Why Toxicology Is Becoming the Backbone of Biocompatibility

A quiet yet significant shift is reshaping biocompatibility evaluation in the medical device industry. Toxicology now sits at its center.

Toxicological reasoning increasingly serves as the structural backbone of modern biological safety assessment. Today, rather than functioning as a supporting discipline, toxicology provides the scientific framework manufacturers and regulators use to interpret chemical findings and establish that device materials pose no unacceptable risk to patients.

The question is no longer whether a medical device passes a test. Regulators want to understand why the device is safe.

This shift is changing how organizations evaluate biological safety. Analytical science, particularly extractables and leachables (E&L) testing, connects directly with regulatory toxicology to translate chemical data into meaningful patient risk evaluations. The complementary standards ISO 10993-17 and ISO 10993-18 form a harmonized framework that guides both chemical characterization and toxicological risk assessment (TRA), enabling a chemistry- and toxicological-based approach to evaluating device safety. 

Biocompatibility assessment has evolved dramatically over the past decade. Historically, many biocompatibility programs relied heavily on standardized, test-driven approaches to demonstrate safety. Manufacturers often selected biological assays from standardized test matrices and ran several of them to produce regulatory data. However, testing a device’s material chemistry or how patients’ exposure to those materials was rarely considered.

Advances in analytical chemistry and evolving regulatory expectations have reshaped this paradigm. Now, regulators expect a clear understanding of the device’s chemistry and the potential patient exposure it poses. Passing a test panel is no longer enough—it’s more important to gather quality evidence.

Manufacturers must understand the chemical composition of a device, how those substances interact with the human body, and whether potential exposures fall within toxicologically acceptable limits.

Globally, regulators have moved toward evidence-based, chemistry-driven safety evaluations. Authorities such as the U.S. Food and Drug Administration (FDA) and the European Union Medical Device Regulation (EU MDR) ask for deeper insight into material chemistry, extractables and leachables, and the toxicological relevance of any identified substances.

Regulators want to know exactly what chemicals a patient may be exposed to and whether these exposures are safe. 

The transformation toward chemical characterization and TRA is closely tied to the regulatory framework governing the biological safety of medical devices. ISO 10993 plays a central role here. The updated versions of ISO 10993-17 and 10993-18 require a chemistry-first approach where toxicology is built on a solid analytical foundation. This regulatory context sets the stage for everything that follows.

ISO 10993-1 requires manufacturers to develop a risk-based biological evaluation plan based on device characteristics, intended clinical use, and patient exposure. This standard states that biological testing should only be conducted when scientifically justified. 

ISO 10993-17 takes chemical results and translates them into a TRA. This TRA includes estimating patient exposure, selecting appropriate thresholds such as tolerable intake values or threshold of toxicological concern (TTC), and systematically addressing uncertainties.

ISO 10993-18 focuses on the chemical characterization process. It outlines the expectations for identifying and quantifying extractables and leachables from device materials. ISO 10993-18 ensures the chemical data generated is scientifically sound, transparent, and reproducible.

Together, ISO 10993-17 and ISO 10993-18 define how chemical characterization should be performed and how the chemical data should be interpreted. Deficiencies arise when this alignment is missing, which can significantly delay submissions or lead to requests for additional testing. Several trends have driven this shift toward chemical characterization and TRA.

Material complexity—Modern medical devices use polymers, additives, colorants, coatings, adhesives and sterilization processes that can introduce chemical variability and potential degradation products. These materials require detailed analytical investigation to fully understand their biological implications.

Advances in analytical sensitivity—Laboratories can now detect substances at extremely low levels. New techniques such as GC-MS, LC-MS, and ICP-MS can now detect trace-level chemical constituents that were previously undetectable. This capability strengthens safety evaluations. It also raises the challenge of determining whether detected trace-level chemicals pose meaningful toxicological risk.

Pressure for transparency—Regulatory authorities expect clear justification for every methodological and toxicological decision. New regulatory guidance emphasizes chemical characterization and TRA over empirical testing alone.

Ethical and economic considerations also drive this change. Risk-based strategies supported by chemical characterization and toxicological evaluation can reduce unnecessary biological testing, including animal studies, while still protecting patient safety.

Chemical characterization studies, required by the FDA, EU MDR, and other global regulators, identify substances that may be released from medical device materials. Data from these studies form the basis for understanding potential patient exposure and evaluating biological risk. Chemical characterization can also reduce reliance on animal testing by enabling mechanistic, chemistry-driven assessments.

Extractables and leachables studies are central to chemical characterization. Extractables are compounds that can be released from a material under exaggerated laboratory conditions, representing the material’s chemical potential. 

Leachables are substances that migrate from the device into the patient under real-world conditions during clinical use, representing actual patient exposure.

Many factors influence the chemical profile of a device, including polymer composition, additives and stabilizers, manufacturing processes, sterilization methods, device aging and storage conditions, and interaction with patient fluids.

Therefore, different device categories present distinct short-term and long-term chemical risk profiles that require tailored analytical strategies for comprehensive chemical characterization. 

After laboratories identify chemical constituents during E&L testing, a TRA translates analytical findings into conclusions about patient safety. A TRA is a central decision-making tool to help answer several critical questions. What substances were found? At what levels? How much would a patient be exposed to? Do those exposures fall within toxicological safety thresholds?

A TRA can also support root-cause analysis when biological tests show unexpected results, informing decision-making early in development and continuous risk management throughout the product lifecycle.

These assessments inform testing needs and provide the scientific rationale regulators now expect. A toxicology-centered approach offers several advantages. 

Reduction of unnecessary biological testing: Medical device manufacturers can address certain biological effects through chemical characterization and TRA rather than conducting additional biological testing.

Improved predictability and clarity in regulatory pathways: Manufacturers can present a clear, scientific explanation of how chemical findings translate into patient-safety conclusions, improving product safety and regulatory readiness.

Enhanced product safety: Early and deeper understanding of chemical composition and exposure helps manufacturers identify potential risks during development.

Better management of material changes and supply chain variables:When materials, suppliers, or manufacturing processes change, TRA provides a structured way to determine whether the resulting chemical profile remains safe.

Ethical advantages: Such as reduced animal testing.

These advantages show why TRA has become central to modern biocompatibility evaluation. The approach strengthens scientific decision-making and aligns closely with evolving regulatory expectations.

Regulators expect to see a clear, traceable analytical workflow from extraction to identification, with a focus on scientific justification and consistency.

Reported thresholds used in chemical analysis must be supported by a documented rationale. Worst-case estimated exposure dose (EEDmax) calculations should be transparent and reproducible. Assumptions regarding device use, patient population, and release conditions must be documented. The selection of toxicological screening limits (TSL), tolerable intake (TI) or threshold of toxicological concern (TTC) must be clearly explained.

If the analytical work is incomplete, inconsistent, or poorly justified, the entire safety assessment becomes unstable. Regulatory reviews frequently highlight deficiencies when these elements are not aligned properly. Common issues include unjustified thresholds, incomplete identification of extractables, poorly justified extraction conditions, inappropriate application of the TTC concept, lack of narrative coherence, incomplete exposure calculations, and general lack of transparency in decision-making.

Ultimately, regulators expect a coherent scientific narrative. That narrative must clearly connect chemical identification, clinical exposure, threshold comparison and final safety conclusions. 

When the chemistry assessment is robust and the toxicology is well-reasoned, the resulting safety evaluation becomes clear, defensible and aligned with international expectations. 

Biocompatibility evaluation in the medical device industry has shifted to a science-driven model grounded in chemistry and toxicology, so manufacturers can no longer rely solely on biological testing to demonstrate patient safety. Chemical characterization now provides the foundation for modern biocompatibility, while TRA translates chemical data and determines if findings pose a safety concern.

Together, ISO 10993-17 and ISO 10993-18 form a balanced framework that integrates chemistry and toxicology into a defensible safety evaluation process. When applied consistently, these standards help manufacturers demonstrate biological safety with scientific rigor and regulatory clarity.

Toxicology no longer plays just a supporting role. It now anchors the connection between analytical science, regulatory expectations, and patient protection. 

Toxicological reasoning is essential for efficient, ethical, and scientifically robust device evaluation. As analytical techniques continue to improve and medical devices grow more complex, the role of toxicology in biocompatibility will expand.

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Dr. Isabel Groh, ERT, DABT, is a senior toxicologist and biocompatibility expert at Hohenstein Medical, where she leads toxicological and biocompatibility evaluations and supports the strategic development of Hohenstein’s medical device safety services. With dual board certifications as a European Registered Toxicologist (ERT) and Diplomate of the American Board of Toxicology (DABT), Dr. Groh brings extensive experience in toxicology, biocompatibility and pharmacology.