Jul 30, 2021 | Biocompatibility, Medical Device Testing
After several years of waiting, the International Organization for Standardization (ISO) approved the release of ISO 10993-23 in January 2021. The standard officially recognizes in vitro as an approved method for understanding, predicting and classifying skin irritation risk in medical devices.
The skin irritation assay uses reconstituted human epidermis (RhE) tissue to detect irritant chemicals extracted from polymeric materials—PVC and silicone—in medical devices. It can also identify low concentrations of strong irritants previously only detectable through in vivo or human patch testing.
One of the most interesting parts of ISO 10993-23’s history is that it almost never saw the light of day. Its unusual origin played a role in why approvals took so long.
“The current in vitro testing guidelines in ISO 10993-23 are the result of the evolution of alternative testing methods initially guided by the European Centre for the Validation of Alternative Methods (ECVAM),” says Nick Hibbard, in vitro scientific research fellow at WuXi AppTec Medical Device Testing. “The initiative outlined the need to develop alternatives to in vivo testing in areas like chemicals and cosmetics. Ultimately, skin irritation testing designed to reduce in vivo testing in the chemical and cosmetic industries found its way to being appropriately applied to the medical device industry.”
Why is ISO 10993-23 significant?
ISO 10993-23 evolved out of ISO 10993-10—an assessment of irritation and sensitization. ISO 10993-10 still contains language around skin irritation, but it will eventually be updated to focus on sensitization. One of ISO 10993-23’s most significant advantages is its potential to reduce in vivo irritation testing. It’s a clear nod to the basic tenets of responsible scientific methodology, the three Rs—replacement, reduction and refinement.
Another advantage of ISO 10993-23 is reliability. It is a reproducible, round-robin-validated assay that can be trusted to deliver scientifically valid results across multiple laboratory settings. Its robustness is also what makes the in vitro assay a valuable safeguard.
When combined with pyrogenicity and cytotoxicity testing, the skin irritation assay is an effective complement to biocompatibility testing manufacturers might perform in the early stages of development. The results of these assessments can help weed out potentially unsuccessful test candidates before they get too far down the manufacturing path.
What do manufacturers need to know about ISO 10993-23?
For the time being, manufacturers should plan to prepare studies for in vitro and in vivo testing. ISO 10993-23 is still very new and it’s unclear how the standard will be interpreted by different regulatory bodies. Parts of Asia and the European Union have already determined in vitro to be the preferred method for skin irritation testing, but even that guidance is applied inconsistently throughout those regions. Other markets have yet to issue guidelines on 10993-23 at all.
But, manufacturers who are still wondering if the in vitro method is appropriate for their device can exercise due diligence by asking themselves four questions:
- Do we know where in vitro methods are fully accepted? Skin irritation assessments in the U.S. and elsewhere still require in vivo assays. Regulatory agencies around the world are working to incorporate the guidance and approve it for use as they see fit. Partnering with a reputable laboratory testing partner can help clarify regulatory guidance for a particular market.
- Do we understand our device’s intended contact point? The approved in vitro methods listed in 10993-23 only detect dermal irritation. Contact points must be located on the skin, not on or in mucosal regions. Alternative methods for mucosal and subcutaneous testing are outlined in ISO 10993-10 under the irritation and sensitization guidance.
- Have we considered every component of our device? It is crucial to understand all the design and development factors present in your device. For example, do you know how the device was sterilized? Do you know details about its coating? Do you know how the device was packaged and what materials were present? Any of these factors could cause an irritant by themselves and undermine your device or, at least, cause delays.
What should manufacturers consider when selecting a testing partner?
Choosing the right laboratory testing partner comes down to a few basic questions. Of course, manufacturers should try working with a partner who understands each regulatory body. They’ll also want someone who stays on top of regulatory updates. But there are a few other factors to consider that will ensure a successful partnership. Ask yourself:
- Does our partner have the proper credentials? The ISO 10993-23 guidance recommends testing under GLP conditions, so make sure your testing partner can follow that directive. ISO certification provides an additional quality standard that ensures a testing partner maintains and improves its business processes.
- Are we prepared to approach potential laboratory testing partners? Being prepared to enlist the help of a testing partner goes back to understanding the device. It is crucial manufacturers consider every component of their devices, especially if they are not planning to undergo a separate sterilization testing program. Unplanned irritants can cause delays and frustration.
What is the future of ISO 10993-23?
It’s unlikely in vitro testing will fully replace in vivo assessments for skin irritation. But ISO 10993-23 gets us a step closer to realizing that vision. As a screening method, however, ISO 10993-23 is a great way to identify small issues with test articles before they become big problems. At the end of the day, evaluating biocompatibility in medical devices is critical to managing risk and keeping patients safe. And ISO 10993-23 is an exciting and effective step in that direction.
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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. 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 4,400 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.”
Jun 7, 2021 | Biocompatibility, Chemistry, ISO10993-18, Medical Device Testing
Testing your medical device properly and preparing a strong regulatory submission is a dynamic yet crucial part of bringing the product to the market. Put simply, the submission stage is not where most manufacturers want to gamble or guess.
That’s where a qualified laboratory testing partner can be useful. It can be invaluable in helping you navigate the ever-changing regulatory landscape and meet the necessary expectations. So, we compiled answers to some of the most frequently asked questions regarding medical device testing and regulatory submissions.
1. How can I minimize delays in the submission review process through testing?
It’s impossible to accurately predict what regulators will ask of you during submission, but you can avoid some of the most common pitfalls if you do your homework and partner with knowledgeable experts. A bit of extra effort upfront can save time and money down the road.
- Use a risk-based approach
ISO 10993-1:2018 sets the stage to thoroughly identify a product’s potential risk starting with chemical characterization. Developing a testing plan to support the safety of your device is not a check-the-box exercise, and test plans need to be justified. With a solid understanding of your device, its intended use, and how the device is manufactured, you can identify potential risks of your device in advance.
- Stay ahead of the standards
Regulatory guidance is continuously evolving. Even if your previous device submissions made it through seamlessly, it is crucial to comply with the most up-to-date methodologies and identify any gaps in what you have versus what you need. Project teams that are unclear on the latest standards should identify partners with current and consistent experience to help navigate the regulatory landscape.
- Provide expert qualifications
In ISO 10993-1:2018 the standard includes ensuring that qualified individuals carry out the biological evaluation, so it matters who you choose to work with. Many regulators request credentials of the medical device evaluation staff to determine credibility and gauge the quality of resulting data. This qualification is most relevant to the toxicology experts involved in your study program. Gather CVs at the onset of work with laboratory testing partners, so the information is readily available for submission.
2. Is there a difference when preparing submissions for the U.S. versus European markets?
Yes. Every regulatory submission, governing body and reviewer is unique, but manufacturers who consider emerging regulatory trends in the early stages can prepare a stronger submission and avoid additional testing or requests for information in the future.
Understanding regulators’ expectations and priorities will help you build a submission that is tailored to the right market. The EU Medical Device Regulation (MDR) is scheduled to go into effect soon, meaning achieving compliance for medical devices across the EU could be a more strenuous effort than it was previously. According to regulatory consultancy The FDA Group, the MDR is four times longer than its predecessor—the EU’s Medical Devices Directive (MDD)—and contains new regulations as well as modifications of preceding ones1.
Also note, the U.S. Food & Drug Administration (FDA) and the EU MDR differ in their approach to assess quality and overall risk profile, device classifications and clinical testing procedures. In addition, devices that were once compliant with MDD may not be under MDR, so working with a lab testing partner that understands the finer points of both regulatory guidelines will be crucial in achieving new approvals and updating legacy ones.
3. Is a pre-submission meeting worth it?
Yes. Pursuing a pre-submission meeting with regulators is a proactive step toward ensuring the viability of your testing strategy. The true value of pre-submission meetings is threefold. They can be used to:
- Clarify final submission expectations
Pre-submission meetings help remove the guesswork. They can determine testing expectations and applicable standards in the market where you plan to submit. With continuous regulatory updates, these meetings can level-set new expectations mid-stream. They are also a great opportunity to identify any missing information prior to submission.
- Improve your planning process
Teams that come to these meetings with specific questions can streamline the planning process and quickly identify areas to focus on and potential pitfalls to avoid. Note, the U.S. FDA will not instruct manufacturers on what to do for next steps; instead, its role is to identify gaps and opportunities for development in their existing plans. This can happen in pre-submission meetings but advanced preparation is key to a successful meeting.
- Refine your testing strategies
Laboratories cannot adjust study parameters after the fact, so using pre-submission meetings to arm them with the most up-to-date parameters can help smooth your submission process. Testing partners are allowed to attend pre-submission meetings to serve as expert counsel, but it is not required.
4. Can I repurpose the strategy from a recent submission package?
Even if your last submission was only a year ago, your technical file likely requires changes and possibly new testing. Relying on past processes and data often results in unforeseen obstacles and may lead to additional information requests. There are several things you can do to minimize questions from regulators:
Testing partners can help you navigate the submission process and identify potential compliance gaps with current regulatory standards. Even if your previous device submissions passed with flying colors, vetting it against the most up-to-date methodologies helps identify any gaps and identify where new test methods or data preparation must change.
- Anticipate additional information requests
Being realistic and preparing for additional information requests is essential. While it might not be possible to completely eliminate them, planning them into your budget and timeline can help mitigate any delays. Your testing partner can also provide support with responding to additional information requests.
- Prepare for future submissions
The regulatory landscape is in constant flux, and regulatory bodies need more information than ever to assess the safety and risks of a device. Keep a log of the requests during each submission process and share the findings among your team. Detailed notes from past submissions and supporting evaluation plans can help set realistic expectations for future projects.
Your submission’s success depends on your ability to plan properly, manage resources effectively and meet regulator expectations. A laboratory testing partner can walk you through everything you need to know—including whether a pre-submission meeting is needed—to ensure your submission proceeds without difficulty.
References:
- The FDA Group. (2021, February 16) MDR vs. MDD: 13 Key Changes. Retrieved from https://www.thefdagroup.com/blog/mdr-vs-mdd-13-key-changes.
To stay up to date on the latest industry news and regulatory changes, follow us on LinkedIn.
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 4,400 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.”
May 4, 2021 | Biocompatibility, Manufacturing, Medical Device Testing, Technical Expertise
The medical device regulatory environment is continuously evolving. As regulatory body expectations become more demanding, manufacturers need to evaluate the safety implications of changes to their devices and processes.
Manufacturing modifications are one example that can affect a medical device’s compliance and possibly end-user safety. Changes to supply chains and manufacturing processes may pose more than just logistical challenges—they can potentially alter a product’s chemical makeup, impact toxicological risk assessments (TRAs) and even put a device’s regulatory approval at risk.
Whether changes to a manufacturing process are planned or reactive, it is critical to understand the implications they may have on a medical device’s material composition and what that means for evaluating biological safety concerns. When modifications to the device or the process occur, ensure your team takes the right steps to protect the end-user and meet or maintain regulatory approval.
Keeping an Eye on Potential Pitfalls
The manufacturer is responsible for identifying, addressing and eliminating potential risks before implementing modifications to the device design or a manufacturing process. There is always the possibility that adjustments may go wrong and cause obstacles or delays. Companies must be intentional in identifying challenges that can affect a device’s chemical makeup at all stages of the product lifecycle.
When design changes occur, there may also be new materials or processes at play. These changes can affect the outcome of chemical characterization and toxicological risk assessments – and could potentially lead to retesting a device altogether. Evaluating device toxicity is critical to gauging potential patient safety risks and assists in gaining regulatory approval.
It is essential to consider the various regulations that device or material modifications could fail to satisfy – as well as new standard updates that may soon come into effect. For example, the updates to ISO 10993 should always be considered when making changes to a device or process.
Even when no red flags from the manufacturing process arise, a modified device may contain new unknown risks. Ensure your team assesses new device risks that could be associated with the changes and undergo further testing when necessary to protect end-user safety. Your testing partner can help you determine when additional testing is needed.
Recognizing the Common Link
For many established products, one variable that sticks out as the most volatile to change is material choice. When an element in your device makeup changes, differences in raw material composition and quality can falter when it’s time to evaluate toxicity.
When proven safe through testing and risk assessment, a device’s material and chemical composition allow it to function accurately and consistently. But, even altering just one component can put the compatibility of these selections in flux, and the impact on your end-user may be unclear. Laboratory testing partners are more than willing to provide their perspective in determining the necessary next steps when there are material changes in a device. They may suggest additional testing such as material characterization, validation testing, biocompatibility and risk assessments to prove the device is still safe and meets regulatory standards.
Innovate While Playing It Safe
Protecting patient safety and maintaining regulatory compliance is the top priority, so it is essential to consider the risks associated with manufacturing and chemical changes and take the necessary precautions to minimize potential hurdles. Addressing obstacles before they arise can support safer products and successful regulatory submission. Modifications aren’t just manageable—they’re an opportunity to strengthen your understanding of a medical device’s chemical composition through purposeful planning and connection with the right partners.
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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. 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.”
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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