Rising regulatory focus on quality control for manufacturing plants, as well as on further safety, testing, and reporting measures necessitates advanced testing equipment and instrumentation in both manufacturing facilities and laboratories. As demand for excellent quality and standard products increases across the medical device industry, medical device manufacturers are expected to run an increasingly rigorous battery of tests to ensure a product’s safety and efficacy, among other factors. And sometimes, the resources necessary to run these tests aren’t within manufacturers’ realms of possibility in terms of the cost or time spent running the tests.

“When doing testing in-house, you have to keep in mind the initial cost of the equipment, the cost to maintain and calibrate the equipment, and the cost to retain people with the technical expertise to run the equipment and perform the testing,” advised Corey Hensel, general manager at DDL Inc., an Eden Prairie, Minn.-based full-service testing lab that provides package, product, and materials testing to the medical device industry.

In-house laboratory functions or equipment can precipitate relatively high fixed costs and capital investment, and expensive instrumentation purchased for in-house use runs the risk of being under utilized. As a result, many firms may turn to specialized organizations to perform the services or equipment required to test, inspect, and/or certify their products. In fact, manufacturers are deciding to partner with firms who provide testing services or equipment—a January 2017 Grand View Research report predicts the global medical device analytical testing outsourcing market to reach $8.3 billion by 2025.

Using a testing service provider has the potential to minimize business risks, hasten product market entry, and reduce costs. Furthermore, the complex medical device manufacturing ecosystem necessitates equipment to provide extremely accurate results, have durability, and be easy to operate. But it can be complicated to determine precisely which aspects of the testing process to outsource, or even if they should be at all.

“The primary factor involved in deciding whether or not to outsource device testing is in-house capacity,” commented Dennis Buchanan, engineering manager at Empirical Testing, one member of the Colorado Springs, Colo.-based family of Empirical companies, which provide a full range of regulatory and quality systems consulting, testing, small batch and prototype manufacturing, and validations services to bring a medical device to market. “Can the internal lab meet the project timeline based on overall company priorities, which may conflict? This is especially true of larger companies with multiple divisions or product lines that utilize the same lab.”

“Building and maintaining a qualified testing laboratory with qualified instruments can be expensive in terms of real cost and opportunity cost,” offered Nancy DiGiulio, vice president of Toxikon Corporation, a Bedford, Mass.-based preclinical contract research organization (CRO) providing in vivo, in-vitro, and analytical testing services for the pharmaceutical, biotechnology, and medical device industries. “Instruments must be purchased, validated, and calibrated. Quality systems, animal welfare programs (if applicable), and other regulatory requirements must be established. Standard operating procedures, protocols, and other quality documents must be implemented as part of a quality management system (QMS). Conducting a successful testing program takes significant resources and operational focus. Will it be more effective for the manufacturer to develop this capability, or will it be more efficient to use a CRO?”

Since time and cost are the main pain points device manufacturers encounter in their device testing, logic would follow to hand most or all of the testing work to an experienced firm. Unfortunately, it’s not that simple. “Medical device testing” is not a catch-all that can be completely passed off to another firm. It can be further broken down into segments like extractable and leachable, material characterization, physical testing, bioburden testing, sterility testing, among many others. As if matters weren’t complicated enough, some of those tests may make more sense to perform in-house, and others to hand off to a specialized firm.

“Some tests may make sense to have in-house as the difference in turnaround time is minimal,” noted Thor Rollins, B.S. RM(NRCM), director of toxicology and E&L consulting at Nelson Laboratories, a Sotera Health LLC company located in Salt Lake City, Utah, that provides full lifecycle microbiology testing services for the medical device, pharmaceutical, tissue, and natural products industries. “Tests without large volumes can have lengthy turnaround times when conducted in-house compared to outsourcing.”

“Most manufacturers want to keep development testing in-house and are more inclined to outsource regulatory testing once a design is frozen,” explained Buchanan. “Performing development testing in-house helps minimize cost and timing, and allows the product development engineers real-time access to test results to make decisions. Outsourcing final product regulatory testing can also help minimize cost and sometimes timing. By outsourcing regulatory testing, the in-house lab capacity can focus on development testing. Also, outsourcing the regulatory testing is typically clearly defined as well as associated costs and timeline.”

For example, OEMs may prefer to keep metrology and part inspection in-house, rather than contracting it out. In order to accomplish that, they may choose to equip their own laboratories with precision measuring tools and instruments. Further, manufacturers may seek to perform more measurements as close as possible to the machine tool making the parts. This has the potential to save time—there’s no need to wait for the quality lab to make measurements if shop-floor operators are making them.

As a result, metrology technology companies are refining their hardware to operate faster and be robust enough to work in the shop environment, either in-line or in-process. These companies are also tweaking their software to accomplish more automatically, while providing important information from the shop floor to the C-suite. One area where this is becoming prevalent is the orthopedic implant market.

“We have several successful installations globally with some of the largest orthopedic implant manufacturers,” commented Michael Bertelli, technology manager, metrology equipment for The L.S. Starrett Company, an Athol, Mass.-based global manufacturer of precision measuring tools and gages, metrology systems, custom engineered granite solutions, custom gaging, force and hardness testing solutions, and more. “Recently, we have noticed an increase with orthopedic knee inspection. The requirements on the floor are to measure non-standard geometry with our systems and software, which is achieved with a 2D profile fit algorithm. This can be a free-form profile fit or a fit result constrained to a datum structure per the manufacturer’s drawing and inspection plan. This profile fitting software can be utilized on a variety of our video-based systems. With the right application, the profile inspection process can be automated of the condyle surfaces of a knee.”

Moving from the time and cost of performing medical device testing, OEMs may also not have personnel with the right set of experiences. If a company seeks to make a long-term investment in device testing, it may make sense to hire staff who are experienced in that particular area. But this naturally produces cost tradeoffs—the time spent training this new staff will lengthen the time-to-market for any product still in development.

“Testing programs are successful when directed by trained, experienced, and qualified personnel,” explained DiGiulio. “Subject matter experts play a critical role in assessing product development needs, test requirements, and study designs. An experienced staff brings real benefits from speed of data analysis, operational efficiencies, enhanced reliability, the ability to support data reviews, and numerous other intangibles. Will the manufacturer be committed to the ongoing recruiting and development of these specialized roles?”

When utilizing a specialized firm for testing, these subject matter experts are precisely what OEMs are granted access to. But even then, there must be consideration paid to “the required test methods and confidence in the lab’s capability and experience in performing the required testing,” Buchanan said. “The only way to establish confidence in a lab’s capabilities is through on-site audits and experience/relationship with the lab and their key personnel.”

Finally, the U.S. Food and Drug Administration’s (FDA) perspective on results generated by the device maker itself versus that of a third-party testing provider is important to take into account. Though it is assumed no one is skewing results in favor of passing tests, an outsider’s results may be more palatable to a regulatory body simply because they’re not as closely tied to the device as the manufacturer.

“Another consideration is with impartiality,” noted Rollins. “It is often beneficial to have an independent lab involved when performing validation tests in order to have some separation from the results.”

“Consider whether regulatory bodies look more favorably upon tests conducted by reliable third parties versus in-house test results,” added DiGiulio. “Using an external laboratory may remove testing bias, or the perception of testing bias, facilitating the path for regulatory approval.”

Expanding the Range of Possibilities
Medical device testing service providers are feeling the squeeze on two fronts. Increasingly stringent regulatory requirements precipitate more tests required, consequently prompting OEMs to ask more and more of their testing providers. Simultaneously, the newer materials, smaller parts, and electronics being used in modern healthcare equipment necessitates expansion of existing test methods as well as development of entirely new ones.

An expansion of test methods is impossible without corresponding innovation in the equipment and instrumentation used to perform the tests. Newer orthopedic technology, for example, is manufacturing the need for testing at far lower forces than ever before.

“Since the emergence of indication-specific extremity products, the need for low-force testing has increased significantly over the past three to five years,” noted Buchanan. “New testing equipment has allowed the capability to test at low forces (less than 100N) with confidence. The electromechanical test systems available now are definitely much more suited for low force testing than the typical servo-hydraulic test systems.”

The so-called “fourth industrial revolution” or “Industry 4.0” trend is also impacting the equipment used for device testing. Industry 4.0 is a catchy name for the current trend of automation and data exchange in manufacturing technologies. It may include technologies that leverage cyber-physical systems, the Internet of Things, cloud computing, and cognitive computing to create a “smart factory” capable of ultimately monitoring processes and making decentralized decisions. Testing and inspection is a crucial part of the process, and is at the top of OEMs’ wish lists for eventual full automation and testing service providers are responding in kind.

“Increased automation and interconnectivity between instruments and laboratory information management systems (LIMS) brings a real benefit of throughput, speed, and more accurate data reporting,” stated DiGiulio. “In some cases, we have doubled our capacity simply by adding advanced analytical equipment—with automation, the same staff levels can focus less on manual and repetitive tasks and more on value-added scientific activities.”

Biocompatibility testing has come under the microscope recently as well, thanks to last year’s changes in both European Medical Device Regulations (MDR) and the FDA guidance document for ISO 10993. The update was sorely needed—some of the biocompatibility tests are over 40 years old, and devices are only increasing in complexity. The changes to each set of regulations are relatively similar in that they stress a risk-based approach to biocompatibility testing as the new standard for the medical device industry and necessitate a more comprehensive plan to be put in place for biological evaluation.

“With regards to biocompatibility, there are new in-vitro alternatives on the horizon,” said Rollins. “New science and techniques as well as new applications of science for medical devices are allowing us to more effectively evaluate the safety of medical devices without using animals. These techniques include a new irritation test performed on Reconstructed Human Epidermis (RHE) cells, loop methods for thrombogenicity, and chemical analysis to evaluate systemic toxicity and genotoxicity. There is even a possibility of using chemical analysis to evaluate sensitization.”

The recent release of ASTM guidelines is also provoking the development of new testing methodologies and equipment. ASTM F3287-17, entitled “Standard Test Method for Nondestructive Detection of Leaks in Packages by Mass Extraction Method,” was released just last December. The guidelines speak specifically to detecting leaks in packaging. Leaks in medical product packages affect both quality and consumer safety. They can arise from imperfections in package material or the components designed to seal the package, allowing unwanted gases, liquids, or microbiological contaminants.

“The newest addition to the packaging testing services we offer is Mass Extraction Leak testing,” offered Wendy Mach, packaging section leader at Nelson Laboratories. “With the new publication of ASTM F3287 Dec. 2017, the ability to perform container closure testing with a non-destructive method is now available. This test method is highly sensitive and the test article is available for investigation if failures are detected. Another advantage includes the fast turnaround time—other container closure integrity test methods can take days to process, whereas a set of 30 units can be processed in less than 30 minutes with mass extraction.”

While updates to testing methodology or equipment may result from changes to regulatory guidelines or be affected by trends in medical technology, sometimes companies observe the equipment used for certain types of testing is becoming obsolete. For example, optical comparators—devices that apply the principles of optics to inspect manufactured parts—use overlays made of plastics like Mylar or vinyl to measure the dimensions and geometry of a part against prescribed limits. The problem is, these charts take up a lot of space, and can be expensive to store. They were in desperate need of a digital upgrade.

“We have been able to revolutionize the inspection method of using antiquated Mylar overlays,” explained Bertelli. “We have replaced these stacks of plastic sheets that are expensive to create, store, manage, calibrate, and replace with a digital overlay. These digital overlays are all electronically stored and managed within a company’s electronic storage protocol, eliminating the costs associated with physical Mylar charts.”

Digitizing this method of inspection aligns with Industry 4.0 trends, and minimizes human error even further during the testing process.

“We have seen the need in the market to transition from subjective inspection methods like Mylar overlays to more robust methods like collecting variable data on critical part geometry,” Bertelli continued. “Removing human influence is one critical step to controlling the manufacturing process. We typically achieve this level of control with 2D profile fitting software. This process allows the operators to inspect non-traditional geometries—like knee and hip implants—during various steps of manufacturing.”

Studying for Future Tests
The increasing complexity of medical device development and broader device diversity as years pass is only going to make testing more difficult, putting a greater strain on service providers and equipment manufacturers to stay ahead. Reliable and reproducible tests must still be possible for devices using cutting-edge materials, pharmaceutical products, embedded electronics, or any number of space-age innovations on the horizon.

“The increased complexity and broader diversity of medical devices is making testing more difficult,” said Hensel. “There are new materials, smaller parts, and more electronics in the newest devices. These changes require expansion of existing test methods and development of new ones. With the increased scrutiny of the safety and efficacy of the new devices, more robust validation of test methods is required.”

This evolution in medical technology and consequential increased focus on safety and efficacy imparts “the need for faster and more sensitive testing, which will be a driving force behind advancements in the testing industry,” commented Mach. “As methodologies becomes more sensitive, the determination of what defines acceptable levels through risk analysis will play a more prevalent role.”

Medical devices should be designed with the end in mind. Unfortunately, some factors that impact testing aren’t considered until the end of the design process, or even until just before clinical or regulatory submissions. For example, what if a certain material in the device doesn’t hold up to common disinfectants or sterilization processes? Medical device makers might not know about this until it’s too late, resulting in (another) reprocessing crisis. Testing firms should be consulted with during the design stage as a trusted partner.

Additionally, regulatory constraints won’t slow down—new guidelines for testing surface at the exponential level that new devices are introduced. To truly provide the partnership that OEMs need, independent laboratories must be cognizant of the latest guidelines, both in the United States and elsewhere.

“In the future, labs will have improved efficiency to increase responsiveness,” predicted Buchanan. “Device testing is the last piece of the puzzle required for regulatory submission and labs are typically pressured to make up for a blown timeline.”

“For independent labs to adequately meet device manufacturers’ needs, they will become proactive in developing ISO and ASTM standards,” Buchanan went on. “It will be necessary to have a thorough understanding of both domestic and international regulatory requirements as well as the capability to provide regulatory strategy and guidance.”

Breakthroughs in a number of areas in science are creating new tools and methods incorporated into the science of toxicology. Over the past decade, FDA scientists have made enormous efforts to upgrade their toxicology toolboxes, most recently taking shape in a “Predictive Toxicology Roadmap.” The document addresses areas that could benefit from improved predictivity, like identifying rare (“idiosyncratic,” as the FDA phrases it) toxicities or characterizing potential non-genotoxic carcinogens. It also outlines promising new technologies in the area of predictive toxicology, like microphysiological systems (tissues- or organs-on-a-chip) and in-vitro alternatives to help reduce the number of animal tests. The six-part framework aims to furnish new or enhanced FDA engagement in the science of toxicology, and could open up a realm of testing possibilities for the area.

“The FDA’s recently published Predictive Toxicology Roadmap will anticipate the future evolution of toxicology testing,” concluded DiGiulio. “Based on these changes, the medical device industry has been taking more time to understand their devices, with respect to the materials used in the manufacturing; chemicals introduced during manufacturing; and the duration, frequency, and conditions of use in both preclinical and clinical setting. Manufacturers are taking more time to understand the nature of the materials that they use, talking to suppliers when necessary, and seeking out any available test data that may be relevant to the overall safety evaluation. We believe that in the future, Risk Assessment evaluations may become more commonly used in clinical trials. Medical device manufacturers will work more with consulting partners to develop approaches that meet regulatory requirements efficiently and effectively.”