By Sean Fenske, Editor-in-Chief

Change is a scary thing. But with change comes an ongoing evaluation of the rules and regulations impacted by that change. Within the healthcare sector, this can affect safety. When dealing with patients who are already facing a medical issue, their safety is paramount. As a result, testing to ensure products are working correctly and causing no harm to them in unintended ways is critical.

This leads to the upcoming revisions being planned for ISO 10993-1, which provides oversight and guidance on how biocompatibility testing is to be performed and when it needs to be used. Ensuring this testing is conducted properly and when appropriate can determine whether or not a product gains the required regulatory approval or clearance to reach the marketplace.

Fortunately, experts from Nelson Labs offered their insights on the upcoming changes to ISO 10993-1 and the impact this will have on device manufacturers. In the following Q&A, Nicholas Christiano, MS, MBA, Global Segment Lead—Biological Safety, Jeni Lauer, Ph.D., Expert Consultant, and Chris Parker, MS, MBA, Principal Consultant, address several questions around this ISO document and the changes being made.

Sean Fenske: What is ISO 10993-1? What does it cover? Why is it important?

Nicholas Christiano: ISO 10993-1 is the cornerstone of the ISO 10993 series, which governs the biological evaluation of medical devices. Specifically, Part 1 outlines the framework for evaluating biocompatibility of medical devices based on their intended use, type of body contact (e.g., surface, implant, mucosal), and duration. It offers a risk management-based process to determine what biological tests are appropriate for a given device. It also provides guidance for integrating biological testing with chemical characterization, toxicological risk assessment, and clinical history.

It’s important for several reasons. It ensures patient safety by requiring all devices to undergo evaluation for potential biological risks like cytotoxicity, sensitization, and systemic toxicity. Also, it’s recognized by regulatory bodies (e.g., FDA, EU MDR, etc.) as a standard for biocompatibility. Finally, ISO 10993-1 reduces reliance on animal testing by promoting smarter, science-based approaches.

Dr. Jeni Lauer: Great overview by Nick. Just to add, biocompatibility is the evaluation of the potential harm or other effects a medical device can pose to patients, clinicians, or non-clinical caregivers. A biocompatibility evaluation according to ISO 10993-1 strives to determine if the materials comprising the device, the manufacturing processes used to produce the device, and the manufacturing environment where the device is produced generate any unnecessary risk to exposed individuals. The ISO 10993-1 standard provides a framework for how to perform these evaluations such that the outcome is uniform, regardless of who is performing the evaluation. The goal is to arrive at a conclusion of device safety.

Fenske: Why were changes made? Were they necessary?

Dr. Lauer: The ISO standards are reviewed and updated routinely, approximately every five years. People interested in such topics meet regularly to discuss possible improvements. These people include representatives from regulatory bodies, medical device manufacturers, and technical consultants, such as representatives from the Nelson Labs Expert Advisory Services group. These discussions help frame and orient the formal review process. Therefore, when a large change is made to a standard (such as what is pending for ISO 10993-1), it is built over years of discussions between experts around the world. As things change in the medical device community, these changes must be reflected in the ISO standards, so yes, these changes are necessary.

Chris Parker: Since scientific and regulatory advances have increased significantly over the last 10 years, the standards need to keep up. The changes to ISO 10993-1 are intended to ensure medical device manufacturers are provided the tools to review every material/manufacturing process, potential hazard, reasonable misuse, and patient/user population so maximum information can be provided for drawing a conclusion of safety. Medical devices are becoming increasingly more complex in their intended use and materials of construction, including advanced chemistries and ever-blurring lines between devices, drugs, and combination products. Further, advances in new approach methods (in vitro alternatives) are being brought further to the forefront of regulatory expectations in medical device evaluations.

Christiano: The newest ISO 10993-1 revision includes changes that are both necessary and timely. As my colleagues mentioned, there are several reasons for this.

• Evolving science: Advances in analytical chemistry and toxicology allow a better understanding of potential risks without animal testing where applicable and highlight requirements for those making these decisions.
• Global regulatory alignment: To harmonize better with regional regulations (e.g., EU MDR, FDA) and improve clarity.
• Further promoting a risk-based approach: The earlier versions were interpreted more like a checklist, which led to unnecessary or inappropriate testing.

The changes ensure the standard reflects current best practices, promotes ethical science, and avoids over-testing while preserving patient safety.

Fenske: What is meant by a risk-based approach? How is this different from the previous version?

Christiano: A risk-based approach means decisions on biological evaluation are made by assessing potential risks based on chemical composition, device use, and exposure duration. In addition, existing data is evaluated before initiating any new testing. Lastly, toxicological risk assessments are considered a central tool.

Now, ISO 10993-1 emphasizes the use of chemical characterization and literature data first when applicable. Testing is performed only when there’s a residual risk that can’t be addressed through existing knowledge. The requirements of those conducting these assessments are highlighted. Also, device failure risk mitigation is introduced.

Parker: Essentially, a risk-based approach to biocompatibility evaluations aims to move medical device evaluations away from a checkbox testing approach, so the totality of available information can be used to assess for safety. This means biological effects (formerly known as biological endpoints) can be addressed using chemical characterization, clinical data, and other information instead of testing. It encourages and requires identification and subsequent mitigation of hazards as necessary, followed by continuous monitoring throughout the lifecycle of the device.

Dr. Lauer: I’d like to add that the risk-based approach is not used solely in the medical device community. It is applied to other areas such as banking. This strategy identifies possible hazards and the risks associated with those hazards and prioritizes the ones identified to be most significant. Some hazards are more likely to occur and are subsequently associated with greater risk to patients. Mitigating risk associated with those hazards should be prioritized over hazards less likely to occur or those associated with little patient risk. The previous version of ISO 10993-1 (from 2018) included some movement toward the risk-based approach, but it provided a framework of biological endpoints that needed to be evaluated for each type of medical device. Providing this framework of biological endpoints requiring evaluation in the 2018 version was like having training wheels on the evaluation process. The updated version of ISO 10993-1 removes (or loosens) those training wheels.

Fenske: What is chemical characterization, and how is that affected by these changes?

Christiano: Chemical characterization (covered in ISO 10993-18) is the process of identifying and quantifying chemical substances that may leach or extract from a medical device. It involves the evaluation of the toxicological risk of those substances.

In the revised ISO 10993-1, chemical characterization is elevated to a starting point for biological evaluation. A robust chemical characterization may eliminate the need for animal tests if the toxicological profile is well understood. It places more responsibility on manufacturers to conduct scientifically justified assessments up front.

Dr. Lauer: Previously, I mentioned biological endpoints, or what are now called biological effects in the new ISO 10993-1 standard. Some of these endpoints/effects are related to systemic toxicity or specialized forms of toxicity, such as genotoxicity or carcinogenicity. Testing for these effects can be done in animals, or it can be done through analytical chemistry testing (also referred to as chemical characterization). Animal testing has ethical concerns as well as being costly and time-consuming when evaluating genotoxicity or carcinogenicity because these effects take a long time to develop. Analytical chemistry testing allows you to isolate potentially harmful substances from a medical device and compare those amounts with known toxicity profiles created from prior animal or clinical tests. This reduces the need for animal testing while protecting patients, clinicians, and users from risks associated with potential toxins. There is added scrutiny being applied to the risk of genotoxicity in the updated ISO 10993-1 standard, and this may increase the need for chemical characterization.

Fenske: How is biocompatibility affected by the changes?

Dr. Lauer: Biocompatibility, per se, is not affected, but the complexity of evaluating biocompatibility will be dramatically changed. Additional requirements in the updated standard will come with lengthier evaluations and a stronger emphasis on the qualifications of the individuals performing those evaluations. Currently, many medical device manufacturers perform their biocompatibility evaluations and documentation processes internally. The new standard may require further education or outsourcing of the assessments due to the need to demonstrate qualifications. One’s ability to explain the rationale behind the risk assessment will be crucial to the success of the discussion, so writing expertise will be more important for risk assessments performed under the updated ISO 10993-1 standard.

Christiano: Just to expand on what Jeni said, biocompatibility is now viewed through a broader, more integrated lens. It’s no longer just about passing tests—it’s about understanding interactions between device materials and the body. Non-animal testing strategies are encouraged when supported by chemical and clinical data. The changes require better documentation, justification, and rationale for chosen testing strategies and more interdisciplinary collaboration (e.g., toxicologists, chemists, and material scientists) to assess risk. Ultimately, these changes promote smarter and safer testing with fewer unnecessary animal studies

Fenske: What device manufacturers are most affected by these changes and what should they do in anticipation of preparing for them for their next product development lifecycle?

Parker: Any manufacturer that creates devices that are repeat use, contain absorbable/degradable materials, or have leachable compounds that may bioaccumulate in tissues will be most affected. For these types of devices, how the duration of contact is calculated, in conjunction with increasing requirements for chemical characterization and biological effects to be assessed, will significantly change the evaluation rigor required. To best prepare for the upcoming change, manufacturers with these types of devices will want to review the intended use of their device and consider performing pilot work and proactive information gathering, including comparative (predicate) material reviews, to optimize future assessment efficiency.

Christiano: To expand a bit on Chris’ list, the most affected manufacturers will be those with implantable, long-term use devices or novel materials. In addition, device manufacturers relying on default testing packages without deep chemical analysis, smaller or newer companies that haven’t yet adopted risk-based documentation practices, manufacturers of devices with a high risk of misuse or off-label use, and manufacturers of reusable devices will also be most affected.

In anticipation, these companies should strengthen partnerships with experts in toxicology and analytical chemistry. They should also implement a comprehensive risk assessment framework early in product development. Conduct early material and extractables/leachables studies when applicable and maintain clear documentation and justification for all testing decisions. Companies should train employees to be knowledgeable about the newest standardization releases and all applicable guidance documents. Finally, stay informed on regional regulatory interpretations (e.g., FDA’s guidance on ISO 10993 vs. EU MDR).

Dr. Lauer: Essentially, be afraid…be very afraid!

On a serious note, at Nelson Labs, we’ve been making our sponsors aware of the pending changes where appropriate so they can be ready for when the revision publishes. As my colleagues explained, certain types of devices will be impacted more dramatically than others. For example, how the duration of contact is being calculated will change for products that are used repeatedly, absorbable/degradable, or have certain other characteristics. In the past, if your device was used five minutes/day for a month, the duration of use would be calculated as 5 minutes/day x 31 days for 155 minutes (~2.5 hours). This would put the device into a category of limited use duration (≤24 hours). Under the new guidelines, each day the device is used (no matter the duration) counts as one day, so 31 days of use puts that device into the long-term duration category. Long-term use carries added risk for patients, so the device will need a more thorough evaluation to mitigate these risks.

Preparing for the transition should include contacting an expert with knowledge of the updates in this guidance document. Also, ensure your internal teams are all aware of the changes because, going forward, a greater collaboration between quality, regulatory, and engineering teams will be needed as each of these individuals contributes a piece to the puzzle. They should also consider the possible impact of the ISO 10993-1 update on planned device changes. Is it better to speed up a planned device change, or is it better to wait and see how the new standard will be interpreted by the regulatory agencies?

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 medical device manufacturers?

Parker: Once the new revision is published—likely later in 2025—it will be key for manufacturers to keep an eye out for the regulatory recognition/acceptance of various elements of the standard. ISO standards are written by a global set of experts, but different regulatory regions and bodies may not accept certain portions of the standard. Consequently, it will be critical to ensure the approach used in an ISO 10993-1 evaluation considers all relevant regulatory expectations.

Christiano: I’ll add that biocompatibility is no longer just a testing requirement; it is a strategic component of device safety and regulatory success. As such, there are several takeaways with regard to this. First, begin biological risk evaluation early. Also, don’t underestimate the power of a strong chemical characterization program; it can save time and costs while reducing the need for animal testing. Cross-functional collaboration is more important than ever; regulatory, R&D, quality, toxicology, and materials science must work in sync. In addition, consider investing in training your teams on ISO 10993 changes, risk assessment, and documentation. Finally, the updated ISO 10993-1 standard reflects a maturing industry where science, safety, and ethics are better balanced, and manufacturers who adapt will benefit from faster approvals and stronger product safety profiles.

Dr. Lauer: I’ll conclude by encouraging medical device manufacturers to obtain a copy of the ISO 10993-1 draft as soon as possible or speak with people who have knowledge of its content. These changes are likely to increase the costs related to biocompatibility evaluations (documentation and testing), which need to be factored into the framework of budget planning. The added costs may come with reduced innovation because medical device makers may crunch the numbers and decide developing a new device or creating the next generation device may not be cost-effective.

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