In an increasingly complex world, one size rarely fits all. In most preclinical studies, testing services can be bought off-the-rack and fulfill all the needs and desires of a device manufacturer or drug developer/sponsor. But sometimes, a custom fit is necessary. WuXi AppTec offers customized, state-of-the-art services for preclinical studies, which support product development, regulatory submissions, and marketing claims. Here, we explore the level of custom services available and why they are crucial to product research and development.
The cornerstones of customized preclinical testing
The landscape of preclinical testing services presents a conundrum: standard services versus tailored solutions. The distinction lies in the degree of customization. Standard testing services offer broad applicability but limited flexibility or nuance. In contrast, customized testing provides a boutique experience, fostering closer and more detailed collaboration between clients and scientists to meticulously define project-specific requirements and create solutions.
Navigating preclinical studies can be a complex endeavor, marked by unexpected developments and shifts in direction. Clients must have confidence in their testing facility’s commitment to transparency and efficiency. Trust in this context is not merely about adherence to timelines and protocols but also about the agility and adaptability of the testing process.
One of the cornerstones of seamless custom testing involves the early and continuous involvement of a multidisciplinary team of experts, including preclinical scientists, surgeons, veterinarians, pathologists, and toxicologists. Their role extends beyond scientific consultation to include pragmatic, real-world solutions tailored for unique study designs.
Involving these specialists from the project’s inception is not just a proactive measure for issue prevention; it’s a strategic move to enhance the study’s efficiency and reliability. This foresight optimizes the immediate research process and ensures the generation of robust, credible data capable of withstanding rigorous scrutiny long into the future.
Practical advantages to customized preclinical testing
Engaging in tailored preclinical studies presents a range of advantages for device manufacturers and drug developers. A prime example of this is the integration of efficacy and biocompatibility endpoints within a single study framework.
While this approach has advantages and challenges, its success hinges on meticulous planning and execution, potentially conserving valuable resources. It requires a comprehensive understanding of the client’s immediate and long-term objectives and a thorough evaluation of the sample product’s design and its historical testing background.
Tailored preclinical studies expand the possibilities of using in vivo and in vitro models to specifically address the unique aspects of product applications. WuXi AppTec can also lean on specialized models to fill niches not adequately covered by standard testing protocols, including:
Routes of administration or surgical models to mimic intended clinical use,
Orthobiologic models for bone repair,
Excisional wounds for advanced wound care analysis,
Bacterial infection models to test antimicrobial efficacy,
Subcutaneous tumor models for oncology research,
Adapted standard biocompatibility tests for more specific material interactions.
WuXi AppTec’s study-specific models combine the latest scientific literature with its team’s extensive experience in model development. Client representatives are often invited to participate on-site during development, facilitating direct training and ensuring a seamless transition from benchtop experimentation to in vivo model development.
This collaborative approach enhances the transition phase and ensures that drug developers and device manufacturers have a consistent, replicable foundation for initiating pivotal Good Laboratory Practice (GLP) studies, thereby bolstering the robustness and reliability of their research outcomes.
Future-proofing customized testing
One way to future-proof customizable preclinical testing services is to scrupulously maintain the sophistication and integrity of animal facilities. This demonstrates a commitment to precision, reliability, and ethical practices in all research endeavors.
WuXi AppTec’s facilities are maintained through rigorous and regular inspections by various regulatory agencies, alongside client and internal department audits. Such thorough oversight ensures that WuXi AppTec’s team is consistently engaged in a process of learning and improvement.
Equally important to the company’s strategy is an ongoing investment in the professional growth of its staff. This includes refresher training, new skills development, and continuing education, ensuring the team remains at the forefront of evolving practices in customized preclinical study services. WuXi AppTec also prioritizes employee satisfaction and retention, recognizing that a motivated and stable workforce is essential for preserving valuable experience and providing a continuity of knowledge for future projects. This commitment extends to a meticulous vetting process for subcontractors, ensuring that every aspect of the service ecosystem aligns with the company’s stringent quality benchmarks.
A final word
In a world where change is the only constant, customization emerges as a critical element, particularly in preclinical studies. Recognizing that not all research inquiries can be adequately addressed by standard, off-the-shelf solutions is central to this understanding.
WuXi AppTec’s custom preclinical testing services offer clients a simple yet profound advantage: flexibility and expert guidance. This unique combination empowers drug developers and medical device manufacturers to embark on ambitious preclinical studies that may deviate from the norm or entail greater complexity. WuXi AppTec’s expertise is a resource and a catalyst, enabling clients to navigate the intricacies of bespoke preclinical studies with assurance and precision.
In March 2023, the European Parliament handed medical device manufacturers some breathing room when it amended the Medical Device Regulation (MDR) to allow for a longer compliance period for certain medical devices and in vitro diagnostic devices. The move was welcomed by device manufacturers, who were given additional time to prepare products for market and to properly consider some of the recent changes in European regulation.
The news may prompt manufacturers to slow down or pause submissions, with some of the time pressure alleviated. But this could put programs in jeopardy and worsen the same backlog the new timeline seeks to fix.
What is the New Timeline?
The amended process will stagger the submission deadlines for devices, prioritizing those with greater potential patient risk. Conformity assessments for devices with the highest risk (class IIb and III) would be due in 2027 under the new timeline, and lower-risk devices in 2028.
Manufacturers must meet certain conditions to benefit from the extension. These include ensuring devices comply with MDR’s predecessors, the Medical Device Directive (MDD) and the Active Implantable Medical Device Directive. They must not have any significant changes in design or purpose and cannot pose an unacceptable risk to patient health and safety.
Device manufacturers also need to meet 2024 milestones. They must formally apply for an extension by May 26, 2024, and must have a written agreement in place with one of Europe’s notified bodies (NBs) by September 26, 2024.
Potential Relief for NBs
Device manufacturers are not the only ones breathing a sigh of relief following the new timeline. European health ministers have described a regulatory “perfect storm” on the horizon since MDR was introduced in May 2021. Prior to MDR, there were 125 certified NBs in Europe. After it took effect, that number fell to around 20. As of September 2023, the figure had risen to 40, but that is still too few to handle the submissions from medical device manufacturers.
By October 2023, NBs had received 17,846 applications and certified 5,599 of those. Submissions will continue to pour in right up until the May 26, 2024, deadline, and an early survey of NBs estimated that only 7,000 devices could be certified by then. That number will likely be exceeded, but still, existing NBs are overwhelmed, and at the current pace will be unable to clear the backlog.
Like manufacturers, NBs are unable to relax despite the new timeline. They must continue appropriate surveillance per MDD guidelines and assess and audit applications for extension by the May 2024 deadline.
Choosing an NB and understanding ‘state-of-the-art’
When MDR was first conceived in 2021, it required any medical device on the European market to be designated “state-of-the-art.” The phrase is mentioned 12 times in the original MDR guidance but is never properly defined. The E.U.’s Medical Device Coordination Group (MDCG) definition of state-of-the-art devices refers to best practices but does not make it clear whether it refers to the devices themselves, the techniques or analytical methods used, or the clinical trials for regulatory approval.
The uncertainty surrounding this language has and will continue to create challenges for device manufacturers and NBs. All parties could find themselves in limbo as they collectively navigate MDR, gain clarity on amendments, and grapple with new expectations.
The deadline extension also gives manufacturers a chance to choose a NB if they don’t have one. These trusted partners can help manufacturers complete applications, submit new applications, fill any gaps in testing data and organize their device’s submission. It also gives manufacturers more time to consult with their NB and come to a consensus on elements of MDR such as defining “state-of-the-art” for their product(s).
The Effect of ISO 10993-17:2023
Evaluating potential risks will certainly play a crucial part in considering if a medical device is state-of-the-art or not. MDR Article 10 specifically addressed risk management systems and outlines a long-term process but doesn’t provide significant detail.
While ISO 10993-18:2020 provided guidance for manufacturers to investigate the materials in their devices, ISO 10993-17:2023 specifies the process and requirements for the toxicological risk assessment (TRA) of medical device constituents. The methods and criteria used to assess whether exposure to a constituent is without appreciable harm are also specified. Some of the concepts introduced or further developed in the updated standard include:
Tolerable intake (TI): Expressed as micrograms per kilogram of body weight per day (µg/kg/day), TI is an estimate of the daily exposure of an identified constituent over a specified period—based on body weight—that is considered to be without appreciable harm to health.
Tolerable contact level (TCL): Represented in micrograms per centimeter squared of tissue at the contact site (µg/cm2), TCL estimates the surface-contact exposure to an identified constituent that is without appreciable irritation.
Worst-case estimated exposure dose (EEDmax): Represents an exposure dose that is the maximum value for a specific intended clinical-use scenario. EEDmax is expressed in micrograms per kilogram body weight per day (µg/kg/day) or or μg/cm2.
Margin of safety (MOS): A unitless ratio of the TI to the EEDmax.
Identified constituent: An identified constituent is one for which molecular structure information is complete. The identity of a constituent can be obtained via non-targeted or targeted analytical approaches, as described in ISO 10993-18.
Total quantity (TQ): Expressed as micrograms (µg), total quantity, in μg, present in or on, or extracted from the medical device (e.g. from an exaggerated or exhaustive extraction study)
Toxicological screening limit (TSL): The cumulative exposure dose to an identified constituent over a specified period that will be without appreciable harm to health. However, the TSL is not applicable to neonates, metals, VOCs, and unknown or incompletely identified constituents.
Release kinetics: Refers to the quantity of a constituent that is released from a medical device as a function of time. Experimental release kinetics are usually generated in a leachables or simulated-use chemical characterization study with multiple time points. ISO 10993-17:2023 also provides guidance around calculating assumed release based on the TQ of a constituent.
Final Thoughts
The extension to the MDR deadline is a welcome relief to both regulators and manufacturers, but there is still much work to be done on both sides. The ISO 10993-17 updates provide additional detail and direction to the toxicological risk assessment process, but it may take time to understand the extent of recognition for some of the new concepts. Meanwhile, the state-of-the-art concept raised in MDR will also require extra time and testing. The number of NBs may be increasing, but slowly, meaning there are still limited resources and long queues. The new timeline gives breathing space, but manufacturers will still need to work at full speed to avoid long delays. For manufacturers who, justifiably, find the entire process confusing, finding a trusted lab partner can ease the burden of navigating the new regulatory horizon.
The latest update to ISO 10993-17:2023 introduces significant changes to how medical device manufacturers and toxicologists can estimate and incorporate constituent release into the toxicological risk assessment (TRA) process. We explore the concept of release kinetics and the novel idea of “assumed release.”
Understanding release kinetics can lead to a more accurate estimate of potential risk in the TRA, but practical challenges limit its application to a few compounds (i.e., targeted analytes). Assumed release, on the other hand, may offer an alternative approach through exposure adjustments based on the fewest number of days in each device category.
We also examine the regulatory implications of these changes. Regulators across the industry are still adapting and clarifying their positions on the new guidance in ISO 10993-17:2023. For medical device manufacturers, understanding and integrating these new concepts into TRAs is vital for addressing various biological endpoints, achieving regulatory success, and keeping patients safe.
How does ISO 10993-17:2023 explain release kinetics?
Release kinetics is a new term in ISO 10993-17:2023. Release kinetics is defined as the quantity of a constituent released from a medical device as a function of time. Experimentally, release kinetics data can be obtained in a simulated-use or leachables study that evaluates the extractables profile at different time points.
ISO 10993-17:2023 indicates that release kinetics are obtained using targeted approaches. However, truly targeted approaches require a reference standard and are only feasible for one or very few compounds of interest. Therefore, the more commonly conducted non-targeted simulated-use or leachables studies would not necessarily be considered release kinetics studies. However, they provide a profile of constituent release over designated time points and serve to refine exposure estimates in the toxicological risk assessment (TRA).
Introducing ‘assumed release’
ISO 10993-17:2023 also introduces a new concept called assumed release. That is, when experimental release kinetics data are not available, exposure can be assumed to occur based on the fewest number of exposure days for each category (e.g., 2 days for prolonged, 31 days for exposure up to 1 year, and 366 days for exposure greater than 1 year). Adjusting a maximum total quantity extracted by 2, 31, or 366 provides a profile of assumed release.
How will assumed release affect the TRA?
TRAs based on exhaustive extractables studies have become increasingly complex in recent years. The large number and quantity (e.g., µg/device) of chemicals extracted in these studies generally yield unfavorable TRAs, which then leads to device manufacturers needing to conduct additional biocompatibility testing or follow-up chemistry (e.g., simulated-use studies) to mitigate concerns.
The simulated-use study provides a more realistic extractables profile due to the clinically relevant extraction conditions (solvent and temperature). Data are collected at multiple time points, so toxicologists can refine exposure estimates in the TRA based on what and how much is released and when. Experimental studies provide helpful information for the TRA, but if they’re conducted following the original extractables study, it can take months to complete the chemistry study followed by the TRA.
Using assumed release data could offer an alternative to this path, potentially reducing the need for follow-up biological or chemical testing saving time and resources. For example, if evaluating a long-term implant (> 1 year), the data from the exhaustive study can be adjusted by 2, 31, and 366 days to provide a profile of assumed release.
These values can then be compared to the appropriate tolerable intakes for those exposure durations to evaluate acute/subacute, subchronic, and chronic exposure. Applying these adjustments to the data already available can potentially reduce the need for follow-up biological or chemical testing.
The regulatory perspective on assumed release
Industry toxicologists and regulators are still grappling with the application of assumed release and potential limitations. ISO 10993-17:2023 stipulates that for a toxicological risk to be acceptable, it must be substantiated by evidence indicating that the assumed release is conservative in relation to the intended use of the medical device. This requirement underscores the need for expert judgment in interpreting the results.
Whether global regulators are prepared for a shift toward assumed release data is a matter of time. Since ISO 10993-17:2023 has been published, EU notified bodies may expect immediate compliance, considering it is the current state-of-the-art. Also, regulators just recently released their recognition of the standard, and assumed release is within the scope of recognition.
The industry is progressing towards a better understanding of ISO 10993-17:2023, but there is still a journey ahead regarding widespread application and regulatory harmonization.
A final word
Keeping up with regulatory revisions is only half the battle for device manufacturers—they must also navigate new challenges in real time. A TRA that includes information around release kinetics, assumed release, or estimated release in the form of a non-targeted simulated-use or leachables study, allows toxicologists to refine the exposure assessment, ultimately creating a better understanding of potential risk. Because the TRA can address several biological endpoints (e.g., systemic toxicity, carcinogenicity, genotoxicity, developmental and reproductive toxicity), generating a TRA that appropriately evaluates potential risk is invaluable. Manufacturers with questions or concerns about their in-house capacity or capability to collect and apply this new data may consider engaging an experienced lab testing partner for help.
At the end of 2022, one of the world’s largest manufacturers of PFAS (per- and polyfluoroalkyl substances) announced it would stop making the compounds and discontinue using them across its entire product portfolio by the end of 2025. The company explained that PFAS are critical in manufacturing many standard products—i.e., batteries, phones, automobiles, airplanes, semiconductors, medication and medical devices—but that significant questions exist about their long-term impact to humans and the environment.
PFAS boasts some of the strongest carbon-fluorine bonds in organic chemistry, creating an almost unparalleled durability and resistance to degradation. While useful in applications, this stability also makes PFAS highly persistent in the environment and biological organisms, leading to their nickname, “forever chemicals.” This persistence, combined with the widespread use of PFAS, has led to significant environmental contamination and growing concerns about potential health effects.
Health studies have linked certain PFAS (specifically, PFOA and PFOS) to various adverse health outcomes, including, but not limited to, cholesterol changes, immune system effects, cancer (for PFOA), and developmental effects or delays in children. These concerns have increased regulatory scrutiny and reduction efforts for certain PFAS. However, scientists agree that additional research is needed to fully understand PFAS substances’ impacts.
It’s apparent that an abrupt phasedown or phase-out of PFAS could have a significant and multifaceted impact on medical device manufacturers and biopharma product companies. The repercussions could range from immediate supply chain disruptions to long-term product development and manufacturing challenges. But let’s start at the beginning.
How is PFAS currently used in medical devices and biopharma products?
PFAS’ unique properties allow for several applications in medical devices and biopharmaceutical products. Their chemical stability, resistance to heat and chemicals and non-stick characteristics make them valuable in some specialized fields. Specific applications include:
Coatings for medical devices: PFAS coatings can reduce friction and improve durability in catheters and guidewires, making them easier and safer.
Implantable devices: Implantable medical devices, including heart patches, vascular grafts and stents, may use PFAS materials because of their biocompatibility and durability inside the human body.
Drug delivery: In biopharmaceutical applications, PFAS may be used in controlled drug delivery systems like transdermal patches, implantable pumps and intramuscular depot injections. Their chemical stability ensures the drug’s integrity is maintained, and their biocompatibility allows for safer interaction with bodily tissues.
Containers & packaging: PFAS might be found in containers or packaging used in pharmaceutical manufacturing due to their resistance to corrosive substances and ability to create barrier layers. This is particularly important for ensuring the purity and effectiveness of medications.
Respiratory devices: Membrane filtration systems and reactor components can contain PFAS because of their ability to repel moisture and resist thermal degradation.
It’s clear that PFAS provides significant advantages in some applications, but their potential environmental and health impacts should give the industry pause. Medical device and biopharma product manufacturers who are not considering alternatives or at least looking more closely at their PFAS usage could be left behind. The need to balance performance with safety and environmental sustainability is real, but the scrutiny these substances receive cannot be ignored. Luckily, these industries have options.
PFAS alternatives
PFAS’ unique properties make reformulating or replacing them challenging. But getting a head start on possible alternatives now is a smart move. The suitable option depends on several factors, including the project’s timeline, a device’s specific application and the biophysical qualities required. Each of these strategies requires a nuanced understanding of the functional requirements of the original PFAS application and the implications of any changes.
The most straightforward strategy is bypassing PFAS altogether by opting for materials that don’t require PFAS’ high-performance characteristics. This might involve switching to natural materials or other synthetic alternatives. Either way, finding materials that meet all the functional requirements of the original PFAS-containing product without compromising on quality or performance will require time and additional research.
Shorter-chain PFAS compounds are not entirely risk-free, but they are generally believed to be less harmful than their longer-chain counterparts. They tend to have a lower potential for bioaccumulation and are more rapidly excreted from the body. Manufacturers can reformulate products using shorter-chain PFAS, which may still provide some of the desirable properties of the traditional PFAS but with potentially reduced environmental and health impacts.
Innovating entirely new materials or chemistry is the most promising route for long-term success and the most difficult. This approach may offer a sustainable and safe alternative to PFAS, addressing environmental and health concerns while still fulfilling necessary functional roles. The challenge here is the extensive R&D needed to create novel compounds or explore new combinations of existing materials.
Ultimately, the goal in reformulating or replacing PFAS is not just to find a direct substitute but to rethink the material requirements of products and processes, potentially leading to more innovative, sustainable, and safe solutions. A shift of this magnitude requires collaboration among manufacturers, scientists, regulatory agencies and lab partners to ensure that the solutions developed are effective and responsible.
How to prepare for a PFAS phasedown or phase-out
Preparing for the discontinued use of PFAS requires a thoughtful, detailed strategy from medical device and biopharma product manufacturers. Here are nine actions leaders in these industries are already taking to stay ahead of the shift. These can be done in tandem or in a different order; it’s just important that these actions are taken:
Action 1: Conduct a comprehensive material audit. Inventory all products and components in your portfolio that use PFAS to understand the scope of impact. This will help identify which products need immediate attention and can help prioritize strategies.
Action 2: Assess supply chain vulnerabilities and product availability. This will help identify critical dependencies and bottlenecks, allowing for creating backup plans and minimizing disruptions.
Action 3: Begin researching alternative materials. Finding reliable alternatives ensures product quality and safety are maintained and helps avoid potential regulations banning PFAS.
Action 4: Find trusted external partners. Collaborations can accelerate the development of viable alternatives and provide access to cutting-edge research and technologies.
Action 5: Engage early with regulatory bodies. Early engagement can help navigate the complex regulatory landscape efficiently and reduce the time to market for redesigned products. This can also generate important regulatory feedback on any new materials.
Action 6: Diversify suppliers and look for alternative materials. Diversification reduces the risk of supply chain disruptions and potential monopolies or unfair price hikes. Remember, with any regulatory ban, there will undoubtedly be a grace period. Be sure to maintain enough PFAS-based products to provide stability during the transition.
Action 7: Educate staff about new processes and materials. Training ensures a skilled workforce capable of handling new materials and processes effectively. Also keep customers, suppliers, and other partners informed about changes.
Action 8: Monitor market developments and technological advances. Pay attention to how competitors manage the phase-out. This will help in strategic planning and alleviate market-based surprises or risks.
Action 9: Assess the environmental and health impacts of PFAS use. Be sure this assessment aligns with broader corporate social responsibility goals and contributes to internal and external messaging.
Each action toward a PFAS-free future is critical in mitigating the immediate challenges its discontinuation poses. Proactive steps also prepare companies for long-term success in a rapidly changing regulatory environment. It’s about maintaining product integrity, ensuring regulatory compliance and preserving customer trust.
A final word
The real possibility of a phasedown or phase-out of PFAS compounds poses a big challenge for medical device and biopharma product manufacturers. This shift requires a reassessment of manufacturing processes and materials and a fundamental rethink of industry norms and safety standards. This evolution is imperative for environmental sustainability and public health, but it may also be overwhelming for organizations navigating these waters alone.
This is where the value of a trusted laboratory partner becomes clear. Such collaborations highlight shared knowledge, specialized expertise and innovative technologies essential for significant transitions. A lab partner can help dissect the intricate web of material specifications, regulatory landscapes and environmental impacts, providing bespoke solutions that align with customer goals. This collaboration isn’t just about adapting to a PFAS-free era; it’s about seizing an opportunity to innovate and ethically advance toward a safer and more sustainable future.
Cytotoxicity testing is one of the standard biocompatibility tests for nearly all medical devices irrespective of their duration and nature of patient contact per ISO 10993-1:2018 and the U.S. FDA’s Guidance on the Use of ISO 10993-1 (2020). Although cytotoxicity testing is useful as a screening tool, it is not a definitive indicator of device safety since in vitro tests do not fully represent the complex in vivo environment of the human body.
Consequently, cytotoxicity failures (i.e., positive test results) should be evaluated with other relevant biocompatibility endpoints to determine device safety. In the following sections, we explore risk management strategies for medical device cytotoxicity failures, focusing on two case studies demonstrating the importance of a comprehensive approach to evaluating device safety. The approaches described below relied upon data from material reviews, chemical characterization and toxicological risk assessment, and other biocompatibility endpoint data per ISO 10993-1:2018.
Case Study 1: Limited Contact – Surface Device, Intact Skin
In the first case study, an intact skin-contacting medical device with limited duration (less than five minutes in clinical use) was tested for biocompatibility in compliance with ISO 10993-1:2018. This included the MEM elution cytotoxicity assay, the Guinea Pig Maximization assay and the Intracutaneous Irritation test.
The MEM elution cytotoxicity assay failed with grade “4” (severe) cytotoxicity at all three observed time points (24, 48 and 72 hours). The Guinea Pig Maximization test and the Intracutaneous Irritation test produced passing results with no sensitization or irritation noted in normal saline or sesame oil extracts. Chemical characterization and toxicological risk assessment were not conducted as they would not be standard recommendations for a limited-duration device with intact skin contact.
The materials used in the device’s construction were reviewed to identify potentially cytotoxic compounds, and polychloroprene was identified as a potential cause for cytotoxicity failure. Polychloroprene (i.e., a synthetic black rubber) was one of the materials used to construct the device. It is also used as a positive control for the MEM elution cytotoxicity assay and thus is expected to be associated with cytotoxicity failure. Because a likely cause for the cytotoxicity failure was identified—and the sensitization and irritation results were favorable—the toxicological risk was considered acceptable for the nature and duration of patient contact (i.e., < 5 min with intact skin).
Case Study 2: Limited Contact – Externally Communicating Device, Blood Path, Indirect
In the second case study, an externally communicating indirect blood path medical device with limited duration exposure (up to eight hours in clinical use) was tested using a battery of biocompatibility testing. This testing included the MEM elution cytotoxicity assay, the Guinea Pig Maximization assay, the Intracutaneous Irritation test, Acute Systemic Toxicity and Hemolysis – Extract Method.
This device showed mild but passing (grade 2/4) cytotoxicity at 24 hours, increasing to a failing level (moderate; grade 3/4) for cytotoxicity at 48 and 72 hours. The device passed the sensitization and irritation testing in normal saline and sesame oil extracts. The device also demonstrated no signs of acute systemic toxicity or hemolysis using the extract method.
Chemical characterization was conducted, and toxicological risk was evaluated based on the extractables results. Several citrates, acrylates, methacrylates and metals were identified in the extractables, all of which are known to have cytotoxic potential. However, the Margin of Safety (MOS) values were greater than 10 for all the potentially cytotoxic compounds identified above. Thus, the toxicological risk was considered acceptable.
Based on the information obtained from the chemical characterization data, toxicological risk assessment, and other relevant biocompatibility test results, the toxicological risk was considered acceptable for the nature and duration of patient contact (i.e., up to 8 hours with indirect blood contact).
When Cytotoxicity Failure Happens
Every medical device requires a biological evaluation, the specifics of which are outlined in ISO 10993-1:2018 and the U.S. FDA’s guidance on ISO 10993-1: 2020, to identify potential risks resulting from the product’s materials and manufacturing processes.
Cytotoxicity testing is a primary screening biocompatibility assay required for nearly all medical devices. According to Section 10 of ISO 10993-5:2009, “cytotoxicity data shall be assessed in relation to other biocompatibility data and the intended use of the product.” Hence, cytotoxicity failures (i.e., a positive test result) should be evaluated with all other relevant biological endpoints to determine device safety. The following flowchart outlines how WuXi AppTec toxicologists determine the most appropriate steps to take when the potential for cytotoxicity is identified.
A final word
A thorough understanding of the materials used in the device’s construction and the manufacturing processes are critical aspects of medical device development and safety evaluation, as these can significantly impact cytotoxicity test results. Certain materials, such as metals, alloys, rubber, adhesives, antibiotics, anticoagulants, ethylene oxide residuals, lubricants and plasticizers, are associated with potential cytotoxicity failures. Hence, understanding the properties and potential risks of the various materials and processes is essential for interpreting cytotoxicity assay results. Cytotoxicity results are part of the screening process for the evaluation of medical devices but should not be considered a definitive indicator of device safety. Instead, a comprehensive risk management approach that considers all relevant data, which may include chemical characterization, toxicological risk assessment, other biocompatibility testing, materials/process review and the intended clinical use of the device, should be employed to determine the overall safety of the device.
