Zachary Remillard and Sandi Schaible , WuXi AppTec10.03.22
Extractables and leachables (E/L) testing is a crucial part of preparing a medical product for regulatory submission. Regulatory expectations have shifted, and complete chemical characterization is quickly becoming the standard expectation. Too often, manufacturers are caught off guard by evolving regulations or a lengthy testing process that can adversely impact their submission timelines.
Medical device manufacturers should not be left in the dark during E/L testing. An experienced laboratory testing partner should provide clear communication before the device is delivered, stringent benchmarks based on current regulatory expectations, and support after testing is complete. This column details what manufacturers should expect from their laboratory testing partners from the moment the device arrives until after the final E/L report is delivered.
Testing purposes: Laboratory testing partners need details about the product and purpose of the final E/L report to provide an accurate quote and timeline. Is the product a combination product, a long-term implantable device, or a medical device with limited contact time? Is the testing for a regulatory submission or R&D purposes? Are manufacturers submitting to the U.S. Food and Drug Administration, the European Commission, or another regulatory body? These are just a few of the questions the laboratory testing partner may initially ask.
Test article requirements: Expectations are also established for the number of devices required to complete E/L testing. Manufacturers typically submit finished devices with designed packaging—often the same products that are sent to hospitals—but in some cases, a manufacturer may want to complete E/L testing before a product is complete. The laboratory testing partner will request the appropriate number of devices from the outset, including extra devices to use as a buffer should unexpected or additional testing be required but also understanding the value of test devices to manufacturers. Having enough products readily available reduces testing delays and keeps the project on schedule.
Customizing an E/L test plan: Some manufacturers may approach E/L testing with a clear idea of what they need. Others may not be up to date with the most current technical platforms or regulatory expectations. In either case, laboratory partners will collaborate with them on the testing strategy to ensure clarity, set expectations, and execute according to the plan. Manufacturers that need more guidance in developing a comprehensive plan for E/L testing can expect to work with technical experts knowledgeable in the most current requirements. They will collaborate to develop a customized strategy for their product and design an appropriate study protocol. Manufacturers will also be assigned a single point of contact with the laboratory testing partner; that individual plays a pivotal role in keeping manufacturers informed as E/L testing proceeds to keep the project on budget and on schedule.
Testing timeline: With testing purposes and requirements solidified, the laboratory point of contact will communicate a testing timeline. An experienced laboratory partner will hold themselves to the agreed-upon timeline once test articles are received. Creating a realistic schedule is important to keep a project moving toward submission and to avoid costly delays.
Article receipt and timeline confirmation: The clock for E/L testing starts the moment that a manufacturer’s devices arrive at the laboratory. Some testing partners may let a project sit until they have the time and staff to begin testing, but in an ideal scenario, the project will be scheduled immediately. The final testing timeline and report deadline are confirmed upon receipt.
The extraction phase: E/L testing can include leachables, simulated use, exhaustive, and exaggerated studies. Exaggerated and exhaustive studies test how a product will react when exposed to extreme temperatures or solvents; simulated-use and leachables testing uncovers compounds that are expected to be released (i.e., leached) during standard clinical use. The former provides a “worst-case scenario” for risk, while the latter measures expected patient exposure under clinically relevant conditions. The extraction phase may seem straightforward, but at times can be a critical point for communication. Perhaps a product leaks or degrades unexpectedly when in contact with a certain solvent. Should such a situation occur, expect the laboratory contact to inform the client immediately and create a risk mitigation plan to keep the testing timeline intact while also prioritizing patient safety.
The analytical phase: The extract is analyzed by several methods, depending on project needs. These may include gas chromatography-mass spectrometry (GC-MS/GC-MS-QToF) for volatile to semi-volatile compounds; liquid chromatography-mass spectrometry (LC-MS/LC-MS-QToF) for semi-volatile or non-volatile compounds; inductively coupled plasma mass spectrometry (ICP-MS) for elemental materials; and headspace-gas chromatography mass spectrometry (HS-GC-MS) for volatile compounds and residual solvents. Extracts should be placed on instruments within 24 hours to preserve sample stability. If this is not possible, the laboratory testing partner should be able to justify the stability of those extracts, per the guidance set forth in ISO 10993-12:2021 “Biological Evaluation of Medical Devices – Part 12: Sample preparation and reference materials.”
The data interpretation and review phase: After the analytical results have been collected, the most critical part of the process begins. All compounds must be identified by experts through elucidation. Scientists compare the analytical data against commercially available libraries, when available. LC-MS does not have commercially available identification tools; therefore, a lab testing partner will often turn to its own proprietary database to assist with identification. Complete chemical characterization is essential as regulatory bodies continue to scrutinize submissions with unknown compounds. When unknowns are present, it is virtually impossible for the toxicologist to assess the device’s toxicological risk accurately. All unidentified chemicals must be considered carcinogenic or genotoxic. When this conservative approach is applied, unknown compounds in E/L reports often lead to additional chemistry or biocompatibility testing.
Manufacturers should expect that same level of thoroughness today or risk delays, repeat testing, or even rejected submissions. Laboratories that consider complete chemical characterization impossible or an added step—and charge more for the service—should be avoided at all costs.
As regulatory reviewers’ understanding of chemical characterization advances, so do the questions they have around study technical details. A laboratory testing partner should have the capability to support the project through the submission process by providing additional technical information to support these regulatory inquiries.
Complete chemical characterization is a highly technical process that requires collaboration and communication between manufacturers and laboratory testing partners. Properly vetting testing facilities and establishing testing timelines prior to shipping test articles can prevent costly delays in the submission process. By understanding each step of the E/L testing process and pursuant timeline requirements, manufacturers can better prepare to keep their projects on track and submit their devices with confidence.
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and a U.S. delegate for ISO 10993 part 13 and the particulates committee.
Zachary Remillard is a chemistry operations manager at WuXi AppTec Medical Device Testing and has been in the medical device testing industry for five years. He earned a bachelor of arts degree in chemistry from Williams College, with a concentration in biochemistry and molecular biology.
Medical device manufacturers should not be left in the dark during E/L testing. An experienced laboratory testing partner should provide clear communication before the device is delivered, stringent benchmarks based on current regulatory expectations, and support after testing is complete. This column details what manufacturers should expect from their laboratory testing partners from the moment the device arrives until after the final E/L report is delivered.
The Planning Phase
An experienced laboratory testing partner will engage medical device manufacturers in extensive conversations about testing requirements and methodologies before test articles are shipped. Clear communication can prevent delays or the need for repeat testing. Tentative timelines are also established at this time.Testing purposes: Laboratory testing partners need details about the product and purpose of the final E/L report to provide an accurate quote and timeline. Is the product a combination product, a long-term implantable device, or a medical device with limited contact time? Is the testing for a regulatory submission or R&D purposes? Are manufacturers submitting to the U.S. Food and Drug Administration, the European Commission, or another regulatory body? These are just a few of the questions the laboratory testing partner may initially ask.
Test article requirements: Expectations are also established for the number of devices required to complete E/L testing. Manufacturers typically submit finished devices with designed packaging—often the same products that are sent to hospitals—but in some cases, a manufacturer may want to complete E/L testing before a product is complete. The laboratory testing partner will request the appropriate number of devices from the outset, including extra devices to use as a buffer should unexpected or additional testing be required but also understanding the value of test devices to manufacturers. Having enough products readily available reduces testing delays and keeps the project on schedule.
Customizing an E/L test plan: Some manufacturers may approach E/L testing with a clear idea of what they need. Others may not be up to date with the most current technical platforms or regulatory expectations. In either case, laboratory partners will collaborate with them on the testing strategy to ensure clarity, set expectations, and execute according to the plan. Manufacturers that need more guidance in developing a comprehensive plan for E/L testing can expect to work with technical experts knowledgeable in the most current requirements. They will collaborate to develop a customized strategy for their product and design an appropriate study protocol. Manufacturers will also be assigned a single point of contact with the laboratory testing partner; that individual plays a pivotal role in keeping manufacturers informed as E/L testing proceeds to keep the project on budget and on schedule.
Testing timeline: With testing purposes and requirements solidified, the laboratory point of contact will communicate a testing timeline. An experienced laboratory partner will hold themselves to the agreed-upon timeline once test articles are received. Creating a realistic schedule is important to keep a project moving toward submission and to avoid costly delays.
Article receipt and timeline confirmation: The clock for E/L testing starts the moment that a manufacturer’s devices arrive at the laboratory. Some testing partners may let a project sit until they have the time and staff to begin testing, but in an ideal scenario, the project will be scheduled immediately. The final testing timeline and report deadline are confirmed upon receipt.
The Testing Phase
Once manufacturers and laboratory testing partners are on the same page with regards to E/L study methodology and timeline, testing can proceed. Every project is different and will have different technical requirements, but the testing protocol generally remains the same. Phases include:The extraction phase: E/L testing can include leachables, simulated use, exhaustive, and exaggerated studies. Exaggerated and exhaustive studies test how a product will react when exposed to extreme temperatures or solvents; simulated-use and leachables testing uncovers compounds that are expected to be released (i.e., leached) during standard clinical use. The former provides a “worst-case scenario” for risk, while the latter measures expected patient exposure under clinically relevant conditions. The extraction phase may seem straightforward, but at times can be a critical point for communication. Perhaps a product leaks or degrades unexpectedly when in contact with a certain solvent. Should such a situation occur, expect the laboratory contact to inform the client immediately and create a risk mitigation plan to keep the testing timeline intact while also prioritizing patient safety.
The analytical phase: The extract is analyzed by several methods, depending on project needs. These may include gas chromatography-mass spectrometry (GC-MS/GC-MS-QToF) for volatile to semi-volatile compounds; liquid chromatography-mass spectrometry (LC-MS/LC-MS-QToF) for semi-volatile or non-volatile compounds; inductively coupled plasma mass spectrometry (ICP-MS) for elemental materials; and headspace-gas chromatography mass spectrometry (HS-GC-MS) for volatile compounds and residual solvents. Extracts should be placed on instruments within 24 hours to preserve sample stability. If this is not possible, the laboratory testing partner should be able to justify the stability of those extracts, per the guidance set forth in ISO 10993-12:2021 “Biological Evaluation of Medical Devices – Part 12: Sample preparation and reference materials.”
The data interpretation and review phase: After the analytical results have been collected, the most critical part of the process begins. All compounds must be identified by experts through elucidation. Scientists compare the analytical data against commercially available libraries, when available. LC-MS does not have commercially available identification tools; therefore, a lab testing partner will often turn to its own proprietary database to assist with identification. Complete chemical characterization is essential as regulatory bodies continue to scrutinize submissions with unknown compounds. When unknowns are present, it is virtually impossible for the toxicologist to assess the device’s toxicological risk accurately. All unidentified chemicals must be considered carcinogenic or genotoxic. When this conservative approach is applied, unknown compounds in E/L reports often lead to additional chemistry or biocompatibility testing.
Manufacturers should expect that same level of thoroughness today or risk delays, repeat testing, or even rejected submissions. Laboratories that consider complete chemical characterization impossible or an added step—and charge more for the service—should be avoided at all costs.
Post-Testing Support
Once samples have been extracted and analyzed, an E/L report is generated. A good laboratory testing partner doesn’t end the conversation when the final report is submitted, however. Rather, a good partner will make experts available to manufacturers in order to answer any regulatory questions that come up during the submission process in relation to the technical data produced.As regulatory reviewers’ understanding of chemical characterization advances, so do the questions they have around study technical details. A laboratory testing partner should have the capability to support the project through the submission process by providing additional technical information to support these regulatory inquiries.
Communication and Collaboration are Key
Every E/L testing project is unique—devices will be subjected to extractions, analyzed on a specific platform, and require data interpretation—but there are several opportunities to develop a customized plan. Given the importance of chemical characterization in a device’s journey toward regulatory clearance, manufacturers should expect concierge-level treatment from their lab partners at every stage of the process.Complete chemical characterization is a highly technical process that requires collaboration and communication between manufacturers and laboratory testing partners. Properly vetting testing facilities and establishing testing timelines prior to shipping test articles can prevent costly delays in the submission process. By understanding each step of the E/L testing process and pursuant timeline requirements, manufacturers can better prepare to keep their projects on track and submit their devices with confidence.
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi AppTec Medical Device Testing, specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and a U.S. delegate for ISO 10993 part 13 and the particulates committee.
Zachary Remillard is a chemistry operations manager at WuXi AppTec Medical Device Testing and has been in the medical device testing industry for five years. He earned a bachelor of arts degree in chemistry from Williams College, with a concentration in biochemistry and molecular biology.