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What are Chemical Characterization (ISO 10993-18) and Toxicology Risk Assessment (ISO 10993-17); and How Do They Benefit Biocompatibility Evaluations for Medical Devices?
In simple terms, what does the biocompatibility assessment of medical devices involve?
The biocompatibility of medical devices can often seem like a daunting black hole to those without specialized training.
ISO 10993 series (consisting of over 20 parts) guides to assess the biocompatibility of medical devices in various aspects including testing methods, risk assessment, and documentation requirements.
Global regulatory bodies such as the US FDA or EU MDR also often reference the ISO 10993 series (or their accepted version) when evaluating the safety and effectiveness of medical devices for approval and market clearance.
The overall biological evaluations/endpoints (excluding the required physical and/or chemical information) to determine the biocompatibility of a medical device are:
1) Cytotoxicity, 2) Sensitization, 3) Irritation, 4) Material Mediated Pyrogenicity (MMP), 5) Acute Toxicity, 6) Subacute Toxicity, 7) Subchronic Toxicity, 8) Chronic Toxicity, 9) Implantation, 10) Hemocompatibility, 11) Genotoxicity, 12) Carcinogenicity, 13) Reproductive/developmental Toxicity, 14) Degradation.
The specific number of biological evaluations/endpoints out of these 14 that should be assessed for a medical device depends on its category (e.g., surface, implant), contact type (e.g., intact skin, breached surface, bone/tissue), and contact duration (e.g., >24h, >30 d) as outlined in Table A.1 derived from ISO 10993-1 in the FDA guidance document.
Two examples:
Example 1. Looking at depicted Table A.1., one sees a skin device of any contact duration only needs three assessments to establish its biological safety including cytotoxicity, sensitization, and irritation.
Example 2. Comparatively, a breached-surface device with contact duration of >30 days demands several more endpoint assessments, in addition to cytotoxicity, sensitization, and irritation, such as MMP, system toxicity (acute, subacute, Subchronic, and chronic), implantation, genotoxicity, and carcinogenicity.
These required evaluations are many for Example 2, leading to delayed market access for patients who may critically need the device as well as, not surprisingly, very costly and time-consuming for the company.
Now, you may ask: Is there a way to reduce the number of biological assessments to meet regulatory requirements while ensuring a device’s safety for its targeted patients?
YES, there is.
You can utilize chemical characterization (ISO 10993-18) and toxicological risk assessments (ISO 10993-17) to establish the safety of your medical device and potentially waive animal studies for several biological evaluations including system toxicity (acute, subacute, subchronic, and chronic), genotoxicity, and carcinogenicity.
Table A.1. Derived from ISO 10993-1 in the FDA guidance document
What is chemical characterization (ISO 10993-17) and what is toxicological risk assessment (ISO 10993-17) of a medical device?
Briefly, part 18 of the ISO 10993 series helps identify and control any harmful substances in medical devices. It uses steps like figuring out what the device is made of, checking for any added chemicals, and testing if these materials release any chemicals during use (known as extractable & leachables – E&L). It also helps identify any breakdown products of degraded/resorbable materials that might be harmful. For E&L, it offers guidance on how an extract should be collected and what mediums to use (i.e. polar, non-polar, and semi-polar solvents).
In combination with part 18, part 17 of ISO 10993 lays out the necessary steps for conducting a toxicological risk assessment of certain components found in the E&L of medical devices, which is an integral part of the overall biological evaluation process. This guideline assists to:
- Determine if the materials in the medical device could potentially harm health.
- Calculate safe levels of exposure based on body size and a specified period.
- Estimate the highest possible exposure for each material and assess the associated toxicological risk.
- Evaluate the overall toxicological risk based on safe exposure levels and the highest estimated exposure for each material.
The image in Figure 1. visualizes the medical device chemical characterization (ISO 10993-18) and toxicological risk assessment (ISO 10993-17).
Which biocompatibility endpoints can be addressed by relying on E&L data and leveraging ISO 10993-17 toxicological assessments?
Generally, toxicological assessments can address the following biocompatibility endpoints for a medical device before most regulatory bodies around the world:
- Acute toxicity
- Subacute toxicity
- Subchronic toxicity
- Chronic toxicity
- Genotoxicity
- Carcinogenicity
- Reproductive toxicity
- Developmental toxicity
How much time and cost a company can save with chemical characterization (ISO 10993-18) and toxicology assessments (ISO 10993-17)?
Using Example 2. from above, a sponsor/company needs to submit biological evaluations for the following endpoints: Cytotoxicity, Sensitization, Irritation, MMP, acute toxicity, subacute toxicity, Subchronic toxicity, chronic toxicity, implantation, genotoxicity, and carcinogenicity.
When including chemical characterization as part of the testing strategy, a company can save on average US$170,000.00 and trim 20 weeks (5 months) off the timeline at least. The details are outlined in Table 2.
Even if a simulated extraction study needs to be performed (due to high safety concerns after chemical characterization), there would still be considerable cost savings going with this approach.
Saving time and cost sounds amazing, but is the toxicology assessment of E&L as sensitive as animal testing to assess a device's safety?
- Chemical characterization and toxicological assessment methods expose the device to worst-case scenarios in three different solvent environments, enabling a thorough evaluation of extractable or leachable substances for insights into its safety profile under various conditions.
- Animal testing lacks precision due to the inability to replicate controlled environments, resulting in higher margins for errors and inaccuracies. It primarily focuses on observable signs like organ changes or death and cannot thoroughly assess the toxicological harm of each leached substance.
- Toxicological assessment evaluates multiple endpoints and intake routes (oral, dermal, inhalation), offering a comprehensive understanding of the device’s potential human health effects, enhancing result reliability, and ensuring a more accurate biological safety assessment.
- Outputs from chemical characterization and toxicological assessment methods can facilitate root cause analysis if needed by transferring findings to materials.
- The use of chemical characterization and toxicological assessment methods can significantly improve animal welfare by reducing the need for animal testing, potentially saving at least 200 animal lives (i.e. mice) in compliance with ISO 10993:2 Animal Welfare Requirements.
Which extractable or leachable substances may be present in a medical device?
- Manufacturing residues of the raw materials used e.g., residual monomers, catalysts, initiators.
- Additives used e.g., additives, fillers, colorants.
- Process residues resulting from the manufacture of the final medical device from raw materials mold release agents, lubricants or slip agents, and cleaning agents.
- Material changes due to raw material processing.
- Transfer of substances between used materials or from packaging material.
- Degradation or decomposition products.
How can Chemva assist your company in your biocompatibility process?
Chemva can assist you in preparing the following documents and reports for your medical device biocompatibility submission (or in-house filing):
- Biocompatibility Evaluation Plan (BEP) = A document summarizing what biological evaluations are needed (or not) and how/what test method will be used for such assessment.
- Material Characterization Report = A report summarizing all the raw materials risk assessment including processing conditions.
- Toxicological Risk Assessment (TRA) of E&L data = A report calculating the margin of safety for each released chemical and leveraging such assessments to address relevant biological endpoints (i.e. genotoxicity, chronic toxicity)
- Biocompatibility Testing Summary = A summary of all biological testing that was completed (i.e. cytotoxicity, implantation)
- Biological Evaluation Report (BER) = A comprehensive report that references the BEP document, material characterization report, TRA assessment, and biocompatibility testing summary to establish the device safety for patient use before a regulatory agency such as the US FDA.
Additionally, Chemva can support you with:
- Gap analysis of biocompatibility endpoints
- Changes to material, supplier, or manufacturer
- Establishing materials equivalency for biocompatibility purposes
- Proper materials selection by considering ISO 10993 requirements from the start
- Leachable and extractable design and risk assessment
- Expert reports and technical writing
- Combination products biological assessments
- Coordinating and liaison with CROs to run your biological and chemical characterization experiments
References:
- ISO 10993-1:2018. Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process.
- US FDA. Use of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part1: Evaluation and testing within a risk management process “Guidance for Industry and Food and Drug Administration Staff. September, 2020.
- ISO 10993-17:2023. Biological Evaluation of Medical Devices – Part 17: Methods for the establishment of allowable limits for leachable substances.
- Eric M. Sussman, Berk Oktem, Irada S. Isayeva, Jinrong Liu, Samanthi Wickramasekara, Vaishnavi Chandrasekar, Keaton Nahan, Hainsworth Y. Shin, and Jiwen Zheng. Chemical Characterization and Non-targeted Analysis of Medical Device Extracts: A Review of Current Approaches, Gaps, and Emerging Practices. ACS Biomaterials Science & Engineering 2022 8 (3), 939-963 DOI: 10.1021/acsbiomaterials.1c01119