ISO 10993-18: Chemical Characterization of Extractables & Leachables is a critical step in demonstrating the biocompatibility of medical devices. It defines the framework for identifying and quantifying chemical substances that may migrate from a device’s materials into the body. By evaluating both extractables (compounds released under exaggerated conditions) and leachables (compounds released during normal use), manufacturers can assess safety risks, reduce regulatory delays, and ensure patient protection. At Invision Biomedical, we provide comprehensive E&L testing designed to meet FDA and ISO standards, supporting smoother submissions and safer device outcomes.
Extractables and leachables testing provides critical data during the early stages of product development. By identifying potential toxicological risks before devices reach clinical trials, manufacturers can avoid costly delays, reduce the likelihood of rework, and protect patients from harmful chemical exposures. Early testing builds confidence in both material selection and overall device safety.
Medical devices often interact with drug formulations, packaging, or biological fluids. E&L studies evaluate how device materials respond under these conditions, revealing whether they might release unwanted compounds or degrade over time. This ensures long-term stability and prevents adverse interactions that could compromise device performance or patient safety.
ISO 10993-18 is a recognized standard by global regulators, including the FDA, EMA, and notified bodies in the EU. E&L testing results are often required as part of biocompatibility submissions. Comprehensive data packages aligned with these guidelines streamline the approval process, reduce the likelihood of regulatory pushback, and demonstrate a proactive commitment to compliance.
To identify extractables and leachables with accuracy, advanced laboratory techniques are essential. At Invision Biomedical, we apply highly sensitive analytical tools capable of detecting even trace amounts of compounds across a wide spectrum of chemical classes. By leveraging these technologies, we provide clear, reliable data that withstands regulatory scrutiny and ensures confidence in the chemical safety profile of every device tested.
Extractables and Leachables testing (E&L) of biomedical devices and their components are fundamental test protocols, based on requirements of ISO 10993-13 and 10993-18, performed to chemically characterize device materials, specifically the extractable chemical fraction (“residuals”).
An extractables analysis plan starts with knowledge of the device component materials, an understanding of the potential residuals, and consideration of the data expected out of the analysis. From these follow the specification of extraction conditions including extraction process, solvent , temperature, duration, sample configuration, and extract volume. InVision performs different extraction operations depending on the application. Thus, a choice is made between Soxhlet extraction, reflux extraction, liquid-liquid extraction, mild controlled extended incubation, or thermoplastic polymer dissolution/precipitations for additives analysis. Valid results, especially of trace residuals, require good experimental design and attention to preparation of solvent blank controls and inclusion of test sample replicates.
Mass Spec Lab performs a battery of complementary analytical tests on recovered extracts or leachates with characterization of residual analytes as the ultimate goal. Analytical tests can include gravimetry, UV/VIS analysis, UPLC/PDA-UV/qTof-MS, GC/MS, FTIR and GPC.
Suitable study standards are selected based on the material composition of the biomedical device components. Often, monomers, solvents and additives used in device plastic components are selected. Processing aids such as surfactants, cleaners, and solvents are also good study standard candidates. Establishing method detection limits and response linearity for each of the study standards constitutes “on-the-fly” method validation which demonstrates the suitability, specificity, and sensitivity of the analytical methods for the analysis of study extract or leachate.
Data analysis includes interpretation of the collective data set and critical evaluation of its validity. An objective of this phase is to determine whether the analytical data are self-consistent. InVision acquires authentic standards of identified analytes for qualitative verification and quantification of extract concentrations. Standard study reports submitted to our clients provide a comprehensive compiled data package with sample description, full disclosure of extraction and analytical test methods and validation data, reduced data in support of qualitative and quantitative characterization of the residual fraction, and a summary of results for clarity.
Non-targeted screening is the typical first step in E&L studies of biomedical devices. Since one cannot be certain what analytes will be encountered, non-targeted screening requires state-of-art instrumentation and methods, knowledge of the materials used in the construction of the device and seasoned analytical experts able to interpret complex chemical data. InVision’s long history in conducting E&L studies on a wide range of biomedical materials and devices has resulted in institutional knowledge and data bases that are capable of solving even the most vexing non-targeted screening challenges.
Targeted screening describes a mass spectrometry (MS) workflow used for screening complex solutions or extracts for trace levels of known compounds and, when detected, quantifying their concentration. Accurate MS quantitation at trace levels is challenging and requires careful method development. For difficult targeted screening problems, we consult with our quantitation experts to create accurate and robust methods. Ultra-high performance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC/QToF-MS) and APGC/QTof-MS are both well suited for targeted screening since these modern instrument platforms provide impressive mass accuracy (3-to-5 ppm) for selectivity and sensitivity to as low as 10 ppb depending on the target molecule. Both mass accuracy and sensitivity are essential requirements for effective targeted screening.
First, authentic standards of target compounds are prepared in a similar matrix to the sample (i.e., matrix-matched standards) and are then analyzed with MSE (“MS everything” which is a data acquisition method yielding molecular ions and fragment data in a single run). MSE standard data provide the molecular and fragment ion MS data required for target analyte entry into InVision’s searchable compound library. MSE also provides the quantitative data for analyte standard curves and limits of quantitation generated by our quantification software. InVision currently uses the MetaScope Mass Spectral Library Search Engine within the Progenesis QI (Waters) software suite for targeted screening and QuanLynx (Waters) for quantification. Neutral exact mass data, a minimum of three fragment ion masses, and retention time are included in the compound database entries which are screened during analysis of the test sample.
Test samples are analyzed using the chromatographic conditions of the library standard analysis. Progenesis QI algorithms allow alignment of multiple test replicates, peak identification, deconvolution of detected analyte mass spectra, and scoring of compound matches against the compound library. Detected targeted analytes are then quantitated. Non-detection is revealed by library match scores below a predefined level determined during method development. A QC standard mix is analyzed with the test sample to verify that the instrumental response is within defined limits, typically 85-115% of optimal.
Extractables and leachables testing is more than a regulatory checkbox, it’s a safeguard for patient safety and product success. Partner with Invision Biomedical for precise chemical characterization, regulator-ready reporting, and expert guidance every step of the way.
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