The best combination medical device makers select product materials, process steps, and monitoring strategies in the early stages of product development to ensure biocompatibility and product stability throughout the manufacturing process.
By Sarah Fister Gale
The drug-eluting cardiovascular stent has changed the landscape of medical device manufacturing. These small implantable devices, which incorporate a device that can prop open an artery with a pharmacologic agent that interferes with reblocking after surgery, were among the first successful products to combine two unique medical tools in a single package.
Prior to the drug-eluting stent’s success, few companies were producing or even talking about combination medical devices. Limited to cutting-edge research, they were solely the focus of forward-looking researchers and manufacturers. Today, however, combination medical devices are a common part of the medical industry lexicon.
The U.S. Food and Drug Administration (FDA) defines combination medical devices as products comprised of two or more regulated components, such as a drug and a device, or a biologic and a device, that are combined and produced as a single entity; or those that are comprised of two unique entities, but are packaged together, or packaged separately but intended only to be used together.
Manufacturers are increasingly combining novel technologies that hold great promise for advancing patient care and making treatment options more convenient, customized, and self-regulated. Drug and biologic products can also be used in combination to enhance the safety or effectiveness of either product when it is used alone.
Some more recent examples of successful combination devices include proteins incorporated into orthopedic implants to facilitate bone growth that can stabilize the implant, drug-device inhalation systems for insulin delivery, and implantable timed-release medication delivery systems.
The recent rapid growth of the combination medical device industry is undeniable. Independent firm Navigant Consulting (Chicago, IL) estimates the market has grown 10 percent per year since 2004 when it was an estimated $5.9 billion, to hit $9.5 billion by 2009.
FDA has had an office of combination products since 2004, and there are a growing number of conferences and resources discussing the challenges and triumphs of the latest combination innovations. Christine Ford, event director for PharmaMedDevice, an annual medical device manufacturers’ conference (Norwalk, CT), reports that 30 percent of devices currently in development are combination products and that these devices have become the most popular topic at the events. “Every multibillion dollar medical device company seems to have a combination device in their pipeline,” she says. “And if they don’t, they need to know what’s going on because it’s a big trend.”
Cutting-edge device companies who want to find a foothold in this burgeoning market are scrambling to identify innovative ways to combine device technologies with drugs or biologics that meet a range of medical needs.
The category of products promises to bring new business to these firms–if they can figure out how to produce them successfully. “It has become an emerging growth area, particularly in the last few years, and many firms are looking at these devices as an opportunity for market growth,” says Sharad Rastogi, principal in the life sciences group of PRTM, a management consulting firm (Waltham, MA). “But it’s a high risk, high reward market.”
“It can test a company’s resolve,” adds PRTM’s Sam Baldwin, manager of the life sciences group, who notes that developing the first product in particular can be very difficult. “The time to develop is significantly longer and the cost is much greater than with conventional medical devices. But if you go in with your eyes open you have a good chance of success.”
Regulatory red tape
The rapid growth of this market has left the medical device industry in unfamiliar territory as it figures out how to characterize and regulate this hybrid category of products. Even FDA is struggling to define a roadmap for these devices. While its office of combination products offers guidance and development considerations to manufacturers, it has yet to clearly define a set of good manufacturing practices (GMPs) specific to this product category. That has left companies to define their own path using a combination of drug GMPs (21 CFR 210/211), biologics product standards (21 CFR 610), and medical device quality system regulations (QSRs; 21 CFR 820). Trying to strike that balance correctly is where the challenges begin to pile up.
“The combination product regulatory framework requires a unique perspective on both medical devices and pharmaceuticals/biologics,” says Steven Richter, founder and CEO of Microtest Labs in Agawam, MA. “The first step to producing one of these products on a commercial scale is determining which regulations impact which steps in the process and come up with a plan for process validation.”
A combination product manufacturer must have a robust pharmaceutical GMP system in place that addresses some of the issues with the device QSRs, but the main regulatory foundation must be the drug GMPs, Richter says. “There are a lot of factors to consider to meet FDA standards, and a lot of clean manufacturing environments for devices won’t be sustainable for drug manufacturing.”
Baldwin suggests that manufacturers partner with FDA in the early development stages to ensure they are making sound choices and documenting their progress. “The last thing you want is to get to the end of your project and discover you didn’t validate it properly,” he says. “Working with the FDA, you can make your case for your approach, and they can tell you if you are going in the right direction.”
Medicine takes precedence
Aside from meeting regulatory compliance, combination medical device manufacturing is complex, particularly because it combines two or more distinct and delicate elements that will ultimately be used by the most vulnerable consumers. Because of this, contamination control must be complete and provable at all times.
“Most people who do medical product development are familiar with issues such as temperature and humidity control, airflow maintenance, management of particulates and pyrogens, and gowning,” notes Clair Strow, senior engineer and program manager in the medical division of Foster-Miller, a technology and product development company (Waltham, MA). “But it’s more difficult with combination products because of the subtle differences.”
Devices that have been engineered from plastic, metals, silicon, or other materials have contamination control issues that will differ from the medical or biologic needs of the product. They can also create contamination issues, through off-gassing or particulates, that can contaminate exposed biologic or pharmaceutical material, damaging its efficacy, says Foster-Miller’s Bob Andrews, medical division manager.
Figure 2. A medical device sterility test vessel with a medical device immersed in TSB (Trypticase soy broth). Photo courtesy of Microtest Labs.
Biologics are also more temperature and light sensitive and have shelf life issues that need to be considered–many biologics are only able to maintain stability for a few hours outside of a tightly controlled environment.
If the combination product uses multiple biologics or chemicals, cross-contamination among materials is an additional concern, Strow says.
If a technician is working with a nanoparticle in one cleanroom zone, it could contaminate biologics in another area if the facility uses a common air system. “The pharmaceutical industry is very sensitive to spills,” Strow says. “In a combination product, you have to be extremely careful, particularly of chemicals coming in contact with biologics.”
Depending on the delicacy of the product and the risks in the environment, that might mean the use of gloveboxes, laminar flow hoods, and control over the exhaust air around a fill station, or it could be as extreme as total isolation with separate air handling for the biologic component of the product to prevent particulates and other contaminants from the manufacturing process from coming in contact with biologic material.
Adding to the difficulty is that device material and biologics or chemicals can have conflicting requirements for stability in the manufacturing environment. “Humidity control for a device may be too high for a biologic,” Andrews points out. “But if humidity levels are too low, you can build static in the room that can affect the device.”
This is not an uncommon problem, adds Foster-Miller’s Strow, who recently worked with a client facing just such a dilemma. The client was developing a combination diagnostic product that included chemicals that would be stored in a nylon device. For the chemical to remain viable it had to be dispersed in an environment that maintained 1 to 2 percent relative humidity. The client was producing the product on a commercial scale, packing 100,000 units per 24-hour shift.
“In that environment at the low humidity level, there is a lot of static so materials need to be stable,” Strow points out. The nylon, however, became brittle in the low humidity, ultimately shattering.
Fortunately, they were able to create a solution that allowed the nylon device to be isolated in a 30 percent humidity room. The two elements of the device are now packaged separately using moisture barrier packaging that allows the chemical to remain at low humidity levels and the device to maintain higher humidity. Once the package is opened it must be used within 20 minutes, during which time the humidity levels won’t be an issue.
These kinds of problems can be avoided if proper product development planning is done with all of these issues given careful up-front consideration by the design team before establishing the manufacturing operation, says Andrews of Foster-Miller. “Once the room is assembled it’s much harder to make changes.”
Maintenance and monitoring
Controlling contamination in the environment during manufacturing requires an end-to-end process that ensures the cleanest materials go in and remain clean throughout the manufacturing process. The most successful operations begin contamination control steps well before materials ever enter the facility, says Richter, who notes that at Microtest, new batches of drug or biologic material are tested upon arrival for content, quality, moisture, purity, and contaminants before use.
Storage of device materials is also critical and must be closely evaluated when manufacturing processes are being established for combination devices. From an environmental control standpoint, you must consider both what a material is made of and where it has been, because the storage environment can affect how it performs in the cleanroom, says Strow.
“If I have a particular polymer piece that has been stored in a warehouse that has 90 percent humidity levels, then I bring it into a cleanroom with low humidity, that stored moisture will be sucked to the surface,” he points out. “If you seal a drug product into that polymer, you contaminate your final product.”
Strow suggests that materials be placed in isolation with environmental conditions comparable to the clean environment for 24 hours to stabilize them.
Once the material is in the environment and process steps are taking place, manufacturers should perform round-the-clock monitoring, not just of the cleanroom, but also of the building management system, with a focus on airflow, temperature, humidity, and any motor malfunctions that could compromise the manufacturing or storage spaces, says Microtest’s Richter. They should also include backup generators to ensure the process is continuous.
Richter notes that newer HVAC systems can include specialized levels of pre-filters to eliminate toxic contaminants before they can be released downstream of the manufacturing space. This is particularly important if the device contains hazardous chemicals, such as cytotoxic drugs that could be deadly to personnel.
Figure 3. An analyst inoculates a 96-well plate to perform an endotoxin assay on a combination product. Photo courtesy of Microtest Labs.
Microtest has two 1,500-sq.-ft. manufacturing spaces, each with separate airflow systems and dedicated chillers to manage relative humidity and temperature. The facilities are also designed with walkways above the main room for maintenance and servicing. “It’s critical for the service people to be able to get above the cleanroom to pull filters, change traps, or look for problems,” Richter says. “We can do visual inspection and maintenance freely without compromising the cleanliness of the room.”
The product Microtest manufactures in this space includes a powder stored in an injection system, which makes the risk of airborne particles an issue. This is addressed in the design and management of the room: It incorporates a conductive ESD floor, and high humidity levels above 60 percent to prevent dryness. The HVAC system was designed with an integrated vacuum system to suck out any particles that are generated from equipment or process steps. The company also does ongoing monitoring with particle counters and air samples at critical control points.
To maintain cleanliness and avoid bacterial issues, the sanitation team regularly rotates the intermediate-level disinfectants used to clean the room to prevent resistance. If problems with microbial status of the room arise, a high-level sporicide is used.
Once processing is complete, samples of the finished product are analyzed for contaminants using high-performance liquid chromatography, and the product is bagged and terminally sterilized.
How the product is sterilized at the end of the manufacturing process is one of the most difficult decisions developers of combination medical devices will make, says PRTM’s Baldwin. It’s another decision that must be made early on in the product development process because it can affect every product development and environmental choice that will follow.
With traditional medical devices, sterilization can almost be an afterthought. A common sterilization process is the use of ethylene oxide, which is a potent antimicrobial agent that can kill all known viruses, bacteria, and fungi. But such a strategy could destabilize biologic or pharmaceutical materials that are a part of the product.
“Once you add the biologic or pharmaceutical component, your available sterilization options drop considerably,” Baldwin says, explaining why sterilization methods must be determined well in advance of production. “Sterilization can have critical implications on your design. The companies that have the most success are the ones that include the sterilization group from the start of the design.”
Some options include low-dose or low-temperature radiation; a dry heat sterilization process, which can be an option for most small-molecule combination products; or the drug or biologic may be lyophilized, or rapidly frozen, to stabilize it during sterilization to allow for additional options.
Engineers also need to think carefully about working in an aseptic environment, and they need to be very careful about the bioburden that is brought in on equipment, materials, devices, and most importantly on personnel, Baldwin advises. “That means better training programs, daily operator assessments using touch plates or hand swabs, and a design process that minimizes human interaction.”
Whenever possible, he recommends automating key processing steps to remove the possibility of human error and contamination from the system.
The willingness to look at each product as having an original set of needs and contamination control issues is critical to a successful design process, but that attitude comes more naturally to medical manufacturers than to device manufacturers, who are accustomed to more controlled decision making options. This cultural difference and the need for prioritization of medical materials represent significant challenges for companies looking to move into this niche industry.
“While both elements of a combination device have unique sets of requirements for the manufacturing environment, you have to defer to the needs of the biologic,” says Strow. “They are the key to the device.”
That doesn’t mean the non-biological material should be compromised. Rather, it means the device material, along with the assembly methods, airflow handling, contamination monitoring, room layout, and isolation methods should be chosen based on the requirements of the biology in the product, with device materials selected to complement or coexist with those choices.
The trick is ensuring that you have biocompatibility between the materials, chemicals, biological elements, and the fluids they might come in contact with, says Rob Hodges, biomedical business unit director for STMicroelectronics, a Dallas, TX-based global supplier of microfluidic devices. “In many cases, the things you worry about are easy to handle, and the things you think will be easy take a lot longer than you expected.”
He notes that a big mistake companies make in their first attempt at a combination product is to design the elements independently of each other. “It’s not going to work if you design them separately then bring them together in the end. You need an integrated system from the beginning for the final product to work.”
However, many of the products coming to market now are the result of partnerships between medical device companies and pharmaceutical makers, who each bring a unique set of manufacturing skills and knowledge to the table. The gut reaction in these partnerships is to leave control of the key components of the product in the hands of the experts, who may work in separate labs or organizations. The medical device company designs the delivery mechanism, while the pharmaceutical team develops the drug or diagnostic. But if the two groups work in isolation with intent of combining the two elements later on, they are going to run into trouble, says Hodges.
“There is a lot of interaction between materials that can’t be predicted, especially when you work with biologics,” he points out, adding that engineers in particular don’t expect these kinds of problems because they don’t occur when working with pure electronics.
Hodges learned this lesson the first time he developed a combination product. Working with a diagnostics company, the two teams decided to develop their own sides of the product individually with the goal of bringing them together later on in the project. “We tried to avoid the biology for as long as we could, and we stuck to electronic consumables, because it’s what we knew,” he says of his team. “We later realized that was an impossible approach.”
Hodges learned through that process that many unpredictable problems can arise when you incorporate biologics or drugs into a product, and ST has since added teams of biologists, chemists, physicians, and engineers to its staff who work together in the R&D phase ensure they achieve successful convergence between the technology and the biology.
“Combination products are a nice fit for the semiconductor manufacturing process,” he says, now that ST has the development process figured out. “We are driven by quality. That’s the mindset of semi and it’s the mindset of the medical industry.”
Hodges is currently working on ST’s lab-on-chip combination device, which facilitates the diagnosis of specific diseases or the monitoring of food and water for bacterial contaminants by allowing the rapid detection of particular genetic material in liquid biological samples.
The lab-on-chip product includes a silicon-based MEMS microfluidic chip that is printed with DNA molecules using equipment similar to a very large ink-jet printer. The DNA is arranged in a microarray that requires precision and a contamination-free environment.
“The combination of our historical knowledge of microelectronics with other multidisciplinary teams gives us the potential to develop disruptive innovations,” he says. “It’s the kind of innovation we need for the growth of our future.”
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