ISO Standards Associated with Medical Device Biocompatibility Testing | Part 1
In the realm of medical device development, ensuring biocompatibility is a critical step in safeguarding patient safety and device efficacy. Biocompatibility refers to the ability of a medical device to perform with an appropriate host response when applied as intended. The International Organization for Standardization (ISO) has established a comprehensive suite of standards to guide the testing and assessment of biocompatibility, thereby streamlining the regulatory approval process and promoting global harmonization.
ISO standards cover various aspects of biocompatibility, from material characterization to pre-clinical evaluation. This article delves into the collection of ISO standards associated with medical device biocompatibility testing, describing eight key standards in detail.
- ISO 10993-1: Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process
ISO 10993-1 serves as the cornerstone of biocompatibility testing. It outlines the general principles governing the biological evaluation of medical devices within a risk management framework. This standard emphasizes a tiered approach to testing, starting with the characterization of materials and progressing to in vitro and in vivo assessments based on the device’s nature and intended use.
Tests associated:
- Physical and/or Chemical information
- Cytotoxicity
- Sensitization
- Irritation or Intracutaneous reactivity
- Materiał mediated pyrogenicity
- Acute systemie toxicity
- Subacute toxicity
- Subchronic toxicity
- Chronic toxicity
- Implantation effects
- Hemocompatibility
- Genotoxicity
- Carcinogenicity
- Reproductive / developmental toxicity
- Degradation
- ISO 10993-5: Biological Evaluation of Medical Devices – Part 5: Tests for In Vitro Cytotoxicity
ISO 10993-5 focuses on in vitro cytotoxicity testing, which assesses the potential of a medical device material to cause cell death or inhibition of cell growth. This test is a primary screening tool to identify cytotoxic substances.
Examples of tests:
- Direct contact methods
- Extract dilution methods
Description: Cytotoxicity tests involve exposing cultured cells to the device material or extracts thereof. Cell viability is then assessed using assays such as the MTT assay, where mitochondrial activity (indicative of live cells) is measured.
- ISO 10993-10: Biological Evaluation of Medical Devices – Part 10: Tests for Skin Sensitization
ISO 10993-10 provides guidelines for assessing the potential of medical devices to cause sensitization. Sensitization (e.g. delayed-type hypersensitivity) tests can be used to estimate the potential for contact sensitization by medical devices, materials and/or their extracts, using an appropriate model. Sensitization tests evaluate the potential for allergic reactions.
Examples of tests:
- GPMT (Kligman Guinea Pig Maximization Test)
- LLNA (Murine Local Lymph Node Assay)
- Buehler Sensitization
Description: Sensitization tests like GPMT (Kligman Guinea Pig Maximization Test) involve repeated exposure to assess allergic response potential.
- ISO 10993-11: Biological Evaluation of Medical Devices – Part 11: Tests for Systemic Toxicity
ISO 10993-11 outlines procedures for evaluating the systemic toxicity of medical devices, which includes adverse effects on organs and systems after prolonged exposure. This standard is crucial for devices that have long-term or widespread exposure within the body.
Examples of tests:
- Acute systemic toxicity test
- Subacute and subchronic toxicity tests
- Chronic toxicity tests
Description: Systemic toxicity tests involve administering device extracts or materials to animal models via injection, inhalation, or ingestion and monitoring for clinical signs, hematological changes, and pathological alterations over time.
- ISO 10993-12: Biological Evaluation of Medical Devices – Part 12: Sample Preparation and Reference Materials
ISO 10993-12 provides guidance on the preparation of samples and the selection of reference materials for biocompatibility testing. This standard ensures consistency and reliability in test results.
Scope:
- Preparation of extracts
- Selection of solvents and extraction conditions
- Use of control materials
Description: This standard specifies the methods for extracting device materials using various solvents under defined conditions to produce test extracts that accurately represent clinical exposure scenarios.
- ISO 10993-17: Biological Evaluation of Medical Devices – Establishment of Allowable Limits for Leachable Substances
ISO 10993-17 provides a structured framework for determining allowable limits for leachable substances that may migrate from medical device materials into the body. This standard is essential for ensuring patient safety by defining permissible exposure levels for these substances.
Scope:
- Toxicological assessments
Description: Extraction studies involve simulating physiological conditions to extract substances from device materials. Analytical techniques are then employed to identify and quantify leachable substances. Toxicological assessments evaluate the biological impact of these substances, establishing safe exposure limits to minimize risks and ensure long-term patient safety throughout the device’s lifecycle.
- ISO 10993-18: Biological Evaluation of Medical Devices – Part 18: Chemical Characterization of Materials
ISO 10993-18 focuses on the chemical characterization of medical device materials, which is an essential first step in biocompatibility assessment. It involves identifying and quantifying chemical constituents that may be released from the device.
Examples of tests:
- GC-MS: Gas Chromatography-Mass Spectrometry, used to separate and identify volatile and semi-volatile organic compounds.
- LC-MS: Liquid Chromatography-Mass Spectrometry, ideal for analyzing non-volatile and complex molecules.
- ICP-MS: Inductively Coupled Plasma Mass Spectrometry, used for detecting trace metals and elements.
- FT-IR: Fourier Transform Infrared Spectroscopy, useful for identifying functional groups and molecular structures.
- UV-VIS: Ultraviolet-Visible Spectroscopy, used to measure the absorbance of a sample across the 200–800 nm spectrum.
Description: Chemical characterization involves using advanced analytical techniques to detect and quantify potential leachable substances from the device material, providing critical information on the chemical profile and potential toxicological risks.
- ISO 10993-6: Biological Evaluation of Medical Devices – Part 6: Tests for Local Effects after Implantation
ISO 10993-6 addresses the evaluation of local effects after the implantation of medical devices. This standard is relevant for devices intended for implantation and assesses tissue response at the implant site.
Examples of tests:
- Subcutaneous implantation: Evaluates tissue response when materials are implanted under the skin.
- Intramuscular implantation: Assesses local effects when implanted into muscle tissue.
- Bone implantation: Analyzes response to materials in direct contact with bone.
- Brain implantation: Examines tissue interactions and reactions in neurological tissues.
Testing durations typically span 4 or 13 weeks, depending on the study objectives and regulatory requirements.
Description: Implantation tests involve surgically placing the device material into animal tissue and evaluating the local tissue response over time. Histopathological examination of the tissue surrounding the implant provides insight into inflammation, fibrosis, and other local reactions.
Summary
The ISO 10993 series of standards provides a robust framework for the biocompatibility evaluation of medical devices, ensuring they are safe for human use. These standards encompass a wide range of tests, from initial material characterization to in vitro and in vivo biological evaluations. By adhering to these standards, medical device manufacturers can systematically assess and mitigate potential risks, thereby facilitating regulatory approval and enhancing patient safety. The detailed guidelines within these standards help ensure consistency, reliability, and reproducibility in biocompatibility testing, which is crucial for the successful development and deployment of medical devices in the healthcare market.
About the Author: Dr. Damian Matak
Dr. Damian Matak – an expert in medical device biocompatibility testing, serving as the CEO of ISO 17025-accredited and GLP-certified laboratories, including EBI – European Biomedical Institute and NABI – North American Biomedical Institute. As a member of the Polish Society of Toxicology and the I Local Ethical Committee, Dr. Matak contributes significantly to advancing safety standards in the biomedical field.
