Seven Steps to Successful Combination Product Design
Industry Professionals Share Their Best Practices Regarding the Design and Manufacture of Convergent Technology
Christine Ford, Reed Life Sciences
Shown above is Medtronic’s INFUSE Bone Graft, a prime example of novel combination products reaching the market today. To use INFUSE Bone Graft, surgeons reconstitute the rhBMP-2 powder with supplied sterile water and then apply it to collagen sponges. The sponges are inserted inside each of two LT-CAGE Lumbar Tapered Fusion Devices, which are then implanted between the vertebrae. Photo courtesy of Medtronic.
Many of these difficulties can be minimized by 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 timelines, medical device and OEM companies more easily can manage product development, identify design, development and manufacturing partners as well as anticipate manufacturing and regulatory hurdles.
To provide a well-rounded view of these steps, professionals from Ethox STS Life Sciences Division, The Tech Group and Foster-Miller shared their expertise on specific aspects of combination product design and manufacture.
Technology Forecasting to Ensure Viable Concept Development
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, a design engineering firm in Waltham, MA, advised that “combination product developers can increase their chances for commercial success and ensure effective concept development by using a technology forecasting roadmap.”
When creating a roadmap, it is first necessary to conduct customer research to effectively identify unmet needs in the market. Then, resources can be allocated to find innovative technologies to create new solutions to meet these needs, instead of being allocated to modify existing products for line extensions, which usually are less profitable.
New technologies turn product concepts into reality and can create competitive advantages. As such, 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 potentially can solve customer problems and dominate the market in the long term.
A refined and focused product strategy will guide the formation of a strategic plan, presenting different implications for each of the 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. By mapping out the direction of research and development, efforts in accordance with time horizons and 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. Thus, it is imperative that projects be evaluated 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. By employing effective technology forecasting, combination product developers can eliminate a major source of commercial failure down the road,” Andrews said.
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, NY. Novel combination products can present sterilization challenges. Photo courtesy of Ethox International.
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, a Scottsdale, AZ-based contract manufacturer providing injection molding and assembly (among other solutions) for the device, healthcare and consumer industries. While The Tech Group does not provide turnkey device design solutions, the company generally begins working with customers during the design phase to improve device robustness and performance.
During this phase of design development and ideation, The Tech Group will apply its internally developed DFx process—a collaborative approach to design enhancement. While the typical enhancements focus on areas to improve tooling, molding and assembly characteristics, The Tech Group also will provide valuable feedback including material selection, tolerance analysis and human factors. Thus, the two-fold intent is to improve device performance and manufacturing scalability to high-volume production, according to Randy Hagler, business development manager for the company. By generating ideas for simplified manufacturing processes, The Tech Group can help prevent quality issues, reduced scrap, stabilize the supply chain and improve operating efficiencies.
For The Tech Group, manufacturing challenges provide opportunities to bring more value to customers, Hagler said.
“The greatest benefit of optimizing a product design for manufacturability is reducing or eliminating costly engineering changes,” he added.
Leveraging Prototype Tools
The use of prototype molds and manual assembly fixtures also can contribute significantly to the prevention of defects. This prototyping phase enables the device developer to achieve proof of principle and design feasibility prior to investing in small- and large-scale manufacturing solutions. Corrections and modifications to the components may be accommodated much faster and with reduced costs 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. This can be done by developing small-scale tooling, assembly and test fixtures that effectively will mimic what will happen in large-scale manufacturing. 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, drug stability, sterilization and bio-burden studies
• Building inventory levels in anticipation of market introduction
Optimizing Process Development
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. According to Hagler of The Tech Group, process development is best described as the science and methodologies used to create the manufacturing process for validation. Because process validation often is the target of auditors and inspectors, it can be one of the biggest barriers to commercialization of combination products. It is critical that combination product developers and manufacturers create quality systems that address process validation through standard operating procedures and work instructions as well as use appropriate validation master plans and protocols.
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 then can be duplicated on the production tooling with reduced effort, cost and time. The molding and/or assembly processes then can be validated using the protocol as defined earlier.
“It is important to remember that while using quality tools will yield good parts, it is still necessary to validate the molding process,” Hagler said. “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, followed by device labeling, final packaging, sterilization and distribution for final sale.
One of the most important steps toward commercialization is proving the efficacy of the data the combination product developer is presenting to the FDA. Framed within each of these aspects of product development is the need for assurance that each step supports the regulatory filing strategy. While companies such as The Tech Group generally do not develop a filing strategy for their customers, their comprehensive understanding of the regulatory hurdles the OEM is obliged to clear prior to submission to comply with both pharmaceutical and medical device regulations as well as their experience with past devices are very valuable in commercializing new combination devices.
New Material Considerations
Material selection deserves special attention as a critical part of product design. Material considerations not only include the mechanical and physical performance needs of applications, but also considerations such as advanced material surfaces and biocompatibility.
Material considerations affect device durability, protection, resiliency and consistency of use and therefore should weigh heavily in the design of combination products.
Impact resistance, lubricity, wear resistance and properties 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. Alternatively, materials engineered to interact specifically with the drug or biologic without applying a coating provide a better option.
The unique biocompatibility challenges of combination products require that companies work with a materials supplier that offers a full portfolio of biocompatible 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. Since medical plastics have a propensity for toxicity due to their mold role release, these tests are necessary for getting a product approved by the FDA.
New Thinking in Sterilization
Combination products also introduce unique sterilization challenges. Not only must the manufacturer be certain that all components within a combination product reach a sterile state, but also that all materials are compatible with the sterilization process. In many cases, the package design is expected to facilitate sterilization.
Since 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 more frequently are sterilized by steam or irradiation, ethylene oxide (EO) gas can be just as viable an option if the materials, drugs or biologics and packaging are suitable for this process. However, one of the main challenges to using EO to sterilize combination products 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 (including combination products) that are sterilized using EO 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 each combination product, sterilization commonly is outsourced to experts such as those at the STS Life Sciences division of Ethox International, which offers a range of terminal sterilization services, such as EO and steam, as well as management services for gamma and e-beam.
In general, sterilization methods are determined early in the design process as materials of construction are being selected. While most companies approach Ethox with a sterilization method in mind, the company will confirm that all materials are compatible with the selected method.
Nancy Rakiewicz, manager of Sterilization Validations at Ethox STS Life Sciences Division, advised: “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. 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 (cGMPs) for pharmaceuticals and FDA quality system regulations (QSRs) for medical devices.
Navigating the FDA Application Process
As with all combination product design steps, determining the FDA regulatory pathway is one that should be accomplished as soon as possible. However, because drugs, devices and biological products each have their own types of FDA applications, GMP regulations and adverse-event reporting requirements, there is a great deal of uncertainty about the regulation of combination products.
The FDA has recognized 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 appropriate center responsible for the regulation of the product: 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 as well as numerous guidance documents to help clarify the regulatory process of these innovative new products. However, to avoid surprises and help facilitate a timely review, the FDA recommends that companies discuss jurisdictional issues with the OCP staff in the initial stages of the development process.
Combination Products on the Rise
The converging medical device, pharmaceutical and biologic industries market is poised for rapid growth as new generations of combination products receive FDA approval and go on to achieve commercial success. More than just the pipeline of new products, the combination product market represents all the potential of a rapidly evolving science. The challenges that 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.