Q&A: Extractables and Leachables in Medical Devices
Extractables and leachables (E&L) assessments are critical aspects of medical device regulatory compliance. As the regulatory landscape evolves, manufacturers face increasing complexity in understanding requirements, defining thresholds, and ensuring product safety for patients. Smithers stands as a trusted partner, offering deep expertise and tailored analytical services to guide medical device companies through every stage of the E&L evaluation and compliance.
Q: How do you define "Extractables" versus "Leachables" in a medical device context?
Extractables are chemical compounds that can be released from a medical device material under laboratory conditions, such as exposure to solvents or elevated temperatures. These studies represent worst-case scenarios to identify potential compounds that might migrate from the device. In contrast, leachables are chemical entities that actually migrate under normal clinical use; for medical devices, these may use simulated-use conditions.
Q: Which regulatory frameworks currently govern E&L testing for medical devices?
In the United States, the Food and Drug Administration (FDA ) has draft guidance that closely aligns with ISO 10993-18 for chemical characterization and biocompatibility assessment as a technical foundation with added requirements for full compliance. The FDA has also provided the Chemical List for Analytical Performance (CLAP) that helps laboratories demonstrate analytical studies in a comprehensive extractables and leachables program. The European Union’s Medical Device Regulation (MDR) similarly requires chemical characterization and aligns with ISO 10993-18. The United States Pharmacopeia (USP) and International Council for Harmonisation (ICH) guidelines, such as ICH Q3E, are also relevan t for combination products linking pharma drug products.
Q: What is the significance of the new ICH Q3E guideline for the industry?
ICH Q3E introduces a harmonized approach to the assessment and control of extractables and leachables for drug products, including drug device combination products regulated as pharmaceuticals, but it does not apply to standalone medical devices. Its significance lies in providing a unified framework for complex products with robust risk assessment, testing, and reporting, reducing discrepancies between regions and simplifying global submissions . The risk assessment involves understanding Material & Process, Risk Management (ICH Q9), extending to Product Lifecycle Management, emphasizing patient safety at all stages. This is a draft guideline, currently in public consultation. The guideline emphasizes science- and risk-based strategies, encouraging early identification and control of E&L risks by building on ICH impurity guidelines and risk management.
Q: Can you explain "Regulatory Thresholds"? How do these definitions in ISO 10993-18 align with the thresholds found in USP and ICH guidelines?
Regulatory thresholds are key benchmarks used to evaluate the toxicological risk of compounds identified during E&L testing.
The Safety Concern Threshold (SCT), adopted across all guidelines, is the level below which a leachable is not expected to pose a mutagenic or non-mutagenic toxicity concern. The SCT is dependent on the administration route and duration of use. For mutagenicity threshold concerns, the Threshold of Toxicological Concern (TTC) is applied; for non-mutagenic toxicity endpoints, the Qualification Threshold (QT) is used. The Analytical Evaluation Threshold (AET), covered by both USP and ISO 10993-18 and by ICH Q3E, is an analytical method-specific concentration-based threshold, which determines the concentration above which compounds should be reported and toxicologically evaluated. Aligning multiple guidelines has become necessary due to changes in the landscape of the industry, caused by the innovation of new product deployment. For example, a combination product which integrates a drug and device expects a coherent E&L strategy covering both the drug adhering to USP/ICH pharmaceutical regulation (In the US, regulated by the FDA, Center for Drug Evaluation and Research) and device constituents adhering to ISO regulation (In the US, regulated by the FDA, Center for Devices and Radiological Health).
The thresholds applied in ISO, USP, and ICH guidelines are derived from risk-based assessment; however, the thresholds can be different due to the purpose and application of individual products/devices.
Q: At what stage in the product development lifecycle should a medical device manufacturer begin their E&L assessment?
E&L assessments should begin as early as possible in the product development lifecycle, ideally during material selection and prototype evaluation. Early testing enables identification of potential risks, informs material choices, and prevents costly redesigns or delays later in the process. At the early stage of product development, information gathering for risk assessment is conducted, which typically involves device configuration, material composition, and the determination of the primary mode of action. This follows on to initial material characterization based on the type of product and intended primary mode of action. A drug product utilizes USP standards (at least for products marketed in the US), a medical device would lay its foundation on the guidelines based on ISO 10993. For medical devices, the scoping of Extractables and Leachables follows according to ISO10993-18, addressing the complexity of samples and the analytical techniques at regulatory threshold levels.
Q: Why should manufacturers partner with Smithers for their E&L programs?
Manufacturers benefit from Smithers extensive experience in chemical characterization, risk assessment, and regulatory strategy. Smithers delivers end-to-end support, from study design and method validation to data interpretation and regulatory submission. Their multidisciplinary teams ensure that all aspects of E&L testing are scientifically rigorous and aligned with current global standards.
Smithers regulatory experts partner with industry experts, monitor changes across global markets, and offer guidance on compliance with FDA, EU MDR, ISO, USP, and ICH requirements. Our tailored testing and documentation ensure that clients’ E&L programs meet the highest regulatory standards.
By partnering with Smithers, companies gain access to advanced analytical capabilities, expert guidance on regulatory expectations, and proactive problem-solving to mitigate risks and accelerate time to market. As E&L requirements continue to evolve, partnering with a knowledgeable and resourceful laboratory like Smithers ensures that medical device manufacturers remain compliant, efficient, and competitive. Smithers delivers strategic guidance, cutting-edge analytics, and regulatory expertise that position clients for success in a dynamic global market.
For questions about extractables and leachables testing, chemical characterization, or regulatory thresholds for medical devices, our team of experts is available to provide guidance and support. Contact us to discuss your project and learn how Smithers expertise in extractables and leachables evaluation can help support compliant and scientifically robust E&L programs.