Medical device companies need to become familiar with recent changes to ISO 10993-18, which sets standards for certain device testing. This includes when to schedule testing, how the analytical evaluation threshold functions and more.
Sandi Schaible, WuXi AppTec
The International Organization for Standardization (ISO) released changes to standard 10993-18 in January 2020, affecting the way manufacturers will need to conduct chemical characterization and toxicological risk assessments on products. If your organization didn’t prepare between the announcement this change was coming and the official release of the standard, you will need to work quickly to strategize how you approach the update.
In revising ISO 10993-18 (part 18), the ISO’s goal was to lend consistency to chemical characterization industry-wide. Tests must now be more sensitive and meet standard extraction requirements. As such, it will be more important than ever for you to understand the specifications required during testing and to partner with an external lab that can effectively incorporate these updates during their testing procedures.
When to conduct tests
New rounds of analytical testing will not necessarily be required for all medical devices and their components. Chemical information is important when performing risk assessments, but part 18 makes a distinction between information-gathering and information-generation as viable options for providing such information. Information-gathering involves collecting chemical information that already exists, including test results, while information-generation involves creating new information via new laboratory testing.
When partnering with an external lab, you should present all existing information about the chemical characterization or composite materials of your devices. That way, the testing partner can assess the adequacy of the existing data as the basis for a toxicological risk assessment. If they determine that the existing information is insufficient to complete the assessment, they should recommend additional testing.
Note that information on Safety Data Sheets (SDS) or technical specifications alone will likely not provide enough information for the basis of a risk assessment. If you have relied on these documents in the past, you should be prepared to conduct additional testing.
The analytical evaluation threshold
One of the major updates that testing labs need to take into consideration is the analytical evaluation threshold (AET). The AET ensures chemists and toxicologists are in sync with one another in designing studies. It also requires that toxicological information (including toxicological threshold and exposure assumptions) and information on extraction conditions inform the chemistry test design and execution.
Since chemical characterization relies on an understanding of the level of sensitivity, and the toxicological risk assessment focuses on the threshold at which a chemical could present a risk to patients, collaboration between the two specialties is crucial. And while part 18 recognizes it isn’t always possible to achieve the required AET, you will need to provide a strong justification if the AET isn’t met.
A change to the number of replicates
Another change to note is that manufacturers will need to submit three replicates when they put their devices through chemical characterization testing. If you are unable to, you will likely need to provide additional justification.
In the past, three replicates were often only required if you intended to apply for FDA approval in the U.S. However, with the implementation of the Medical Device Regulation (MDR) in the EU, the number of replicates will be standardized to three.
Changes for prolonged devices
Under the new standard, all medical devices that come into contact with the body for longer than 24 hours will need to undergo exhaustive extractions in the lab. This is another way that the standard will better align EU regulations with the FDA’s. Exhaustive extractions will be relevant for companies that manufacture devices such as infusion sets, insulin pumps and permanent implants.
What is not yet clear is how regulators will interpret the standard for devices that come in contact with the body for less than 24 hours. It remains to be seen whether the expectations for these limited devices will be applied universally or will vary by potential risk to patients (for example, testing catheters that have contact with circulating blood versus lower-risk products such as adhesive bandages).
Standardizing key terminology
Another change brought on by part 18 is distinguishing between the terms “leachables” and “simulated use extractables.” For years, “extractables” has meant an exaggerated, worst-case assessment of chemicals extracted, while the term “leachables” has referred to a more physiologically relevant extraction. In reality, “leachables” is meant to be an analysis of extracted compounds in the matrix, such as drug product in a syringe.
It’s often impossible to measure chemicals in the exact matrix (blood, tissue, etc.) for a medical device, so conducting a “simulated use extractables” study provides a third option. When an actual leachables study is not practical, a simulated use extractables study allows for the use of simulated solvents, such as saline or alcohol/water mixtures.
ISO 10993-18 is a major revision that medical device manufacturers need to be aware of. However, despite its exhaustive level of detail, the standard does not offer a step-by-step set of instructions for conducting chemical characterization. It may be in your best interest to partner with an external testing lab with extensive industry knowledge and experience. That way, you can ensure your device submissions are adequately prepared for the current regulations and the higher level of scrutiny that will be applied to them.
Sandi Schaible is the senior director of analytical chemistry and regulatory toxicology at WuXi Medical Device Testing, located in St. Paul, Minn., specializing in extractables and leachables studies. She is a U.S. delegate and international delegate for ISO 10993 part 18 in chemical characterization, and also a U.S. delegate for ISO 10993 part 13 and the particulates committee (TIR42).
The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design and Outsourcing or its employees.