MAP A PATH TO SUCCESSFUL COMBINATION PRODUCTS

While combination product design often multiplies the complexities of traditional medical device design, the rewards of a successful product can greatly outweigh development challenges. Many of these difficulties can be minimized using a methodical, step-by-step approach to combination product design.

By organizing design processes into a discrete set of steps and clearly defining the development team, goals, and time-lines, medical device and original equipment manufacturer (OEM) companies can more easily manage product development. In addition, manufacturers can more easily identify design, development, and manufacturing partners, while anticipating manufacturing and regulatory hurdles.

IT'S ALL ABOUT CONCEPT

Concept development is perhaps the most important aspect of combination product design because it sets the stage for the success or failure of the product in the market. Robert Andrews, medical division manager at Foster-Miller, Inc. (Waltham, Mass.), says "combination product developers can increase their chances for commercial success and ensure effective concept development by using a technology forecasting road map."

Now part of QinetiQ North America'S Technology Solutions Group, Foster-Miller has developed a transdermal patch, the first of its kind on the market, for G.D. Searle, now a part of Pfizer, Inc. (New York, N.Y.). The company is now working on a stent-coating process to improve the effectiveness of drug-eluting coronary stents for Micell Technologies, Inc. (Raleigh, N.C.), an early-stage biomedical company.

When creating a road map, a company must first conduct customer research to effectively identify unmet needs. The company can then use its resources to find innovative technologies to meet these needs, rather than modifying existing products for line extensions, which are usually less profitable.

New technologies turn product concepts into reality and can create competitive advantages. Thus, the need to search for emerging technologies cannot be overstated. It is imperative for teams to incorporate brainstorming, forward-looking vision, and multidisciplinary knowledge to furnish truly novel solutions. The end result will be product concepts that can potentially solve customer problems and provide long-term market domination.

A refined and focused product strategy will guide the formation of a strategic plan, presenting different implications for three time horizons (short, medium, and long term). This plan will dictate product development direction and must be kept in line with the company'S marketing objectives. Mapping out the direction of research and development efforts in accordance with time horizons, as well as updating plans continually, can help companies shape strategy. Resources can be properly allocated, with heavy resources dedicated to near-term technologies.

Novel solutions are only successful if practical for the combination product developer. Therefore, it is imperative to evaluate projects extensively before embarking on lengthy and costly development programs. "From integration and partnering issues to intellectual property protection concerns, combination products introduce a whole new universe of challenges," Andrews says. "By employing effective technology forecasting, combination product developers can eliminate a major source of commercial failure down the road."

COMBINATION PRODUCT DESIGN

Given the complexity of combination product development, many medical OEMs work with outside engineering firms to develop and industrialize their products. One firm that offers such services is The Tech Group (Lionville, Pa.), which manufactures insulin pens, drug inhalation devices, and dry powder inhaler devices for its clients. The company offers contract manufacturing for drug delivery, healthcare, and consumer industries; its expertise ranges from design conceptualization to scale-up in support of full commercialization.

While The Tech Group does not provide turnkey device design, the company generally begins working with customers during the design phase in order to improve devices and performance. During this design-development phase, the group uses a collaborative approach to design enhancement. While the typical enhancements focus on improving tooling, molding, and assembly characteristics, the company also provides valuable feedback on material selection, tolerance analysis, and human factors.

The group'S two-fold goal is to improve device performance and manufacturing scalability to high-volume production. By generating ideas for simplified manufacturing processes, it can assist in preventing quality issues, reducing scrap, stabilizing the supply chain, and improving operating efficiencies.

For The Tech Group, manufacturing challenges provide opportunities to bring more value to customers. "The greatest benefit of optimizing a product design for manufacturability is reducing or eliminating costly engineering changes," says Randy Hagler, the group'S business development manager.

PROTOTYPE TOOLS

The use of prototype molds and manual assembly fixtures can also contribute significantly to the prevention of defects. This prototyping phase enables the device developer to attain proof of principle and design feasibility prior to investing in small- and large-scale manufacturing tools. Corrections and modifications to the components may be handled more quickly and inexpensively if completed prior to the launch of large-scale production assets.

Upon completion of this device design-prototyping phase, the developer and manufacturer focus on prototyping the manufacturing processes. Developing small-scale tooling, assembly, and test fixtures that effectively mimic what will happen in large-scale manufacturing can do this. Once qualified, these small-scale assets may be used for:

• Multiple analytical purposes such as process development;

• Design verification studies;

• Providing devices for clinical trial studies, drug stability studies, sterilization studies, and bio-burden studies;

• Building inventory levels in anticipation of market introduction.

OPTIMIZATION OF PROCESS DEVELOPMENT

A microbiologist and sterilization technician prepare product and equipment for a sterilization cycle in one of the steam units at the Ethox facility in Rush, N.Y.

Process development is the practice of defining and developing a manufacturing process to accommodate the specific requirements of a given product while meeting process quality and cost objectives. "Process development is best described as the science and methodologies used to create the manufacturing process for validation," says Hagler. "As process validation is often the target of auditors and inspectors, it can be one of the biggest barriers to commercialization of combination products." He adds that combination product developers and manufacturers must create quality systems that address process validation through standard operating procedures and work instructions and that use appropriate validation master plans and protocols.

By employing effective technology forecasting, combination product developers can eliminate a major source of commercial failure down the road.

-Robert Andrews, medical division manager, Foster-Miller, Inc.

For The Tech Group, one of the most important advantages derived from the added investment of small-scale manufacturing systems is enabling the establishment of manufacturing processes prior to the launch of large-scale manufacturing systems. Manufacturing processes established with small-scale assets can then be duplicated on the production tooling with reduced effort, cost, and time. The molding and/or assembly processes can then be validated using the protocol as defined above.

"It is important to remember that while using quality tools will yield good parts, it is still necessary to validate the molding process," Hagler says. "Engineers are often inclined to try new prototype techniques; however, it is best to use workable and proven methods. After all, there are a limited number of ways in which two pieces of plastic can be molded together. The aim of any combination product design is to achieve simplicity and elegance."

Once production assets are qualified and manufacturing processes validated, production molding and assembly can begin. This is followed by device labeling, final packaging, sterilization, and distribution for final sale.

One of the most important steps on the road to commercialization is proving the efficacy of the data the combination product developer is presenting to the U.S. Food and Drug Administration (FDA). Framed within each of these aspects of product development is the need for assurance that each step supports the regulatory filing strategy. Companies like The Tech Group do not generally develop a filing strategy for their customers. But their comprehensive understanding of the pharmaceutical and medical device regulatory hurdles the OEM is obliged to clear prior to submission is valuable in commercializing new combination devices. Just as advantageous is their experience working with earlier devices.

NEW MATERIAL CONSIDERATIONS

Material selection deserves special attention as a critical part of product design. Material considerations include not only the mechanical and physical performance needs of applications but also factors such as advanced material surfaces and biocompatibility.

Material considerations affect device durability, protection, resiliency, and consistency of use and should therefore weigh heavily in the design of combination products. Impact resistance, lubricity, wear resistance, and the ability to withstand load represent the four key mechanical and physical properties that should be evaluated when selecting materials for a combination product.

Advanced material surfaces on combination products are designed to reduce interactions between the drug or biologic and the device. Typically, there are two ways of achieving advanced material surfaces. While coating plastics is one option, this technique generally requires secondary operations that may add time and costs. Materials engineered to interact specifically with the drug or biologic without a coating are a better option.

The unique biocompatibility challenges of combination products require that companies work with a materials supplier that offers a full portfolio of bio-compatible resins to meet their specific requirements. The International Organization for Standardization (ISO) provides standards for the biological evaluation of medical devices (ISO 10993), which include tests and procedures for assessing factors such as type and duration of body contact. Because medical plastics have a propensity for toxicity due to their mold role-release agents-materials applied to mold surfaces to facilitate the release of the molded article-these tests are necessary for FDA approval.

NEW STRATEGIES IN STERILIZATION

Combination products also introduce unique sterilization challenges. The manufacturer must be certain that all components within a combination product reach a sterile state and that all materials are compatible with the sterilization process. In many cases, the package design is expected to facilitate sterilization.

Because traditional device-sterilization procedures can render drugs ineffective, new strategies may need to be developed to ensure product sterility, especially for biological drugs. While combination products are more frequently sterilized by steam or irradiation, ethylene oxide gas (EO) can be just as viable an option if the materials, drugs or biologics, and packaging are suitable for this process.

One of the main challenges in using EO to sterilize combination products, however, is that gas should not be allowed to come into contact with liquids (if present), so the pharmaceutical component must be lyophilized or coated onto the device. In addition, devices that are sterilized using EO, including combination products, must be contained in packages that incorporate a porous membrane. This membrane allows the EO gas to penetrate (and evacuate) the package during the sterilization process.

As a result of the complex components of combination products, sterilization is commonly outsourced to experts like those at the STS Life Sciences Division of Ethox International, which offers a range of terminal sterilization services, such as EO and steam. Ethox STS Life Sciences (Rush, N.Y.) provides microbiology services, reusable medical device validations, biological indicator sales, toxicology/bio-compatibility services, package testing, and steam sterilization services (see photo, p. 23).

The company'S experience working with combination products includes the sterilization of an implant with a drug component in a vial and coated stents, as well as chemical analysis of drug-coated catheters. Ethox also offers management services for gamma and electron beam (e-beam). Irradiation methods such as gamma provide rapid turnaround times for sterile release after exposing the product to a lethal dose of radiation, leaving the product free of harmful microorganisms. When using irradiation, however, impact to functionality of the product must be evaluated (or use considered); this type of sterilization can cause material degradation or chemical breakdown. Ethox can assist in selecting an appropriate irradiation method that will maintain functionality of a customer'S device.

In general, sterilization methods are determined early in the design process, as construction materials are being selected. If, as is common, a company has a sterilization method in mind, Ethox will confirm that all materials are compatible with the selected method.

"When working with a contract sterilization firm, it is critical that the product developers make sterilization specialists aware of any design limitations, such as a pressure vacuum or temperature restriction," says Nancy Rakiewicz, manager of sterilization validations at Ethox STS Life Sciences Division. "In this way, the two companies can develop the best process together, and the sterilization company can run development cycles prior to validating the process."

When considering a sterilization company, it is important to select one that is registered with the FDA for current Good Manufacturing Practices (cGMP) for pharmaceuticals and FDA Quality System Regulations (QSR) for medical devices.

NAVIGATING THE FDA APPLICATION PROCESS

As with all combination product design steps, the FDA regulatory pathway should be determined as soon as possible. Because drugs, devices, and biological products each have their own types of FDA applications, cGMP regulations, and adverse event reporting requirements, however, there is a great deal of uncertainty about the regulation of combination products.

The FDA recognizes that a one-size-fits-all approach will not work for regulation of combination products. Since December 2002, the FDA'S Office of Combination Products (OCP) has overseen the combination product approval process by directing companies to the center responsible for the regulation of a given product. Depending on the situation, that would be the Center for Drug Evaluation and Research, the Center for Devices and Radiological Health, or the Center for Biologics Evaluation and Research.

The OCP has published final rules on the regulation of combination products and numerous guidance documents to help clarify the regulatory process of these innovative new products. To avoid surprises and help facilitate a timely review, however, the FDA recommends that companies discuss jurisdictional issues with OCP staff in the initial stages of the development process.

Daytrana, the first transdermal patch for treating attention deficit hyperactivity disorder in children age six to 12.

COMBINATION PRODUCTS ON THE RISE

The converging medical device, pharmaceutical, and biologic industries markets are poised for rapid growth as new generations of combination products receive FDA approval and go on to achieve commercial success. A successful combination product does not only involve effectively combining a device, pharmaceutical, and/or biologic; it also means effectively uniting science, marketing, and regulatory know-how into a single creation. A pipeline of new combination products and several recently approved devices hold much promise for the industry (see Table 1, p. 26). With combination products estimated to make up 30% of new products under development, the industry can expect to see a growing number of approvals in the coming years.

More than just a pipeline of new products, the combination product market represents all the potential of a rapidly evolving science. The challenges combination product developers face today will diminish as technologies mature, synergies between development partners grow, and the value of combination products is better understood by the medical industry. �