When the International Organization for Standardization (ISO) published 10993-1 in 2018, it marked a paradigm shift in assessing biological safety in medical devices. The standard calls for a biological evaluation of every medical device as part of a risk management strategy. To further support safety in medical devices, ISO revised 10993-18 in 2020 and is currently working on revisions to 10993-17.

The ISO 10993-18 revision set a strict standard for chemical characterization by introducing the analytical evaluation threshold (AET). Patient population, contact type and duration, and the number of devices intended for use are factors used to derive AET. Chemists need to identify and quantify any compounds at or above the AET, so toxicologists can later evaluate the level at which each compound may present a risk to patients (i.e., the margin of safety or MOS). And with MOS, bigger is better.

MOS is a compound’s tolerable intake level (expressed in µg/kg/day) divided by its exposure level. An MOS value above 1 often represents an acceptable toxicological risk. Outcomes at or around 1 require additional expert judgment, and an outcome below 1 may require a risk mitigation strategy—which often means more chemistry.

In addition to the AET, ISO 10993-18 introduced intensified extraction considerations. Exaggerated extractions are generally accepted for limited duration devices (i.e., less than 24 hours of contact with human tissue), but multi-step, exhaustive extractions are recommended for prolonged use (i.e., more than 24 hours) and long-term devices (>30 days). Any compounds at or above the AET identified during extraction studies provide the exposure estimation for the toxicological risk assessment (TRA). Compounds at or above the AET that chemists cannot identify may render the chemistry report inadequate to support the TRA.

Addressing the Deluge of Data

Exaggerated and exhaustive extractions and a low AET can yield hundreds, sometimes thousands, of compounds for toxicologists to assess. During submission preparation, the sheer number of chemicals to identify takes considerably more time and increases the likelihood of an “equivocal” result (i.e., a finding from the TRA for which toxicologists cannot deem the level of risk acceptable given the available information). Equivocal results have become particularly common for long-term and prolonged-use devices due to the required exhaustive extractions and AET.

The regulatory environment continues to evolve and has become harder than ever to navigate. The FDA expects complete chemical characterization data and a toxicological risk assessment for almost all medical devices submitted. In addition to evolving ISO standards, regulators are taking a more conservative approach to submissions.

Meanwhile, for devices submitted in the EU under the Medical Device Regulation (MDR), the expectation is that chemical characterization is done in compliance with ISO 10993-18. The revised ISO standard would be considered “state-of-the-art,” as it is the latest version. Therefore, under MDR, medical devices are required to meet the standard, despite the delay in harmonization.

For manufacturers, the regulatory landscape in the United States and the EU means their products will undergo a higher level of scrutiny than they may have seen in the past. While the FDA has not fully recognized some of the ISO standards, additional guidance is provided in the 2020 guidance on the use of ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” Manufacturers should be familiar with ISO standards, how regulators interpret them and additional requirements from regulatory bodies. External partners can often provide context around expectations and regulatory preferences.

The bottom line is that intensive chemistry requirements are creating massive data sets of chemicals, all of which need to be assessed for biological safety. This deluge of data is making equivocal results far more common than ever before. Fortunately, manufacturers can take steps to mitigate risk and support the safety of their products. The following steps discuss how.

Step 1: Leverage partner experience & expertise

Laboratory partners with extensive experience shepherding hundreds of medical devices a year to regulatory success can be treasured team members. Standards and guidance are often vague, and partners with technical expertise or a presence on regulatory committees can fill essential gaps as manufacturers prepare for submission. As part of its chemical characterization requirement, the FDA expects manufacturers to understand and document data points. A skilled laboratory partner can help identify these data points and gather additional required data, including:

• Materials of construction (including available information on chemical constituents)
• Chemical substances introduced during manufacturing (i.e., mold release agents, process contaminants, sterilization residuals, cleaning agents, packaging, etc.)
• Findings from extractable, simulated-use, targeted or leachable studies

Regulators will also expect to see a rationale for setting the AET and whether the chemistry report met those expectations. Understanding these data can help focus chemical characterization testing if additional rounds are needed. It is also not uncommon for regulators to request CVs from toxicologists to ensure their experience is sufficient to conduct the TRA.

Establishing early communication with partners is paramount to mitigating risk, saving time and managing expectations. Manufacturers can reduce surprises and avoid panic when compounds or unknowns lead to equivocal results by opening lines of communication with technical partners from the start. Close partnership with a toxicologist can ensure timely decision-making if there are potential risks that need to be addressed. Manufacturers can then complete additional testing (i.e., targeted analyses or additional biocompatibility) while the toxicological risk analysis concludes.

Step 2: Start early & anticipate additional testing

Keeping to a submission timeline requires setting realistic, achievable goals along the way. A higher number of chemicals identified in a risk assessment increases the chances of finding chemical(s) of concern. Planning extra time for risk mitigation efforts is the best way to alleviate stress, avoid a time crunch and ensure the program keeps to its schedule.

Step 3: Understand the extent of additional testing

Depending on the chemical(s) of concern, there are numerous risk mitigation strategies that can be implemented. Working with an experienced partner in addressing risks identified in a TRA will help build a successful submission path.

The harsh conditions used in exhaustive extractions—in addition to the AET—often contribute to equivocal findings, so one method of mitigating risk is to conduct a simulated-use extraction. This testing measures the types and amounts of substances expected to be released during clinical use. Conducting simulated-use studies provides chemical information under more physiologically relevant conditions (i.e., human body temperature, saline solutions instead of strong solvents, release kinetics, etc.). These conditions demonstrate more realistic patient exposure to evaluate toxicological risk.

Targeted analysis is a practical option when there is a relatively small number of chemicals of concern and the chemicals’ MOS is at or close to a value of 1. In targeted analysis, chemists will compare the specific chemicals of interest against a standard to precisely quantify those chemicals.

Biocompatibility testing may be another successful risk mitigation option. For example, for absorbable materials, it is important to understand the biological safety of materials as they degrade and absorb in vivo.

Step 4: Stay abreast of the regulatory landscape

Partnering with chemists and toxicologists who have experience navigating the sometimes-ambiguous regulatory environment is crucial for regulatory success. Regulatory expectations are growing as standards evolve, but everyone’s goal is to assess patient risk better and deliver the safest products to market. Experienced technical partners usually have existing relationships with regulators to help manufacturers stay on top of new developments.

During pre-submission meetings, regulators give manufacturers early guidance and feedback on their devices. The meetings can be used to set expectations and provide relevant regulatory updates. They are also helpful in identifying missing information before submission. It is strongly encouraged that every manufacturer schedules a pre-submission meeting with the FDA to support a successful submission. Plus, laboratory partners may be included in pre-submission meetings to serve as expert counsel.

What If Risk Mitigation Fails to Address Equivocal Results?

Sometimes even the best risk mitigation strategies aren’t enough. Investing a multitude of resources into a product with toxicological concerns is frustrating. It may be possible to target specific chemical(s) of concern and eliminate the piece of the device or part of the process where the chemical(s) are introduced, but this option may not always work. If it doesn’t, there are two additional steps manufacturers can take.

First, consider changes in labeling, including instructions for use, technical description, intended purpose and proper medical device use. Imagine a device is evaluated for use in children and adults, but the toxicological risk assessment results show it’s acceptable only for adults. This becomes a manufacturer’s decision to move forward with a labeling change or proceed with additional risk control steps.

The other option manufacturers have when risk mitigation fails to address equivocal results is the least desirable and can be painstaking—redesigning or retooling a device. If chemists cannot identify certain compounds at or above the AET or toxicologists find unknown materials or constituents above the threshold of toxicological concern (TTC), going back to the drawing board may be a manufacturer’s last hope.

The Bottom Line

Equivocal results are going to happen. The evolving regulatory environment and exhaustive extraction requirements have made that the new reality. Risk mitigation strategies can address equivocal results if manufacturers plan for the unexpected and collaborate with experienced laboratory partners.