ISO 10993 Updates in 2026: How Medical Device Makers Can Prepare

# ISO 10993 Updates in 2026: How Medical Device Makers Can Prepare With significant updates to the ISO 10993 series of biocompatibility standards anticipated around 2026, medical device manufacturers must proactively adapt their evaluation strategies to align with evolving regulatory expectations. These changes continue the shift away from a checklist-based approach to a more comprehensive, risk-based framework. The core of this modern approach emphasizes a thorough understanding of a device's material components and manufacturing processes, utilizing chemical characterization and toxicological risk assessment as foundational pillars of the biological safety evaluation. For manufacturers of devices with patient-contacting components, preparing for these updates is not just a matter of compliance but a strategic imperative to prevent significant regulatory delays. Proactive adaptation involves conducting detailed gap analyses of legacy biocompatibility data, updating the Biological Evaluation Plan (BEP) to be a dynamic risk management document, and leveraging regulatory feedback mechanisms like the FDA's Q-Submission program for novel technologies. By embracing this risk-based methodology now, companies can build a robust and defensible biological safety portfolio that meets the requirements of tomorrow. ## Key Points * **Shift to a Risk-Based Framework:** The anticipated updates will further solidify the move from a fixed menu of biological tests to a holistic risk assessment process. The evaluation begins with material characterization, not animal testing. * **Chemical Characterization is Foundational:** A deep understanding of a device's chemical constituents through enhanced extractables and leachables (E&L) testing is becoming a prerequisite for demonstrating biological safety. * **The BEP as a "Living" Rationale:** The Biological Evaluation Plan (BEP) is a critical document that must detail the entire evaluation strategy and provide a robust scientific rationale for the tests selected, as well as any tests that are omitted. * **Proactive Gap Analysis is Essential:** Manufacturers should not wait for the new standards to be formally recognized. They must begin assessing their existing product portfolios now, comparing legacy data against current and future expectations to identify and address potential deficiencies. * **Toxicological Risk Assessment (TRA) is Non-Negotiable:** A comprehensive TRA, compliant with standards like ISO 10993-17, is required to evaluate the health risks of chemicals identified during characterization studies. This assessment is central to justifying the overall safety profile. * **Early FDA Engagement for Novelty:** For devices incorporating novel materials, advanced manufacturing (like 3D printing), or significant changes to an existing design, seeking early feedback via the FDA's Q-Submission program is a critical step to de-risk the regulatory pathway. ## Understanding the Shift: From Checklist to Risk Assessment Historically, biocompatibility evaluation was often treated as a checklist exercise derived from the tables in ISO 10993-1. A manufacturer would identify their device's contact type and duration and perform the prescribed set of tests (e.g., cytotoxicity, sensitization, irritation). While this approach provided a baseline, it often failed to account for the specific risks associated with the device's materials and manufacturing processes. The modern paradigm, which will be further emphasized in future updates, inverts this process. The evaluation now follows a logical, risk-based cascade: 1. **Material and Process Characterization:** It begins with a deep understanding of every material, colorant, and processing aid used, along with the effects of manufacturing and sterilization. 2. **Chemical Characterization (E&L):** If the initial risk assessment indicates a potential for substances to be released from the device, analytical chemistry is used to identify and quantify these extractable and leachable chemicals. 3. **Toxicological Risk Assessment (TRA):** Toxicologists then assess the potential health risks of these identified chemicals at their predicted exposure levels. 4. **Biological Testing:** If the TRA cannot resolve all safety questions or if specific endpoints (like hemocompatibility or thrombogenicity) must be evaluated, targeted biological tests are performed. This approach ensures that animal testing is a last resort, used only when necessary to address specific risks that cannot be characterized through other means. ## Step 1: Conducting a Proactive Gap Analysis for Legacy Devices Manufacturers should not assume that devices cleared or approved years ago will meet future standards. A proactive gap analysis is crucial. Consider a **Class II device with prolonged skin contact**, such as a wearable biosensor patch, that was cleared using biocompatibility data from over five years ago. A structured gap analysis should include the following steps: #### ### 1. Review Existing Biological Test Data * **Standards Version:** Were the original cytotoxicity, irritation, and sensitization tests performed to the current versions of the respective standards (e.g., ISO 10993-5, 10993-23)? If not, document the differences and assess if the deviations impact the data's validity today. * **Test Article:** Was the tested device truly representative of the final, finished product, including all manufacturing and sterilization processes? Any subsequent changes could invalidate the data. * **Data Integrity:** Is the documentation complete, with full study reports from a qualified laboratory? #### ### 2. Assess Material and Manufacturing Documentation * **Full Bill of Materials:** Is there a complete and traceable record of every single raw material, including secondary components like adhesives, inks, and colorants? * **Processing Aids:** Have all chemicals used during manufacturing (e.g., mold release agents, cleaning solvents) been identified and assessed for their potential to leave residues? * **Supplier Changes:** Have any material suppliers changed since the original testing? If so, the new material must be assessed, as "chemically equivalent" does not always mean "biologically equivalent." #### ### 3. Evaluate the Need for Chemical Characterization For the wearable patch example, the original submission may not have included any E&L data. The gap analysis must determine if it is now required. Given the prolonged skin contact and the likely presence of adhesives and polymers, modern FDA guidance would almost certainly expect a robust chemical characterization. The absence of this data is a major gap. #### ### 4. Update the Toxicological Risk Assessment (TRA) If no TRA exists, one must be created. If a TRA was performed, it must be reviewed against the current version of ISO 10993-17. Key questions include: * Does it properly establish a Tolerable Intake (TI) for each identified chemical? * Does it use conservative assumptions for patient exposure? * Does it calculate a Margin of Safety (MOS) and provide a clear conclusion on the acceptability of the risk? ## Step 2: Modernizing the Biological Evaluation Plan (BEP) The BEP is not a one-time document but a comprehensive plan and report that guides the entire biological safety evaluation. To meet evolving standards, it must serve as a robust scientific justification for the overall strategy. #### ### Justifying Test Omissions A key function of the modern BEP is to justify why certain tests from the ISO 10993-1 matrix are *not* necessary. Simply stating that a predicate device did not perform a test is no longer sufficient. A valid justification requires a deep, evidence-based argument. For example, to leverage data from a predicate device, the BEP must demonstrate: * **Equivalence of Materials:** A side-by-side comparison of all patient-contacting materials, confirming they are identical in composition and supplier. * **Equivalence of Manufacturing:** Confirmation that the manufacturing, processing, and cleaning steps are identical and do not introduce new chemical risks. * **Equivalence of Sterilization:** Proof that the sterilization method and parameters are the same and do not cause material degradation that could create new leachables. If these conditions are met, the BEP can present a rationale that the risk profile is identical, thereby justifying the omission of redundant tests. ## Step 3: Executing a Robust Chemical Characterization and TRA For most devices, a combination of E&L testing and a TRA is the cornerstone of the biological safety submission. #### ### The Role of Analytical Chemistry (E&L) An E&L study aims to answer the question: "What chemicals could a patient be exposed to from this device?" The study design is critical and must be scientifically sound. This involves: * **Exaggerated Extractions:** Using aggressive solvents and conditions (e.g., elevated temperatures) to create a worst-case profile of what *could* leach from the device (extractables). * **Simulated-Use Extractions:** Using more clinically relevant conditions to determine what is likely to leach during actual device use (leachables). * **Analytical Techniques:** Employing a suite of sensitive analytical methods (e.g., GC-MS, LC-MS, ICP-MS) to detect and identify a wide range of organic and inorganic substances. #### ### What Regulators Expect in a Toxicological Risk Assessment The TRA translates the E&L data into a statement of patient safety. A high-quality TRA, often running 50+ pages, must be methodical and transparent. It generally includes: 1. **Hazard Identification:** For each identified chemical, the toxicologist researches its potential health effects using scientific literature and toxicology databases. 2. **Dose-Response Assessment:** The toxicologist determines the dose at which a chemical is known to cause adverse effects and establishes a safe exposure level, known as the Tolerable Intake (TI) or Tolerable Exposure (TE). 3. **Exposure Assessment:** Based on the E&L data, the total daily intake (TDI) of the chemical from the device is calculated for a patient. 4. **Risk Characterization:** The TDI is compared to the TI to calculate a Margin of Safety (MOS). Generally, an MOS greater than 1 is considered acceptable, but a higher margin may be needed for more severe toxicological endpoints (e.g., carcinogenicity). ## Navigating Biocompatibility for Novel Materials and Processes For devices using advanced manufacturing like 3D printing or incorporating novel materials, the regulatory scrutiny is even higher. These technologies introduce new variables that must be addressed in the biological evaluation. ### ### Scenario: A 3D-Printed Orthopedic Implant #### What FDA Will Scrutinize * **Raw Material Control:** The purity and consistency of the starting material (e.g., polymer powder, metal powder). * **Manufacturing Byproducts:** The potential for unreacted monomers, oligomers, photoinitiators, or thermal degradation products created during the printing process. * **Post-Processing Effects:** The impact of cleaning, sintering, or surface modification steps on the final device chemistry and surface properties. * **Sterilization Compatibility:** Whether the chosen sterilization method (e.g., gamma, EtO) adversely affects the 3D-printed material, potentially creating new toxicological risks. #### Critical Data to Provide * A comprehensive material and manufacturing characterization that goes beyond standard approaches. * A detailed risk assessment that specifically identifies and mitigates risks unique to the 3D-printing process. * An E&L study designed to capture process-specific residues. * A BEP that proposes a testing plan to address all identified risks, which will likely require more extensive biological testing than a conventionally manufactured device. ## Strategic Considerations and the Role of Q-Submission Given the complexity and expense of biocompatibility evaluation, early engagement with the FDA is a powerful risk-mitigation tool. The Q-Submission program allows manufacturers to obtain feedback on their proposed testing strategies before committing to costly and time-consuming studies. A Q-Submission is most valuable when a manufacturer has: * A device made from novel materials or using an advanced manufacturing process. * A plan to justify omitting several long-term or high-cost biological tests based on chemical characterization and TRA. * Uncertainty about the appropriate analytical methods or toxicological approach for a unique device. The submission should include a draft BEP, the risk analysis, and specific, well-formulated questions for the agency. This dialogue helps ensure the planned strategy aligns with FDA expectations, preventing major review delays down the line. ## Finding and Comparing Biocompatibility Testing Services Providers Choosing the right partner for biocompatibility testing is a critical decision. The complexity of modern evaluations requires more than a standard testing lab; it requires a partner with deep expertise in chemistry, toxicology, and regulatory strategy. When selecting a provider, sponsors should look for: * **Accreditation and Compliance:** The laboratory must be ISO/IEC 17025 accredited and operate under Good Laboratory Practice (GLP) principles as required under 21 CFR Part 58. * **Integrated Expertise:** Look for providers who offer integrated services, including analytical chemistry (E&L), toxicology, and biological testing under one roof. This ensures a cohesive and efficient evaluation process. * **Experience:** The provider should have extensive experience with your specific device type, materials, and intended clinical use. Ask for case studies or examples of similar devices they have supported. * **Regulatory Consulting:** A valuable partner can provide strategic advice on designing the BEP, interpreting results, and responding to regulatory questions. Comparing providers should not be based on price alone. Consider their scientific depth, turnaround times, quality systems, and the level of support they provide throughout the regulatory submission process. > To find qualified vetted providers [click here](https://cruxi.ai/regulatory-directories/biocompatibility_testing) and request quotes for free. ## Key FDA References When developing a biocompatibility strategy, sponsors should refer to the latest FDA guidance documents and relevant regulations. While specific documents are updated periodically, the core principles are found in: * FDA's Guidance: Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." * FDA's Guidance on the Q-Submission Program. * Relevant sections of 21 CFR, including Part 820 (Quality System Regulation), which governs manufacturing controls that are critical for ensuring biocompatibility. Sponsors should always consult the FDA's website for the most current versions of these and other relevant documents. *** *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.*