The International Organization for Standardization (ISO) released long-anticipated changes to standard 10993-18 on January 15, 2020. Updates will impact chemical characterization and toxicological risk assessments of medical devices industry wide, requiring some labs to make adjustments to understand the potential biological hazard of medical devices.
The new version of part 18 includes a number of definitions and informative annexes on general principles to lend consistency to chemical characterization practices industry-wide. In addition to minor clarifications and helpful definitions, more significant changes were made around determining when testing is necessary, designing test sensitivity and standardizing extraction requirements.
Understanding the basics of these updates will help you vet a testing partner that is deeply familiar with the standards and that you can trust to ensure your testing is completed effectively and efficiently.
When do you test?
The updated part 18 clarifies that analytical testing is not necessarily required. While chemistry information is important to performing the risk assessment, the standard makes a clear distinction between chemical information obtained through information gathering and information generated through new chemical characterization testing. Either method is acceptable, provided it yields sufficient information to perform a thorough risk assessment.
· Information gathering: Process of collecting existing chemical information, including available test results, that is relevant to chemical characterization.
· Information generation: Process of producing chemical information via laboratory testing.
Manufacturers should be prepared to present existing information relevant to the chemical characterization of your device or its composite materials to your testing partner. This can include extractables data from a predicate device or from materials of construction, or, for a device with a simple construction, such as a device made of stainless steel, the ASTM certificate of conformance. Your testing partner can assess the adequacy of this existing information as the basis for a toxicological risk assessment. If the existing information is insufficient to complete the assessment, additional information will need to be gathered or produced by testing to enable the toxicological risk assessment.
Note: Information on Safety Data Sheets (SDS) or technical specifications alone will likely not yield enough information to avoid additional testing.
Analytical evaluation threshold (AET)
The update with the most potential to disrupt testing operations in labs not prepared for it is the implementation of the analytical evaluation threshold (AET). The purpose of the AET is to ensure toxicologists and chemists are on the same page. The AET requires toxicological information (including toxicological threshold and exposure assumptions), in addition to information on extraction conditions to inform the chemistry test design and execution. Since chemical characterization requires an understanding of the level of sensitivity (expressed in units such as µg/L), and the toxicologist is concerned with the threshold at which a chemical could present a risk to a patient (as expressed in µg/kg/day), collaboration is critical in designing successful studies. While the standard recognizes it might not always be possible to achieve the required AET, these situations will require justification to support why the AET was not able to be met.
Number of replicates. In the past, manufacturers putting their medical devices through chemical characterization testing – which was not required in the European Union under the Medical Device Directive (MDD) – were often only required to submit three replicates if they intended to apply for FDA approval in the U.S. Now, with the updates to ISO 10993-18 and the implementation of the Medical Device Regulations (MDR) in the EU, three replicates will be standard practice, and testing with fewer than three replicates will likely require additional justification.
Exhaustive extractions for long-term and prolonged devices. The new standard sets the expectation for exhaustive extractions for long-term and prolonged devices. This is already the expectation with the FDA, but now it is the expectation set forth in the standard. This means that all medical devices that come in contact with the body for longer than 24 hours will need to undergo exhaustive extractions in the lab. That includes devices such as infusion sets, insulin pumps and permanent implants. The big question mark remaining is how regulators will interpret the standard when it comes to limited devices, or those that come in contact with the body for less than 24 hours. We’ll be keeping an eye out to see whether expectations for limited devices will vary by potential risk (for instance, testing a catheter that comes in contact with circulating blood but not adhesive bandages), or be applied across the board.
Simulated use extractables is the new leachables. Finally, the standard will speak to the differences between the terms “leachables” and “simulated use extractables.” For years, the industry has used “extractables” to mean an exaggerated worst-case assessment of chemicals extracted and “leachables” to mean a more physiologically relevant extraction. But in reality, leachables, long used in the pharmaceutical industry, is meant to be an analysis of extracted compounds in the matrix (such as drug product in a syringe or vial). It will often be impossible to measure chemicals in that exact matrix (blood, tissue) for a medical device. Look for the industry to utilize simulated use extractables to bridge the gap when an actual leachables study will not be practical but simulated solvents (saline, alcohol/water mixtures) can be used.
Despite the significant level of detail added to the now-approximately 80-page standard, ISO 10993-18 does not offer a step-by-step set of instructions for conducting chemical characterization. It’s more important than ever to enlist the partnership of a testing lab with deep industry knowledge and experience to ensure your regulatory submissions are prepared for increased regulatory scrutiny. To secure your spot in line with WuXi Medical Device Testing, visit https://medicaldevice.wuxiapptec.com/contact-us/.
Sandi Schaible is the Senior Director of Analytical Chemistry and Regulatory Toxicology at WuXi Medical Device Testing, located in St. Paul, Minn. She specializes in extractables and leachables studies. Sandi is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization. She is also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42). WuXi Medical Device Testing offers testing services in St. Paul, Minn., Atlanta, Ga., and Suzhou, China.