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.
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.
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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If your organization is planning for a submission under the Medical Device Regulation (MDR), it’s important to consider outsourcing your testing needs to a testing lab. Working with an experienced partner that is well-versed in the latest standards can save you time, money and manpower.
When selecting a testing partner, it’s important to keep in mind that not all labs are created equal. The quality of your results depends largely upon the skills and expertise of the chemists and toxicologists who carry out the testing, which is why the selection process demands thoughtful consideration. Here are five questions to ask to help you find the right partner for your MDR testing needs.
- Do you have the capabilities to conduct chemical characterization, toxicological risk assessments and biocompatibility testing in-house?
The MDR requires that medical devices undergo a complete biological risk assessment to evaluate chemical, toxicological and biocompatibility conditions before they are approved for market. When developing a test plan, look for a partner that offers all three analytical tests under one roof. A lab that is skilled in all areas and uses highly sensitive analytical methods increases efficiency and helps address all biological endpoints, while minimizing room for error between tests. Working with a partner that doesn’t have all of these capabilities may leave you with no choice but to piecemeal your testing, which could risk miscommunication between parties, loss of information altogether, increased costs and longer timelines.
- What is your track record for complete identification?
The MDR places increased emphasis on the importance of chemistry and toxicology. For this reason, working with a lab that specializes in complete chemical characterization will yield the best results. Ask how long they have been conducting extractable/leachable (E/L) studies and how sensitive their analytical methods are. It may be a red flag if their test methods can’t detect chemicals above the analytical evaluation threshold (AET). If a lab doesn’t use proper methods or equipment, they may not be able to provide the right data for a toxicologist to fully assess risks. Unidentified chemicals or incomplete risk assessments will endanger your entire submission package. You should look for a lab testing partner staffed with experts who can demonstrate a track record of regulatory success.
- What is your approach to reporting unknown chemicals? How often do you report unknowns?
Complete chemical characterization requires identification of every chemical compound in your device found above the AET. While there are commercially available libraries that can help identify some chemicals present in extracts, they are not necessarily reliable in every circumstance. Reporting unidentified compounds can result in an unfavorable risk assessment, which could send you to the back of the line for another round of testing. Having to retest products increases cost and lead times. Ensure your partner has the ability to identify every compound the first time around.
- Do you offer follow-up support once a submission is ready for regulatory approval?
While the testing process is of the utmost importance, seeking out a partner that also provides post-submission support ensures everything runs smoothly from start to finish. If regulators have questions or ask for additional information, your partner should be available to provide guidance. Even after an MDR submission, partnerships should continue on through the lifecycle of the product.
- How does your staff stay up-to-speed on the changing regulatory expectations?
You will want to work with a lab testing partner that is staffed with experts who sit on regulatory committees, are in-the-know with the evolving regulatory landscape and have been doing chemistry, toxicology and biocompatibility on medical devices for several years. Do your due diligence in learning about a lab or CRO’s involvement with regulatory bodies before inking any agreements, so that you can be confident in your submission package.
These questions will put you on the right path to gauge whether a potential testing partner is capable of meeting your needs. To learn more about how to get the most out of your testing services, read “How to maximize your lab partnership: Details pay dividends.”
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.
With the MDR journey well underway, device manufacturers should have their gap analyses complete and road maps to the finish line thoroughly planned out. However, the industry is behind.
Where OEMs Are Now vs. Where They Should Be
Many manufacturers are running behind with their MDR implementation. Depending on how many products they need to test and who is carrying out testing, the process can take months or even years. Many small and mid-size companies are not ready due to limited resources, lack of regulatory knowledge, or simply not knowing where to start. Companies with a larger volume of products may be more at risk, especially if they haven’t begun prioritizing products. However, those with fewer products and less ground to make up should already be working toward MDR compliance. If they’re not, it’s time to put the pedal to the metal.
Deciding on a Path Forward
OEMs have two options to complete pre-clinical device testing. The first is to conduct their own testing using in-house facilities and personnel. Companies that do not already have facilities up and running would have a lot to accomplish before testing can even begin; at this point, building an in-house lab may not be feasible. The alternative option is to outsource testing to a specialized lab or contract research organization (CRO). There are pros and cons to each approach, and selecting the best path forward comes down to several factors unique to the device manufacturer. Following are some criteria to help determine the best path forward.
The Pros of In-House Testing
There are a few advantages to having an in-house testing facility:
- Ownership: Owning the medical device testing process grants a company control over the whole project, from technical insights and cost through timing and submission decisions, etc. Most importantly, medtech firms can re-prioritize products in real-time, if challenges arise. Due to the high demand for testing services in the face of MDR, laboratory testing facilities continue to experience capacity constraints. Handling projects internally allows organizations to avoid competing with other companies for priority or dealing with the headache of securing a spot in line.
- Direct lines of communication: Internal communications may be easier and more efficient because it eliminates outside involvement and could shorten response time.
If an organization elects to take testing in-house, it’s essential to consider the steps needed to run a viable testing facility. As long as the internal team is aware of the latest testing standards, regulatory expectations, has experience with extractables and leachables (E/L) studies, and has written risk assessments on medical device products in the past, they should be in good shape. But be aware the cost savings associated with in-house testing may be offset by the expense of building an internal facility and purchasing standard lab equipment (the latter alone could cost millions of dollars).
Pros of Outsourcing Testing
The greatest downfall of in-house testing ahead of MDR is the unforgiving timeline. In-house testing requires physical space, technology, personnel, expertise, equipment, and more to execute successfully. If a company doesn’t already have these, now may not be the time to take a DIY approach. Due to labs’ specialization, analytical methods, and regulatory knowledge, going the outsourcing route may be the better option for MDR testing. Here are a few reasons why:
- Reputation: Working with a lab may help boost submission credibility in regulators’ eyes. Regulators want to ensure companies have not introduced any biased views in technical files and chemistry reports. Involving an unbiased third party is one way to accomplish this.
- Access to insider knowledge: In-house testing facilities in their infancy won’t have access to extensive chemical databases, as these libraries are built slowly over time. CROs, on the other hand, have visibility to all types of products, regulations, new standards, and questions or requests that may come from regulatory agencies. This visibility allows experienced lab testing partners to adapt quickly and draw upon broad exposure and experiences when dealing with the unexpected. Learnings gleaned from identifications can be leveraged to inform decisions and trends. This process can be harder for in-house labs.
- Recruitment: Staffing an in-house facility with qualified experts can be a complicated, drawn-out process. It is important to hire seasoned chemistry and toxicology experts versus generalists, as experience in the field of medical device testing will make a big difference. Similar to how there are many types of doctors, there are specialized toxicologists and chemists. Some scientists may appear qualified at first glance, but may not have previous experience with E/L testing medical devices, identifying unknown chemicals, or addressing the immune response or toxicity of a specific chemical. Risk assessments require specific tools and methods, and staff must know how to use proper analytical methods. Think of it this way: It wouldn’t be wise to have a primary physician attempt open-heart surgery. Specialization in the field of medical device testing works the same way.
- Timeliness: MDR is a big task, but outsourcing some work to a qualified lab can help reduce the burden of staffing and training, allowing for more focus on other critical tasks. Further, a lab is a good option to ensure testing is done sequentially and all biological endpoints are met. Establishing strong partnerships increases efficiency and eliminates the potential for miscommunication between parties or gaps in information.
Even if outsourcing all testing isn’t the desired route, building a relationship with a lab can help in emergencies, such as equipment failing, staff turnover, or projects outside staffs’ expertise.
General Advice for MDR Planning
Aside from which approach an organization takes to testing, knowing general guidelines is helpful throughout the approval process. Carefully prioritize product lines. Focus on products that have the highest market demand and return on investment. Finally, approach partnerships with transparency—be forthcoming with details, and give lab partners visibility to forecasts, intervals, and timelines. Providing as much detail up front as possible, setting aside privacy concerns, and sharing honest feedback helps ensure long-term success.
There’s no time left to procrastinate, so companies should keep their foot on the gas and take charge of their approach to MDR.