The biocompatibility testing phase is an exciting time for producers of medical devices. It’s the first time you really get to see your device in action, especially if you’re conducting in-vivo or in-vitro testing. It’s also a crucial phase for satisfying regulatory requirements, so the stakes couldn’t be higher. But what happens when your biocompatibility fails? After putting so much time, money and effort into developing a device, a negative result can be devastating. But one failed test doesn’t mean your device is doomed. You simply need to take the proper actions to identify and rectify the cause of the failure so you can move forward in bringing your product to market. Here is your step-by-step guide on what to do if your biocompatibility test fails.
Why did the test fail?
It may seem like an obvious starting point, but the first thing you need to do when a biocompatibility test fails is to determine why it failed. With so many variables present, this is certainly easier said than done. But by analyzing the device and the testing process, you should be able to pinpoint the cause and devise a strategy to move forward.
Analyzing the device
One limitation of biocompatibility testing is that while it provides a comprehensive safety assessment of a new device, it cannot immediately identify the cause of a failed test. To do that, you need to consider all facets of the device and how those could have contributed to a failed test result. Here are some of the major areas to investigate as you work to determine why a test failed.
The first thing to look for are defects in the device tested. These could be as simple as a broken or missing component, faulty wiring or a malfunctioning microchip. For things like wire mesh devices, it could be that the device was not formed to the proper shape before implementation and therefore created significant irritation or some other unforeseen issue. The exact nature of any defect will depend on the device itself, so having design and materials experts involved in the post-testing analysis process will be crucial for identifying potential issues.Although not very common, testing failures can also happen when an inner component of a device comes into contact with the patient when it was not intended to do so. Imagine, for example, that the exterior housing of a pacemaker device became compromised and an interior wire popped out and came into contact with the patient. Defects like these may require a more extensive design review before moving forward in the biocompatibility testing process.In any case, if you determine that a device defect was the likely cause of a negative test result, your next step would simply be to run the test again using a new, non-defective device.
Materials and Manufacturing
One of the most common reasons biocompatibility tests fail is because the materials used to create the device present a safety risk. Many device manufacturers don’t consider this possibility because they follow best practices and only use materials that have been proven to be safe in clinical trials. However, even if you start with commonly used materials, the processing or manufacturing of those materials could introduce risk — perhaps by leaving a residue or releasing a mold agent — that could cause a testing failure. To address this problem, you will need to analyze each phase of your manufacturing operation and conduct additional tests to see if any unknown substances may have been introduced during fabrication.
Just as the materials manufacturing process can introduce risk for a medical device, packaging materials can do the same thing. Packaging can leave residues on a device that could cause any number of adverse results. Finding unexpected chemical compounds in your testing sample may indicate this type of contamination. If you suspect this may be the case, your next step will be to conduct testing to see how the packaging materials interact with the materials in your medical device.
While materials contamination is a simple enough variable to eliminate during preclinical testing, it shows just how important it is for medical device manufacturers to consider the entire supply chain when evaluating the safety of new devices.
One of the best ways to ensure manufacturing and packaging processes don’t compromise the safety of a medical device is by following proper sterilization techniques. Sterilization is critical for preventing contaminating elements of any origin from entering the testing environment. Failure to properly sterilize both the device and the testing equipment used could result in a failed biocompatibility test. As you try to pinpoint the cause of a failed test, assess your sterilization techniques and make sure all materials are handled correctly to help ensure reliable testing results.
It is important to look for defects in the device tested. These could be as simple as a broken or missing component, faulty wiring or a malfunctioning microchip. Although not very common, testing failures can also happen when an inner component of a device comes into contact with the patient when it was not intended to do so. Imagine, for example, that the exterior housing of a pacemaker device became compromised and an interior wire popped out and came into contact with the patient. Defects like these may require a more extensive design review before moving forward in the biocompatibility testing process.
In any case, if you determine that a device defect was the likely cause of a negative test result, your next step would simply be to run the test again using a new, non-defective device.
Analyzing the testing method
If you’ve analyzed the tested device and concluded that everything is in proper order, it’s time to assess your testing procedures. Biocompatibility tests are extremely sensitive in nature and even small changes in the testing process or samples used could create unexpected results. Here are some questions to ask your testing partner as you work together to identify the potential cause of a failed biocompatibility test.
Was the right test chosen?
One of the biggest questions to ask after a failed test result is whether or not you chose the right test in the first place. Experienced testing providers like American Preclinical Services (APS) offer a wide range of testing options for every endpoint, including in-vivo and in-vitro tests that are performed according to ISO, USP and JMHLW guidelines. Choosing the right panel of tests is about more than making sure your device satisfies regulatory ISO10993 requirements. It also means making sure your testing panel takes into account the unique circumstances of the device being tested.
For example, some cytotoxicity tests use a color change in the testing apparatus to determine the cell viabilitylevel of toxins present in the sample. But if the product being tested contains a dye that could be released during testing and create a color change on its own, interfering with the test results, this would obviously be the incorrect test to use.
Identifying what kinds of tests will provide clinically relevant data for your specific device is a key step in making sure your biocompatibility testing is ultimately successful.
Was the right sample chosen?
Along with using the right test, you also need to make sure you’re using the right sample. For example, if you have multiple components of a device that vary in contact duration and contact type, it is imperative to choose the sample that is appropriate for the test(s) selected. Testing multiple samples and retesting is also important, and should be considered as a follow-up step to any negative biocompatibility test result.
Were the proper procedures followed?
If you’ve controlled for all other variables during the testing process, you then have to examine the testing process itself. Were the tests executed correctly? Could contaminants have been introduced at any point due to inappropriate testing procedures? Go back through the testing documentation and look for any errors that may have produced a failed result.
While these kinds of issues are extremely rare with any experienced testing provider, you have to eliminate all possible explanations when determining the cause of a failed test. Testing integrity is of the highest importance to APS, which is why all our facilities are USDA-registered and accredited by ISO17025 and the Laboratory Accreditation Bureau, the Medical Alley Association and the American Association for the Accreditation of Laboratory Animal Care (AAALAC) and ANSI National Accreditation Board (ANAB).
Were results calculated correctly?
As standard practice, b Biocompatibility testing providers use various methods automation whenever possible to ensure the integrity of their results. So, it is extremely rare that an error is made during testing calculations. However, in analyzing a failed test result, you must be exhaustive. This means taking the time to recheck the calibration on any equipment used and recalculate any manual data input or analysis.
Timeline and financial considerations
Every company bringing a new product to market wants to minimize their regulatory risk on the lowest budget possible. So, how you proceed following a failed biocompatibility test will largely depend on your project timeline and your company’s financial resources. You can invest heavily in additional testing to pinpoint an issue, or try a few simple tests and then formulate a strategy based on those results. In any case, APS always recommends conducting at least some additional testing following a failed test result to help identify the true risk associated with a particular device. Sometimes that can be as simple as one follow-up test.
Consider a device that failed a cytotoxicity test. You could conduct a follow-up dilution test, and if you can show that toxicity dissipates with even limited dilution, you may then be able to justify the exposure and risk level in similar clinical conditions. In this case, the device company would incur only a limited cost while being able to move forward in the regulatory approval process. The important thing here is to not only think about your risk level for submission, but also what that risk level looks like after 10 years on the market.
When a failed test isn’t really a failure
In some cases, you may be able to justify a failed test and continue toward regulatory approval without a significant deviation in your project timeline or process. But this will depend on the specific testing results returned.
Continuing the examples of the rabbit test or dilution test presented above, we can see how those negative results could be justified as not being “clinically relevant.” This is the key phrase and should be the basis of any data analysis or justification strategy. But again, APS recommends you always conduct at least some additional testing following a failed test before submitting your device for regulatory approval.
This is why it’s so important to have a trusted testing partner by your side. A company with decades of experience and the latest testing equipment and methodologies can guide your post-test process to help you analyze the results and formulate a path forward. By following this guide to next steps and leveraging the expertise of your testing partner, you can overcome a failed biocompatibility test and succeed in bringing your new product to market.
American Preclinical Services is an industry leader offering comprehensive biocompatibility testing for medical devices. Our 130,000-square-foot campus gives us one of the largest capacities in the world for medical device and drug discovery research. To see how our expert staff and cutting-edge technology could help bring your medical device to market, contact us today.