ISO 10993-1 2026: Preparing Your Biocompatibility Assessments

With the international standard for biological evaluation, ISO 10993-1, expected to see a significant revision around 2026, medical device manufacturers must prepare to adapt their biocompatibility assessment strategies. The upcoming changes are anticipated to continue and formalize the global regulatory shift away from a simple checklist of biocompatibility tests and toward a more integrated, evidence-based, and risk-driven approach. This evolution places greater emphasis on understanding a device's constituent materials and manufacturing processes before any biological testing is considered. For manufacturers, this means the Biological Evaluation Plan (BEP) is no longer a preliminary document but the central pillar of the entire assessment. A robust BEP must function as a comprehensive scientific rationale, meticulously documenting the risk analysis process. It must consider the device's materials, manufacturing inputs, intended clinical use, and the specific nature and duration of tissue contact. This approach, which prioritizes chemical characterization and toxicological risk assessment, aligns with modern regulatory expectations and the ethical principles of reducing animal testing (the 3Rs: Replace, Reduce, Refine). ## Key Points * **Risk-Based Framework is Paramount:** The updated standard will further solidify the move away from a "checklist" approach. The Biological Evaluation Plan (BEP) serves as the core risk assessment document, providing a full scientific justification for the entire evaluation strategy, including which tests are—and are not—performed. * **Chemical Characterization as the Foundation:** A thorough understanding of a device's material composition through chemical characterization (as detailed in ISO 10993-18) is the mandatory first step. This involves identifying and quantifying substances that could be released from the device during use. * **Toxicological Risk Assessment (TRA) Drives Decisions:** Data from chemical characterization is used to conduct a TRA (per ISO 10993-17). This assessment determines if any identified substances pose an unacceptable health risk, and its conclusions can provide powerful justification for reducing or eliminating certain *in vivo* biocompatibility tests. * **Lifecycle Perspective is Essential:** The evaluation must encompass the entire product lifecycle. This includes assessing the biological impact of manufacturing residues (e.g., cleaning agents), sterilization byproducts, and any potential degradation products that may form over the device's intended life. * **Proactive Gap Analysis is Critical:** Manufacturers should begin reviewing their existing biocompatibility documentation for legacy devices. A gap analysis can identify whether the original data meets today's heightened expectations for chemical characterization and risk assessment, especially if materials or processes have changed. * **Early Regulatory Engagement De-Risks Strategy:** For devices with novel materials, complex manufacturing processes, or an evaluation strategy that relies heavily on chemical data to waive testing, engaging with regulatory bodies like the FDA through the Q-Submission program is a valuable strategic step. ## The Evolution of Biocompatibility: From Testing Checklist to Risk Management Historically, biocompatibility evaluation was often perceived as a fixed menu of tests. A manufacturer would consult the matrix in ISO 10993-1, identify the device category and contact duration, and execute the prescribed list of biological tests. While straightforward, this approach could lead to unnecessary animal testing and failed to account for the specific nuances of a device's materials and manufacturing. The modern paradigm, strongly endorsed by FDA guidance and expected to be further codified in the 2026 revision, reframes biocompatibility as a risk management activity. The evaluation is a thought process, not just a testing sequence. The goal is to demonstrate patient safety by first thoroughly understanding the device and then using that knowledge to identify and mitigate potential biological risks. If the risks can be fully characterized and deemed acceptable through other means—such as chemical analysis and toxicological assessment—then extensive biological testing may not be necessary. This shift places the burden of proof on the manufacturer to build a scientific argument for safety, with the BEP serving as the comprehensive record of that argument. ## Deconstructing the Modern Biological Evaluation Plan (BEP) A contemporary BEP is a living document that guides the entire evaluation process. It should be authored by a qualified professional and contain sufficient detail for a regulator to understand the device, the potential risks, and the rationale for the proposed evaluation strategy. A robust BEP should include the following sections: **1. Detailed Device Description** * **Materials of Construction:** A complete list of all materials with direct or indirect patient contact, including CAS numbers, specifications, and suppliers. * **Manufacturing Processes:** A summary of all processes, including molding, machining, surface treatments, cleaning, assembly, and packaging. Identify any processing aids, lubricants, or other chemicals used. * **Sterilization:** The method of sterilization (e.g., EtO, gamma, steam), including details on residuals and byproducts. * **Physical Configuration:** Description of the final finished device and its components. **2. Intended Clinical Use** * **Indications for Use:** What the device is intended to do. * **Patient Population:** The intended users (e.g., adult, pediatric). * **Nature of Body Contact:** The type of tissue the device will contact (e.g., skin, blood, bone). * **Duration of Contact:** Categorization as limited (<24 hours), prolonged (24 hours to 30 days), or permanent (>30 days). **3. Assessment of Biological Endpoints** * Based on the device's categorization, a review of all potential biological effects listed in ISO 10993-1, Annex A. * A clear justification for which endpoints are relevant to the device and require evaluation. For example, a long-term implant will require assessment of chronic toxicity and carcinogenicity, whereas a short-term skin-contacting electrode will not. **4. Review of Existing Information** * **Material Data:** A summary of any available biocompatibility, chemical, or toxicological data on the device's materials from suppliers or literature. * **Clinical History:** Data from previous clinical use of the device or similar devices. * **Literature Search:** A systematic review of scientific literature for relevant data on the materials and similar medical devices. **5. Proposed Evaluation and Testing Strategy** * **Chemical Characterization Plan:** A detailed plan for extractables and leachables (E&L) testing according to ISO 10993-18, including justification for solvents, extraction conditions, and analytical techniques. * **Toxicological Risk Assessment Plan:** An outline of the plan to assess the risk of identified chemicals per ISO 10993-17. * **Biological Testing Plan:** A list of any proposed biological tests. Crucially, this section must include a strong scientific rationale for why each test is necessary and a justification for any standard tests that are being omitted based on the risk assessment. ## The Central Role of Chemical Characterization (ISO 10993-18) Under the risk-based framework, chemical characterization is the foundational activity for most devices, particularly those with prolonged or permanent patient contact. The objective is to create a comprehensive profile of every substance that could potentially be released from the device into the body. This is typically achieved through exaggerated extractables and leachables (E&L) studies. The simplified process involves: 1. **Strategic Study Design:** Selecting appropriate solvents (polar, non-polar, and semi-polar) and extraction conditions (time and temperature) that are more aggressive than physiological conditions to ensure a worst-case scenario. 2. **Extraction:** Exposing the finished, sterilized device to the chosen solvents for the specified duration. 3. **Chemical Analysis:** Using a battery of sensitive analytical chemistry techniques (e.g., GC-MS, LC-MS, ICP-MS) to separate, identify, and quantify the compounds present in the extracts. 4. **Reporting:** Compiling a detailed report that lists all identified compounds, their concentrations, and the methods used to detect them. A common pitfall is failing to design a study that is truly representative of the finished device. The test article must be the final, packaged, and sterilized device to ensure all manufacturing residues and sterilization byproducts are captured in the analysis. ## Leveraging Toxicological Risk Assessment (TRA) (ISO 10993-17) The data from the chemical characterization study feeds directly into the toxicological risk assessment. The goal of the TRA is to determine if the identified chemicals, at their measured quantities, pose an unacceptable risk to patient health. This process, conducted by a qualified toxicologist, generally follows these steps: 1. **Dose Estimation:** Calculating the maximum possible dose a patient could receive of each chemical leachable over the device's lifetime. 2. **Hazard Identification:** Conducting an extensive literature search for each chemical to find existing toxicological data and establish a Tolerable Intake (TI) or Tolerable Exposure (TE)—the maximum daily dose considered safe. 3. **Risk Characterization:** Calculating a Margin of Safety (MOS) for each chemical by comparing the Tolerable Intake to the estimated patient dose. 4. **Conclusion:** If all chemicals have an adequate Margin of Safety, the toxicological risk may be deemed acceptable. This conclusion can then be used to justify that certain biological effects (e.g., systemic toxicity, genotoxicity) are not a concern, potentially eliminating the need for the corresponding *in vivo* tests. ## Scenarios: Applying the Risk-Based Approach ### Scenario 1: A Legacy Class II Orthopedic Implant * **Situation:** A titanium bone screw has been on the market for 15 years with a strong history of safe use. The manufacturer qualifies a new supplier for the raw titanium alloy, which meets the same material standard (e.g., ASTM F136). * **What Regulators Will Scrutinize:** While the material standard is the same, regulators will question if the new supplier's raw material processing could introduce different trace elements or contaminants. * **Actionable Strategy:** 1. Update the BEP to document the supplier change and outline the risk assessment. 2. Conduct a targeted chemical characterization study on the screws made from the new material, specifically using highly sensitive techniques like ICP-MS to compare the elemental impurity profile against the screws from the old supplier. 3. If the profiles are equivalent, or if any new impurities are well below established toxicological safety thresholds, the BEP can conclude that the change presents no new biological risk. 4. This documented, risk-based justification is often sufficient to address the change without requiring any new biological testing. ### Scenario 2: A New Class II SaMD with a Wearable Sensor * **Situation:** A company develops a novel Software as a Medical Device (SaMD) that uses a wearable sensor. The sensor is housed in a unique polymer and is intended for continuous skin contact for up to 14 days. * **What Regulators Will Scrutinize:** The composition of the novel polymer, including any plasticizers, colorants, or processing aids. The adequacy of the E&L study to capture all potential leachables. The scientific rigor of the TRA. * **Actionable Strategy:** 1. Develop a comprehensive BEP that identifies cytotoxicity, irritation, and sensitization as key biological endpoints. 2. Execute an exhaustive E&L study on the final, sterilized sensor housing per ISO 10993-18. 3. Perform a full TRA on all identified leachables per ISO 10993-17. 4. If the TRA demonstrates sufficient margins of safety for all compounds, the BEP can use this evidence to support a testing plan limited to *in vitro* cytotoxicity (ISO 10993-5) and *in vivo* irritation and sensitization tests (ISO 10993-23 and 10993-10). The TRA provides a strong justification for why systemic toxicity testing is not required. ## Strategic Considerations and the Role of Q-Submission This risk-based methodology demands more strategic planning and expertise than a simple checklist approach. For devices that are complex, contain novel materials, or for which a manufacturer intends to heavily leverage chemical data to waive biological testing, early engagement with regulators is a critical de-risking step. The FDA's Q-Submission program is an invaluable tool for this purpose. A Pre-Submission (Pre-Sub) meeting allows a sponsor to present their proposed evaluation strategy and receive direct feedback from the agency before committing significant resources to testing. A Pre-Sub package for biocompatibility should include: * A detailed device description. * The draft Biological Evaluation Plan (BEP). * The proposed chemical characterization protocol. * Specific questions for the FDA regarding the planned approach, such as the adequacy of the extraction conditions or the proposal to waive certain *in vivo* tests based on anticipated TRA results. Gaining alignment with the FDA on the evaluation strategy early in the development process can prevent costly delays and ensure the final submission package meets regulatory expectations. ## Finding and Comparing Biocompatibility Testing Services Providers Successfully navigating the modern biocompatibility landscape requires a partner with deep expertise across multiple disciplines. When selecting a contract research organization (CRO) or testing laboratory, manufacturers should look beyond a simple list of accredited tests. Key qualifications to look for in a provider include: * **Integrated Expertise:** The provider should have strong, collaborative teams in analytical chemistry, toxicology, and biology. A lab that only performs biological tests may not have the expertise to design an appropriate E&L study or conduct a robust TRA. * **Regulatory Knowledge:** The provider should be deeply familiar with current FDA guidance and the nuances of the ISO 10993 series. They should be able to help design a strategy, not just execute a test protocol. * **Advanced Analytical Capabilities:** For chemical characterization, ensure the lab has the right equipment (e.g., high-resolution mass spectrometry) and low detection limits necessary to identify trace-level compounds. * **Accreditation and Quality Systems:** The laboratory should be ISO/IEC 17025 accredited and operate under Good Laboratory Practice (GLP) as required under 21 CFR Part 58 for certain studies. When comparing providers, ask for case studies or redacted examples of their work, particularly their BEPs and TRAs. Discuss their philosophy and approach to risk-based evaluation to ensure it aligns with your strategic goals. To find qualified vetted providers [click here](https://cruxi.ai/regulatory-directories/biocompatibility_testing) and request quotes for free. ## Key FDA references When planning a biocompatibility program for a US submission, sponsors should consult the latest versions of FDA's official documents. Key references include: * FDA Guidance: **Use of International Standard ISO 10993-1, 'Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process'** * FDA Guidance on the **Q-Submission Program** * Relevant sections of the Code of Federal Regulations, such as **21 CFR Part 820** (Quality System Regulation), which governs controls over materials and manufacturing processes. --- This article is for general educational purposes only and is not legal, medical, or regulatory advice. For device-specific questions, sponsors should consult qualified experts and consider engaging FDA via the Q-Submission program. --- *This answer was AI-assisted and reviewed for accuracy by Lo H. Khamis.*