Michael Barbella, Managing Editor09.14.21
Zoë Bacon yearns for a better life.
She dreams of the day she can move about effortlessly, pursuing her favorite pastimes of windsurfing and piano playing. In that illusory world, Bacon is free from the chronic spinal stenosis pain that has ruled the past seven years of her life and kept her tethered to various drugs, devices, and medical treatments.
Bacon imagines herself invincible, living a life of dreams fulfilled.
“After I was diagnosed with spinal stenosis, I did a lot of research about the condition. I got stronger, both physically and mentally,” Bacon said in an online post. “Whilst I manage my symptoms really well, I always think how different my life would be without back pain. I think about what I could achieve and how much more energy I would have. I have had chronic pain for six years now. If a treatment could stop my pain all together, I think I would feel invincible. It would be like the best present anyone could give me.”
Bacon’s best chances of receiving such a gift conceivably rest with iPSpine, an international consortium striving to develop a viable biological solution for lower back pain. Launched in January 2019, the initiative aims to combine iPS (induced pluripotent stem cells) and biomaterials to regenerate deteriorating intervertebral discs.
The biomaterials, according to consortium data, would act as a preparative agent, mechanically stabilizing the affected intervertebral disc(s) and creating a regenerative-friendly environment for the patient-extracted stem cells that laboratory clinicians reprogram into iPS.
Assisting iPSpine’s efforts is SpineServ, a German company specializing in the mechanical testing of surgical implants, instruments and implant materials. The firm is working with the Institute of Orthopaedic Research and Biomechanics at the University of Ulm (Germany) to devise specific testing and software for the consortium’s spinal stenosis treatment. The software will incorporate artificial intelligence that will allow clinicians to accurately measure both disc degeneration and regeneration.
SpineServ and Ulm researchers also are developing a mobile spinal load simulator so iPSpine’s partners have easy access to biomechanical tests. The simulator will be one meter high, one meter wide, and one meter deep for easy transport; its larger inspiration features an infrared camera system equipped with sensors that react to specimen markers. The larger simulator also can deliver kinematic analyses that are accurate down to the 10 nanometer range.
The simulator mimics turning, bending, and lifting movements, can test both shock and shear loads, and can examine the effectiveness of stiffening. “We can simulate physiological strain so realistically that we can reliably predict how the implant will behave in the human boy,” Prof. Dr. Hans-Joachim Wilke, a SpineServ advisory board member and head of the iPSpine’s project partners in Ulm, told the press.
Such predictions have become essential as orthopedic implant manufacturers strive to produce reliable, durable solutions for an increasingly active patient population.
Appropriate testing of orthopedic implants generally must include knowledge of basic mechanical and materials concepts; anatomy surrounding the device; and biomechanics of the implant, the body, and the interface between the body and implant.
To better gauge the trends and market forces driving orthopedic testing and analysis, Orthopedic Design & Technology spoke with numerous industry professionals over the last few weeks. Those who provided input included:
Michael Coladonato, senior regulatory specialist, and Lisa Ferrara, Ph.D., technical director, at Element Materials Technology Group, a global provider of testing, inspection and certification services for various markets.
Mark Escobedo, senior sales engineer at Westpak, a third-party, independent test laboratory in San Diego and San Jose, Calif., specializing in package testing and validation for the medical device industry.
Mikaelle Giffin and Christopher Pohl, associate toxicologists at Nelson Labs, a Sotera Health company. The Salt Lake City-based firm provides laboratory testing and expert advisory services worldwide.
Lisa Olson, senior vice president, Global Laboratory Services, at NAMSA, a medical device-focused, full continuum contract research organization whose solutions include medical device testing; regulatory, reimbursement and quality consulting; and clinical research services for both medical device and in-vitro diagnostic clients.
Michael Barbella: Please discuss the latest trends in testing methodologies for orthopedic products.
Michael Coladonato and Lisa Ferrara: The latest trends in testing methodologies for orthopedic products involve the development of a comprehensive battery of tests that evaluate medical products as an entire “system.” Implementing testing to evaluate how the implant performs is one part of the assessment. However, it is vital to evaluate how the implant integrates and functions with the other components that accompany the medical device, such as the instruments, the surgical approach, potential software, and the biological environment. This changes the way the testing and evaluation should be approached. Assessment of each discrete unit within the system must be analyzed, as well as evaluation of the system as a whole.
Mark Escobedo: Like all medical devices, orthopedic devices have to maintain sterility following distribution from the point of manufacture to the point of end use. Looking at that concept from a high level, that seems fairly routine. However, orthopedic devices come in a variety of different sizes to accommodate the patient. This creates a unique situation where the device can be sent back to the manufacturer. The device may then get repackaged, need to be sterilized again, and sent back out to another hospital. How do you test for that? Are there a number or cycles that make sense? We have helped clients develop their test plan to meet this need. Each company will have specific needs depending on the product type and how the product moves through the distribution environment.
Mikaelle Giffin: With the newly updated ISO 10993-18 we have seen a trend in notified bodies, where it is now the expectation to identify and assess any compounds which have been measure above the AET in the extractables/leachables testing. Furthermore, because lab and instrument variation produce known uncertainty factors which directly impact the derivation of an appropriate AET, notified bodies have been expecting lab specific, verified uncertainty factors for each type of analytical chemistry process (GC/MS, LC/MS, etc.) in order to ensure that the correct AET is set for the device and its expected patient exposure.
Lisa Olson: More and more, NAMSA is observing chemical characterization of orthopedic products. Although the biocompatibility requirements haven’t changed, regulators are looking for thorough chemical analysis of extractables. And, in some cases with devices that have coatings, more unique materials or bioabsorbable properties. These analyses are being extended to leachable and time-course studies to reveal the chemical properties over time.
Christopher Pohl: The biggest questions from regulatory bodies is whether or not the chemistry study was conducted in such a way to adequately assess for compounds that have a variable response factor in the instruments. The Analytical Evaluation Threshold (AET) must be low enough to address this issue, and it is starting to hit the limit of detection at this point.
Barbella: What are the most pressing challenges facing orthopedic device testers, and what kinds of solutions are available them?
Coladonato and Ferrara: Keeping up with the pace of new and novel technologies where the test standards need to be slightly modified to accurately assess the nuances of novel orthopedic devices. The medical device industry is rapidly changing, therefore orthopedic device testers must adapt quickly and effectively in order to provide appropriate test strategies that both meet regulatory requirements while taking into consideration the nuances of novel medical devices.
Escobedo: Our focus is primarily on the packaging that protects the product. We need to show the packaging maintains sterility. Currently, we use two test methods that are destructive to the packaging. In addition, one test method is qualitative in nature. This can translate into a requirement for a relatively large sample size as the qualitative data collected is considered attribute data. Once we are done testing the packaging, the device is no longer sterile. Non-destructive package testing technology does exist, but it requires custom fixturing. The challenge for us would be to offer a non-destructive test that is a “one size” fits all. If we could offer a non-destructive method on packaging of any size or shape then this could reduce the number of samples required.
Giffin: As previously discussed, notified bodies are expecting that an appropriate AET is established before testing takes place. This provides a challenge when testing these devices as these expected AET concentrations can often fall below the instrument’s sensitivity levels. In these cases more devices have to be pooled and extracted appropriately in order to meet each instrumentations specific levels of detection/quantification. But on the flip side, if multiple devices can be used at a time than that AET must be further adjusted in order to reflect the actual expected exposure per single device. This is an exciting, multi-leveled challenge in which solutions are still be investigated as more information becomes available. The current best solution for manufacturers and testers of these devices is to thoroughly identify the worst-case scenario of patient exposure when using these devices. Then, using that scenario, work together to ensure that the correct AET is set before any testing is completed so that the results can accurately show the expected patient exposure when using the device.
Olson: As with all devices, the evolving regulatory expectations for testing approaches can be challenging. The standards written in a broad fashion, appropriately so, to address myriads of device types. But this also means it can be difficult to prospectively understand what regulators require throughout testing.
Pohl: To go along with the concern listed above, the AET needs to be so low, that it is at the edge of what current science can do. This is a problem that is exacerbated when multiple devices can be used simultaneously. The most devices, the AET needs to be at or lower than the limit of detection of the instrument.
Barbella: How is 3D printing/additive manufacturing impacting orthopedic device testing?
Coladonato and Ferrara: The 3D printing of implants and tooling have grown at an exponential rate over the last few years. There is significant market appeal with the ability to print complex designs and open architectures that allow for tissue ingrowth, thus creating a potential for improved healing.
The ability to rapidly print prototypes and production parts have revolutionized orthopedic implants. Multiple manufacturers have expanded their business by adding printing capabilities, resulting in the rapid growth for additively manufactured orthopedic devices. However, the validation of additive manufacturing for implants must address the manufacturing processes and risks for the Quality System, which would include the testing of every lot, as well as the necessary testing needed to fulfill regulatory requirements.
Escobedo: The ability of 3D printing of orthopedic devices is a huge breakthrough. The ability to take a CT scan of the body and create an actual replica of the body part is here. It has the promise to solve many different issues including size, inventory, patient comfort, and I would go so far to say faster time to recovery. Additionally, it could actually reduce or eliminate Distribution testing. Think about the hospital of Medical Group having a system where the orthopedic device is produced and sterilized onsite. This could even eliminate packaging of the device. Additive manufacturing has the potential to greatly reduce the distribution channel from hundreds of miles to a few hundred feet. Why would you even need to conduct distribution testing at that point as the risk of a sterility breach would be minimized? I am not saying that 3D printing of devices would eliminate all testing. You still need to show the device being printed has the same strength and characteristics of a predicate device to last many years or even a lifetime. However, if you look at it from standpoint of eliminating packaging and Distribution testing and the headache of returned devices, there is a lot of potential to reduce costs.
Olson: It puts a focus on the materials and can shift what is considered design freeze and thus, the point in development where analytical and biological testing is applied. But, as biocompatibility testing is more focused on the materials and the effects from processing, these methods are not impacted.
Barbella: How has patient-specific and customized implants impacted the testing methods for orthopedic devices?
Coladonato and Ferrara: Patient-specific and customized implants are beginning to have greater market presence. Medical facilities are working towards implementing the printing of implants in the clinical setting. This would allow the physician to virtually pre-plan the surgery and further tailor the implant to the patient’s anatomy with refinement of the anatomical placement and fit.
The ability to print patient-specific implants in the clinical setting requires a collaborative effort involving the manufacturers of the printers, quality specialists, design and test engineers, regulatory specialists, medical staff, and surgeons to evaluate multiple facets of the printing process and device designs to ensure the safety of printed devices and altered designs.
Giffin: I personally have heard multiple presentations discussing the path to individualized medicine. While this is exciting, it does create some challenges when trying to design the appropriate extractables and leachables testing. When performing an extractables study we want to use the worst-case scenario, which often means that we want to extract the largest device and greatest number of those devices that could be exposed to a patient. With having multiple, customizable sizes, identifying a worst-case scenario may become more challenging and manufacturers may have to test more devices or prepare larger “monster” devices that would never be used in a patient in order to create that worst-case scenario. This creates some further challenges though as then since it is understood that this device would never be used in an actual patient, theoretical calculations would be required in order to try and scale the amount of extractables measured from the device to a more appropriate patient exposure.
Olson: In many cases, patient–specific and customized implants are still leveraging a basic platform of design and materials. Testing must consider the “worst-case” use and processing scenario and then develop a plan to evaluate the safety risks. Fundamentally, it comes back to materials: they have to be well understood and this means the standard biological and chemical evaluations should be considered to determine how risks can be appropriately modelled.
Pohl: This is an interesting one. Typically, when testing, a “worst-case” sample is needed when testing for biocompatibility, and this is usually the largest device that is available. However, if it is customizable, what is the “worst-case,” or largest device? Testing can always be done on a device that is larger than would ever go into the human body, but then there is a higher chance of failing due to a compound or an unknown in the chemistry report.
Barbella: In what ways has the EU’s MDR impacted orthopedic device testing?
Coladonato and Ferrara: The EU MDR includes the General Safety and Performance Requirements (GSPRs), which have replaced the MDD Essential Requirements. Non-clinical testing is critical in supporting CE marking and compliance to the GSPRs. The EU MDD lists mandatory standards (harmonized standards) for non-clinical testing, a similar list is available for the EU MDR, however the EU MDR list of standards is more comprehensive and notified bodies require manufacturers to begin using the latest version of the applicable standards one year following the standard being published.
Escobedo: We haven’t seen much of an impact from the EU’s MDR on orthopedic device testing or even medical devices in general, however, we help companies with a subset of the overall testing required for development. By the time we see the device, it has gone through rigorous design control, manufacturing, packaging, and sterilization. We then guide the clients through the distribution testing requirements and even expiration labeling. We have assisted in a few gap assessments and conducted some testing there, but there was also a significant delay from the coronavirus. We may see more activity related to the EU MDR in the future.
Olson: The MDR is definitely causing device manufacturers to look at their portfolios to determine what products need to be retained and which may need to be discontinued because the requirements for testing have expanded. Not only that, the requirements for evaluation are now ongoing—it isn’t test it and forget it, but a program of continual evaluation is needed.
Barbella: How have new materials and technological advancements like AI impacted orthopedic device testing?
Coladonato and Ferrara: Artificial Intelligence (AI) has entered into the medical device arena with multiple opportunities for improving diagnostics and treatment processes. It will provide intelligent systems that can learn and provide faster diagnostic and treatment options specific to each patient, while monitoring the patient’s treatment compliance. AI will be the catapult for customized medicine. The challenge lies in the testing and evaluation of AI’s safety, efficacy, accuracy, cybersecurity, and learning capabilities. Therefore, each application that will incorporate AI will most likely require customized pre-clinical and clinical evaluation strategies specific to the technology at hand. Assessment of the cumulative system that incorporates AI will require detailed risk assessment and mitigation plans with an evaluation of the system in the manner it is intended to function, as well as how the system can fail. Assessment of safety and efficacy, as well as cybersecurity, compliance, and risk will require in-depth detailed test plans.
Olson: AI can help avoid some of the efficacy testing by getting deeper and more advanced in the theoretical modelling. Then, testing can be better targeted or devices with unsuitable designs can be re-worked before going to testing. But ultimately, global regulators still have their expectations for bodies of testing that haven’t changed which simply can’t be addressed with AI.
Barbella: What strategies are being used to test orthopedic instruments, since there are no existing published guidelines for instruments?
Coladonato and Ferrara: Strategies to assess the integration of the instrument with the implant, the tissue environment and placement, the strength and durability are all factors to take into account when testing orthopedic instruments. The most common test strategy utilized for orthopedic instruments is usability testing coupled with a risk-based biocompatibility assessment. This approach can allow for the most accurate assessment of the instruments with respect to safety and effectiveness.
Olson: The horizontal guidance documents and standards for devices can still be leveraged to provide a basic direction for testing. Then, it is a matter of evaluating the device and its use to determine which risks are probable and create a test plan to look at those endpoints.
Barbella: How do you expect orthopedic device testing to evolve over the next five to 10 years?
Escobedo: Many other companies will be getting into the 3D orthopedic device space. Companies will have to show that the devices have the characteristics of a predicate device that was manufactured in a more traditional way. Characteristics in terms of strength, either tensile or compression, or cyclic loads as examples. If the device is custom the quantity manufactured could easily be just one. Clearly, we cannot perform destructive testing on that device. To determine that the device meets the required specifications, the test methods will have to be non-destructive. This will drive the need to be develop new test methods using various technologies to provide the information required for the device.
Giffin: Currently, the expected extractables testing that is performed on these types of devices is performed under exaggerated conditions (50°C for 72 hours) and then after those 72 hours the extract is measured and assessed. Using a specific example of pure metal alloy implants, it is possible that potential residuals remain on these devices which are expected to be eliminated by the patient within 30 days. However, when analyzed some of these residuals may be measured at or above the established limits of exposure. This then requires more testing and understanding as the limits for many elements and compounds are well established and accepted by many notified bodies. A more appropriate way of evaluating some of the devices may be to perform simulated use extractions, where the extractions are done at lower temperatures and sampled over consecutive days. This type of testing may be able to provide a more relevant data and provide better kinetic information as to how these residuals could reduce over time. In the future I can see more instances of simulated use testing being performed in order to better understand the actual patient exposure.
Olson: As with most devices, I think we will see in-vitro methods gain prominence as well as more chemical and materials evaluations to leverage non-animal alternatives. However, when animal safety and efficacy studies are performed, I believe we will see more efforts to leverage all of the possible data from each study.
Pohl: I would expect to see more additives that are embedded into the devices, especially if it is 3D printed. For example, we are seeing more cases of Vitamin E impregnated devices. I expect to see others as well.
She dreams of the day she can move about effortlessly, pursuing her favorite pastimes of windsurfing and piano playing. In that illusory world, Bacon is free from the chronic spinal stenosis pain that has ruled the past seven years of her life and kept her tethered to various drugs, devices, and medical treatments.
Bacon imagines herself invincible, living a life of dreams fulfilled.
“After I was diagnosed with spinal stenosis, I did a lot of research about the condition. I got stronger, both physically and mentally,” Bacon said in an online post. “Whilst I manage my symptoms really well, I always think how different my life would be without back pain. I think about what I could achieve and how much more energy I would have. I have had chronic pain for six years now. If a treatment could stop my pain all together, I think I would feel invincible. It would be like the best present anyone could give me.”
Bacon’s best chances of receiving such a gift conceivably rest with iPSpine, an international consortium striving to develop a viable biological solution for lower back pain. Launched in January 2019, the initiative aims to combine iPS (induced pluripotent stem cells) and biomaterials to regenerate deteriorating intervertebral discs.
The biomaterials, according to consortium data, would act as a preparative agent, mechanically stabilizing the affected intervertebral disc(s) and creating a regenerative-friendly environment for the patient-extracted stem cells that laboratory clinicians reprogram into iPS.
Assisting iPSpine’s efforts is SpineServ, a German company specializing in the mechanical testing of surgical implants, instruments and implant materials. The firm is working with the Institute of Orthopaedic Research and Biomechanics at the University of Ulm (Germany) to devise specific testing and software for the consortium’s spinal stenosis treatment. The software will incorporate artificial intelligence that will allow clinicians to accurately measure both disc degeneration and regeneration.
SpineServ and Ulm researchers also are developing a mobile spinal load simulator so iPSpine’s partners have easy access to biomechanical tests. The simulator will be one meter high, one meter wide, and one meter deep for easy transport; its larger inspiration features an infrared camera system equipped with sensors that react to specimen markers. The larger simulator also can deliver kinematic analyses that are accurate down to the 10 nanometer range.
The simulator mimics turning, bending, and lifting movements, can test both shock and shear loads, and can examine the effectiveness of stiffening. “We can simulate physiological strain so realistically that we can reliably predict how the implant will behave in the human boy,” Prof. Dr. Hans-Joachim Wilke, a SpineServ advisory board member and head of the iPSpine’s project partners in Ulm, told the press.
Such predictions have become essential as orthopedic implant manufacturers strive to produce reliable, durable solutions for an increasingly active patient population.
Appropriate testing of orthopedic implants generally must include knowledge of basic mechanical and materials concepts; anatomy surrounding the device; and biomechanics of the implant, the body, and the interface between the body and implant.
To better gauge the trends and market forces driving orthopedic testing and analysis, Orthopedic Design & Technology spoke with numerous industry professionals over the last few weeks. Those who provided input included:
Michael Coladonato, senior regulatory specialist, and Lisa Ferrara, Ph.D., technical director, at Element Materials Technology Group, a global provider of testing, inspection and certification services for various markets.
Mark Escobedo, senior sales engineer at Westpak, a third-party, independent test laboratory in San Diego and San Jose, Calif., specializing in package testing and validation for the medical device industry.
Mikaelle Giffin and Christopher Pohl, associate toxicologists at Nelson Labs, a Sotera Health company. The Salt Lake City-based firm provides laboratory testing and expert advisory services worldwide.
Lisa Olson, senior vice president, Global Laboratory Services, at NAMSA, a medical device-focused, full continuum contract research organization whose solutions include medical device testing; regulatory, reimbursement and quality consulting; and clinical research services for both medical device and in-vitro diagnostic clients.
Michael Barbella: Please discuss the latest trends in testing methodologies for orthopedic products.
Michael Coladonato and Lisa Ferrara: The latest trends in testing methodologies for orthopedic products involve the development of a comprehensive battery of tests that evaluate medical products as an entire “system.” Implementing testing to evaluate how the implant performs is one part of the assessment. However, it is vital to evaluate how the implant integrates and functions with the other components that accompany the medical device, such as the instruments, the surgical approach, potential software, and the biological environment. This changes the way the testing and evaluation should be approached. Assessment of each discrete unit within the system must be analyzed, as well as evaluation of the system as a whole.
Mark Escobedo: Like all medical devices, orthopedic devices have to maintain sterility following distribution from the point of manufacture to the point of end use. Looking at that concept from a high level, that seems fairly routine. However, orthopedic devices come in a variety of different sizes to accommodate the patient. This creates a unique situation where the device can be sent back to the manufacturer. The device may then get repackaged, need to be sterilized again, and sent back out to another hospital. How do you test for that? Are there a number or cycles that make sense? We have helped clients develop their test plan to meet this need. Each company will have specific needs depending on the product type and how the product moves through the distribution environment.
Mikaelle Giffin: With the newly updated ISO 10993-18 we have seen a trend in notified bodies, where it is now the expectation to identify and assess any compounds which have been measure above the AET in the extractables/leachables testing. Furthermore, because lab and instrument variation produce known uncertainty factors which directly impact the derivation of an appropriate AET, notified bodies have been expecting lab specific, verified uncertainty factors for each type of analytical chemistry process (GC/MS, LC/MS, etc.) in order to ensure that the correct AET is set for the device and its expected patient exposure.
Lisa Olson: More and more, NAMSA is observing chemical characterization of orthopedic products. Although the biocompatibility requirements haven’t changed, regulators are looking for thorough chemical analysis of extractables. And, in some cases with devices that have coatings, more unique materials or bioabsorbable properties. These analyses are being extended to leachable and time-course studies to reveal the chemical properties over time.
Christopher Pohl: The biggest questions from regulatory bodies is whether or not the chemistry study was conducted in such a way to adequately assess for compounds that have a variable response factor in the instruments. The Analytical Evaluation Threshold (AET) must be low enough to address this issue, and it is starting to hit the limit of detection at this point.
Barbella: What are the most pressing challenges facing orthopedic device testers, and what kinds of solutions are available them?
Coladonato and Ferrara: Keeping up with the pace of new and novel technologies where the test standards need to be slightly modified to accurately assess the nuances of novel orthopedic devices. The medical device industry is rapidly changing, therefore orthopedic device testers must adapt quickly and effectively in order to provide appropriate test strategies that both meet regulatory requirements while taking into consideration the nuances of novel medical devices.
Escobedo: Our focus is primarily on the packaging that protects the product. We need to show the packaging maintains sterility. Currently, we use two test methods that are destructive to the packaging. In addition, one test method is qualitative in nature. This can translate into a requirement for a relatively large sample size as the qualitative data collected is considered attribute data. Once we are done testing the packaging, the device is no longer sterile. Non-destructive package testing technology does exist, but it requires custom fixturing. The challenge for us would be to offer a non-destructive test that is a “one size” fits all. If we could offer a non-destructive method on packaging of any size or shape then this could reduce the number of samples required.
Giffin: As previously discussed, notified bodies are expecting that an appropriate AET is established before testing takes place. This provides a challenge when testing these devices as these expected AET concentrations can often fall below the instrument’s sensitivity levels. In these cases more devices have to be pooled and extracted appropriately in order to meet each instrumentations specific levels of detection/quantification. But on the flip side, if multiple devices can be used at a time than that AET must be further adjusted in order to reflect the actual expected exposure per single device. This is an exciting, multi-leveled challenge in which solutions are still be investigated as more information becomes available. The current best solution for manufacturers and testers of these devices is to thoroughly identify the worst-case scenario of patient exposure when using these devices. Then, using that scenario, work together to ensure that the correct AET is set before any testing is completed so that the results can accurately show the expected patient exposure when using the device.
Olson: As with all devices, the evolving regulatory expectations for testing approaches can be challenging. The standards written in a broad fashion, appropriately so, to address myriads of device types. But this also means it can be difficult to prospectively understand what regulators require throughout testing.
Pohl: To go along with the concern listed above, the AET needs to be so low, that it is at the edge of what current science can do. This is a problem that is exacerbated when multiple devices can be used simultaneously. The most devices, the AET needs to be at or lower than the limit of detection of the instrument.
Barbella: How is 3D printing/additive manufacturing impacting orthopedic device testing?
Coladonato and Ferrara: The 3D printing of implants and tooling have grown at an exponential rate over the last few years. There is significant market appeal with the ability to print complex designs and open architectures that allow for tissue ingrowth, thus creating a potential for improved healing.
The ability to rapidly print prototypes and production parts have revolutionized orthopedic implants. Multiple manufacturers have expanded their business by adding printing capabilities, resulting in the rapid growth for additively manufactured orthopedic devices. However, the validation of additive manufacturing for implants must address the manufacturing processes and risks for the Quality System, which would include the testing of every lot, as well as the necessary testing needed to fulfill regulatory requirements.
Escobedo: The ability of 3D printing of orthopedic devices is a huge breakthrough. The ability to take a CT scan of the body and create an actual replica of the body part is here. It has the promise to solve many different issues including size, inventory, patient comfort, and I would go so far to say faster time to recovery. Additionally, it could actually reduce or eliminate Distribution testing. Think about the hospital of Medical Group having a system where the orthopedic device is produced and sterilized onsite. This could even eliminate packaging of the device. Additive manufacturing has the potential to greatly reduce the distribution channel from hundreds of miles to a few hundred feet. Why would you even need to conduct distribution testing at that point as the risk of a sterility breach would be minimized? I am not saying that 3D printing of devices would eliminate all testing. You still need to show the device being printed has the same strength and characteristics of a predicate device to last many years or even a lifetime. However, if you look at it from standpoint of eliminating packaging and Distribution testing and the headache of returned devices, there is a lot of potential to reduce costs.
Olson: It puts a focus on the materials and can shift what is considered design freeze and thus, the point in development where analytical and biological testing is applied. But, as biocompatibility testing is more focused on the materials and the effects from processing, these methods are not impacted.
Barbella: How has patient-specific and customized implants impacted the testing methods for orthopedic devices?
Coladonato and Ferrara: Patient-specific and customized implants are beginning to have greater market presence. Medical facilities are working towards implementing the printing of implants in the clinical setting. This would allow the physician to virtually pre-plan the surgery and further tailor the implant to the patient’s anatomy with refinement of the anatomical placement and fit.
The ability to print patient-specific implants in the clinical setting requires a collaborative effort involving the manufacturers of the printers, quality specialists, design and test engineers, regulatory specialists, medical staff, and surgeons to evaluate multiple facets of the printing process and device designs to ensure the safety of printed devices and altered designs.
Giffin: I personally have heard multiple presentations discussing the path to individualized medicine. While this is exciting, it does create some challenges when trying to design the appropriate extractables and leachables testing. When performing an extractables study we want to use the worst-case scenario, which often means that we want to extract the largest device and greatest number of those devices that could be exposed to a patient. With having multiple, customizable sizes, identifying a worst-case scenario may become more challenging and manufacturers may have to test more devices or prepare larger “monster” devices that would never be used in a patient in order to create that worst-case scenario. This creates some further challenges though as then since it is understood that this device would never be used in an actual patient, theoretical calculations would be required in order to try and scale the amount of extractables measured from the device to a more appropriate patient exposure.
Olson: In many cases, patient–specific and customized implants are still leveraging a basic platform of design and materials. Testing must consider the “worst-case” use and processing scenario and then develop a plan to evaluate the safety risks. Fundamentally, it comes back to materials: they have to be well understood and this means the standard biological and chemical evaluations should be considered to determine how risks can be appropriately modelled.
Pohl: This is an interesting one. Typically, when testing, a “worst-case” sample is needed when testing for biocompatibility, and this is usually the largest device that is available. However, if it is customizable, what is the “worst-case,” or largest device? Testing can always be done on a device that is larger than would ever go into the human body, but then there is a higher chance of failing due to a compound or an unknown in the chemistry report.
Barbella: In what ways has the EU’s MDR impacted orthopedic device testing?
Coladonato and Ferrara: The EU MDR includes the General Safety and Performance Requirements (GSPRs), which have replaced the MDD Essential Requirements. Non-clinical testing is critical in supporting CE marking and compliance to the GSPRs. The EU MDD lists mandatory standards (harmonized standards) for non-clinical testing, a similar list is available for the EU MDR, however the EU MDR list of standards is more comprehensive and notified bodies require manufacturers to begin using the latest version of the applicable standards one year following the standard being published.
Escobedo: We haven’t seen much of an impact from the EU’s MDR on orthopedic device testing or even medical devices in general, however, we help companies with a subset of the overall testing required for development. By the time we see the device, it has gone through rigorous design control, manufacturing, packaging, and sterilization. We then guide the clients through the distribution testing requirements and even expiration labeling. We have assisted in a few gap assessments and conducted some testing there, but there was also a significant delay from the coronavirus. We may see more activity related to the EU MDR in the future.
Olson: The MDR is definitely causing device manufacturers to look at their portfolios to determine what products need to be retained and which may need to be discontinued because the requirements for testing have expanded. Not only that, the requirements for evaluation are now ongoing—it isn’t test it and forget it, but a program of continual evaluation is needed.
Barbella: How have new materials and technological advancements like AI impacted orthopedic device testing?
Coladonato and Ferrara: Artificial Intelligence (AI) has entered into the medical device arena with multiple opportunities for improving diagnostics and treatment processes. It will provide intelligent systems that can learn and provide faster diagnostic and treatment options specific to each patient, while monitoring the patient’s treatment compliance. AI will be the catapult for customized medicine. The challenge lies in the testing and evaluation of AI’s safety, efficacy, accuracy, cybersecurity, and learning capabilities. Therefore, each application that will incorporate AI will most likely require customized pre-clinical and clinical evaluation strategies specific to the technology at hand. Assessment of the cumulative system that incorporates AI will require detailed risk assessment and mitigation plans with an evaluation of the system in the manner it is intended to function, as well as how the system can fail. Assessment of safety and efficacy, as well as cybersecurity, compliance, and risk will require in-depth detailed test plans.
Olson: AI can help avoid some of the efficacy testing by getting deeper and more advanced in the theoretical modelling. Then, testing can be better targeted or devices with unsuitable designs can be re-worked before going to testing. But ultimately, global regulators still have their expectations for bodies of testing that haven’t changed which simply can’t be addressed with AI.
Barbella: What strategies are being used to test orthopedic instruments, since there are no existing published guidelines for instruments?
Coladonato and Ferrara: Strategies to assess the integration of the instrument with the implant, the tissue environment and placement, the strength and durability are all factors to take into account when testing orthopedic instruments. The most common test strategy utilized for orthopedic instruments is usability testing coupled with a risk-based biocompatibility assessment. This approach can allow for the most accurate assessment of the instruments with respect to safety and effectiveness.
Olson: The horizontal guidance documents and standards for devices can still be leveraged to provide a basic direction for testing. Then, it is a matter of evaluating the device and its use to determine which risks are probable and create a test plan to look at those endpoints.
Barbella: How do you expect orthopedic device testing to evolve over the next five to 10 years?
Escobedo: Many other companies will be getting into the 3D orthopedic device space. Companies will have to show that the devices have the characteristics of a predicate device that was manufactured in a more traditional way. Characteristics in terms of strength, either tensile or compression, or cyclic loads as examples. If the device is custom the quantity manufactured could easily be just one. Clearly, we cannot perform destructive testing on that device. To determine that the device meets the required specifications, the test methods will have to be non-destructive. This will drive the need to be develop new test methods using various technologies to provide the information required for the device.
Giffin: Currently, the expected extractables testing that is performed on these types of devices is performed under exaggerated conditions (50°C for 72 hours) and then after those 72 hours the extract is measured and assessed. Using a specific example of pure metal alloy implants, it is possible that potential residuals remain on these devices which are expected to be eliminated by the patient within 30 days. However, when analyzed some of these residuals may be measured at or above the established limits of exposure. This then requires more testing and understanding as the limits for many elements and compounds are well established and accepted by many notified bodies. A more appropriate way of evaluating some of the devices may be to perform simulated use extractions, where the extractions are done at lower temperatures and sampled over consecutive days. This type of testing may be able to provide a more relevant data and provide better kinetic information as to how these residuals could reduce over time. In the future I can see more instances of simulated use testing being performed in order to better understand the actual patient exposure.
Olson: As with most devices, I think we will see in-vitro methods gain prominence as well as more chemical and materials evaluations to leverage non-animal alternatives. However, when animal safety and efficacy studies are performed, I believe we will see more efforts to leverage all of the possible data from each study.
Pohl: I would expect to see more additives that are embedded into the devices, especially if it is 3D printed. For example, we are seeing more cases of Vitamin E impregnated devices. I expect to see others as well.