Combination Products: Marrying Materials, Medicines, and Manufacturing

Combination products are becoming increasingly important in the medical device space. Defined as products composed of any combination of a drug, device, or biological agent, combination products are predicted to become market leaders in the future, perhaps totaling 50% of all U.S. medical device activity in the next few years, according to the Medical Development Group.

An array of combination products--including drug-eluting stents, pacing leads with steroid-coated tips, and antimicrobial catheters--are developed using raw materials to which active pharmaceutical ingredients (APIs) are added during the manufacturing process. However, the complex partnering of such materials as polymers and plastics with APIs can often be achieved only by overcoming a variety of technological challenges associated with determining drug-elution rates, preventing mechanical stresses, and avoiding excessive heat. Solving these issues requires not only expertise in unifying materials and drugs but also the active collaboration of materials experts and medical device manufacturers.

Living in a Material World
Manufacturing combination products requires a delicate balancing act between a material matrix and the pharmaceutical agent it releases into the body. Thus, to ensure success, combination products must be designed with matrices that can release drugs at the rate required by the medical application. The drug-release rate, in turn, is affected by the material's degradation and mechanical properties.

"OEMs seek to market products that will deliver a certain amount of a drug at a certain rate," remarks Bryan Wickson, manager, polymers and medical devices at Exova (Mississauga, ON, Canada). "Or they may want to develop a device with a coating that is expected to dissipate completely over a certain period of time." In both cases, determining the rate at which the drug must be released has an important bearing on the type of material that will be selected for the application.

When developing materials for such combination products as stents or wound dressings, the first criterion for the materials supplier is to determine how the API will be released from the material, Wickson says. For example, in the case of a matrix made from poly(lactic-co-glycolic acid), or PLGA, drugs may dissolve or may be be leached or extracted out of the matrix.

The next critical issue, according to Wickson, involves adjusting the drug-release rate. In the case of PLGA, one method is to adjust the PLGA-copolymer ratio, which affects the degradation rate of the matrix and, therefore, the drug-release rate. The other is to change the porosity or the crystallinity of the material. If the combination device material features both amorphous and crystalline properties, changing the ratio of amorphousness to crystallinity can affect the drug-release rate.

"Let's say you are developing a combination product that is supposed to elute an API relatively quickly," Wickson comments. "You can choose a base matrix material with rapid dissolution or degradation properties, accelerating drug release. Or you can change the matrix to make it somewhat porous, providing more surface area to release the drug quicker." For example, if the base matrix consists of a semicrystalline material combining both amorphous and crystalline properties, the drug would likely be in the amorphous phase, Wickson says. Changing this ratio to boost the concentration of the drug in the amorphous phase results in accelerated drug release. Conversely, decreasing the concentration of the drug in the amorphous phase slows the drug-release rate. The correct drug-release rate is essential, Wickson adds, because it enables the device to remain in the body until the revascularization process is complete.

The drug-release rate of a combination product is also dependent on the base material's mechanical properties, including its radial, flexural, and tensile strength. "Sometimes, a drug can act essentially as a filler," Wickson notes. "In such cases, when you load a drug into a base resin such as an elastomer, the mechanical or physical properties of the resin change. For example, the drug can make the material stiffer and less elastomeric."

When designing materials for combination products, suppliers often do not know what the drug-loading levels will eventually be, Wickson notes. "Thus, a materials specialist may assume at the outset of a project that a device will have a drug-loading level of 10% whereas it will, in fact, turn out to be 30%. That difference will have a huge effect on the mechanical properties of the material." For example, different drug-loading levels can change a material's elastic, flexural, or radial-strength properties. While higher levels can improve a material's stiffness in some situations--in effect promoting greater reinforcement capability--they can also make the material too brittle, rendering it too unstable to be implanted in the body.

Hot Products
Manufacturing combination products presents a host of processing challenges, one of the most difficult of which is working with heat-sensitive APIs. Exova, for example, experienced extrusion-related problems when developing a material for a cardiovascular stent. "Extruding polymers generally involves high temperatures," Wickson says, "but high temperatures can cause the API to degrade. However, using a low temperature to reduce thermal degradation exposes the API to shear forces." The company solved this problem by adding an ingredient to the polymer to lower its melt temperature, enabling the manufacturer to process the combination product below 100°C, instead of closer to 200°C.

Also dedicated to addressing the problem of API heat sensitivity, Momentive Performance Materials (Columbus, OH), has developed a material specifically designed for extruding combination products and components at low temperatures. "The active ingredients in combination products can often be degraded by exposure to the high temperatures that are required when curing silicone elastomers by conventional thermal methods," explains Mel Toub, the company's applications development manager, elastomers. "Our method for overcoming this limitation is to provide UV-curable materials, an alternative curing system that does not require high temperatures and, therefore, may be more compatible with heat-sensitive additives."

UV-curable silicone elastomers consist of a silicone rubber base and a photoactive platinum catalyst that yield a cured silicone rubber part when blended together and briefly exposed to UV light, a process that requires little thermal input, Toub explains. "As with all platinum-catalyzed silicone elastomers, UV-curable silicone rubber is cross-linked by a hydrosilylation reaction. This reaction results in a vulcanized part with no cure by-products, making it particularly well suited for healthcare applications." In addition, the physical properties of cured silicone rubber are similar to those of silicone elastomers that have undergone heat curing, making them suitable for combination products.

To develop extrudable materials suitable for manufacturing API-containing medical devices, Momentive collaborated with Specialty Silicone Fabricators (SSF; Tustin, CA), a contract molder and extruder of combination products that grappled with the temperature-stability issues associated with pharmaceutical agents and the narrow process window this limitation places on manufacturers. "While liquid-silicone and high-consistency rubbers can be molded or extruded at any temperature, high-temperature processes destabilize the drug," remarks Mark Paulsen, SSF's director of business development. "On the other hand, processing these materials at low temperatures extends the curing cycle from a half hour to an hour or even longer. Momentive's UV-curable material enables us to cure materials at close to room temperature--a work-around that represents a big breakthrough."

Mixing and Matching
When using standard thermal-cure materials for molding or extruding components used in combination products, SSF begins the manufacturing process by sourcing the API and then confirming its identity, as stipulated in Title 21, Section 211 of the Code of Federal Regulations. The identity of the API, Paulsen notes, is typically confirmed using Fourier transform infrared spectroscopy.

Regardless of whether the API will be added to a thermoplastic or silicone material, most molding or extrusion processes involve elevated temperatures. Thus, the next step involves determining the drug's temperature stability using differential scanning calorimetry.

Once the contract manufacturer knows the pharmaceutical agent's maximum processing temperature, it selects an optimal matrix material in collaboration with clients--such as a thermoplastic, bioresorbable thermoplastic or silicone material. "We pick the optimal matrix material with an eye toward three things: API compatibility, elution-rate targeting, and the fabrication method and scalability," Paulsen remarks.

After selecting the material and determining the maximum processing temperature, the manufacturer optimizes the process for mixing the API and matrix material together, depending on the process most appropriate to the application. Several different types of mixing equipment are available for performing this step, including two- and three-roll mills; a speed mixer that provides dual asymmetric centrifugal forces; a machine that mixes materials using low-frequency, high-intensity acoustical energy; and low- to high-viscosity mixers.

"Typically, the drugs used in combination products are supplied in their purest forms as powders," Paulsen explains. "The challenge is, how do you mix it into a silicone that, for example, is the consistency of Vaseline? And how do you do it without having to hand-stir the mixture? Thus, we're always looking for mixing processes that are hands-off and can be easily validated."

Having chosen a material, determined the material's temperature stability, and mixed the ingredients, SSF validates the mixture using in-house high-performance liquid chromatography testing to ensure that it is homogenous. Testing includes, but is not limited to, total-drug-content and elution-rate profiling. Employing rheometry to measure how the liquid mixture will flow in response to applied forces, the company then determines the appropriate time-temperature parameters required to completely cure the product. Before processing commences, the company develops acceptance criteria, typically in collaboration with the client.

Living with Imperfections
While Paulsen will not venture to say whether combination products represent the future of medicine, he affirms that they are becoming a growing part of the medical device sector. However, in the quest to optimize materials and corresponding processing techniques for this burgeoning area, it is incumbent upon materials developers and manufacturers alike to ensure that their materials and processes remain commercially viable.

Highlighting the occasional disconnect between developing manufacturing processes and the demands of doing business, Wickson notes that startups often approach Exova to produce prototypes for combination products based on processes that are simply not cost-effective. And in other cases, established companies use manufacturing processes that fly in the face of commercial realities.

"Some manufacturers use processes that can yield products with the desired properties, go into clinical trials, and even complete much of the FDA clearance procedure," Wickson says. "But sometimes, they have to go back to the basics and completely redo their fabrication processes with cost consciousness in mind."

For example, manufacturers often overlook the fact that the materials used in production-scale fabrication processes are likely to be impure. When polymers are manufactured, such residual chemicals as monomers, solvents, or catalysts containing heavy metals can form. However, when using such polymers for commercial purposes, it would be very expensive to purify them. "While it is acceptable in a university setting or in very small runs to distill monomers before commencing with polymerization, this is out of the question in the commercial world," Wickman says. "Manufacturers are going to buy them in bulk, and they're not going to redistill and purify them to 99.99% purity. It's just not feasible. So, you have to design devices from the get-go based on knowing that you're working with impure starting materials."

The price for failing to understand the impacts of material impurities are potentially steep. "Impurities in the material could degrade the drug," Wickson says, "or they could prevent drug release." To prevent such issues, manufacturers should be aware of the effects of material purity levels on material-drug interactions. If they fail to do so, they may have to develop purification procedures after the fact, show that the degradation products caused by the impurities are safe, or modify the design of the combination device to change the release rate. "However, all of these options are commercially unviable," Wickson adds.

Thinking ahead will become even more critical as companies developing combination products increasingly turn to the use of biologics such as peptides, Wickson notes. "I think that biologics are going to find their way more and more into combination products. However, this move will be challenging because the biotech industry has completely different manufacturing demands from those in the pharmaceuticals sector. Their testing and QC-type procedures are also different." Thus, as the industry pioneers new combination products, it will have to rise to the challenge of meeting new technological demands.