By Sean Fenske, Editor-in-Chief
 
When a patient needs a medical device that will be in contact with their body for an extended period, whether inside or outside the body, the last thing they want to be concerned with is a toxin leaching out of it. Ensuring this hazard is avoided is the idea behind chemical characterization testing.
 
Due to inconsistent results, regulatory agencies are beginning to take a more stringent position on this type of test protocol. As such, there is some confusion among device makers and their supply chain about what is required and how it needs to be accomplished. Uncertainty of regulations is never a welcome factor for medical device firms.
 
To attempt to clarify the situation, Matthew R. Jorgensen, Ph.D., DABT, senior toxicologist and chemistry expert at Nelson Labs Expert Advisory Services, shared his insights and experience in the following Q&A. He offers a more in-depth definition of chemical characterization, changes from the regulatory aspect, and what considerations device manufacturers need to keep top of mind.
 
Sean Fenske: What is chemical characterization as it relates to medical device testing?
 
Dr. Matthew R. Jorgensen: There are many ways in which medical devices, which are designed and intended to help people, may actually do more harm than good. One of the potential risks involves the device unintentionally poisoning the user. Some devices are invasive, such as a brain implant, and use novel polymeric materials. It is important to know if those materials could leach out chemicals that cause chronic toxicity or cancer. Medical device manufacturers are required to ensure their devices do not present an unacceptable risk of harm. Global regulatory bodies review the evidence provided by manufacturers to ensure they have adequately safeguarded against unintentional poisoning prior to device clearance.
 
Medical device chemical characterization is the process of collecting information on the identity and amount of chemicals released from a medical device into the body so they can be screened to know if they are poisonous or not. There is a framework of standards and regulatory guidance around this process. ISO 10993-1 is the overarching document for evaluation of medical device biocompatibility; it recommends devices be screened for poisons. ISO 10993-18 describes in detail the types of tests that should be executed in the poison-screening process. ISO 10993-17 describes the data evaluation process for understanding results—“How do I know if this detected chemical is too poisonous for use in a device?” In addition to the standardized backdrop, regulators have additional expectations on the level of rigor that goes into these analyses and evaluations.
 
Fenske: For what types of devices does chemical characterization have to be performed?
 
Dr. Jorgensen: Any device that has prolonged or permanent contact with the body might be required to have chemical characterization. Devices in those categories generally require systemic repeated dose toxicity evaluation (sub-acute, sub-chronic, and chronic), and depending on the contact duration, genetic toxicity and carcinogenicity. In many cases, evaluation of chronic toxicity or carcinogenicity would be impossible without chemical characterization and toxicological risk assessment.
 
Every device that receives a CE Mark in the European Union (EU) needs to have supporting chemical information due to the requirement of the MDR that devices in the EU be free from carcinogens, mutagens, and reproductive toxicants above a threshold of 0.1% by mass. Chemical characterization may be needed to address that requirement.
 
Additionally, many manufacturers are choosing to perform chemical characterization as a means of generating background data on their devices to be used in change evaluations.
 
Fenske: What is the FDA paying the most attention to with regard to chemical characterization testing?
 
Dr. Jorgensen: Regulatory expectations of chemical characterization have evolved rapidly as the FDA has become aware of issues and built up finesse and expertise in this area. Today, the most important issue is the analytical evaluation threshold (AET), which is the sensitivity of analysis required, and the way this threshold is calculated. We often see submissions get rejected on the basis of the AET being inadequate. Key to choosing the best AET are the dose-based threshold (DBT) used and the uncertainty factors used by the lab. The proper DBT should be selected by a toxicologist, and the uncertainty factors should be determined through specific statistical measurements across many compounds by the lab.
 
The FDA also has a renewed interest in “method suitability” information. I use quotation marks because this is an ill-defined and nebulous term from lab to lab and within regulatory bodies themselves. The intention in requesting method suitability is not for a full method validation (this is often impossible for an extractables study), but rather, to produce and include at least some information that supports the use of the method for the task at hand. This information could be, for example, spike and recovery data for a range of compounds taken through the complete sample preparation and analytical process.
 
Fenske: Why has the agency seemingly changed how it views chemical characterization?
 
Dr. Jorgensen: Folks in manufacturing can be a bit hard on the FDA for critical analysis of the chemistry in their submissions, but there is a good reason for the current scrutiny. Five years ago, the medical device industry shifted to frequently using chemical characterization and toxicological risk assessment to evaluate systemic toxicological endpoints. At the time, toxicologists and regulators took chemical data at face value. Through some widely published comparative studies across labs, however, it became clear methods, data quality, and reported results varied significantly even when the same devices were tested. The inconsistency across labs brought into sharp focus that chemicals—potential poisons—were often not being detected or reported by some labs. Therefore, in order to protect against unreported toxins by lower quality labs, the FDA began to scrutinize. The result has been that today, we confidently see a much larger number of compounds being reported by labs; with this, the cost and time of chemistry studies has increased dramatically.
 
Fenske: Does the medical device industry need new/revised guidance on chemical characterization? What should such guidance include?
 
Dr. Jorgensen: The industry has 10993-18, which was updated in 2020 to be much more expansive. The FDA has a specific interpretation of this document, however, that is yet to be openly published. We need written guidance that will be uniformly accepted by the FDA—guidelines that go down to the level of detail they expect for compliance. This should include the specific scope and method for calculation of uncertainty factors for AET: Does this need to be independently calculated for each analytical method? How many compounds are needed for computation of the relative standard deviation (RSD) of relative response factors (RRFs)? What are the criteria for including/excluding compounds from the RSD of RRFs? Expectations for demonstration of method suitability will also be critical to specify.
 
Fenske: How is chemical characterization being handled for the EU’s MDR?
 
Dr. Jorgensen: In the EU, the situation is a bit more straightforward when compared to the U.S., as notified bodies have viewed ISO 10993-18 more literally and accept it comprehensively. If you can defend your process via the standard (as written) and through scientific means, it should be accepted.
 
Fenske: Do you have any additional comments you’d like to share based on any of the topics we discussed or something you’d like to tell orthopedic device manufacturers?
 
Dr. Jorgensen: Chemical characterization can be an engineer or regulatory manager’s best friend. Chemistry for medical devices today brings tremendous transparency regarding ingredients used by your upstream suppliers. For example, we often find DEHP in devices thought to be DEHP free, with the surprise finding being rooted in poor disclosure upstream. If chemistry and toxicological risk assessment is going to be used to support biocompatibility in a submission to U.S. FDA, it is critical to have a conversation with the toxicologist who will be performing the risk assessment first, as they will set the needed sensitivity for the study. Additionally, I would suggest initiating a pre submission meeting with FDA to get consensus on some study details before initiating.

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