ISO 10993 Part-1 to 23 – Biological Evaluation of Medical Devices

ISO 10993-Biological evaluation of medical devices is a series of international standards that outline the biological evaluation of medical devices. These standards are published by the ISO and are used to assess the potential risks associated with the use of medical devices on living organisms. The evaluation process aims to ensure the safety and compatibility of medical devices with biological systems.

The ISO 10993 series consists of different parts, each focusing on specific aspects of biological evaluation. The parts included in ISO 10993 series are:

• ISO 10993-1: Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process
• ISO 10993-2: Biological evaluation of medical devices – Part 2: Animal welfare requirements
• ISO 10993-3: Biological evaluation of medical devices – Part 3: Tests for genotoxicity, carcinogenicity, and reproductive toxicity
• ISO 10993-4: Biological evaluation of medical devices – Part 4: Selection of tests for interactions with blood
• ISO 10993-5: Biological evaluation of medical devices – Part 5: Tests for in vitro cytotoxicity
• ISO 10993-6: Biological evaluation of medical devices – Part 6: Tests for local effects after implantation
• ISO 10993-7: Biological evaluation of medical devices – Part 7: Ethylene oxide sterilization residuals
• ISO 10993-8: Biological evaluation of medical devices – Part 8: Selection of reference materials
• ISO 10993-9: Biological evaluation of medical devices – Part 9: Framework for identification and quantification of potential degradation products
• ISO 10993-10: Biological evaluation of medical devices – Part 10: Tests for irritation and skin sensitization
• ISO 10993-11: Biological evaluation of medical devices – Part 11: Tests for systemic toxicity
• ISO 10993-12: Biological evaluation of medical devices – Part 12: Sample preparation and reference materials
• ISO 10993-13: Biological evaluation of medical devices – Part 13: Identification and quantification of degradation products from polymeric medical devices
• ISO 10993-14: Biological evaluation of medical devices – Part 14: Identification and quantification of degradation products from ceramics
• ISO 10993-15: Biological evaluation of medical devices – Part 15: Identification and quantification of degradation products from metals and alloys
• ISO 10993-16: Biological evaluation of medical devices – Part 16: Toxicokinetic study design for degradation products and leachables
• ISO 10993-17: Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances
• ISO 10993-18: Biological evaluation of medical devices – Part 18: Chemical characterization of materials
• ISO 10993-19: Biological evaluation of medical devices – Part 19: Physico-chemical, morphological and topographical characterization of materials
• ISO 10993-20: Biological evaluation of medical devices – Part 20: Principles and methods for immunotoxicology testing of medical devices
• ISO 10993-21: Biological evaluation of medical devices – Part 21: Evaluation of medical devices and their materials for systemic toxicity
• ISO 10993-22: Biological evaluation of medical devices – Part 22: Guidance on nanomaterials
• ISO 10993-23: Biological evaluation of medical devices – Part 23: Tests for irritation

ISO 10993-1:2018 – Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process

ISO 10993-1:2018 provides guidance on the biological evaluation of medical devices, emphasizing the importance of incorporating a risk management approach throughout the evaluation process.

The standard outlines the principles and methods for evaluating the potential biological hazards associated with medical devices to ensure patient safety. The evaluation process involves the assessment of materials used in the device, including their potential interactions with the body and the potential for the release of harmful substances (e.g., leachable and extractable substances). It also covers the various tests and studies that may be required to evaluate the biological safety of a medical device.

Key components of ISO 10993-Biological evaluation of medical devices include:

1. Risk management process: The standard emphasizes the need for a systematic risk management process when evaluating medical devices. This approach involves identifying hazards, estimating risks, and implementing necessary control measures to minimize potential adverse biological effects.
2. Biological safety assessment: The standard provides guidance on the biological safety assessment of medical devices, considering factors such as device classification, duration of contact with the body, and the nature and extent of patient contact.
3. Material characterization: ISO 10993-1:2018 discusses the importance of characterizing the materials used in the medical device, including their chemical composition, physical properties, and potential for degradation.
4. Biological testing: The standard presents an overview of the various biological tests that may be necessary based on the type of medical device and its intended use. These tests may include in vitro cytotoxicity testing, sensitization tests, irritation tests, and systemic toxicity testing, among others.
5. Biological evaluation endpoints: ISO 10993-1:2018 covers different biological evaluation endpoints, including local effects, systemic effects, and potential effects on specific patient populations (e.g., pregnant women).

It’s essential for medical device manufacturers and regulatory bodies to follow ISO 10993-1:2018 when conducting the biological evaluation of medical devices. Compliance with this standard helps ensure that medical devices are safe for use and minimize potential risks to patients and users.

ISO 10993-2:2022-Biological evaluation of medical devices — Part 2: Animal welfare Requirements

ISO 10993-2:2022 provides guidelines for conducting biological evaluations of medical devices that involve the use of live animals. The standard emphasizes the importance of minimizing the use of animals for testing purposes and promoting animal welfare.

The key objectives and considerations of ISO 10993-2 include:

1. Justification of animal use: The standard stresses the importance of justifying the use of animals in testing and encourages the exploration of alternative testing methods, such as in vitro and computational approaches, to reduce reliance on animal studies.
2. Reduction, refinement, and replacement (3Rs): ISO 10993-2 supports the principles of the 3Rs, which promote the reduction of the number of animals used, refinement of testing techniques to minimize animal suffering, and replacement of animal tests with non-animal alternatives whenever possible.
3. Animal welfare and care: The standard outlines requirements for the humane care and handling of animals used in testing. It emphasizes the need for appropriate housing, feeding, and veterinary care to ensure the well-being of the animals.
4. Study design and statistical considerations: ISO 10993-2:2022 provides guidance on the design of animal studies, including appropriate sample sizes and statistical analysis, to ensure the reliability and relevance of the data obtained.
5. Reporting and documentation: The standard requires comprehensive reporting of all aspects of the animal study, including methodologies, results, and any adverse effects observed during the testing.

By adhering to ISO 10993-2:2006, medical device manufacturers and researchers can conduct animal studies in a responsible and ethical manner, promoting the welfare of the animals, while ensuring that the medical devices’ safety is adequately assessed.

ISO 10993-3:2014-Biological evaluation of medical devices — Part 3: Tests for Genotoxicity, Carcinogenicity and Reproductive Toxicity

ISO 10993-3:2014 provides guidance on the evaluation of medical devices for potential genotoxic, carcinogenic, and reproductive toxicity risks.

Genotoxicity refers to the ability of a substance to damage the genetic material of cells, potentially leading to mutations and other genetic alterations. Carcinogenicity refers to the ability of a substance to cause cancer, and reproductive toxicity relates to adverse effects on the reproductive system or the developing fetus.

ISO 10993-3:2014 outlines the following key aspects:

1. Test methods: The standard describes the test methods to assess the genotoxic, carcinogenic, and reproductive toxicity potential of medical devices. These methods include both in vitro (tests performed outside a living organism) and in vivo (tests performed on living organisms) techniques.
2. Choice of tests: The standard provides guidance on selecting the appropriate tests based on the nature of the medical device, its intended use, and the potential routes of patient exposure to device materials.
3. Evaluation and interpretation of results: ISO 10993-3:2014 offers guidance on interpreting the test results and determining the potential risk of genotoxic, carcinogenic, or reproductive effects associated with the medical device.
4. Combination of test results: The standard emphasizes the need to consider the results of these tests in combination with other biological evaluation data to form a comprehensive risk assessment for the medical device.

Complying with ISO 10993-3:2014 ensures that medical devices are thoroughly evaluated for potential genotoxic, carcinogenic, and reproductive toxicity risks. Manufacturers use this information to make informed decisions about the safety and biocompatibility of their medical devices, taking appropriate measures to mitigate any potential risks identified during the evaluation process.

ISO 10993-4:2017-Biological evaluation of Medical Devices — Part 4: Selection of Tests for Interactions with Blood

ISO 10993-4:2017 provides guidance on the selection of appropriate tests to evaluate the interactions between medical devices and blood components. The evaluation is crucial to assess the potential risks associated with the contact of medical devices with blood and blood-related materials.

Key aspects of ISO 10993-4:2017 include:

1. Biological interactions: The standard focuses on the interactions that medical devices may have with blood components, such as red blood cells, white blood cells, platelets, and plasma proteins. It considers both the immediate and long-term effects of these interactions.
2. Test selection: ISO 10993-4:2017 helps medical device manufacturers identify and select relevant tests to assess the potential adverse effects that the device’s contact with blood may cause. These tests may include hemolysis, coagulation, platelet activation, and complement activation tests, among others.
3. Risk assessment: The standard emphasizes the importance of conducting a comprehensive risk assessment based on the results of the selected tests. This assessment helps manufacturers determine the safety and biocompatibility of the medical device when it comes into contact with blood.
4. Blood contacting devices: ISO 10993-4:2017 is particularly relevant for medical devices that come into direct or indirect contact with blood or blood components, such as intravascular catheters, vascular grafts, and blood bags.

By following ISO 10993-4:2017, medical device manufacturers can ensure that they adequately evaluate the potential risks associated with blood interactions, helping them design safer and more compatible medical devices for use with blood.

ISO 10993-5:2009-Biological Evaluation of Medical Devices — Part 5: Tests for in Vitro Cytotoxicity

ISO 10993-5:2009 provides guidance on conducting in vitro tests to assess the potential cytotoxic effects of medical devices and their materials.

Therefore, Cytotoxicity testing is a critical part of the biological evaluation process for medical devices as it helps assess how the device or its components interact with cells and tissues. The tests aim to identify any adverse effects on cell viability and function that may occur upon exposure to the medical device material.

Key aspects of ISO 10993-5:2009 include:

1. In vitro testing: The standard focuses on in vitro testing, meaning that the tests are performed outside a living organism using cell cultures. In these tests, cells are exposed to the materials from the medical device, and their response is evaluated.
2. Cell types: ISO 10993-5:2009 provides guidance on selecting appropriate cell types to use in the cytotoxicity tests based on the intended use of the medical device and the target tissue.
3. Test methods: The standard outlines different test methods to assess cytotoxicity, including direct contact tests, indirect contact tests, and extract tests. These tests vary in their approach to evaluate the potential toxic effects of the device or its components on cells.
4. Evaluation of results: ISO 10993-5:2009 includes criteria for evaluating the test results, such as cell morphology, cell viability, and any changes in cell function.
5. Biocompatibility assessment: Cytotoxicity testing is one of the key components of the biocompatibility assessment of medical devices, and its results are used in conjunction with other biological evaluation data to determine the overall biocompatibility profile.

By following ISO 10993-5:2009, medical device manufacturers can ensure that their products are subjected to appropriate cytotoxicity testing, helping to identify any potential cytotoxic effects and ensuring the safety of the device for its intended use.

ISO 10993-6:2016-Biological evaluation of medical devices — Part 6: Tests for local Effects after Implantation

ISO 10993-6:2016 provides guidelines for evaluating the potential local biological effects that medical devices may have on tissues and organs after implantation into the body.

When a medical device is implanted, it comes into direct contact with the surrounding tissues and organs. The local biological response to the implantation is critical to assess to ensure the device’s safety and biocompatibility.

Key aspects of ISO 10993-6:2016 include:

1. Local effects assessment: The standard provides guidance on the evaluation of local tissue responses to the implanted medical device. It covers various factors, such as inflammation, tissue reactivity, and any adverse effects on adjacent structures.
2. Test methods: ISO 10993-6:2016 outlines different test methods that can be used to assess local effects after implantation. These methods may include histopathological evaluation, assessment of tissue response, and other specific tests depending on the type and intended use of the medical device.
3. Implantation duration: The standard considers both short-term and long-term implantation durations, as some medical devices are intended for temporary use, while others may be intended for permanent implantation.
4. Material characterization: ISO 10993-6:2016 emphasizes the importance of characterizing the materials used in the medical device to understand their potential interactions with the surrounding tissues and organs.
5. Biological evaluation endpoints: The standard provides guidance on the selection of relevant biological evaluation endpoints to assess the local effects after implantation accurately.

By following ISO 10993-6:2016, medical device manufacturers can conduct comprehensive evaluations of the local biological effects of their products after implantation. This ensures that any potential adverse reactions are identified, and appropriate measures can be taken to enhance the safety and biocompatibility of the medical device.

ISO 10993-7:2008-Biological evaluation of medical devices — Part 7: Ethylene Oxide Sterilization Residuals

ISO 10993-7:2008 provides guidelines for assessing the potential biological risks associated with ethylene oxide (EO) residuals that may remain on medical devices after undergoing sterilization using ethylene oxide gas.

Ethylene oxide is commonly in use for sterilizing medical devices due to its effectiveness in killing microorganisms. However, residual ethylene oxide or its by-products left on the device after sterilization can pose potential risks to patients if not adequately removed.

Key aspects of ISO 10993-7:2008 include:

1. Residual analysis: The standard describes the methods for measuring and analyzing ethylene oxide residuals on medical devices. These methods help determine the amount of EO residuals present on the device surface or in its packaging.
2. Biocompatibility assessment: ISO 10993-7:2008 provides guidance on how to interpret the analytical data to assess the potential biological risks associated with the detected EO residuals.
3. Risk management: The standard emphasizes the importance of incorporating the evaluation of EO residuals within the overall risk management process for the medical device.
4. Maximum allowable levels: ISO 10993-7:2008 provides information on the maximum allowable levels of EO residuals on medical devices to ensure patient safety.

By following ISO 10993-7:2008, medical device manufacturers can assess the potential risks associated with ethylene oxide residuals on their devices after sterilization. This helps ensure that EO sterilization is performed correctly and that the device’s biocompatibility is not compromised due to excessive residual EO levels.

ISO 10993-10:2021 – Biological Evaluation of Medical Devices — Part 10: Tests for Skin Sensitization

ISO 10993-10:2021 provides guidance on conducting tests to assess the potential for medical devices and their materials to cause skin sensitization reactions in patients.

Skin sensitization refers to an allergic response that occurs when the immune system reacts to a substance upon initial exposure and causes an allergic reaction upon subsequent exposure.

Key aspects of ISO 10993-10 include:

1. Sensitization testing: The standard outlines different test methods to evaluate the potential for a medical device or its materials to cause skin sensitization reactions. These tests are typically conducted on animals or using alternative in vitro methods.
2. Evaluation and interpretation of results: ISO 10993-10:2021 provides guidance on how to evaluate and interpret the test results to determine the skin sensitization potential of the medical device or its materials.
3. Biocompatibility assessment: Sensitization testing is an essential component of the overall biocompatibility assessment of medical devices to ensure patient safety.
4. Risk management: The standard emphasizes the importance of incorporating skin sensitization testing within the overall risk management process for medical devices.

ISO 10993-11:2017 – Biological Evaluation of Medical Devices — Part 11: Tests for Systemic Toxicity

ISO 10993-11:2017 provides guidelines for conducting tests to assess the potential systemic toxicity of medical devices and their materials.

Systemic toxicity refers to the adverse effects that a substance or medical device may have on the entire organism when it is absorbed into the bloodstream and distributed throughout the body.

Key aspects of ISO 10993-11:2017 include:

1. Test methods: The standard outlines various test methods to assess systemic toxicity. These methods include acute toxicity tests, subchronic toxicity tests, and chronic toxicity tests, among others. The choice of tests depends on the duration of contact with the device and the intended use of the medical device.
2. Animal testing: Systemic toxicity testing is typically conducted on animals, where the medical device or its extracts are administered to animals, and their responses are observed over a specified period.
3. Endpoints and observations: ISO 10993-11:2017 provides guidance on the relevant endpoints to evaluate during the systemic toxicity testing, such as changes in body weight, clinical signs, organ weights, and histopathological observations.
4. Biocompatibility assessment: Systemic toxicity testing is an essential component of the overall biocompatibility assessment of medical devices to ensure patient safety.
5. Risk management: The standard emphasizes the importance of incorporating systemic toxicity testing within the overall risk management process for medical devices.

Also, ISO 10993-11:2017, medical device manufacturers can evaluate the potential systemic toxicity risks associated with their products. The results of tests help to ensure that the medical device is safe for use.

ISO 10993-12:2021 – Biological Evaluation of Medical Devices — Part 12: Sample Preparation and Reference Materials

ISO 10993-12:2021 provides guidelines for sample preparation and the use of reference materials when conducting biological evaluations of medical devices.

Key aspects of ISO 10993-12 include:

1. Sample preparation: The standard outlines procedures for preparing medical device samples for biological testing. Proper sample preparation is essential to ensure accurate and reproducible test results.
2. Reference materials: ISO 10993-12 provides guidance on the use of reference materials during the biological evaluation process. Reference materials serve as control samples to compare the responses of test samples and help validate the test methods.
3. Biological evaluation endpoints: The standard considers various biological evaluation endpoints and the appropriate sample preparation methods for each endpoint.
4. Quality control: ISO 10993-12:2021 emphasizes the importance of quality control measures during sample preparation to maintain the reliability of test results.

ISO 10993-13:2010 – Biological Evaluation of Medical Devices — Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices

ISO 10993-13:2010 provides guidelines for identifying and quantifying degradation products that can be released from polymeric medical devices during their use.

Polymeric materials are common in medical devices, and their degradation over time leads to the release of various compounds and substances. It is essential to assess the potential biological effects of these degradation products to ensure the safety and biocompatibility of the medical device.

Key aspects of ISO 10993-13:2010 include:

1. Sample preparation: The standard outlines procedures for preparing the polymeric medical device samples for the identification and quantification of degradation products.
2. Analytical methods: ISO 10993-13:2010 provides guidance on the analytical methods to identify and quantify degradation products. These methods may include spectroscopy, chromatography, mass spectrometry, and other analytical techniques.
3. Identification of degradation products: The standard helps identify the specific substances released during the degradation process and assess their potential biological effects.
4. Quantification of degradation products: ISO 10993-13:2010 provides guidance on quantifying the amounts of degradation products released from the medical device.
5. Biocompatibility assessment: The identification and quantification of degradation products are essential components of the overall biocompatibility assessment of medical devices.

By following ISO 10993-13:2010, medical device manufacturers can assess the potential risks associated with the degradation products of polymeric medical devices.

ISO 10993-17:2002 – Biological Evaluation of Medical Devices — Part 17: Establishment of Allowable Limits for Leachable Substances

ISO 10993-17:2002 provides guidelines for establishing acceptable limits for substances that may leach from medical devices and come into contact with the patient’s body.

Leachable substances are compounds which release from a medical device due to contact with body fluids, temperature, or other environmental conditions. These substances may include residual chemicals from the device manufacturing process, degradation products, or additives from the materials used in the device.

Key aspects of ISO 10993-17:2002 include:

1. Definition of leachable substances: The standard provides a definition of leachable substances and their significance in the biological evaluation of medical devices.
2. Sample preparation: ISO 10993-17 outlines procedures for preparing the medical device samples to determine the presence and quantity of leachable substances.
3. Analytical methods: The standard provides guidance on the analytical methods used to identify and quantify leachable substances from the medical device.
4. Biocompatibility assessment: ISO 10993-17:2002 emphasizes that the determination of allowable limits for leachable substances is a critical part of the overall biocompatibility assessment of medical devices.
5. Risk management: The standard emphasizes the importance of considering the potential risks associated with leachable substances and establishing appropriate allowable limits to ensure patient safety.

By following ISO 10993-17:2002, medical device manufacturers can determine acceptable limits for leachable substances and ensure that the medical device complies with regulatory requirements and is safe for its intended use. These guidelines help identify and mitigate potential risks associated with leachable substances, ensuring the overall biocompatibility of the medical device.

ISO 10993-18:2020 – Biological Evaluation of Medical Devices — Part 18: Chemical Characterization of Medical Device Materials within a Risk Management Process

ISO 10993-18:2020 provides guidelines for the chemical characterization of materials used in medical devices as part of the biological evaluation process.

Moreover, Chemical characterization involves the identification and quantification of the chemical components present in the medical device materials. This information is essential for assessing the potential biological risks associated with the use of the device.

Key aspects of ISO 10993-18:2020 include:

1. Material identification: The standard provides guidance on identifying the chemical composition of medical device materials, including polymers, metals, ceramics, and other substances used in the device’s construction.
2. Extractable and leachable substances: ISO 10993-18:2020 addresses the assessment of extractable and leachable substances from the medical device materials. Extractable substances are compounds that can be extracted from the material under specific laboratory conditions, while leachable substances are compounds that can migrate from the material into the patient’s body during use.
3. Analytical methods: The standard outlines various analytical methods which are in use for chemical characterization, including spectroscopy, chromatography, mass spectrometry, and other techniques.
4. Risk management: ISO 10993-18:2020 emphasizes the integration of chemical characterization within the overall risk management process for medical devices. The results of chemical characterization contribute to the biological safety assessment of the device.
5. Regulatory considerations: The standard addresses the importance of considering regulatory requirements related to chemical characterization and biocompatibility assessment of medical devices.

Furthermore, with ISO 10993-Biological evaluation of medical devices, manufacturers can conduct comprehensive chemical characterization of materials, helping to identify potential hazardous substances and ensuring the overall safety and biocompatibility of the medical device.

ISO 10993-23:2021 – Biological Evaluation of Medical Devices — Part 23: Tests for Irritation

ISO 10993-23:2021 provides guidelines for conducting tests to evaluate the potential irritation response of medical devices and their materials on living tissues.

Irritation testing assesses the potential for medical devices to cause irritation, inflammation, or other adverse effects on tissues and mucous membranes when they come into contact with the body.

Key aspects of ISO 10993-23 include:

1. Test methods: The standard outlines different test methods, used to assess irritation, such as skin irritation tests, eye irritation tests, and mucous membrane irritation tests.
2. Evaluation and interpretation of results: ISO 10993-23 provides guidance on evaluating and interpreting the test results to determine the irritation potential of the medical device or its materials.
3. Biocompatibility assessment: Irritation testing is an essential component of the overall biocompatibility assessment of medical devices to ensure patient safety.
4. Risk management: The standard emphasizes the importance of incorporating irritation testing within the overall risk management process for medical devices.

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Also read: ISO Certifications for Medical Devices