Mark Crawford, Contributing Writer03.03.22
Medical device testing remained steady during 2021. Testing needs by medical device manufacturers (MDMs) reflected the fluctuations in the medical/healthcare market as it continued to rebound from the COVID-19 slowdown. A good portion of the testing work in 2021 related to the need for European Medical Device Regulation (MDR) remediation requirements and the constantly evolving regulatory expectations within the extractables and leachables (E&L) space. However, labs have been limited in their ability to add more capacity due to delays and the lack of external resources and workers.
“We are bringing as much testing in-house as possible due to poor external testing vendors and long lead times,” said Jim Kasic, chairman and founder of Boulder iQ, a contract consulting firm that provides quality, product development, manufacturing, and contract EO sterilization services.
The increasing prevalence of chronic diseases, combined with the increased complexity and diversity of devices, has driven demand for specified equipment to test each component and function of the devices. “Changing and more complex regulations have also necessitated the need to validate equipment and processes,” said Matt Pasma, program manager for DDL, an Eden Prairie, Minn.-based provider of package, product, and materials testing for the medical device and pharmaceutical industries.
The prevalence of COVID-19 continues to present challenges to testing facilities, with many staff now working remotely and constant logistical challenges regarding sample delivery, supply issues, and MDMs putting their projects on hold. “A consolidation in third-party manufacturers [custom suppliers] has also added to supply chain disruption through inconsistent processes, discontinued inventory, and delays due to insufficient workforce,” Kasic added.
In fact, many companies are experiencing more supply chain disruptions now than they did during the height of the pandemic. MDMs are involving more staff, trusted supply chain partners, and even supply-chain consultants to find solutions.
“In the medical space, where the primary procurement lead has been the R&D engineer or engineering management, COVID-19 has brought an additional level of scrutiny to the supply chain,” said Maciej Jakucki, technical director for medical device testing for Element Materials Technology, a Cincinnati, Ohio-based provider of medical device testing and regulatory consulting services. “The number of master service and quality agreements that we are being asked for is much higher today, and they take time to process and often have legal involvement. Companies are looking for fewer, more reliable vendors and focusing on consolidating and leveraging their total spends.”
Despite these testing challenges, the pace of innovation is picking up dramatically. “COVID-19 demonstrated to all of us that medical products can be developed differently and, in some cases, faster,” said Lisa Olson, senior vice president of global laboratory operations for NAMSA, a medtech contract research organization that provides end-to-end development services. “We are seeing quicker iterations and improvements in devices and faster decision making on prototype development.”
Latest Trends
Two years after the escalation of the pandemic, COVID-19 continues to cause some ongoing shortages of reagents and materials, and may have had the effect of placing qualified, experienced scientists in higher demand. “Overall, testing volumes continue to increase, but this appears to be primarily attributable to changing regulatory requirements, rather than COVID-19,” said Taryn Meade, director of biological evaluation consulting for Jordi Labs, a Mansfield, Ma.-based full-service testing laboratory for medical device manufacturers.
One of the most frustrating parts of COVID-19 is the unreliability it has created in the supply chain—materials or components there one day are gone the next, with no firm date for them to be available again. This makes it virtually impossible to estimate reliable lead times.
“We never know when we place an order if we will have an issue with backorder,” said Don Tumminelli, technical manager for client services for HIGHPOWER Validation Testing & Lab Services, a Rochester, N.Y.-based provider of validation and testing services for the medical device industry. “These unknowns can affect turnaround times of projects. We have also been impacted by staffing shortages due to COVID-19 outbreaks with some of our partners and contract labs, which definitely slows down projects from time to time.”
Early in the pandemic, the focus of most testing shifted from the highly complex, minimally invasive types of devices to devices intended to manage the COVID-19 response. “While it was critical to respond to the global crisis, seeing the shift in focus from critical devices managing chronic disease or traumatic events to personal protective equipment, pulmonary support, and disposables reduced the focus on innovation,” said Olson.
“However, in the last six months, we have observed a renewed focus on devices that are really pushing medical innovation forward in areas like cardiology and neurology.”
Digital simulation and related validation are also on the rise. There is more demand for earlier R&D support using tools like finite element analysis and computational fluid dynamics to evaluate complex design situations; furthermore, heat transfer, fluid mechanics, materials science, electromagnetic interference, and wireless connectivity interactions must also be understood.
“The complex interactions between these components need to be modeled appropriately,” said Jakucki. “Digital simulation services have also expanded with cloud-based analyses, artificial intelligence and data science, and validated test standards for different medical components or implants.”
The needs for specialized equipment to test the functionality of devices continue to evolve to adapt to changes with regulations. “For instance, universal test systems designed to test drug delivery systems are improving capabilities and reducing lead times for testing these systems,” said Pasma. “The newer technology allows more control with increased measurement precision during each test.”
Changes to the Medical Devices Directive (MDD) and MDR, as well as changes to parts of ISO 10993-18:2020 (for example, replicates, analytical evaluation threshold, intensified extractions) have “created a tremendous amount of toxicology E&L testing necessary in the medical products industry,” said Kasic. “This has resulted in long lead times—for example, six months for a one-month test. Traditional biocompatibility testing is also backed up significantly.”
Such modifications transcend the written recommendations of relevant industry standards. “The FDA, in particular, continues to express evolving requirements for analytical sensitivity and method verification controls, and reduced tolerance for the uncertainty that is inherent within the extractables/leachables screening process,” said Meade.
The significantly increased testing volume resulting from changes in regulatory requirements, as well as evolving recommendations from the FDA around identification confidence in medical device screening studies, has created a need for greater automation and improved accuracy in compound identification. Jordi Labs is developing specialized software that aids the mass spectrometry identification process by automating certain portions of the process. “We have recently deployed the first phase of this software, and are optimistic about the expected gains in efficiency and accuracy of the data interpretation process,” added Meade.
What OEMs Want
Testing requirements are very project-specific, but overall, MDMs are seeking greater analytical precision, cleanroom conditions for delicate components and products, and improved packaging testing.
“We are seeing an increase in requests for force-testing solutions for packaging, as well as for information regarding options for various force-testing applications such as puncture testing, peel testing, and tensile testing,” said Jacob Morales, force division engineer for The L.S. Starrett Company, an Athol, Ma.-based manufacturer of precision measuring tools and gauges, force-testing solutions, and a wide range of metrology systems.
There is also significant demand for testing of syringes, auto-injectors, and especially medical connectors under the ISO 80369 standard. “We also perform a lot of testing for pre-filled syringes, auto-injectors, and pen injectors,” said Pasma. “The bulk of this testing is for physical and mechanical performance to measure attributes such as leakage, break loose, extrusion force, and deliverable volume as outlined in the ISO 11040 and ISO 11608 series of standards.”
Cleaning validations are also on the rise, due to upcoming stricter standards. “As the new cleaning standard AAMI ST98 is on its way to being published, there has been much speculation and anxiety in the industry regarding what to expect,” said Tumminelli. “Many MDMs fear the FDA will be retroactive and void older or existing studies when comparing to the new requirements. I do not believe this will be the case, unless an MDM’s study design is very far off from what is currently being done throughout the industry.”
New Advances and Approaches
The shutdown of several ethylene oxide (EO) sterilization facilities by the FDA in 2019-2020 reduced overall EO capacity in the U.S. To meet the high demand for EO, Boulder iQ provides outsourced process equivalency services for EO sterilization. Process equivalence demonstrates that two or more pieces or sets of equipment deliver the same validated sterilization process.
“The equipment does not need to be physically identical, but must be capable of running the processes within defined, validated process limits,” said Kasic. “Our new service includes rigorous internal procedures to conduct process equivalence from equipment in other facilities. This allows companies to easily transition to a new piece of equipment, switch sterilization vendors, or have more than one sterilization vendor.”
As industry and regulatory agencies gradually move away from animal testing toward a more risk-based approach, with a decrease in in-vivo models, the efficiency of testing will increase. The EU leads the trend in exploring other methods of biocompatibility testing to find alternatives to current ISO 10993-1 methods. “These newer methods may also eliminate the need for some materials/reagents that are increasingly difficult to obtain, and are costly,” said Tumminelli.
With the shift toward more analytical analysis—especially chemical characterization followed by risk assessments to put the data in context—the detection limits of instruments have become incredibly important. The expectation for quantitation continues to drive lower detection limits, with the belief that better quantitation and identification will allow far more effective safety assessments for patients. “However,” said Olson, “the device methods are all screening methods using extractions that elute chemicals in a far different pattern than well-designed APIs. We can see analytes at far lower levels than before, but understanding what they are and the risk they present is the next challenge.”
Inspection methods that provide faster and more reliable, sensitive, and traceable data are in high demand by MDMs as they try to improve efficiencies, reduce risk, streamline approvals, and control costs. Seal quality inspection is a critical step to ensure medical device package integrity. A leading seal quality test is airborne ultrasound technology, which tests seals with a quick, accurate, non-destructive, and non-invasive method that provides high levels of sensitivity and reliability. This is especially beneficial for Class III medical devices—implanted medical devices that are used to support life or prevent potential risk of illness or injury—which must retain their biocompatibility. Roughly 10 percent of all medical devices fall under this category. Airborne ultrasound is ideal for a wide range of material types, including Tyvek, paper, foil, film, aluminum, plastic, and poly.
“Airborne ultrasound technologies are non-subjective and provide MDMs with a highly accurate seal-testing solution that improves quality, throughput, and process control, while greatly reducing product waste and cost, as well as risks for defects and recalls,” said Oliver Stauffer, CEO of PTI Inspection Systems, a Hawthorne, N.Y.-based provider of non-destructive inspection technologies for the life science industries.
The process works by passing the pouch seal in a direct line between an ultrasonic transmitter and receiver. Ultrasound waves propagate through the package seal, causing the reflection of sound waves. Defects are identified by measuring the variation of the reflected signal strength.
“Airborne ultrasound pulses sound through the seal at 1,000 pulses per second,” continued Stauffer. “It can be used as an online or offline analytical tool. Advanced digital imaging software tools for process control provide in-depth seal quality analysis, including a pixel-by-pixel evaluation of seals in a high-resolution image that characterizes overall quality and uniformity of the seal.”
Internet of Things Connectivity
Everybody wants to see the data—whether it is the manufacturer looking for real-time results, the patient wearing a smart device, or the regulator who is reviewing a submission. How data is generated, connected, and protected is a key issue as MDMs invent a steady flow of increasingly complex wireless devices.
Jakucki attended CES in Las Vegas in January and was astonished by the amount of connected devices related to the medical space that were presented, especially wearables. Blood pressure, heart rate, electrocardiograms, respiratory rate, and stress distribution mapping were just a few of the wearables on display.
“These consumer electronics have connectivity and electrical requirements, but the validation of the effectiveness and accuracy of the ‘medical’ data are minimal,” said Jakucki, who had several conversations with the manufacturers about the testing and validations required for wearables and the pathway for evaluating them as medical devices. “Performing a clinical validation under the Institutional Review Board and evaluating patient data is very different than using another consumer electronic to say the product accuracy is within 95 percent of another device and therefore validated. Some of these companies are interested in taking the next step with their wearable and receiving clearance for a medical device, but uncertain about the regulatory pathway and the costs involved. There is a significant difference between a consumer electronic and a medical device.”
Additive Manufacturing
Additive manufacturing (AM) continues to bring new innovative medical devices to market. Material selection is a top consideration in this process. A durable, easy-to-use, non-brittle material is preferred; however, seeing how temperature and various environmental conditions affect these materials has created new challenges to the testing process. Just because an AM material is durable at room temperature does not mean it will last after an accelerated aging cycle or an environmental conditioning cycle where it is exposed to temperatures of 55-80°C or even extreme cold, which can cause devices and materials to act differently. All these factors (including testing) must be considered when selecting a material for AM.
Another reason AM needs to be qualified is because it introduces additional risk. The two main risk areas are the strength of the additive process and wear debris generated from the final product.
“New material is being created with every build, so going through an effective and functional IQ/OQ/PQ [installation qualification/operational qualification/performance qualification] process is critical,” said Jakucki. “On the product side, wear debris can come from impact, fatigue, or residual powder and needs to be minimized. Customers are asking for size and morphology evaluation on the nano scale to evaluate these risks.”
AM is also used to make parts that support the testing equipment.
“Specialized fixturing made with 3D printing to support samples in the tester can be more easily produced, and with the increasing quality of industrial grade 3D printing, those fixtures can be used for higher-capacity testing,” said Morales. “For 3D-printed medical devices, force testers can be used for testing 3D printing methods, such as infill, structure, layer height, setting temperature, to quality test usable equipment/parts produced with additive manufacturing.”
Healthcare systems and MDMs are keenly interested in bringing AM technology into the clinical setting—also called point-of-care manufacturing—so devices can be patient-specific and the supply chain greatly simplified. The FDA has put out several guidance documents and is soliciting questions to help MDMs and hospitals navigate these regulatory “gray” areas still being developed. 3D-printed guides and anatomic models have been implemented in the point-of-care setting and are becoming more common. “However, the quality system requirements a medical OEM is held to, compared to the general hospital operations, are quite different,” Jakucki added. “The challenge is getting hospitals to think about quality and risk like an MDM does. Hospitals need to implement the same scale of functional processes and checks—modified for point-of-care where relevant—and prove to FDA that they can reliably control the manufacturing process.”
Regulatory Challenges
Regulatory agencies are increasingly focused on the validation of test methods—especially the quality of data, including repeatability and reproducibility. There is also a shift toward more deterministic methods for testing. This allows companies to receive more statically sound data to evaluate if their products are conforming to the standard. These changes have brought about unique challenges in how tests are performed and how they are validated.
For example, the medical device industry and testing labs face significant challenges in implementing the E&L testing requirements of ISO 10993-18:2020, as well as meeting FDA expectations. Over the last year, the FDA has requested the utilization of increasing conservative measures to mitigate areas of uncertainty or potential inaccuracy within E&L testing.
“Since these expectations are not published in standards or guidance documents and are consistently evolving, meeting them has presented a challenge for the medical device industry,” said Meade. “Examples include requests for large uncertainty factors to mitigate the effects of variation in analytical instrument response, shifting requirements for sample preparation verification, and improved levels of organic compound identification confidence. In some cases, these expectations exceed the capability of current technology, given the limitations of instrument sensitivity, commercially available reference standards, and organic compound databases. Furthermore, for certain medical device types, the FDA has expressed reluctance to accept simulated use study designs, making a clinically relevant toxicity evaluation challenging.”
The latest revision of the accelerated aging protocol ASTM F1980-21, released in December 2021, has several primary changes that pertain to medical devices and the effect of moisture or lack thereof on their materials, especially during accelerated aging. “Historically,” said Mark Escobedo, senior sales engineer for WESTPAK, a San Jose, Calif.-based independent test laboratory specializing in product and package testing for medical devices, “the protocol has primarily been focused on packaging, with the product being secondary; however, now ASTM F1980-21 brings them both into primary focus.”
The new revision stresses 1) the importance of knowing the potential moisture driven degradation mechanisms of all materials, 2) the effect of dry accelerated aging conditions [low relative humidity (RH) levels] on the product, and 3) the possibility of drying out materials—primarily polymers and adhesives used in the product—to moisture levels lower than likely to be experienced during real-time aging. Information is also provided on the use of humidity on products and the shelf stability of a sterile barrier system.
“F1980-21 allows for controlled humidity during aging studies,” added Escobedo. This will be product-focused and pertain to only a small number of products. Manufacturers will need to rely on the datasheets provided by the vendor to determine material sensitivity. “For materials needing controlled RH, the new revision suggests targeting a range of 45 percent to 55 percent RH unless material data suggest a higher or lower level,” said Escobedo. “The rationale for controlled or uncontrolled RH conditions should be documented.”
Moving Forward
MDMs often ask testing labs to do the impossible, especially short turnarounds within unrealistic time periods. Only so much speeding up can be accomplished—some tests simply take the time they take. For example, an in-life period test of 14 days will still take 14 days.
With any testing project, the earlier an MDM starts, the better.
“Safety testing is typically the last step before a submission, which means that it is usually subject to all of the earlier delays,” said Olson. “Plan for enough time. Assume that there could be results that require investigation and start your testing as soon as you get to design and process lock.”
OEMs sometimes consider doing testing in-house to save money or time. Before doing this, they should complete a careful assessment of total cost, including the equipment and costs for equipment maintenance, calibration, extra staffing, and training. Time is also a critical aspect to consider, especially if a test needs to be completed quickly in order to meet a deadline.
“For most MDMs, it is still more cost-efficient in the long run to outsource their testing,” said Pasma. “Having a third-party lab perform testing also provides a more independent and less biased view of the data.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books.
“We are bringing as much testing in-house as possible due to poor external testing vendors and long lead times,” said Jim Kasic, chairman and founder of Boulder iQ, a contract consulting firm that provides quality, product development, manufacturing, and contract EO sterilization services.
The increasing prevalence of chronic diseases, combined with the increased complexity and diversity of devices, has driven demand for specified equipment to test each component and function of the devices. “Changing and more complex regulations have also necessitated the need to validate equipment and processes,” said Matt Pasma, program manager for DDL, an Eden Prairie, Minn.-based provider of package, product, and materials testing for the medical device and pharmaceutical industries.
The prevalence of COVID-19 continues to present challenges to testing facilities, with many staff now working remotely and constant logistical challenges regarding sample delivery, supply issues, and MDMs putting their projects on hold. “A consolidation in third-party manufacturers [custom suppliers] has also added to supply chain disruption through inconsistent processes, discontinued inventory, and delays due to insufficient workforce,” Kasic added.
In fact, many companies are experiencing more supply chain disruptions now than they did during the height of the pandemic. MDMs are involving more staff, trusted supply chain partners, and even supply-chain consultants to find solutions.
“In the medical space, where the primary procurement lead has been the R&D engineer or engineering management, COVID-19 has brought an additional level of scrutiny to the supply chain,” said Maciej Jakucki, technical director for medical device testing for Element Materials Technology, a Cincinnati, Ohio-based provider of medical device testing and regulatory consulting services. “The number of master service and quality agreements that we are being asked for is much higher today, and they take time to process and often have legal involvement. Companies are looking for fewer, more reliable vendors and focusing on consolidating and leveraging their total spends.”
Despite these testing challenges, the pace of innovation is picking up dramatically. “COVID-19 demonstrated to all of us that medical products can be developed differently and, in some cases, faster,” said Lisa Olson, senior vice president of global laboratory operations for NAMSA, a medtech contract research organization that provides end-to-end development services. “We are seeing quicker iterations and improvements in devices and faster decision making on prototype development.”
Latest Trends
Two years after the escalation of the pandemic, COVID-19 continues to cause some ongoing shortages of reagents and materials, and may have had the effect of placing qualified, experienced scientists in higher demand. “Overall, testing volumes continue to increase, but this appears to be primarily attributable to changing regulatory requirements, rather than COVID-19,” said Taryn Meade, director of biological evaluation consulting for Jordi Labs, a Mansfield, Ma.-based full-service testing laboratory for medical device manufacturers.
One of the most frustrating parts of COVID-19 is the unreliability it has created in the supply chain—materials or components there one day are gone the next, with no firm date for them to be available again. This makes it virtually impossible to estimate reliable lead times.
“We never know when we place an order if we will have an issue with backorder,” said Don Tumminelli, technical manager for client services for HIGHPOWER Validation Testing & Lab Services, a Rochester, N.Y.-based provider of validation and testing services for the medical device industry. “These unknowns can affect turnaround times of projects. We have also been impacted by staffing shortages due to COVID-19 outbreaks with some of our partners and contract labs, which definitely slows down projects from time to time.”
Early in the pandemic, the focus of most testing shifted from the highly complex, minimally invasive types of devices to devices intended to manage the COVID-19 response. “While it was critical to respond to the global crisis, seeing the shift in focus from critical devices managing chronic disease or traumatic events to personal protective equipment, pulmonary support, and disposables reduced the focus on innovation,” said Olson.
“However, in the last six months, we have observed a renewed focus on devices that are really pushing medical innovation forward in areas like cardiology and neurology.”
Digital simulation and related validation are also on the rise. There is more demand for earlier R&D support using tools like finite element analysis and computational fluid dynamics to evaluate complex design situations; furthermore, heat transfer, fluid mechanics, materials science, electromagnetic interference, and wireless connectivity interactions must also be understood.
“The complex interactions between these components need to be modeled appropriately,” said Jakucki. “Digital simulation services have also expanded with cloud-based analyses, artificial intelligence and data science, and validated test standards for different medical components or implants.”
The needs for specialized equipment to test the functionality of devices continue to evolve to adapt to changes with regulations. “For instance, universal test systems designed to test drug delivery systems are improving capabilities and reducing lead times for testing these systems,” said Pasma. “The newer technology allows more control with increased measurement precision during each test.”
Changes to the Medical Devices Directive (MDD) and MDR, as well as changes to parts of ISO 10993-18:2020 (for example, replicates, analytical evaluation threshold, intensified extractions) have “created a tremendous amount of toxicology E&L testing necessary in the medical products industry,” said Kasic. “This has resulted in long lead times—for example, six months for a one-month test. Traditional biocompatibility testing is also backed up significantly.”
Such modifications transcend the written recommendations of relevant industry standards. “The FDA, in particular, continues to express evolving requirements for analytical sensitivity and method verification controls, and reduced tolerance for the uncertainty that is inherent within the extractables/leachables screening process,” said Meade.
The significantly increased testing volume resulting from changes in regulatory requirements, as well as evolving recommendations from the FDA around identification confidence in medical device screening studies, has created a need for greater automation and improved accuracy in compound identification. Jordi Labs is developing specialized software that aids the mass spectrometry identification process by automating certain portions of the process. “We have recently deployed the first phase of this software, and are optimistic about the expected gains in efficiency and accuracy of the data interpretation process,” added Meade.
What OEMs Want
Testing requirements are very project-specific, but overall, MDMs are seeking greater analytical precision, cleanroom conditions for delicate components and products, and improved packaging testing.
“We are seeing an increase in requests for force-testing solutions for packaging, as well as for information regarding options for various force-testing applications such as puncture testing, peel testing, and tensile testing,” said Jacob Morales, force division engineer for The L.S. Starrett Company, an Athol, Ma.-based manufacturer of precision measuring tools and gauges, force-testing solutions, and a wide range of metrology systems.
There is also significant demand for testing of syringes, auto-injectors, and especially medical connectors under the ISO 80369 standard. “We also perform a lot of testing for pre-filled syringes, auto-injectors, and pen injectors,” said Pasma. “The bulk of this testing is for physical and mechanical performance to measure attributes such as leakage, break loose, extrusion force, and deliverable volume as outlined in the ISO 11040 and ISO 11608 series of standards.”
Cleaning validations are also on the rise, due to upcoming stricter standards. “As the new cleaning standard AAMI ST98 is on its way to being published, there has been much speculation and anxiety in the industry regarding what to expect,” said Tumminelli. “Many MDMs fear the FDA will be retroactive and void older or existing studies when comparing to the new requirements. I do not believe this will be the case, unless an MDM’s study design is very far off from what is currently being done throughout the industry.”
New Advances and Approaches
The shutdown of several ethylene oxide (EO) sterilization facilities by the FDA in 2019-2020 reduced overall EO capacity in the U.S. To meet the high demand for EO, Boulder iQ provides outsourced process equivalency services for EO sterilization. Process equivalence demonstrates that two or more pieces or sets of equipment deliver the same validated sterilization process.
“The equipment does not need to be physically identical, but must be capable of running the processes within defined, validated process limits,” said Kasic. “Our new service includes rigorous internal procedures to conduct process equivalence from equipment in other facilities. This allows companies to easily transition to a new piece of equipment, switch sterilization vendors, or have more than one sterilization vendor.”
As industry and regulatory agencies gradually move away from animal testing toward a more risk-based approach, with a decrease in in-vivo models, the efficiency of testing will increase. The EU leads the trend in exploring other methods of biocompatibility testing to find alternatives to current ISO 10993-1 methods. “These newer methods may also eliminate the need for some materials/reagents that are increasingly difficult to obtain, and are costly,” said Tumminelli.
With the shift toward more analytical analysis—especially chemical characterization followed by risk assessments to put the data in context—the detection limits of instruments have become incredibly important. The expectation for quantitation continues to drive lower detection limits, with the belief that better quantitation and identification will allow far more effective safety assessments for patients. “However,” said Olson, “the device methods are all screening methods using extractions that elute chemicals in a far different pattern than well-designed APIs. We can see analytes at far lower levels than before, but understanding what they are and the risk they present is the next challenge.”
Inspection methods that provide faster and more reliable, sensitive, and traceable data are in high demand by MDMs as they try to improve efficiencies, reduce risk, streamline approvals, and control costs. Seal quality inspection is a critical step to ensure medical device package integrity. A leading seal quality test is airborne ultrasound technology, which tests seals with a quick, accurate, non-destructive, and non-invasive method that provides high levels of sensitivity and reliability. This is especially beneficial for Class III medical devices—implanted medical devices that are used to support life or prevent potential risk of illness or injury—which must retain their biocompatibility. Roughly 10 percent of all medical devices fall under this category. Airborne ultrasound is ideal for a wide range of material types, including Tyvek, paper, foil, film, aluminum, plastic, and poly.
“Airborne ultrasound technologies are non-subjective and provide MDMs with a highly accurate seal-testing solution that improves quality, throughput, and process control, while greatly reducing product waste and cost, as well as risks for defects and recalls,” said Oliver Stauffer, CEO of PTI Inspection Systems, a Hawthorne, N.Y.-based provider of non-destructive inspection technologies for the life science industries.
The process works by passing the pouch seal in a direct line between an ultrasonic transmitter and receiver. Ultrasound waves propagate through the package seal, causing the reflection of sound waves. Defects are identified by measuring the variation of the reflected signal strength.
“Airborne ultrasound pulses sound through the seal at 1,000 pulses per second,” continued Stauffer. “It can be used as an online or offline analytical tool. Advanced digital imaging software tools for process control provide in-depth seal quality analysis, including a pixel-by-pixel evaluation of seals in a high-resolution image that characterizes overall quality and uniformity of the seal.”
Internet of Things Connectivity
Everybody wants to see the data—whether it is the manufacturer looking for real-time results, the patient wearing a smart device, or the regulator who is reviewing a submission. How data is generated, connected, and protected is a key issue as MDMs invent a steady flow of increasingly complex wireless devices.
Jakucki attended CES in Las Vegas in January and was astonished by the amount of connected devices related to the medical space that were presented, especially wearables. Blood pressure, heart rate, electrocardiograms, respiratory rate, and stress distribution mapping were just a few of the wearables on display.
“These consumer electronics have connectivity and electrical requirements, but the validation of the effectiveness and accuracy of the ‘medical’ data are minimal,” said Jakucki, who had several conversations with the manufacturers about the testing and validations required for wearables and the pathway for evaluating them as medical devices. “Performing a clinical validation under the Institutional Review Board and evaluating patient data is very different than using another consumer electronic to say the product accuracy is within 95 percent of another device and therefore validated. Some of these companies are interested in taking the next step with their wearable and receiving clearance for a medical device, but uncertain about the regulatory pathway and the costs involved. There is a significant difference between a consumer electronic and a medical device.”
Additive Manufacturing
Additive manufacturing (AM) continues to bring new innovative medical devices to market. Material selection is a top consideration in this process. A durable, easy-to-use, non-brittle material is preferred; however, seeing how temperature and various environmental conditions affect these materials has created new challenges to the testing process. Just because an AM material is durable at room temperature does not mean it will last after an accelerated aging cycle or an environmental conditioning cycle where it is exposed to temperatures of 55-80°C or even extreme cold, which can cause devices and materials to act differently. All these factors (including testing) must be considered when selecting a material for AM.
Another reason AM needs to be qualified is because it introduces additional risk. The two main risk areas are the strength of the additive process and wear debris generated from the final product.
“New material is being created with every build, so going through an effective and functional IQ/OQ/PQ [installation qualification/operational qualification/performance qualification] process is critical,” said Jakucki. “On the product side, wear debris can come from impact, fatigue, or residual powder and needs to be minimized. Customers are asking for size and morphology evaluation on the nano scale to evaluate these risks.”
AM is also used to make parts that support the testing equipment.
“Specialized fixturing made with 3D printing to support samples in the tester can be more easily produced, and with the increasing quality of industrial grade 3D printing, those fixtures can be used for higher-capacity testing,” said Morales. “For 3D-printed medical devices, force testers can be used for testing 3D printing methods, such as infill, structure, layer height, setting temperature, to quality test usable equipment/parts produced with additive manufacturing.”
Healthcare systems and MDMs are keenly interested in bringing AM technology into the clinical setting—also called point-of-care manufacturing—so devices can be patient-specific and the supply chain greatly simplified. The FDA has put out several guidance documents and is soliciting questions to help MDMs and hospitals navigate these regulatory “gray” areas still being developed. 3D-printed guides and anatomic models have been implemented in the point-of-care setting and are becoming more common. “However, the quality system requirements a medical OEM is held to, compared to the general hospital operations, are quite different,” Jakucki added. “The challenge is getting hospitals to think about quality and risk like an MDM does. Hospitals need to implement the same scale of functional processes and checks—modified for point-of-care where relevant—and prove to FDA that they can reliably control the manufacturing process.”
Regulatory Challenges
Regulatory agencies are increasingly focused on the validation of test methods—especially the quality of data, including repeatability and reproducibility. There is also a shift toward more deterministic methods for testing. This allows companies to receive more statically sound data to evaluate if their products are conforming to the standard. These changes have brought about unique challenges in how tests are performed and how they are validated.
For example, the medical device industry and testing labs face significant challenges in implementing the E&L testing requirements of ISO 10993-18:2020, as well as meeting FDA expectations. Over the last year, the FDA has requested the utilization of increasing conservative measures to mitigate areas of uncertainty or potential inaccuracy within E&L testing.
“Since these expectations are not published in standards or guidance documents and are consistently evolving, meeting them has presented a challenge for the medical device industry,” said Meade. “Examples include requests for large uncertainty factors to mitigate the effects of variation in analytical instrument response, shifting requirements for sample preparation verification, and improved levels of organic compound identification confidence. In some cases, these expectations exceed the capability of current technology, given the limitations of instrument sensitivity, commercially available reference standards, and organic compound databases. Furthermore, for certain medical device types, the FDA has expressed reluctance to accept simulated use study designs, making a clinically relevant toxicity evaluation challenging.”
The latest revision of the accelerated aging protocol ASTM F1980-21, released in December 2021, has several primary changes that pertain to medical devices and the effect of moisture or lack thereof on their materials, especially during accelerated aging. “Historically,” said Mark Escobedo, senior sales engineer for WESTPAK, a San Jose, Calif.-based independent test laboratory specializing in product and package testing for medical devices, “the protocol has primarily been focused on packaging, with the product being secondary; however, now ASTM F1980-21 brings them both into primary focus.”
The new revision stresses 1) the importance of knowing the potential moisture driven degradation mechanisms of all materials, 2) the effect of dry accelerated aging conditions [low relative humidity (RH) levels] on the product, and 3) the possibility of drying out materials—primarily polymers and adhesives used in the product—to moisture levels lower than likely to be experienced during real-time aging. Information is also provided on the use of humidity on products and the shelf stability of a sterile barrier system.
“F1980-21 allows for controlled humidity during aging studies,” added Escobedo. This will be product-focused and pertain to only a small number of products. Manufacturers will need to rely on the datasheets provided by the vendor to determine material sensitivity. “For materials needing controlled RH, the new revision suggests targeting a range of 45 percent to 55 percent RH unless material data suggest a higher or lower level,” said Escobedo. “The rationale for controlled or uncontrolled RH conditions should be documented.”
Moving Forward
MDMs often ask testing labs to do the impossible, especially short turnarounds within unrealistic time periods. Only so much speeding up can be accomplished—some tests simply take the time they take. For example, an in-life period test of 14 days will still take 14 days.
With any testing project, the earlier an MDM starts, the better.
“Safety testing is typically the last step before a submission, which means that it is usually subject to all of the earlier delays,” said Olson. “Plan for enough time. Assume that there could be results that require investigation and start your testing as soon as you get to design and process lock.”
OEMs sometimes consider doing testing in-house to save money or time. Before doing this, they should complete a careful assessment of total cost, including the equipment and costs for equipment maintenance, calibration, extra staffing, and training. Time is also a critical aspect to consider, especially if a test needs to be completed quickly in order to meet a deadline.
“For most MDMs, it is still more cost-efficient in the long run to outsource their testing,” said Pasma. “Having a third-party lab perform testing also provides a more independent and less biased view of the data.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. His clients range from startups to global manufacturing leaders. He also writes a variety of feature articles for regional and national publications and is the author of five books.