ISO 10993-1 Updates 2026: How Medical Device Makers Should Prepare

## ISO 10993-1 Updates: A Strategic Guide for Medical Device Manufacturers With significant updates to the international standard for biocompatibility, ISO 10993-1, anticipated to be finalized and adopted in the coming years, medical device manufacturers must begin strategically evolving their approach to biological evaluation. This shift moves beyond a simple "checklist" of biological tests and demands a more integrated, risk-based methodology centered on a deep understanding of device materials and manufacturing processes. The core of this evolution is a "chemistry-first" mindset, where rigorous chemical characterization and toxicological risk assessment become the foundation of the entire biological evaluation. For manufacturers of both new and existing devices, this change requires a proactive revision of internal processes, from R&D and quality systems to regulatory strategy. Successfully navigating this new landscape means demonstrating a comprehensive understanding of a device's material constituents and justifying its biological safety based on robust scientific principles, with a clear goal of reducing reliance on animal testing where scientifically justified. This article provides a detailed framework for preparing for these changes, ensuring a smoother regulatory review process. ### Key Points * **Shift from Testing to Risk Management:** The updated approach de-emphasizes a checklist mentality in favor of a holistic biological risk assessment, fully integrated with the device's overall risk management file (per ISO 14971). * **Chemical Characterization is Foundational:** Comprehensive extractables and leachables (E&L) testing is no longer an optional step for many devices; it is the starting point for evaluating biocompatibility for permanent implants, long-term use devices, and devices with other higher-risk features. * **Toxicological Risk Assessment (TRA) is Critical:** E&L data is meaningless without a TRA performed by a qualified toxicologist. The TRA must evaluate identified compounds and establish a margin of safety to justify that the device is safe for its intended use. * **Stronger Justification for *In Vitro* Methods:** Regulatory bodies like the FDA expect a robust scientific rationale for using *in vitro* methods to replace traditional *in vivo* animal tests. This justification must be pre-planned and documented in the Biological Evaluation Plan (BEP). * **BEP and BER as Living Documents:** The Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER) are not static documents. They must be updated throughout the device lifecycle to reflect changes in materials, suppliers, manufacturing, or new scientific knowledge. * **Legacy Device Gap Analysis is Essential:** Manufacturers cannot assume that existing data for devices already on the market will meet future expectations. A systematic gap analysis is necessary to identify and address potential deficiencies. ## Understanding the New Paradigm: A Risk-Based Approach The fundamental change driven by the latest revisions to ISO 10993-1 is the move from a testing-centric to a risk-management-centric process. In the past, manufacturers might select biocompatibility tests from the matrix in Annex A of the standard based on device category and contact duration. The new paradigm requires a more thoughtful, evidence-based approach that begins long before any biological testing is initiated. This process is documented in the Biological Evaluation Plan (BEP), which serves as the roadmap for the entire evaluation. The BEP is not just a list of proposed tests; it is a comprehensive risk assessment that considers: 1. **Materials of Construction:** Detailed identification of all materials with direct or indirect patient contact. 2. **Manufacturing Processes:** Analysis of any residues from manufacturing, such as processing aids, cleaning agents, sterilization residuals, or colorants. 3. **Physical Properties:** The device's physical form, geometry, and surface characteristics. 4. **Existing Information:** A thorough review of clinical history, literature, and supplier data for the specific materials used. Based on this initial assessment, the BEP outlines a strategy to address potential biological risks, with a clear preference for using chemical and *in vitro* data before resorting to *in vivo* animal testing. ## Implementing a Chemical Characterization-First Methodology For many devices, particularly those with prolonged or permanent patient contact, the cornerstone of the modern biological evaluation is chemical characterization. This involves identifying and quantifying the chemical substances that may be released from a device during its clinical use. ### Step 1: Designing a Rigorous E&L Study An effective extractables and leachables (E&L) study is critical. The goal is to simulate the physiological environment and device use duration to create a "chemical profile" of the device. Key considerations include: * **Extraction Solvents:** Using a combination of polar (e.g., saline), non-polar (e.g., hexane), and semi-polar (e.g., isopropyl alcohol) solvents to extract a wide range of chemical species. * **Extraction Conditions:** The time and temperature of extraction should be scientifically justified. For permanent implants, exaggerated conditions or exhaustive extraction methods are typically required to model the lifetime of the device. * **Analytical Techniques:** A suite of highly sensitive analytical chemistry techniques is needed to identify and quantify the extracted compounds. This typically includes Gas Chromatography-Mass Spectrometry (GC-MS) for volatile and semi-volatile compounds and Liquid Chromatography-Mass Spectrometry (LC-MS) for non-volatile compounds. ### Step 2: Conducting a Toxicological Risk Assessment (TRA) Once the E&L study yields a list of chemical compounds, a TRA is performed to assess the risk each substance poses to the patient. This complex assessment must be conducted by a qualified toxicologist. The process involves: 1. **Hazard Identification:** Identifying the potential toxicity of each compound based on scientific literature and toxicological databases. 2. **Dose-Response Assessment:** Determining the Tolerable Intake (TI) or Tolerable Contact Level (TCL) for each compound—the maximum amount a patient can be exposed to daily without an appreciable health risk. 3. **Exposure Assessment:** Calculating the worst-case patient exposure dose based on the quantities measured in the E&L study. 4. **Risk Characterization:** Comparing the patient exposure dose to the Tolerable Intake to calculate a Margin of Safety (MOS). A sufficiently large MOS provides confidence that the chemical poses a negligible risk. A comprehensive TRA can often be used to conclude that certain biological endpoints (like systemic toxicity) are adequately addressed, potentially eliminating the need for corresponding animal tests. ## Justifying *In Vitro* Methods and Documenting the Rationale A key objective of the updated ISO 10993 series is to adhere to the "3Rs" principle: **Replacement, Reduction, and Refinement** of animal testing. Regulatory bodies increasingly expect manufacturers to use validated *in vitro* methods where possible. However, simply substituting an *in vivo* test with an *in vitro* one is not enough; the choice must be supported by a strong scientific justification documented in the BEP and BER. A defensible rationale should include: * A clear statement of the biological endpoint being evaluated. * A summary of the limitations of the historical *in vivo* test. * Evidence demonstrating that the chosen *in vitro* method is sensitive, specific, and relevant for the material and endpoint in question. * References to scientific literature, validation studies, or other recognized standards that support the use of the alternative method. This proactive documentation shows regulators that the testing strategy was deliberate and scientifically sound, not an arbitrary choice. ### Scenario: Updating a Nonabsorbable Hemostatic Sponge Let's consider a legacy device: a nonabsorbable expandable hemostatic sponge intended for prolonged contact with internal tissue. The original submission may have relied on a standard battery of *in vivo* tests. To meet current expectations, the manufacturer must update its biological evaluation. #### What FDA and Notified Bodies Will Scrutinize * **The Completeness of the Chemical Characterization:** Regulators will expect an exhaustive E&L study that fully characterizes the potential leachables over the device's contact duration. They will question the extraction parameters and the analytical evaluation threshold (AET) used to ensure no potentially toxic compounds were missed. * **The Scientific Rigor of the TRA:** The TRA will be closely reviewed. They will verify the qualifications of the toxicologist, the sources used to establish tolerable intake levels, and the conservatism of the assumptions used to calculate the margin of safety. * **The Link Between Chemistry and Biological Endpoints:** The BER must clearly connect the dots. It must explain *how* the chemical characterization and TRA results address specific biological risks like systemic toxicity, genotoxicity, and carcinogenicity, justifying why certain animal tests were not performed. #### Critical Performance Data to Provide * A complete E&L report with detailed methodology and results. * A comprehensive TRA report signed by a qualified toxicologist. * An updated BEP (the plan) and BER (the final report) that synthesize all available data—chemical, *in vitro*, and any necessary *in vivo* tests—into a cohesive argument for the device's biological safety. The report must explicitly state the final conclusion: that the device is safe for its intended use. ## A Gap Analysis Strategy for Legacy Devices For devices already on the market, manufacturers must perform a gap analysis to determine if their existing biocompatibility data is sufficient. 1. **Step 1: Inventory and Review Existing Documentation:** Gather all historical biocompatibility test reports, material specifications, supplier certificates, and manufacturing process descriptions. 2. **Step 2: Compare Against Current Standards and Guidance:** Evaluate the existing data against the latest version of ISO 10993-1 and relevant FDA guidance documents. Ask critical questions: * Was chemical characterization performed? If so, was it sufficiently rigorous by today's standards? * Was a formal TRA conducted? * Are the materials and manufacturing processes identical to when the original testing was done? * Does the existing data address all relevant biological endpoints for the device's intended use? 3. **Step 3: Identify and Document Gaps:** Create a formal report detailing where the legacy data package falls short of current expectations. For example, the original submission may lack E&L data and a TRA. 4. **Step 4: Develop and Execute a Remediation Plan:** Based on the identified gaps, create a plan to generate the necessary data. This might involve commissioning a new E&L study and TRA, or performing specific *in vitro* tests to address an unaddressed endpoint. The rationale for this plan should be documented in a new BEP. ## Strategic Considerations and the Role of Q-Submission This updated approach to biocompatibility requires significant expertise in analytical chemistry, toxicology, and regulatory science. For devices with novel materials, complex manufacturing processes, or borderline risk profiles, early engagement with the FDA can be invaluable. The FDA's Q-Submission program allows manufacturers to request feedback on their proposed testing strategy *before* executing it. Submitting a detailed BEP as part of a Pre-Submission (Pre-Sub) allows a company to gain alignment with the agency on its proposed chemical characterization methods, TRA approach, and justifications for using *in vitro* tests. This can prevent costly delays and additional information requests during the final marketing submission review. As a best practice under 21 CFR regulations, thorough documentation is key to a successful submission. ## Key FDA References When planning a biocompatibility program, sponsors should refer to the latest FDA guidance documents and recognized standards. Generic, broadly applicable references include: * FDA's Guidance on the Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." * FDA's Q-Submission Program Guidance. * Relevant sections of the Code of Federal Regulations, such as 21 CFR Part 820 (Quality System Regulation), related to production and process controls that can impact biocompatibility. Sponsors should always consult the FDA's website for the most current versions of these documents. ## Finding and Comparing Biocompatibility Testing Services Providers Successfully navigating the updated ISO 10993-1 requirements often necessitates partnering with an expert contract research organization (CRO) or testing laboratory. When selecting a provider, it is crucial to look beyond price and evaluate their technical and regulatory expertise. Key qualifications to look for include: * **ISO/IEC 17025 Accreditation:** This ensures the lab has a robust quality management system and is technically competent to perform the testing. * **Expertise in E&L and TRA:** The lab should have experienced analytical chemists and board-certified toxicologists on staff who are familiar with current FDA and EU MDR expectations. * **Regulatory Track Record:** Inquire about their experience supporting successful 510(k), De Novo, and PMA submissions. A good partner will act as a consultant, helping you design a scientifically sound and cost-effective testing strategy. * **Integrated Services:** A lab that can perform the E&L testing, conduct the TRA, and help write the BEP and BER can streamline the process and ensure a cohesive final report. To find qualified vetted providers [click here](https://cruxi.ai/regulatory-directories/biocompatibility_testing) and request quotes for free. *** 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.*