Hybrid medical devices: Clean, lean, drug-dispensing machines
06/01/2005
Medical manufacturers are finding creative ways to make implantable drug-delivery devices that stand up to strict sterility guidelines and the volatile conditions of the human body
By Sarah Fister Gale
Hundreds of thousands of hybrid medical devices are surgically implanted into patients every year. These devices, which include stents, medication pumps, and biosensing microchips, are changing the way patients live with many common diseases because they reduce the need for frequent invasive medical procedures, offer alternative methods for drug delivery, and in some cases, save lives.
Multiple components add complications
There are many contamination challenges involved with producing medical devices that incorporate multiple components and materials, all of which must perform without fault for weeks or months at a time under the stressful conditions of the human body. Carotid artery stents, insulin pumps and information-delivering microchips are just a few of these hybrid tools in various stages of development and use in the market today.
Manufacturers face significant challenges in bringing these devices to market: They are under constant pressure to ensure the highest standards of quality and sterility for these tools that combine electronics, drugs and other materials into individual mechanisms. Whether these devices distribute drugs, open arteries, or capture and deliver critical medical information, regulations demand rigorous testing, verification and regular audits of the facilities and their procedures to ensure patient safety. They fall under the highest scrutiny because the impact of a contamination issue in a patient whose immune system is already compromised is potentially devastating.
While bio/pharmaceutical manufacturers are well-versed in the rules and regulations governing the creation, filling and packaging of purely medical products, when the drugs or materials are combined with plastic, metal and electronic components, the production process becomes far more complex. Their intricate designs, which integrate a variety of methods and production processes to combine the elements of micromanufacturing and biotechnology, must seamlessly meld the highest standards of device and pharmaceutical production methodology.
The goal for every manufacturer in this field is to produce a product that is sterile with no chance of particulate or microbiologic contamination once it is implanted or injected into the patient. It also must be manufactured using materials that will not be rejected by the body or interfere with the function of any of its organs. These devices must be guaranteed not to erode, degrade or dislodge while they are in the body, which is a volatile and corrosive environment, and they must be easily retrieved or disposed of when their functions are complete.
To manage these quality and contamination-control challenges, device manufacturers have embraced a variety of processes and materials. They rely on traditional sterilization techniques in cleanroom conditions and incorporate automated manufacturing procedures whenever possible. They also work with a broad range of materials, including everything from titanium alloy and plastics to biodegrading natural inert compounds that the body won’t reject, to ensure the device materials are acceptable and reliable throughout the duration of their applications.
Device giants lead the way
The most well-known devices in this category are stents and insulin pumps designed by medical device giants such as Medtronic, a leading medical technology company (Minneapolis, Minn.) and Boston Scientific Corp., a worldwide developer, manufacturer and marketer of medical devices (Boston, Mass.). In varying stages of development, these tools give patients suffering from diabetes and other chronic diseases a chance at a freer lifestyle and a drug-delivery process that more naturally mimics the body’s own normal functions.
For example, an insulin pump that can be implanted in the abdomen, which is in clinical trials at Medtronic, will deliver tiny bursts of insulin around the clock (see Fig. 1). “It will simulate the normal function of the pancreas, instead of requiring patients to give themselves daily shots,” says Dave Powell, director of manufacturing and manufacturing engineering for Medtronic. It will also be controllable by an external handheld remote control, enabling patients to deliver additional doses when needed.
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The parts, which include a titanium pump, circuit board and electronic components, are machined off-site by third-party vendors and assembled at Medtronic’s Northridge, California, manufacturing operation in an ISO Class 8 (Class 100,000) cleanroom. “Because it’s still being produced in low volumes, most of the assembly is done by hand,” Powell says. During assembly, the rigorously trained personnel follow strict aseptic manufacturing guidelines that have been validated for this product. They also conduct frequent bioburden, particulate and pyrogen testing in the cleanroom to prove continued safe conditions. “We take every precaution,” Powell says. “We make sure the levels in the room are running cleaner than our sterility process requires.” Frequent reviews of test results also ensure that the sanitation team can identify and react to contamination issues long before they present risks.
Because Medtronic doesn’t load the pumps with insulin prior to shipping, the pumps can be terminally sterilized with ethylene oxide without any risk to the drug within. Before sterilization, the pumps are filled with a sterile degassed fluid to prevent the accumulation of bubbles that can impact timing when the insulin is later added. When the sterilization is complete, the pump is placed in a sterile package and sealed with gas-permeable lids. The pumps are shipped with a separate refill kit that includes a sterile custom syringe used by the physician to withdraw the fluid from the sealed chamber and replace it with insulin.
With stents, the manufacturing process and associated contamination-control issues are more complex. The slightest contamination breach in a carotid artery stent could cause the patient to have a cerebral embolism, says Matthew Jenusatis, president of Boston Scientific’s Peripheral Interventions business. Boston Scientific currently distributes NexStent, a carotid stent developed and manufactured by EndoTex Interventional Systems (Cupertino, Calif.) that has been approved in Europe and is in clinical trials in the U.S. “Used in combination with the Boston Scientific FilterWire EZ embolic protection system, these devices offer patients a less-invasive treatment alternative to the traditional surgical procedure known as a carotid endarterectomy,” Jenusatis says.
The NexStent consists of a laser-cut, rolled sheet of nitinol. The rolled sheet design enables the stent to adapt to multiple diameters in tapered or nontapered configurations, providing customized treatment of stenotic lesions in the carotid arteries.
“Our main worry with carotid stents is particulate matter that could come off the stent and go downstream from the artery creating a blockage,” explains Jenusatis. Particulate contamination from a carotid stent can be caused by three different scenarios: particulates from the manufacturing environment that are brought into the patient on the stent; particulates that are caused by the body in reaction to a stent that is not sterile; and blockage material that breaks loose due to a crack or other breach of integrity in the body of the stent.
To avoid these risks, strict quality and sterility procedures are followed in the NexStent manufacturing process. The stents are produced in an ISO Class 8 (Class 100,000) cleanroom, and the nitinol is polished to an ultrasmooth sheen. During manufacturing, the stent is regularly tested for particulate and bacterial contamination and goes through a terminal ethylene oxide sterilization prior to use.
To further protect patients, the Filter Wire system is also implanted and acts as a butterfly net, sitting downstream of the stent to catch any potential particulates before they cause trouble. The Filter Wire is also manufactured in an ISO Class 8 cleanroom and terminally sterilized before use. “This is a major procedure, so we want to be sure there are minimum complications,” he says.
Diminutive drug-delivery devices
Beyond stents and pumps, the medical device world is pushing its boundaries, searching for new ways to more seamlessly combine drugs and technology within the manufacturing process.
At the most innovative end of the spectrum are the tiny implantable devices that are loaded with drugs or other materials and equipped with tiny valves or sensors to regulate drug delivery. Like the implantable insulin pump, these self-contained devices are either preprogrammed or are sensitive to changes in the patient’s physiology to release the drug into the body only and exactly as needed.
MicroCHIPS, Inc., a medical device manufacturing company in Bedford, Massachusetts, is at the cutting edge of this field with its patented technology based on tiny silicon or polymeric microchips containing up to hundreds or thousands of microreservoirs that store any combination of drugs, reagents or other chemicals for timed released, says John Santini, president and chief scientific officer. “These devices have an array of reservoirs that can be filled with anything from pain medication or medicine to proteins, hormones or other pharmaceutical compounds.”
The potential advantages of these microchips include small size, low power consumption, absence of moving parts, and the ability to store and release multiple drugs or chemicals from a single device (see Fig. 2).
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The MicroCHIPS device may also be used to house tiny biosensors that deliver information from within the body, enabling doctors to track a condition over a period of months. Using biosensors in implantable applications is complicated, Santini admits, because they are so sensitive to the chemicals in the body and are quickly destroyed. “Trying to make a more durable biosensor is a battle against biology-you can’t win.” Instead, MicroCHIPS uses many short-term sensors, each of which is hermetically sealed into an individual well on the device, where it remains safely stored until it is needed.
Whether the reservoirs are filled with biosensors or drugs, doctors implant the devices in the patient under sterile hospital conditions, and complex release patterns can be achieved by opening the microreservoirs on demand using preprogrammed microprocessors or external remote control devices. “This enables the doctor to deliver multiple doses of medication that will serve the patient for months at a time without continuous injections or invasive procedures,” Santini says. “The goal is to create a system that gives us the greatest control over when we can expose the contents of each well to the body.”
Not only does that mean the device must have a systematic, timed delivery method, it must also have a way to protect the contents of each well until it is required for use-which could be weeks or months after implantation-and be sure the formulation of the drug is stable enough to survive that time in the relatively high temperatures of the human body. That usually means the drug is in a solid or semisolid state when it is placed in the reservoir, Santini says.
The nonmedical components of the device are produced outside of the MicroCHIPS facility using a standard cleanroom microelectromechanical systems (MEMS) foundry process. According to Santini, the sanitation-control issues for this production process center on eliminating any particulate contamination, organic or microbiologic matter, and the manufacturer follows the same contamination control guidelines that would be used in a chip manufacturing process.
The internal components that make up the timed-release technology for the device include a microprocessor, multiplexer, battery, a wireless antenna, and telemetry technology. These elements are autoclaved then laser-welded into a titanium can the size of a pace maker with open reservoirs on the surface. “Because they are sealed into the can, they pose no exposure risk to patients, which means those internal elements need no further sterilization,” Santini says.
The devices are then shipped to MicroCHIPS where they are filled in a portable ISO Class 5 (Class 100) cleanroom environment. “When we produce the devices, we have to make sure the drug is sterile, the wells are sterile and the seals are sterile,” he says of the process.
For each filling procedure, the cans are first sterilized at high heat then placed by personnel into the custom-built filling station. The filling process is automated, with personnel monitoring the process but not interacting with the devices, to reduce risk of accidental contamination due to human error.
The built-in customized filling unit moves the devices precisely to within a micron of the required filling location, then sterile drugs are passed through a sterile filter into an injector needle and placed directly into each well. The wells are then sealed, typically with a thin layer of sterile metal alloy produced by MicroCHIPS. “The seals are the most integral part of the success of the device,” Santini says.
The sealed wells are connected to the electronic components, which will later be programmed to open each seal and release the content of the wells based on the needs of the patients. The entire device is then sterilized using ethylene oxide. “The ethylene oxide doesn’t impact the drug because it is safely protected inside the wells,” Santini says.
Once the device is sterilized and sterility testing has been conducted, it is placed in a standard sterile pouch and delivered to the doctor who will implant it into a patient in a sterile hospital environment.
“Verification is the biggest challenge for us right now,” Santini says of the MicroCHIPS manufacturing process, which is still in clinical trials. “The elements we use are on a very small scale so we are always thinking about strategies to validate sterility.”
Because MicroCHIPS is still in its research phase, it hasn’t established its current Good Manufacturing Processes (cGMPs) yet, however it did qualify the sterility processes for animal testing and qualified all of its bioburden tests.
Natural materials have appeal
MicroCHIPS is also researching the possibility of producing a passive implantable drug-delivery device that has no electrical components or batteries. Instead, the seals would be made from varying densities of polymers, and would rely on a controlled degradation process for the timed release of the drugs. “Each seal will degrade in a sequence using chemistry as its trigger,” he says.
The idea of a naturally degrading device, in which a drug or other medical element is encased in an organic shell that degrades with time, has gained a lot of attention in the biomedical world because it avoids the risks associated with implanting foreign materials that can be rejected by the body, removes corrosion issues, and eliminates the need for device removal. These natural devices are less drastic because often the body does not register their presence. However, the challenge in producing organic devices is finding a natural material that will protect the drugs and offer a controllable degradation process that can be timed to the exact drug-release needs of the patient.
Hyaluron (Burlington, Mass.), a contract manufacturer of aseptically filled liquid parenterals and medical devices in vials and syringes, produces a substance called hyaluronic acid that is used for just such applications. “Hyaluronic acid is a carbohydrate-based chemical the body produces naturally,” says Myron F. Dittmer, Jr., vice president of quality engineering. “It’s used to lubricate joints and it promotes healing after injuries.”
 Figure 3. Hyaluronic acid is inert, stable and slow to degrade, making it an ideal substance for the timed release of drugs. Photo courtesy of Hyaluron. |
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In Hyaluron’s product, active drugs are injected into the inert hyaluronic acid (see Fig. 3) where they are trapped until the acid degrades enough to release them. Because it is inert, the acid is not recognized as foreign by the body so no antibodies are produced that could potentially cause an immunologic event. In addition, its viscous state makes it an ideal substance for a long-term, implantable, natural drug-delivery system because it is stable and slow to degrade, Dittmer says.
To produce the inert material, Hyaluron begins with a sterile hyaluronate powder produced by Genzyme Corporation, a biotechnology company in Cambridge, Massachusetts. In an aseptic ISO Class 5 (Class 100) cleanroom environment, Hyaluron converts the powder in bulk to its viscous state.
They begin by placing the powder in a 316L stainless-steel vessel that has been electropolished and steam sterilized. “The high chromium content is easiest to clean and resists rust or corrosion,” Dittmer says of the vessel. “It is critical that we avoid any corrosion because the oxides will degrade the hyaluronic acid.”
The powder is deposited in the vessel through one of several ports at the top. Then, an alcohol buffer is pumped into another port through a pharmaceutical-grade sterile filter. An internal stainless-steel mixing blade impeller then blends the material.
The mixing continues over the course of several days, with several additional doses of buffer added until the material reaches the desired viscosity. Each batch of buffer is pumped through a new port with an unused sterile filter. Gowned personnel monitor the process and test air, surfaces, and their gowns for microbial contamination every time they enter the room or interact with the vessel. The filters are also tested before and after their single use to ensure there are no holes or tears that could cause breaches in contamination control. Once the final filter test is completed, each filter is discarded. “If we have an excursion, the testing won’t help us save the product, but it will let us know that it’s happened and help us pinpoint the cause,” Dittmer says.
Once the desired consistency is reached-about the density of wet paste or a viscosity rating of 1,000,000 to 3,000,000 centipoise (cps)-a connection to an outfeed tube is made between the bottom of the vessel and the filling pump. The material is pumped into biobags, syringes or other designated vessels in an ISO Class 5 (Class 100) area using a high pressure vacuum to push the material through a sterile filter. “The filter is there in case the vacuum fails and material is pulled back into the vessel during filling,” he says.
Depending on the needs of clients, the final packaged product may be terminally sterilized with ethylene
oxide or gamma radiation, or shipped directly for furth-er manufacturing.
Most clients use further sterile filling techniques to shape the hyaluronic acid and inject their drugs into the material for final use. However, in some cases Hyaluron will either inject the client’s drugs into the material in-house or, using a customized formula, mix the drug directly with the acid during the dilution process.
All of Hyaluron’s sterility steps and testing meet the national standards for U.S. Pharmacopeia, as well as European and Japanese standards, and they are regularly audited by clients and regulators.
The future
These devices are only the beginning of what the medical community will soon be able to accomplish with implantable medical devices. Research is being done right now on implantable microchips that gather and disseminate biological information. The VeriChip from Applied Digital Solutions, an innovative security company (Delray Beach, Fla.), is a miniaturized, implantable radio-frequency identification device for use in a variety of identification and information applications. About the size of a grain of rice, each VeriChip contains a unique verification number that can be used to access a subscriber-supplied database providing personal related information.
Similarly, devices such as the SmartPill from SmartPill Diagnostics, developer of Ambulant Capsule Technology (Buffalo, N.Y.), and the PillCam Endoscopy capsule, made by Given Imaging Ltd. (Yoqneam, Israel), could eliminate invasive exploratory procedures by allowing patients to swallow a medical device that can capture photos, video and environmental data as it progresses through the body. The information transmitted from the device to external processors would allow doctors to make critical diagnoses without the risks and pain associated with surgical procedures.
As with any cleanroom industry, however, the more complex the research and the smaller the technology, the greater the challenges will be to maintain sterile manufacturing conditions. And nowhere is sterility more important than in the production of tools used invasively with medically vulnerable patients. “In this field, contamination control is about safety more than anything,” Dittmer says. “When patients are immune-suppressed, sterility is critical.” III