materials^[2]. It is important to note that the whole device and not just the component materials are assessed.^[2].

Key Aspects of Biological Evaluation

Mandatory risk-management activity: Biological evaluation of medical devices is a mandatory part of the conformity assessment and a risk-management activity that needs to be planned in advance according to ISO 10993-1 and ISO 14971^[3].

• General principles: ISO 10993-1:2018 specifies the general principles governing the biological evaluation of medical devices within a risk management process^[4]. It covers:
  • Evaluation of existing relevant data from all sources
  • Identification of gaps in the available data set
  • Identification of additional data sets necessary to analyze the biological safety of the medical device
  • Assessment of the biological safety of the medical device^[4] 
• Applicability: The standard 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 or the user’s body if the medical device is intended for protection^[4]. It is applicable to biological evaluation of all types of medical devices, including active, non-active, implantable, and non-implantable medical devices^[4].

Conducting a Comprehensive Biological Evaluation

A thorough biological evaluation can help reduce the need for extensive biological testing. The process involves:

• Gathering and evaluating existing relevant data from all sources
• Identifying gaps in the available data set
• Determining additional data sets necessary to analyze the biological safety
• Assessing the biological safety of the medical device

By following this systematic approach, manufacturers can optimize their biological evaluation process and ensure compliance with regulatory requirements.

Documentation

1. Biological Evaluation Plan (BEP): Provides information on product safety and the strategy implemented to evaluate the device’s safety in compliance with available standards and guidelines^[15].
2. Biological Evaluation Report (BER): A collective summary of all the data generated and/or gathered based on the BEP, used to support the biological safety of the medical device during clinical use^[15].

Overview of ISO 10993-1:2018

ISO 10993-1 is the most widely used standard for assessing the biocompatibility of medical devices and materials, providing a framework for determining the appropriate biocompatibility steps for planning a biological evaluation^[5]. The FDA’s Biocompatibility Guidance on Use of ISO 10993-1 provides clarification and information on the use of International Standard ISO 10993-1 to support applications to the FDA^[2]. Biological evaluation plans should be part of a structured plan within a risk management process, as per ISO 10993-1:2018 and ISO 14971^[6].

Key Principles of ISO 10993-1:2018

1. Risk management approach: ISO 10993-1:2018 provides a risk management approach, requiring manufacturers to assess the nature, duration, and intensity of contact between the medical device and the body to determine the level of testing needed^[9].
2. Categorization of medical devices: The standard outlines the general categorization of medical devices based on the nature and duration of their contact with the body^[4]. The ISO 10993 standard divides medical devices into three main categories: surface devices, externally communicating devices, and implant devices^[8]. The choice of test program for a device in a given category depends on the duration of the contact^[8].
3. Evaluation process: ISO 10993-1:2018 covers the evaluation of existing relevant data from all sources, identification of gaps in the available data set, and the identification of additional data sets necessary to analyze the biological safety of the medical device^[4]. The standard 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 or the user’s body, if the medical device is intended for protection^[4].
4. Applicability: ISO 10993-1:2018 is applicable to biological evaluation of all types of medical devices including active, non-active, implantable and non-implantable medical devices^[4].
5. Animal 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^[7].

ISO 10993-1:2018 provides guidelines for the assessment of biological hazards arising from risks, such as changes to the medical device over time, and breakage of a medical device or medical device component which exposes body tissue to new or novel materials^[4]. A thorough biological evaluation, as outlined in the standard, can help reduce the need for extensive biological testing by identifying and addressing potential risks early in the process^[5].

Evaluating Biological Hazards and Risk Management

The FDA’s guidance document titled “Use of International Standard ISO 10993-1” assists industry in preparing various applications for medical devices that come into direct or indirect contact with the human body^[12]. The purpose of the guidance is to help determine the potential for an unacceptable adverse biological response resulting from contact of the component materials of the device with the body^[1]. It provides further clarification and updated information on the use of International Standard ISO 10993-1, including recommendations for risk-based approaches to determine if biocompatibility testing is needed^[1].

Risk-Based Approach in Biocompatibility Testing

1. Determining the need for biocompatibility testing: A risk-based approach is used to determine if biocompatibility testing is necessary, as stated in the FDA Guidance document^[6]. This approach takes into account factors such as the nature of the medical device, its duration of contact with the body, and the anatomical location of its use^[12].
2. FDA-modified matrix: ISO 10993-1 should be used in conjunction with the FDA-modified matrix to determine the relevant biocompatibility endpoints for an evaluation^[12]. The FDA-modified matrix is used to evaluate local and systemic risks based on the characteristics of the medical device^[12].
3. Recommendations for specific devices: The guidance includes recommendations for biocompatibility test article preparation for devices with submicron or nanotechnology components and for devices made from in situ polymerizing and/or absorbable materials^[1]. It also provides biocompatibility recommendations when certain materials only contact intact skin^[1].

Challenges in Implementing Alternative Approaches

The integration of alternative approaches in medical device biocompatibility testing has been slower compared to other industrial sectors due to the absence of specialized validation processes and regulatory skepticism^[7]. Obstacles to implementing additional in vitro tests for other toxicity endpoints include:

• Technical difficulties
• Slow adaptation of existing protocols
• Regulatory distrust
• Lack of public interest
• Cross-sectorial harmonization
• Open access to information^[7]

Re-evaluation of Biological Evaluation

The biological evaluation must be re-evaluated in case of changes in any of the following aspects^[13]:

By following a risk-based approach and considering the various factors outlined in the FDA guidance and ISO 10993-1, manufacturers can effectively evaluate biological hazards and manage risks associated with their medical devices. A comprehensive biological evaluation can help reduce the need for extensive biological testing by identifying and addressing potential risks early in the process^[5].

Biocompatibility Testing and Data Analysis

Biocompatibility testing is a crucial aspect of the biological evaluation process, ensuring that medical devices are safe and compatible with biological systems. Testing must be conducted in compliance with Principles of Good Laboratory Practice (GLP) and/or ISO/IEC 17025 to maintain the highest standards of quality and reliability^[5]. Laboratories, such as TÜV SÜD, offer a comprehensive range of GLP-compliant biocompatibility testing services according to the ISO 10993 series of standards^[5].

The “Big Three” biocompatibility tests, which are essential for almost all medical devices, include:

1. Cytotoxicity: Evaluates the potential for a material to cause cell death or damage. ISO 10993-5 provides guidance and requirements for assessing the cytotoxic potential of medical device materials^[7].
2. Irritation: Assesses the potential for a material to cause local tissue damage or inflammation. ISO 10993-23 supports the use of the in vitro reconstructed human epidermis (RhE) assay as the preferred method over traditional in vivo animal tests for skin irritation testing^[7].
3. Sensitization: Evaluates the potential for a material to cause an allergic or hypersensitivity reaction. ISO/TS 11796:2023 provides detailed guidance on conducting an in vitro sensitization validation study for medical devices^[7].

Preparing Test Articles

When preparing test articles for biocompatibility testing, consider the following:

• Test articles should be prepared in the final finished form or as a representative test article^[12].
• For devices with submicron or nanotechnology components, evaluate their potential impact on biocompatibility^[12].
• When testing in situ polymerizing and/or absorbable materials, consider the potential for biological response resulting from device mechanical failure^[12].

Chemical Characterization

ISO 10993-18:2020 focuses on the chemical characterization of medical device materials within a risk management process^[10]. It provides a framework for identifying and, if necessary, quantifying constituents of a medical device to identify biological hazards and estimate and control biological risks from material constituents^[10]. 

The following steps are involved:  

• identification of materials of construction,
• characterization of materials of construction via identification and quantification of their chemical constituents,
• characterization of the medical device for chemical substances introduced during manufacturing,
• estimation of potential medical device or materials of construction to release chemical substances under clinical use conditions,
• and measurement of chemical substances released from a medical device under its clinical conditions of use^[10].

Reducing the Need for Extensive Biological Testing

A comprehensive biological evaluation can help reduce the need for extensive biological testing by identifying and addressing potential risks early in the process^[5]. This approach aligns with ethical efforts to reduce animal testing and reflects a combined industrial and regulatory commitment to advancing biocompatibility evaluation methods^[7].

By following the guidelines set forth in the ISO 10993 series of standards and working with experienced partners like TÜV SÜD and NAMSA, manufacturers can ensure that their medical devices undergo thorough and compliant biocompatibility testing, ultimately leading to safer and more effective products for patients^[5][14]. 

Regulatory Considerations and Compliance

Compliance with key regulations and standards is essential for ensuring the safety and effectiveness of medical devices. Manufacturers must adhere to guidelines set forth by regulatory bodies and international standards to obtain approval and market their products^[7]. The following regulatory considerations are crucial for medical device manufacturers:

FDA Guidance on ISO 10993-1

The U.S. Food and Drug Administration (FDA) provides guidance on the use of International Standard ISO 10993-1 for medical devices^[1]. This guidance is applicable to various types of applications, including:

1. Premarket Applications (PMAs)
2. Humanitarian Device Exemptions (HDEs)
3. Investigational Device Applications (IDEs)
4. Premarket Notifications (510(k)s)
5. De Novo requests^[1]

The guidance document, issued by the Center for Devices and Radiological Health and the Center for Biologics Evaluation and Research, aims to assist manufacturers in determining the potential for an unacceptable adverse biological response resulting from contact with the device materials^[1]. Comments on the guidance can be submitted online or mailed to Dockets Management at the FDA^[1].

EU Medical Devices Directive and CE Marking

Within the European Union, the Medical Devices Regulation 2017/745 requires medical devices to comply with general safety and performance requirements(GSPR). Safety assessments are guided by the toxicological and other studies recommended in the ISO 10993-1/EN 30993-1 standard^[8].

Test specifications depend on a complex combination of factors, including the type of medical device or material, its intended use, and the nature and duration of contact between the device and the body^[15].

Conclusion

As we have explored throughout this article, complying with ISO 10993 for the biological evaluation of medical devices is a complex but essential process for ensuring patient safety and meeting regulatory requirements. By understanding the key principles of ISO 10993-1:2018, evaluating biological hazards, and conducting thorough risk management, manufacturers can navigate this process effectively. A comprehensive biological evaluation, which includes chemical characterization, can help reduce the need for extensive biological testing by identifying and addressing potential risks early in the development process.

Ultimately, adherence to regulatory requirements and international standards, such as ISO 10993, is crucial for obtaining approval and marketing medical devices globally. By working with experienced partners and following the guidelines set forth in the ISO 10993 series of standards, manufacturers can ensure the safety and effectiveness of their products, protecting patients and maintaining compliance with regulations. Investing in a robust biological evaluation process is not only an ethical responsibility but also a key factor in the success of medical devices in the market.