The industry’s foundational understanding of vetting medical device risk has taken a hit during the transition to the EU MDR. It has forced manufacturers, laboratory testing partners and regulators alike to reevaluate traditional approaches and tailor methodology to assess concerns specific to each device.

This transition has been challenging for nearly everyone. With the industry swamped responding to a global pandemic, capacity across the board is strained which could limit manufacturers’ ability to make the most of the delayed MDR deadline. Fortunately, there is still hope: Companies can improve their chances for a successful transition by leveraging their knowledge of their medical devices and understanding what each device’s categorization under the MDR means to its testing strategy.

Push for Collaboration
Before jumping into the process of device evaluation, manufacturers need to have a reliable team to support this effort. Capacity constraints in manufacturing companies have led to an expansion of roles and responsibilities for many positions. As a result, many employees feel stretched thin or underqualified in some aspects of their jobs. Rather than facing this battle alone, both lab testing partners and Notified Bodies (NBs) are pushing for greater collaboration.

EU regulators are promoting a more involved approach to submissions. Reaching out for a pre-evaluation of testing strategies is encouraged, but the opportunity could be limited by availability of the regulators. As qualification expectations for developing promising testing strategies are increasingly important (i.e., NBs requesting the CVs of the scientist responsible for the risk assessment), companies need to confirm that they have the necessary expertise to gain valuable feedback from pre-evaluation conversations with regulators to create thorough strategies.

If they find that they do not have the necessary expertise, a viable alternative may be to lean on their laboratory testing partners. The laboratories can develop and document strategies, as well as provide an added perspective of broader relevant experience and established relationships with regulators to inform this process.

Recognizing and addressing gaps in expertise can empower companies to take the necessary next steps in their device evaluation confidently. Involving partners can absolve some of the pressure to work quickly and deliver high-quality submissions.

Vital Nuances of Device Categorization

Device categorization may have potential pitfalls, but it plays a pivotal role in determining the necessary requirements for the biological evaluation of a medical device. While interpretations of the exact categories vary between the FDA and MDR, there are factors to consider relevant to both regulatory bodies, and being aware of them can help manufacturers avoid over- or under-testing.

The categorization process helps determine the endpoints that must be addressed for a device to gain regulatory approval. Many regulatory bodies have their own take on categorization, but the MDR refers back to guidance in ISO 10993-1:2018. This guidance provides a helpful table in Annex A.1, which displays the key determinants that manufacturers need to have a clear understanding of when approaching this process: The nature of body contact and the contact duration.

A device’s category can affect which standards apply and, in turn, which endpoints or tests are required for regulatory submission. An important factor, especially in response to COVID-19, is the role of ISO 18562-1:2017 for devices in contact with gas pathways. From masks to shields to respirators, these devices are subject to additional biological endpoints for evaluation beyond those recommended by ISO 10993-1:2018 (e.g., particulates, and testing under clinically relevant environmental conditions, flow rates, and time durations). If manufacturers aren’t aware of applicable standards before categorization, the implications could drastically delay timelines and increase costs.

For companies that are unsure of how to find common ground between what a guidance says and how its interpretation applies to their device, find a partner who works with these standards frequently. Whether it is lab testing partners or regulatory agencies themselves, the repercussions of not asking these questions could be devastating.

Based on Annex A.1 (ISO 10993-1:2018), the two cornerstones of categorization are the nature and duration of contact. Without a firm grasp of these elements, manufacturers could face significant setbacks by misinterpreting testing parameters or facing negative feedback from NBs.

Nature vs. Not Sure

The nature of the device’s body contact is a significant element guiding correct categorization. A manufacturer must recognize there are two facets to determine the nature of contact: Category and contact. The first step is to separate devices into one of three subcategories: Devices that come in contact with the body’s surface, externally communicating devices or implanted devices. The nature of body contact breaks these buckets apart further, aiming to understand if the device will contact intact skin, blood, tissue, bone, etc.

An extensive understanding of the intended clinical use of a device is vital for this step, as misinterpretations could lead to under or over-testing. For example, a device for wound healing may be seen as a skin surface contact device, but the device contacts a compromised surface. Therefore, it is critical to consider the systemic exposure to extractable and leachable chemicals. Doing so will impact the test plan by introducing additional endpoints to the biological evaluation.

Another example is a device is used to cut soft tissue, where the device may come into contact with blood, but its purpose is not to cut blood vessels. The device could erroneously be categorized as having direct blood contact and result in additional unnecessary testing. Careful consideration when defining product nature is vital to the success of the device—and to conserve time and money.

The Downfalls of Duration

Under the EU MDR, there are three categories of body contact duration. As contact duration increases, the necessary requirements also increase. The body contact categories identified in ISO 10993-1:2018 are slightly different from the EU MDR categories.

ISO 10993-1:2018 divisions include:

• Transitory: Less than 1 minute
• Limited: Less than or equal to 24 hours
• Prolonged: 24 hours to 30 days
• Long–term: 30 days and longer

Comparatively, the MDR has three patient contact duration divisions:

• Transient: Less than 60 minutes
• Short-term: Greater than 60 minutes to 30 days
• Long-term: Greater than 30 days

Contact duration can also affect the analytical evaluation threshold (AET), where the dose-based threshold (DBT) used in its calculation is based on the duration of device exposure. Incorrect duration assignment could result in deficiencies in chemical characterization and complications during toxicological risk assessment. Furthermore, contact duration helps derive tolerable intake values for the toxicological risk assessment. Incorrect assessment of contact duration has far-reaching effects, that if miscalculated, can jeopardize multiple facets of study design.

When it comes to the duration of exposure, the cumulative exposure of short-term contact devices can become a significant detail that shifts the actual duration to a prolonged or long-term category. Understanding the pattern of clinical use and the impact on the device evaluation strategy could prevent surprises down the road.

Regulatory interpretations of duration are the final factor that can cause complications. For example, with the publication of ISO 10993-18:2020, expectations for chemical characterization based on duration have varying interpretations between the United States and the European Union. If a transient duration device gains approval in the United States, the FDA might not require chemistry testing. However, when submitting the device for approval in the EU, chemistry data for these same devices may be needed.

There may be a different interpretation for each regulatory body regarding chemical characterization requirements. For example, ISO states that manufacturers need “sufficient chemical information,” and MDR says the device needs to “meet specific chemical specifications.” In addition, submissions to the MDR require thorough documentation for each component’s materials of construction, including supplier names and specifications for each material. Working with testing partners and NBs can increase understanding of applying these interpretations and expectations.

Predicting Pitfalls

Understanding the intricacies of identifying a device’s category requires a focused, methodical approach, but there is no need to go through it alone. Lab testing partners and regulators are ready to support this process as best they can. An important note with regulators, especially, is to recognize the value of their time. The response to the global pandemic is adding even higher pressure to their timelines to keep and approve critical devices on the market. Coming prepared with pointed questions or recognizing when expertise is outside your area of knowledge can allow the opportunity to bring in the right partners and deliver more value out of these conversations.

An area where lab or regulatory support may be particularly helpful is during review and MDR submission for legacy devices. Many of these are at high risk of gaps in documentation, as several ISO standards may not have been in place during their initial approval and MDR applications require risk assessments that are up to current standards. Padding timelines with the space to dig into this review process is vital.

Lastly, standard misconceptions can also lead to potential pitfalls in the categorization process. It is a lengthy process for standards to be officially adopted (harmonized) by the European Union, especially with the limited number of experts involved. For example, ISO 10993-18:2020 yet to be officially adopted. When a standard is considered state of the art, it takes precedent, even if the standard is not harmonized. While it may be tempting to use other evaluation procedures, NBs may not accept them.

Evaluating Endpoints

Establishing the correct device categorization and identifying the biological endpoints for evaluation can better equip manufacturers for a successful testing strategy. Device categorization has a significant impact on the test strategy. Still, the keys to a successful submission are understanding the device, knowing the regulatory requirements and having the necessary expertise to support medical device evaluations.

While an increasingly complex and customized approach to assessing risk takes hold in this industry, slowing down to ask meaningful questions, building quality partnerships and committing to continuous learning to remain up to date will be vital to a company’s success.