Apr 21, 2021 | Medical Device Testing
Medical device biological safety evaluations have advanced significantly over the last ten years, and regulatory requirements are quickly evolving as well. Turnkey evaluation of testing requirements has progressed into a more device-specific evaluation of risks. It is essential for manufacturers to consider how the changes put in place by ISO 10993-18 will impact their product’s testing needs and any historical compliance of chemical characterization studies.
Complying with the new standard requires a variety of highly sensitive and selective analytical equipment, robust databases and, above all, the expertise to sift through data and identify all chemical constituents. Manufacturers are reevaluating their products to ensure past testing strategies still hold up to current regulatory expectations. To understand how the industry got to this point and forecast where it is headed, we need to start from the beginning.
E/L Gains Momentum
When E/L testing first gained a foothold with medical devices in the early 2000s, methods were focused on qualitative measures. Testing did not generally attempt to quantify the amount of specific chemical constituents present but rather verify major materials present and evaluate total extractable residue.
As certain products were facing public litigation, such as pelvic mesh and breast implants, renewed scrutiny around the risks presented by implantable devices quickly caused the expectations for chemical characterization to be more rigorous, selective and quantitative.
As the decade progressed, even more analytically selective and sensitive techniques emerged, and chemical characterization requirements tightened. Regulators responded with an increased focus on testing device materials and a growing interest in customizing testing to better suit medical devices. In 2016, the US FDA Draft Guidance on ISO 10993-1 reaffirmed the value of chemical characterization when evaluating medical devices.
Recent E/L Testing Trends
Expectations grew along with advanced test methods and equipment that could accommodate increasing regulatory requirements. The 2016 US FDA guidance on the use of ISO 10993-1 required two to three solvents per instrumentand three replicates, thus increasing the investment that companies made during biological safety evaluations.
Around 2017, regulatory agencies began requiring exhaustive extractions (that is, multiple extractions on the same device) for permanent implants. Then in 2018, regulators published a revised version of ISO 10993-1, putting new guidance in place. Specifically, it made chemical characterization and the subsequent risk assessment fundamental components in assessing device safety.
This expectation meant submissions must examine chemistry information and risk assessment to drive their biocompatibility test strategy, and manufacturers must provide justification to support final submissions. Additionally, reviewers examined the training and qualifications of the expert personnel performing these tests.
Internally, the U.S. FDA showed increasing alignment around chemical characterization and toxicological risk assessments, asking how those play into evaluating a device’s biological safety. By 2019, reviewers began requiring exhaustive extraction on prolonged devices as well as permanent devices, which extended the timeline needed to perform testing and increased associated costs.
E/L Testing Today & Going Forward
The publication of ISO 10993-18:2020 marked a significant milestone for the medical device industry. The 2020 revision continued to push expectations and the subsequent approach forward.
This revision provided increased guidance for tailoring chemical characterization to each device by establishing thresholds based on device size, duration and type of patient contact, and the target patient population. For example, reviewers began expecting confidence intervals for identification and implemented the analytical evaluation threshold (AET) as a common baseline for chemistry studies. The AET is essential to achieving an accurate risk assessment. It also helps avoid regulatory scrutiny by requiring qualified chemists to work alongside toxicologists.
The methodologies that laboratories employ today are evolving rapidly, perhaps even faster than the standards themselves. Thus, the concept of “state-of-the-art” procedures is gaining attention as regulators’ expectations grow in tandem with the industry’s capabilities. This is evident with the September 2020 release of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” As we near the upcoming publication of ISO 10993-17, toxicological risk assessments are positioned next to advance the practices in place. Still, manufacturers may find these latest regulations challenging to keep up to date with the continuously evolving regulatory landscape.
Keeping Up with Chemistry
If you have not conducted E/L testing in recent years, it may be time to consider retesting to satisfy the evolved science and regulations. For many products, testing conducted prior to the publication of ISO 10993-18:2020 may need reevaluation according to the new guidance.
Given the new role that chemical characterization has taken in testing and the new expectations to identify biological concerns, it is critical to consider E/L testing as an essential ingredient in preparing a successful medical device submission. Looking to dive further into the details? Check out a detailed recap about ISO 10993 in “Planning and Predicting for ISO 10993: Part 18 & Part 17.“
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WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions – and has received ESG (Environment, Social and Governance) A Ratings from Morgan Stanley Capital International since 2019. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,200 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”
For more information, please visit: http://medicaldevice.wuxiapptec.com/
Jan 28, 2021 | Chemistry, ISO10993-18, Medical Device Testing
Consideration of regulatory approval should be top of mind when making minor changes to current devices on the market to mitigate potential setbacks. The industry approach to chemistry testing is evolving rapidly, and any adjustments could put a device’s approval at risk. Whether a manufacturer alters a device’s nature or changes a material supplier, consider reviewing past biological evaluation data for potential gaps.
With the increased requirements for chemical characterization following ISO 10993-18:2020, regulators may view alterations as a chemical constituent concern. Changes to your device could likely require retesting to reduce future risk. Keep your device on track for approvals and in compliance by bringing in your testing partner when making any adjustments that could affect the material composition of the product.
A New Approach to Chemistry
Chemical characterization and toxicological risk assessments evaluate devices based on the nature and duration of device contact with the end-user. Devices face more scrutiny from regulators than ever before to meet the latest revision requirements to ISO 10993-18, which was released in early 2020.
To determine testing parameters and support a chemical characterization program to meet ISO 10993-18:2020, laboratories need an in-depth perspective on the production process, use scenarios and many other details to paint a clear picture of the device’s chemical constituents. That said, results may identify everything down to the mold release agents during extractable/leachable (E/L) testing. If previous data did not investigate to this same level, comparing past and present medical device risks might be inaccurate.
For example, if a lab identifies a carcinogenic, mutagenic or reproductive toxicant (CMR) substance, or the level of unknowns is above the AET (analytical evaluation threshold), the device will likely need additional chemical characterization. Rather than risk receiving this feedback in an additional information request, manufacturers need to resolve their potential concerns before submission approval. Medical device companies should be aware of the signals that could show that their device may present a risk.
Red Flags for Reviewers
In some cases, companies may not realize the impact of altering their device’s nature or duration. In others, they may not recognize the impact a minor adjustment can have on device composition. Looking for these red flags for reviewers takes practice and a cross-functional approach to planning.
New Patient Populations
Expanding patient populations for clinical use could also put device compliance at stake. Devices intended for pediatric patients require lower body weight assumptions and CMR substances may be considered a more significant concern. For instance, many low-risk devices with high volume, single patient use are constructed using PVC containing phthalates, which typically is a cost-effective option. Regulators are vigilant in reviewing the risks of this material and ensuring the exposure levels are safe for the intended patient populations. If a device’s original population resulted in an acceptable margin of safety for such chemicals, but the new one does not, past chemical characterization data may not be sufficient to support product safety.
Extended Duration
Any changes to exposure duration, specifically extending it in a manner that puts it into a new contact category, will likely require extensive chemical characterization. For example, initial chemical characterization testing on a limited duration device may have been done in an exaggerated study, utilizing a higher dose-based threshold (DBT) for the AET. If the device is now considered to have long-term contact, the initial extractable/leachable testing may no longer be appropriate for the new duration of contact, and further chemistry testing may be recommended. An exhaustive extraction with a lower DBT would then be expected based on the requirements of ISO 10993-18:2020.
New Suppliers
When adding or changing suppliers, proceed with caution and consider testing the material even if the previously used material is an exact match. Like-materials are not all interchangeable or created equally. Often, a material that appears to have the same chemical profile can have significantly different impurities or additives that can produce drastically different chemical characterization profiles. Analyzing these materials is essential to maintaining compliance – and laboratories are eager to play a larger role in material selection.
Bring in Partners Sooner
Rather than making it through the design phase without understanding potential biological risks, bring your testing partner in early for guidance and support. If there are necessary changes to your device, intended population, duration or suppliers, check with your lab testing partner about how this may impact previous or upcoming biological evaluation strategy. Identifying these red flags and addressing the potential hurdles can help consolidate timelines, save money and decrease the likeliness of additional information requests.
Understanding how changes like material modifications, production adjustments or patient population expansions can impact your device will ultimately set you up for a smoother regulatory process. For additional background on the thinking behind medical device chemistry testing, read our blog, “Extraction techniques: Designing the right studies to get the answers you need.”
WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”
For more information, please visit: http://medicaldevice.wuxiapptec.com/
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Nov 2, 2020 | Chemistry, ISO10993-18, Medical Device Testing, Regulatory
Manufacturers are not the only ones facing challenges due to the updates to ISO 10993 and other recent regulatory changes. The evolving standards are also affecting testing labs. Previous industry projected timelines and costs are becoming less feasible with today’s regulatory requirements and capacity constraints. These circumstances have left manufacturers asking important questions, such as why timelines have increased and why testing partners now advise companies to provide additional information or retest.
These questions are all valid, and it is time for testing labs to pull back the curtain to address them. To put it simply – the answers boil down to changes in expectations, process and availability.
Expectation Changes
Most lab testing partners and manufacturers generally knew what to expect from the ISO 10993-18:2020 updates, but it was a waiting game to see how the U.S. Food and Drug Administration (FDA) would interpret them. Part 18 was published in January, and the FDA has been communicating additional expectations through presentations at various venues such as conferences and scientific forums. However, they have not formally documented expectations in guidance as of yet, and shifts in expectations continue as new information is submitted. The dust has yet to settle with the latest update to the standard and FDA expectations.
Manufacturers that have performed testing recently (as recent as late 2019) are seeing gaps in their testing compared to what the FDA is requesting. The FDA website states it will accept testing from the previous standard until July 10, 2022, but reality may prove otherwise. There may be additional information that can be provided to bring your testing up to FDA standards, but in many scenarios, it may be best to start testing from scratch.
In 2020, the FDA increased the expectations of chemical characterization. They are now probing deeper and asking for more technical evidence than ever before. For a submission to be successful, laboratories and manufacturers will need to justify everything – why they chose particular solvents, why they conducted the extraction in a specific way, why they selected a particular method of preparation, and what documentation supports each decision. Ensuring you have the justification to back up your testing takes time and resources. It’s essential to build this into your timeline and budget.
Shifting Process
With increased regulatory expectations comes more responsibility for lab partners. Regulatory bodies are demanding that labs identify all compounds found above the analytical evaluation threshold (AET). If they cannot identify the compounds or provide details to inform the chemical structure, it could negatively impact your timelines, as retesting may be your only option.
No matter the stage of the medical device, pre-clinical to post-submission, manufacturers will need to plan accordingly for shifting expectations. You may receive more submission questions from the FDA than in the past and will need to change your process and timeline accordingly when entering the regulatory review process. Prepare to get additional information requests and allocate time to answer them. Depending on how long ago you performed the testing, responding to an additional information request may mean further testing and require a substantial amount of time.
If you’re still in the testing stage, be sure you’re partnering with a testing lab well-versed in what these process changes mean to your budget and timelines. Quality testing procedures may cost more initially but will save time on unexpected delays or additional testing down the road. It’s crucial to give the lab time to reflect and provide thoughtful, scientifically-sound justifications and recommendations.
Limited Availability
Labs are filling up, and fast, due to the shifting regulatory expectations and delays raised in 2020. Additionally, the medical device industry is transitioning to the E.U. Medical Device Regulation (MDR) requirements. The increased effort to achieve this is putting a significant amount of stress on the labor market. More rigorous testing means less capacity of analysts, laboratory techs and data analysts. Expediting your testing is rarely an option in the current climate. The longer you wait to communicate your submission strategy and timeline with testing labs, the longer it will take to secure a spot in line.
What You Can Do
Testing partners are sympathetic to what these changes mean to manufacturers, and they are doing everything they can to make the testing and submission process as streamline as possible. The best way to establish a productive partnership is to plan accordingly. Trust your well-vetted laboratory’s experience, and build time for additional information requests into your timeline. Try to avoid rushing to the finish line. Design testing plans to produce data with longevity.
Achieving the level of quality necessary to earn regulatory approval may mean larger budgets and extended timelines, but in the long-term, it will save time and money. By understanding the challenges that can compound into timeline delays – expectation, process and availability changes – and taking them into account when you approach your lab testing partner, you can work together to achieve successful studies.
Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.
For more information, please visit: http://medicaldevice.wuxiapptec.com/
For early access and exclusive content sent straight to your inbox, subscribe today to our premium content.
Aug 18, 2020 | MDR, Medical Device Testing
Having a clear understanding of the chemistry required for regulatory submission is not an easy feat. Chemistry background knowledge is crucial when making decisions regarding study design and preparing a device for submission. With this insight, you can gain more value out of your next extractables/leachables (E/L) tests and avoid over- or under-testing.
It is essential to design an extraction technique tailored to your device. Every device is unique and will require a customized approach. Incorrect testing will not yield proper results and could delay timelines by months. You can only accurately access risks after identifying a device’s materials through appropriate testing.
Sandi Schaible, Senior Director of Analytical Chemistry and Regulatory Toxicology at WuXi AppTec Medical Device Testing, walks through the different extraction types and more in our webinar: “Extraction Techniques: Designing the Right Studies to Get the Answers You Need.”
Schaible starts by diving into the various factors and challenges with:
- Exhaustive extractions
- Exaggerated extractions
- Simulated use extractions
- Leachables
She also discusses the current expectations of different regulatory bodies and provides two case studies using different extraction techniques. Additionally, Schaible explores the updates of ISO 10993-18:2020, while providing insight on how to apply the revision to your testing plan.
In this webinar, you will learn more about the different techniques, the challenges associated with them and much more to help familiarize yourself with the chemistry process and how to determine the method most compatible with your device.
Watch now.
Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 3,900 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.
