Keeping Pace

Keeping Pace

Biocompatibility testing must innovate to stay in step with new medical technology.

Mark Crawford • Contributing Writer

Understanding how materials and structural designs affect the biocompatibility of a medical device must be considered at the point of device conceptualization. This especially is true as devices become smaller, more complex and more multi-functional.

“True assessment of the biocompatibility of an orthopedic device can’t just be reduced to its constituent material components,” said James Fentress, product development engineer for Research Triangle Park, N.C.-based Gilero Biomedical, a provider of device design and development services for the medical device industry. “Two orthopedic devices made from identical materials, but implanted in different locations in the body (experiencing differing device loadings) may not have the same biocompatibility. For other devices like IV sets, a more reductive approach can be used where the devices are constructed using materials known to be biocompatible based on prior similar experience.”

More complexity also brings increased scrutiny from the U.S. Food and Drug Administration (FDA) and other agencies—especially in Europe—that are expanding their requirements for biocompatibility testing. The requirements include more complete biocompatibility panels as well as chemical characterization of the product.

Several years ago manufacturers were allowed to perform limited biocompatibility panels and refer to the history of use of their selected materials—now, however, programs are expected to be more comprehensive.

“For example,” said Lisa Olson, vice president of testing and service development for WuXi AppTec, a China-based contract research organization with facilities in Minneapolis, Minn., Atlanta, Ga., and Philadelphia, Pa., that provide in-vitro and in-vivo biocompatibility testing, “now more implant time points must include short-, mid- and long-term time points or more genotoxicology testing. This requires more test articles and, more importantly, additional time to complete.”

The same holds true for materials characterization. Olson noted that U.S. Pharmacopeia Chapter 661 used to be sufficient for providing information on material chemistry and biocompatibility, but more extensive extractables and leachables testing is being required.

Bone contact device biocompatibility testing also has become more extensive. Agencies in the U.S., Europe and Asia are requiring full ISO 10993-biocompatibility standard testing for orthopedic bone contact devices.

Today, regulatory agencies such as the U.S. Food and Drug Administration want more analytical information, especially regarding materials. Photo courtesy of NAMSA.

“In the past, device manufacturers used to be able to comply with just subcutaneous testing for implant data,” said Don Palme, senior principal scientist with Minneapolis, Minn.-based NAMSA, a global contract research organization that provides compliance services to the medical device industry. “Now agencies want more analytical work, especially regarding materials and concentrations—for example, not only concentrations of carriers but also exhaustive extraction studies looking for materials that may elute from a device.”

“Medical OEMs are beginning to demand validated processes for coatings that have been tested to biocompatibility standards such as the USP Class VI criteria,” said John Kalinowski, account manager-technical sales at The Electrolizing Corporation of Ohio in Cleveland, which provides metal finishing and coatings for the medical device industry. “This testing does not replace the need to complete their own FDA certification to ISO 10993, but it can greatly simplify their efforts because of some overlap in testing requirements.”

Innovation Design = Innovative Testing
New innovations in orthopedic devices are forcing regulatory agencies and biocompatibility testers to adjust their biocompatibility methods and requirements to make certain that new device designs, materials and functions do not cause health problems.

“For example, with orthopedic devices, design efforts for new devices tend to focus on improvements in bone growth around an implant, bone growth into the implant, or even resorbable implants, where the implant itself is supplanted with native tissue over time,” said Fentress. “Depending on the variety of specific methodologies used to accomplish these improvements, each may require a different approach for assessing biocompatibility.”

“Customers are requiring more combination studies, such as toxicology with implant end points,” added Palme. “This may require different study designs and protocols. Combination products can also be more complicated to test because there is a device part and a drug part, and each one has a different FDA guide that needs to be followed.”

A number of combination products, where a biologic or drug is combined with the orthopedic implant, are designed to promote the growth or reclamation of bone. Because a drug or biologic is intrinsic to the device, the assessment of its safety, including relevant effects on biocompatibility, no longer are limited to device effects alone. This usually means that the complete preclinical assessment of device safety follows a dual route, assessing the localized and systemic effect of the drug/biologic delivery and the biocompatibility of the device. In the earlier stages these two issues are assessed separately; however, a final assessment of the ultimate device also must be done.

This can be a bit tricky because the pharmaceutical safety of the drug/biologic must be understood, not only from a systemic point of view but also from a local perspective—where it is in the body. If a drug is used in the combination device, the rate of elution of the drug from the device must be understood, as well as the kinds of effects the eluting drug may have in the area of implantation. Sometimes the challenge is that the device design will have a direct effect on this rate of elution, such as the level of porosity intrinsic to the eluting surfaces, or the rate of device resorption (for example, when a resorbable implant contains an active pharmaceutical).

Another reason novel devices may require different biocompatibility approaches concerns the properties of the materials, especially newer materials that have less history behind them.

“Many materials that are generally well understood to be biocompatible in bulk form, no longer are when they begin to wear,” said Fentress. “This requires testing in the lab to assess wear under expected device loading, followed by animal tests and later, human subjects.”

Laboratory testing analyzes the wear of the devices based on expected forces and number of repetitions, occasionally using existing devices or materials as controls. Understanding the wear behavior of new designs is necessary before advancing to animal models. For truly novel materials, a staged approach may be required. First, comparably inexpensive testing can be done with the material, such as testing the fundamental biocompatibility properties of the bulk material (cytotoxicology and sensitization, for example). Any material that fails to pass this more fundamental testing generally would not be considered suitable for use in an implant. This data then could be coupled with laboratory mechanical testing to justify appropriate testing in an animal model.

The wear properties of the device always should be understood prior to conducting further testing, especially the way wear particulates from a device potentially may generate an immunological response from the host. “Though not directly related to biocompatibility, the wear of resorbable implants, in addition to their natural resorption rate, directly affects the structure of the devices,” said Fentress. “For these devices, the implant must maintain its designed structural integrity until adequately supplanted by native tissue.”

A good example of particulates causing an immunological response is the breakdown of high-density polyethylene (HDPE). Polyethylene implanted in bulk form generally is biocompatible—although the human body recognizes the substance as foreign, the material is walled off and long-term effects are rare.

“However, when the same material is used in an orthopedic implant that sees repeated high forces, such as what might be seen if the HDPE was used to form part of the surface of an acetabular cup used in hip replacements, the frictional forces start to wear the material,” said Fentress. “It’s the released wear materials that become a problem.”

The particulates are small enough that they can be picked up by neutrophils and macrophages. These cells, part of a greater immunological response, may attempt to digest (phagocytize) the wear material by releasing degradative enzymes and other factors that also can increase the immunological response.

“The problem escalates in a process known as ‘frustrated phagocytosis’ because HDPE, like many implantable materials, can’t be broken down by these cells,” Fentress continued. “This leads to accumulations of dead cells, with the continued presence of the particles attracting even more attention. Activated macrophages can then fuse into larger cells called foreign body giant cells. The presence of these cells and others, after the recovered insult of the initial surgery, tend to act as beacons indicating a chronic immunological response.”

Biological-Based Products
Biological-based products also are requiring some unique approaches to sample preparation and testing. Simple extracts of biological-based extracts significantly can change the properties of the device, causing artifacts that wouldn’t be found clinically.

“Much more thought has to go into the decision on the choice of extraction solvents, ratios or temperatures,” said Olson. “Biological-based products frequently break apart under extraction and that also has to be considered when preparing the treatment doses while ensuring the extract isn’t substantially affected. For traditional devices, we are seeing an increase in the level of materials characterization, ranging from simple target metals leaching to complete extractables and leachables profiles.”

For resorbable implants, the material that comprises the implant eventually is supplanted by the body’s native tissues as the implant degrades. These materials affect biocompatibility testing because the biocompatibility assessment time points are dependent on the time period required for total resorption of the material—the point at which the implant has disappeared and the surrounding tissue has reached a steady state.

More medical device companies also are adding biologically active materials to their devices and implants, such as stem cells and growth factors.

“The FDA, however, expects good scientific reasoning to support these decisions,” cautioned Palme. “Some companies seem to be adding these components simply for product differentiation because stem cells and growth factors are ‘hot’ right now and have strong marketing potential. This is not a good enough reason for the FDA—they want to see the data that shows this increases efficacy.”

One of the biggest factors in testing orthopedic devices is related to colorants and bio-absorbable/drug combination devices. Most colorants in medical devices typically are not a big biologic concern. Some pigments, however, are carcinogenic and long-term exposure from these colorants could create future health risks.

The Medical Device Blog (www.meddevice.blogspot.com) indicates the FDA is scrutinizing the use of colorants in medical devices more closely. To streamline the approval process, it recommends addressing the following questions the FDA likely will ask if there are colorants in the device:

• What are the colorants? Identify by chemical name and Chemical Abstracts Service (CAS) number.
• What are the colorant weight percents in each component and total colorant weight per device?
• Submit colorant material safety data sheets (MSDS)
• Are the colorants in 21CFR 73, 74, or 81?
• Have the colorants been used in any U.S.-approved predicate devices?

“Most colorants that are used in devices are well categorized and occur in very small amounts,” said Thor Rollins, biocompatibility expert with Salt Lake City, Utah-based Nelson Laboratories, which performs biocompatibility testing and helps companies develop biocompatibility validations for devices. “However, the regulatory agencies treat the possible exception and not the rule so the burden is on the company to demonstrate, through chemical testing, the amount of colorant that leaches and then perform a toxicological assessment on that amount.”

On the Horizon
One of the most exciting advancements on the biocompatibility front is the increased effort to develop in-vitro alternatives to some animal testing methods. Thrombosis, sensitization, irritation and genotoxicity all have in-vitro models that are being evaluated to see if they will serve as realistic alternatives to animal tests.

“These possible replacements are more animal-friendly and would reduce the turnaround time for the testing,” said Rollins. “For example, the animal sensitization test takes eight to nine weeks to perform, whereas the in-vitro test could be closer to four weeks and possibly even less once we are able to streamline the test process.”

Another development is a new American Society for Testing and Materials (ASTM) standard for the degree of mineralization of bone (DMB) that will become available in the next 12 to 18 months.

“The new standard for osteoinductive lot release testing significantly could change how DMB is tested for bioactivity for lot release and distribution,” said Palme. “The ASTM test requires a specific number of animals/implants and sets the pathology scoring method; in the past each organization dealing with DMB could set its own procedure. Moving this forward through ASTM was strongly supported by the FDA.”

A rapidly expanding area of interest is the increased use of antimicrobial materials or drugs in combination with implanted devices. This, in part, is driven by U.S. Department of Health and Human Services directives on reimbursement regarding nosocomial infections.

“There are huge potential markets here because, in most cases, the only therapy for an infected device is to surgically remove it,” said Palme. “However, as most of the materials that are antimicrobial are also toxic, this will be detected using the standard biocompatibility tests. This is why medical device companies need to work with labs that have experience testing these materials for safety as well as for efficacy, which for a combination product is a new requirement that most medical device companies don’t normally deal with. Working with an independent consultant who can provide expertise and direction to support a product team is highly recommended.”

Although they love the extra work that increased regulatory scrutiny brings, a big challenge for most biocompatibility labs simply is trying to keep up with industry demand.

“With toxicology testing one of the biggest hurdles is space,” commented Rollins. “The tests require a lot of square footage, so many labs are investing back into the facilities to meet the demand and not pass delayed timelines onto the sponsor due to capacity constraints. This is also a benefit that results from developing the in-vitro tests, since the special constraints are much less with an in-vitro test.”

More implant time points must include short-, mid- and long-term time points or more genotoxicology testing. This requires more test articles and, more importantly, additional time to complete. Photo courtesy of WuXi AppTec.

WuXi AppTec has added more options to its implant models to better address clinical relevance. The company recently expanded its chemistry capabilities to better address the extractable/leachable panels needed as a result of ISO 10993-1 and 10993-18.

“While the equipment was readily available, choosing the right suite was a bit more challenging,” explained Olson. “Most important to the program was making sure we had the right team in place to be able design the studies in the right way for clients. Testing medical devices takes a unique expertise and viewpoint. Testing has to be relevant to the risks of medical materials, and not all chemistry labs consider that aspect. We have also changed the paradigm of how we recommend testing programs, providing our clients access to a toxicologist so that programs are designed based on the data they already have and the most relevant risks associated with their devices.”

Olson also is excited about the trend that links chemistry to biocompatibility, which she views as a crucial turning point in safety evaluations.

“Better test programs can be designed because the toxicologists will have better information to work from,” she said. “For example, some chemical entities are highly toxic at low levels, but can be relatively hard to remove from materials. A standard extract might not be stringent enough to detect the presence of the risk. The chemical evaluation may also point out the need to re-design standard biocompatibility to detect whether a biologic risk really exists.”

Conducting chemical characterizations for a submission sometimes can be the deciding factor in justifying longer animal tests, Rollins pointed out. Chemical characterization looks for leachables and extractables that come loose from a device.

Leachables are compounds that detach under normal use, whereas extractables are larger sets of chemical compounds that use exaggerated conditions to mimic long-term exposure to the body. These conditions usually include harsh solvents and high temperatures in an effort to determine which materials will degrade and detach (and in what concentrations) over a long period of exposure.

“The benefit of this testing is to hopefully demonstrate that your material and processing does not leach large amounts off your device,” said Rollins. “A toxicologist can then look at these compounds and the published literature to determine if the compounds are below the known limits for the product’s intended use.”

Rollins reported that, with increased scrutiny from the FDA, he is seeing less risk-based approaches being accepted and more of a “check the box” approach to the initial submission. There also are some areas, such as genotoxicity, where the FDA does not recognize international standards and applies its own guidance to testing.

“This makes the initial safety validation tougher for companies and labs since we see inconsistencies from reviewer to reviewer,” said Rollins. “Since we are not always able to predict the regulatory requirements, we recommend that companies consult with their regulatory body on their testing plan before starting the tests.”

Fentress recommends starting as inexpensively as possible. Be sure the mechanical laboratory performance of the device is well understood across the full range of forces and durations expected during use. Also be certain the biocompatibility of the bulk material used to fabricate the device is well understood. “If it’s a combination device using a drug or biologic, ensure that the elution mechanism is understood and that both the local and systemic effects of the drug/biologic are categorized,” he advised.

Ultimately, one of the biggest challenges is speed. Because biocompatibility testing can be the longest lead time item for a device to make it to market, the process should be as lean as possible to reduce any wasted time and provide accurate results as soon as possible, within the limits of the tests. “Lean principles can shorten timelines of any test,” said Rollins, “but the in-vivo tests are limited to dwell time, which cannot be shortened. This is why the in-vitro alternatives are so promising.”

“When speed to market is of importance, the art is in designing a novel technology into a device without lengthening the preclinical and clinical testing requirements, or other regulatory requirements to the point where the venture becomes prohibitively expensive,” said Fentress.

This can be accomplished by understanding the relationship of the new technologies to existing technologies and knowing what kind of testing needs to be done to assess the safety and effectiveness of new features or feature sets.

“If you have an ultimate device design that does several new things, it may be easier to break the design into a series of devices, each device introducing one new aspect,” suggested Fentress. “Although this is admittedly a huge generalization, it tends to be true in most cases. Walking this balance between feature sets and testing requirements allow designers and companies to start getting new devices to the people who need them, as quickly as possible.”

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 such as Kohler. He also writes a variety of feature articles for regional and national publications and is the author of five books. Contact him at [email protected].