Another top testing concern is how materials withstand different methods of sterilization, especially since the U.S. Food and Drug Administration (FDA) released its final guidance on “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling Guidance for Industry and Food and Drug Administration Staff” in March 2015. Even if their products were already cleared prior to this guidance, many medical device manufacturers (MDMs) are conducting additional testing to ensure their medical devices can meet these higher levels of scrutiny.
Overall, orthopedics is a fairly traditional market when it comes to designs, materials, and testing. MDMs are comfortable with traditional, tried-and-true measurement tools, such as hand tools, coordinate measurement machines (CMM), and optical comparators (OC) that have been around for decades. They have had success using these methods and do not want to create any uncertainty with the FDA by introducing new testing methods. However, some forward-thinking companies are taking notice of advanced dimensional quality inspection services and automated systems that provide much tighter pass/fail screens, resulting in higher-quality products.
What OEMs Want
Tests in high demand for orthopedic products are dose audits, bioburden testing, biocompatibility testing, materials compatibility testing (limits of reuse), low temperature sterilization validations, and human factors testing of devices. In the microbiological space, OEMs continue to request cleanliness evaluations using cytotoxicity and endotoxin analysis. Biological evaluation plans and chemical evaluation testing are frequently requested. The generation of wear debris is also a top concern, especially regarding the morphology and quantity of particulate released during testing.
“OEMs are looking for a set of tests and results that can be used to demonstrate compliance with global requirements and regulatory needs,” said Pamela Gwynn, principal engineer for health sciences for UL LLC, a Northbrook, Ill.-based provider of testing, certification, management system registration, and training services.
Speed to market is a critical factor for every device manufacturer. The trick is putting together a set of tests that are comprehensive and meet regulatory expectations, without over-testing, which adds time and cost. OEMs want faster turnarounds, particularly on projects that test validation for either new manufacturers or manufacturing changes. Test labs are often expected to be completed ahead of schedule in order to make up time from delays that can occur during the product development cycle.
“We use a custom scheduling system on our 90-plus test frames to find the best optimization of equipment and allow for last-minute, large-volume projects to help clients save time,” said Maciej Jakucki, department manager for medical device testing for Element, a Cincinnati, Ohio-based provider of mechanical, microbiological, materials, and packaging testing for the medical device industry.
Ryan Harper, business development director for Pacific BioLabs, a Hercules, Calif.-based contract research organization that provides microbiology, toxicology, and analytical chemistry testing, reports a significant increase in the number of reusable device reprocessing validation studies over the last three years. “Reprocessing has been a focus of the FDA since the 2015 outbreak at the Ronald Reagan UCLA Medical Center, where the root cause of the outbreak was identified as insufficient reprocessing procedures,” said Harper. “Shortly after the outbreak, the FDA updated its guidance on validating reprocessing instructions for reusable medical devices.”
Performing a risk assessment for safety of a medical device is becoming a requirement these days. It no longer makes sense to check box biocompatibility testing without knowing the true risk of the device, which is determined through material and process evaluations. “Once the risk is known, then we choose testing to mitigate risks that cannot be answered through these evaluations,” said Thor Rollins, consulting manager for Nelson Laboratories LLC, a Salt Lake City, Utah-based provider of microbiological testing. “The industry is just now starting to shift its paradigm toward other types of testing—for example, in-vitro and chemical testing.”
Other top requests from OEMs are biocompatibility testing, human factors testing on devices, and additional efficacy testing in low-temperature sterilization processes, such as hydrogen peroxide and ethylene oxide (EtO). “Concerning biocompatibility testing, many legacy devices may only have historically conducted a cytotoxicity test; however, the same device in 2017 may also require an irritation or sensitization study as well,” said Gary J. Socola, president of HIGHPOWER Validation Testing and Lab Services Inc., a Rochester, N.Y.-based provider of device cleaning, packaging, and sterilization validation services. “It is important that MDMs be familiar with the ISO 10993 series of biocompatibility standards.”
Chemistry and new in-vitro alternatives are a new trend in testing. Currently, medical devices are tested using animals to determine safety. This is an outdated and flawed approach since it relies on a single point and cannot accurately predict safety for any population group, ranging from adults to neonatals. These new tests are more accurate and also faster and cheaper compared to traditional animal models. For example, the in-vitro irritation test uses reconstituted human epidermis cells (RHE) to mimic the response that occurs in human skin. RHE cells are subjected to extracts of the medical devices and observed for negative impacts. This, combined with selected biochemical assays, can predict the irritation potential of the device.
An international “round robin” of in-vitro irritation testing was recently completed by more than 10 different labs, including Nelson Labs and the FDA. “This data is being analyzed by a biostatistician to determine if the method is robust enough and is also being compared to the animal model to determine if it’s a suitable substitute for the in vivo test,” said Rollins. “When I saw the results they looked very good; official results are due at any time.”
The hope, notes Rollins, is that the data is strong enough to compel the FDA to allow the test in lieu of animal testing. Besides saving animals, this approach also has the potential to be quicker and cheaper for MDMs. “The same effort is starting with the sensitization tests,” he added. “Even though there are end points that still need to be achieved with in vivo testing, I hope the industry will be able to use extractable and leachable testing and these potential in-vitro alternatives to replace the need for many of the animal tests that are currently done for medical devices—saving time, money, and animals.”
Advanced metrology equipment is also coming into the orthopedic space. For example, Level 3 Inspection, a Stuart, Fla.-based provider of advanced dimensional quality inspection services, has developed advanced equipment that provides 10,000 or more measurement points, finding smaller flaws standard equipment cannot detect that could become serious problems.
Most OEMs and suppliers are highly invested in decades-old traditional measurement methods and tools, including hand tools, CMMs, and OCs. These machines are not as precise as more advanced metrology systems on the market today. Newer equipment can provide advanced dimensional quality inspection services and automated systems for precision manufactured components—resulting in a much tighter screen for pass/failure.
For example, CMMs probe the surface in hundreds of points to gather XYZ coordinates of the touch points. The areas between these touch points, however, are not evaluated and can contain flaws that impact performance. If no variance shows between these touch points, both MDMs and the FDA assume continuity exists, which may not be an accurate conclusion.
“These assumptions inherent with traditional metrology sometimes allow non-conforming parts to escape into the marketplace and be implanted in patients,” said Bill Greene, CEO for Level 3 Inspection. “This can possibly lead to catastrophic failure of the implant, followed by revision surgery, and substantial financial settlements.”
There are, however, new technologies that can eliminate this risk. For example, Level 3 Inspection has built and patented its automated “Smart Inspection Station,” which allows high-speed and comprehensive dimensional inspection. The station tests the entire surface geometry with millions of data points at spacings as small as 5 to 7 microns if needed. This type of high-accuracy visualization leads to faster decision-making, less scrap, and months of time saved in optimizing precision manufacturing processes.
Greene indicates an overall cost savings of 20 to 30 percent is possible by using these methods through improved quality and performance (reduced failure) over the lifecycle of the product. This does not include money saved by reducing losses from potential litigation, or pain and suffering from patients.
Despite more accurate results, many MDMs are reluctant to invest in this technology because it could be viewed as disruptive by the FDA. According to Greene, when an orthopedic company uses modern metrology with 10,000-times more information and discovers that their parts are not quite as uniform as they had thought, they notify the FDA and the FDA halts production until every step of the process is requalified. “Therefore, when we work with orthopedic companies, we have been limited to new product introduction where there's no chance of upsetting legacy parts production and product sales,” said Greene.
Sterilization and Cleanliness
As devices become smaller and more complex, using new composite materials, new adhesives, and even 3D-printed parts, variables that may have had minimal effect on larger devices can have significant impacts on small devices. Good examples are complex structures with lumen or small internal areas that can be problematic with efficient extraction or cleaning processes.
Therefore, more complex testing methodologies are needed to challenge these devices under worst-case conditions in order to get them into the U.S. and European markets as quickly as possible. MDMs are often involved in the process, which may include having a complex device disassembled or even cut to test its worst-case locations. Validation laboratories are therefore challenged when trying to validate sterilization efficacy or device cleaning—especially complex devices with long narrow lumens.
“For biocompatibility and cleaning, very small devices may require larger sample sizes in order to meet the minimum requirements for some of these tests,” said Socola. “For example, a very small dental post may only have a surface area of 0.5 cm²—but in order to run the battery of biocompatibility tests on this device, the sample size may reach into hundreds of devices.”
“In terms of design and technology, more companies are taking into consideration how to clean, disinfect, and sterilize their device during the design stage,” added Harper. “The 2015 FDA guidance has made it more challenging for devices to pass the validation since the guidance recommends performing several reuse cycles before the validation to show that soil does not build up within or on the device over time. Soil buildup is something the FDA has seen on devices after many uses and would obviously affect patient safety.”
Electronics embedded in complex devices can also be a challenge for cleaning and sterilization. Steam sterilization is the preferred method of sterilization, but often complex devices cannot be exposed to steam because of the electronics they contain. These devices also cannot be submerged in disinfectants or liquids, making the disinfection process or cleaning process more challenging. Common reprocessing sterilization methods for reusable medical devices that cannot withstand high temperatures and moisture are ethylene oxide and hydrogen peroxide sterilization methods. For non-reusable medical devices, radiation methods such as gamma and e-beam are common. “However,” noted Harper, “all these methods affect electronics differently and these impacts should be considered when designing the device.”
Complex, multifunctional products may be regulated differently according to intended use. Regulations continue to evolve, which can make global acceptance more challenging. Cybersecurity and interoperability of devices are also top concerns for manufacturers. Testing for electronics embedded in medical devices also depends on expanding markets and how the device is used in or on the body. With the publication of requirements for both the home healthcare and emergency use environments, medical equipment destined for those environments may have additional testing requirements, such as voltage fluctuations, temperature and humidity differences, human factor (usability) considerations and electromagnetic capability differences.
“Although the 60601 series of standards is widely recognized for use around the globe, specific versions of the standard can vary from country to country,” noted Gwynn. “This difference can require manufacturers to demonstrate compliance with three different versions of the 60601-1 (Part 1) standard, for example—not to mention the various versions of the collateral and particular standards [that] may apply to the product.”
“Biocompatibility is another concern for various devices, including orthopedics,” said Rudy Pina, lab director for Dynatec Scientific Laboratories, an El Paso, Tex.-based provider of biocompatibility testing, sterility assurance, and cleanroom certifications. “Regardless of an orthopedic product’s classification as single-use or reusable, the FDA wants additional information to better understand the specific formulation of materials—for example, ultrahigh molecular weight polyethylene.”
One way to smooth the submission and approval process is by identifying a predicate and relevant data prior to starting the testing process. Understanding your indication and being able to find the right information using a literature review or side-by-side testing is critical to a project’s success (and a shortened timeline).
“We often see projects where this information is not available at the beginning, which can result in challenges during the FDA review,” said Jakucki. “We work with a variety of regulatory consultants, as well as leverage our in-house expertise to mitigate these risks for our clients. FDA also offers pre-submission meetings, which can add value to the project and submission plan. Manufacturers are more successful if they can start the project with an understanding of what is needed and appropriate FDA feedback.”
In June 2016, the FDA issued final guidance that clarifies and expands how manufacturers of medical devices that come into contact with the human body should comply with the ISO 10993-1 standard for biological evaluation of devices within risk management frameworks. FDA guidance on ISO 10993-1 compliance had not been updated since 1995; the new guidance makes several new recommendations regarding risk-based biocompatibility approaches, chemical assessment, and biocompatibility test article preparations for devices utilizing nanotechnology.
Tapping into the most current thinking of the FDA, and utilizing its pre-submission process to pre-screen new device validations and their associated test protocols, help streamline the submission process. Although this may not decrease the amount of required testing, or make testing of the device go any faster once it’s started, it will save time and money in the long run.
“By spending the time upfront to have the FDA review labeling and test methodologies prior to running the validations,” said Socola, “the MDM saves precious time on the back end of any 510(k) submission, especially if it avoids repeat testing that could be identified in an FDA Request for Additional Information letter.”
Think Testing First
Testing is an essential element in a successful product launch. Knowing which materials and processes work best for meeting product performance specifications and regulatory expectations early during the design process streamlines production, improves quality, and saves money. Testing protocols also tend to be a weak spot for engineers, so building a relationship with an experienced testing firm can answer many questions. Test labs are experienced with many different options and can often make recommendations on setups that help MDMs develop the most efficient and effective testing protocols.
“We don’t try to be design engineers, and we don’t expect our clients to be test engineers,” said Jakucki. “This is important when designing fixtures, understanding data acquisition, and machine control.”
Engineers can also make wrong assumptions about a process or a design element, especially if they are feeling hurried by a short timeline. Sometimes they are unsure how to approach investigation and compliance of devices that have unique characteristics, or constructions not addressed by the standard. They may believe that evaluation of these features and/or constructions cannot be accomplished—which is often not the case. “Working with a test house to understand the unique nature of the device and analyze the construction allows for development of requirements and test protocols to address the unique nature of the device,” said Gwynn.
Engineers may also underestimate the end-use environment. What does the device go through on a day-to-day basis within a central service department? Devices are exposed to a wide variety of chemicals used in disinfection and device cleaning. Without seeing it first hand, it’s hard for engineers to grasp the amount of abuse a typical device goes through during normal handling, decontamination, packaging, and sterilization. There is also the impact of the sterile storage and transport of devices to and from the operating room and the central service department, as well as the other environments the devices must pass through on their way to the hospital or surgery center.
“All these factors contribute to how well the device will hold up after multiple uses,” said Socola. “A limits-of-reuse study should be conducted, capturing at a minimum the cleaning and sterilization that a device is subjected to over time. Many engineers may lack an understanding of how microorganisms can withstand the decontamination and sterilization processes, or how a poorly designed device can be perfectly safe when used on a patient when it is new, but accumulate soil and grow harmful bacteria over time in areas that cannot effectively be cleaned and sterilized.”
Ultimately, developing a relationship with a trusted testing partner, and relying on its recommendations upfront during the design process, will lead to shorter, more cost-effective timelines and greater product success. This is especially true as orthopedic products become more complex.
“There are no short cuts when validating the cleaning, packaging, and sterilization of reusable medical devices—only challenges that require a dedicated staff with scientific minds that allow us to overcome these challenges,” added Socola.
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. Contact him at email@example.com