When drug-eluting stents came on to the market they teamed a good pharma idea — drugs that stop tissue scarring — with a good device idea — stents that keep arteries open. Since then, the market has seen an explosion of many other products that combine the talents of manufacturers, pharmaceutical, and biologic companies. Combination products, as they are commonly called, are any combination of drug, device, or biologic. A biologic is a drug, vaccine, or antitoxin that is synthesized from living organisms or their products. Drug-eluting stents are a well-known combination product but the category also includes prefilled syringes, coated plates, and wireless drug-delivery systems.

Help from the FDA

In 2002, the FDA created the Office of Combination Products, OCP, to help guide companies through the regulation process. “The regulatory responsibility for combination products continues to reside separately in the FDA's drug, biologic, and device centers: the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), and the Center for Devices and Radiological Health (CDRH),” says Christine Ford, Event Director for the trade show PharmaMedDevice. “The OCP helps companies by assigning the primary agency for jurisdiction, coordinating reviews involving more than one agency, and developing regulations and guidance for both premarket review and postmarket regulation,” she adds.

The primary agency is determined by the product's Primary Mode of Action, PMOA, defined by the FDA as the single mode that provides the most important therapeutic activity. In cases where the PMOA is unclear, the OCP makes assignments based on similar products and relevant experience at the three centers. They encourage companies to get involved with the OCP as early as possible to answer questions and avoid delays.

More than stents

Stents from Conor Medsystems Inc., Menlo Park. Calif., are different from conventional surface-coated stents and are intended specifically for drug delivery. Rather than retrofitting a bare metal stent with a drug coating, Conor's stent design incorporates hundreds of small holes, each acting as a reservoir for drug-polymer compositions. In addition, proprietary structural elements called “ductile hinges” create drug reservoirs in stent struts. Ductile hinges are specially contoured features that absorb most of the mechanical stresses as a stent expands inside an artery. This stress-absorption mechanism lets other structural elements of the stent, including drug-polymer reservoirs, remain relatively deformation-free. This means reservoirs built into stent struts don't compromise strength, scaffolding, or flexibility. Also, since the reservoirs are largely non-deforming during stent expansion, the drug-polymer composition in the reservoirs will not be extruded, fractured, or otherwise disrupted as the stent expands. This in turn lets Conor use polymers in its reservoirs which do not have the level of elasticity, adhesion, and other properties required in surface coatings.

The I-vation TA drug-delivery system releases drugs to the back of the eye to treat ocular diseases. The screw-like device is a non-ferrous metallic scaffold coated with a polymer from SurModics Inc., Eden Prairie, Minn., which is then coated with triamcinolone acetonide. The helical design maximizes surface area for drug delivery and ensures secure anchoring of the implant against the sclera.

Another combination product uses wireless technology to actively control the release of drugs in the body over a prolonged period. The key component in the technology from MicroChips, Bedford, Mass., is its proprietary reservoir arrays. Any combination of drugs or biosensors can be stored within the reservoirs, protecting contents from the environment (a patient's body) until they are needed. Preprogrammed microprocessors, wireless telemetry, or sensor feedback loops can provide active control of the opening of the reservoirs to initiate drug release or expose enclosed biosensors, giving the physician or patient greater control over therapy. Alternatively, layers or other polymeric matrices, can passively control release or exposure of the reservoir contents in applications that do not require microprocessors or power sources.

MicroChips president John Santini says “reservoir drug-delivery systems may have applications in congestive heart failure, diabetes, osteoporosis, and orthopedics.” So far the devices have been tested only in dogs, but “if all goes as planned we could begin human safety trials for passive reservoir systems for drug delivery within three years and for active sensing systems in three to five years,” he adds.

What to consider, what's different

The OCP has not yet stipulated Good Manufacturing Practices (GMP) specifically for combination products. Christine Ford notes “the OCP says both Current Good Manufacturing Practice (cGMP) regulations for pharmaceuticals and Quality System (QS) regulations for medical devices apply to combination products produced as a single entity or packaged together.” Biological product regulations also might apply.

Draft guidance says it is generally not necessary for manufacturers of combination products to maintain separate manufacturing systems to ensure compliance. Because of the overlap among regulations, the FDA says that compliance can generally be reached by using a hybrid approach that draws upon cGMP and QS regulations.

“It's important to recognize that each component of a device has to meet certain safety and stability standards,” says Christina Giuliano, Conference Manager, PharmaMedDevice. “Combining one entity with another can produce a completely different effect. You could increase the effectiveness of the device, or alter or diminish it. The combination product development process requires an extra step to make sure each component maintains its safety and effectiveness as a single entity and when it's combined.” For instance, a device-biologic must be engineered for mechanical soundness both before and after the addition of the biologic. The biologic must also sustain the same metabolic activity when added to the device. Therefore, it is necessary to ensure that each component meets required standards and that the entire combination product as a whole is safe.

Steven Richter, president of MicroTest, Agawam, Mass., says his company tests combination products to pharma regulations. “For example, we're working on a medical-device injector that goes through the skin and has a drug component,” he notes. “So it's a drug-delivery device married to a drug. We manufacture the drug, including the product and batch-record release. We use a GMP platform with an emphasis on pharmaceutical release of product. This lets us test medical devices and manufacture pharmaceuticals,” he adds.

Sterilizing

The most common method for sterilizing combination products is ethylene oxide, EO. “Many of the drugs in combination products may not be compatible with irradiation sterilization because of the impact radiation may have on the drug itself, says Bill South, Manager, EO Test Center Operations at Steris Corp., Mentor, Ohio. “When we receive a new product for validation we look at the physical limitations for each part of the product. That might include sensitivity to moisture, temperature, or pressure. We'll design the process to make sure we don't exceed these limits and damage the product.” Getting the right variables can be a balancing act. “We need to make sure the end item is sterile and yet the process doesn't destroy the components,” he adds.

Sterilizing combination products with gamma irradiation carries its own set of rules. “The procedure for dose setting and testing tolerance is more complicated because in most cases you have parts that are tolerant to radiation, and some that are significantly less tolerant,” notes Betty Howard, Gamma Technology Center Manager at Steris. “So we look for a dose that is high enough to cover the sterility needs of both parts. Usually the chemical, or biological part is made in such a way that it doesn't have a high contamination level. The plastic, metallic, or ceramic surface of the device component is probably the piece with the most contamination.”

One way Howard's team deals with combination products is to change its state, which often includes freezing or lyophilization. “A protein-based liquid product, or one with protein or active component in it, is often more stable in a solid state than a liquid. An example might be implantable tissue-based products. Also things such as bone putties are liquid or semi-solid and then frozen before irradiation. They're shelf stable at room temperature but they're not irradiated at room temperature.”

Howard suggests considering gamma stable materials at the start of a design of a combination product. “There are often different grades of the same material. Start designing with something that has a chance to survive, and has good tolerance. Then add a process that pretreats the product to reduce the bioburden. Low bioburden will lower the overall dose required to make it sterile. Likewise, the higher the dose the more likely there will be problems with the active compound.”

Make Contact
Conor Medsystems, www.conormed.com

FDA's Office of Combination Products, www.fda.gov/oc/combination

MicroChips Inc., (781) 275-1445, www.mchips.com

Microtest, www.microtestlabs.com

PharmaMedDevice, (800) 518-6672, www.pharmameddevice.com

Steris Corp., www.steris.com

SurModics, www.surmodics.com