From Here to 2020: Hurdles Facing Combination Products

With each passing year, combination products are growing in importance. However, because they represent a marriage between traditionally discrete technology and market sectors--the medical device and pharmaceutical industries--designing, characterizing, testing, and manufacturing combination products poses a range of unique engineering challenges. Some of these challenges were the subject of a conference session titled "New Innovations in Drug Device Combination Products" at BIOMEDevice Boston, April 10, 2013.

Combo Products: A Realm of Their Own

Manufacturers that have decided to tackle combination products are in a different realm from those that manufacture standard medical devices, explains Bill Welch, chief technology officer at Phillips-Medisize Corp. (Hudson, WI), which will be exhibiting at MD&M East, Booth #3501. Their first challenge, he notes, is to establish the appropriate facility infrastructure and quality system, a task that Phillips-Medisize has embraced, for example, by adding a 2° to 8°C cold-chain storage area at its campus in Menomonie, WI, to produce such combination products as pens and autoinjectors.

But after the infrastructure and quality systems are in place, engineering challenges take over. "This is a common theme," Welch emphasizes. "Whether the delivery method is injection, inhalation, or skin absorption, the biggest challenge in fabricating combination devices is to reduce variation in both the device and the drug formulation. You need to characterize both of them and determine the interactions between them. Accomplishing this task tends to be a long, iterative process."

For example, to produce such combination products as dry-powder inhalers, engineers must first ensure that all the device components meet critical product measurement (CpK) specifications, dimensionals, and performance criteria. But that's not all. Then, they must ensure that the particle distribution of the drug itself is within specifications. "What happens if the particle size or distribution of the drug itself changes?" Welch asks. "Suddenly, the combination product doesn't behave as it should. You're not delivering the same amount of the drug to the lungs as you did during the testing phase."

To prevent such downstream control issues, engineers must approach product development from two different directions, Welch says. One is to minimize variation, and the other is to develop devices that can accommodate as much variation as possible from the incoming drug formulation. "That's where it gets into statistics and simply understanding what the capabilities are on the drug side, what the capabilities are on the device side, and what level of variation both of them can accommodate while still providing the correct drug delivery to the patient."

Different problems are posed when manufacturers develop autoinjectors, according to Welch. First, the force-to-fire (FTF) measurement must be correct, and second, the device must be able to deliver the complete dose in the specified period of time--an especially critical issue for combination products that incorporate biologics. "All the engineering work to solve these problems happens up front," Welch says, "As you go through development scale-up-- starting with single-cavity molds and small supplies of purchase components--you expand to multicavity molds, managing the interactions between the cavities. As you scale up, you're testing, testing, testing to ensure that all the combinations of plastic and other components continue to produce the same FTF and consistent drug delivery over a consistent timeframe."

Making Combo Products

Containing from seven to 15 molded components, three to five purchased components, and the drug cartridge itself, Phillips-Medisize's combination products are made primarily of plastics. Each incoming component is validated and then subjected to a control plan to manage variability so that every part is of known quality and capability. Producing an end product to specifications always comes back to the process window at which the device is validated and how that window is controlled to ensure uniform product output time after time.

In addition to validating a combination device's physical and mechanical components, engineers must characterize the active agent itself. "Whether the drug has been chemically synthesized or it's a biologic," Welch says, "it all starts with characterizing the drug and what it takes to deliver it in a consistently timed fashion--whether it's an autoinjector, an inhaler, or a patch system." However, because biologics typically have larger molecules than synthesized drugs, biologic-based combination products can have different viscosities from drug-based devices, requiring different characterization steps.

Testifying to the expanding importance of combination products and the need to ensure that they are manufactured according to quality standards, FDA in February issued a final rule on combination product cGMPs, addressing in particular single-entity devices such as prefilled syringes and copackaged products such as convenience kits. "With the recent publication of 21 CFR Part 4, FDA is going to put more and more emphasis on quality structures as they relate to the manufacture of combination products," remarks Cheryl Norder, director of quality and regulatory at Phillips-Medisize. "The greater focus on companies making these products over the next several years will ensure that they have the controls in place to effectively manage both the device and the drug or biologic." While devices are still regulated separately from drugs and biologics, these diverse elements are now being focused together, Norder adds.

Future Challenges

The advent of 21 CFR Part 4 is a tacit acknowledgement that manufacturers of combination products will face a range of unique challenges in the next few years. These challenges, according to Welch, will include the incorporation of electronics, miniaturization, usability, and cost.

While few combination products fabricated by contract manufacturers currently incorporate electronics, electronics are being integrated into some of these products to achieve enhanced drug-delivery performance, data logging and collection capability, and user interface functionality. "Merging combination products and electronic components is a really interesting area," Welch notes. "But rather than just having to work on understanding interactions between the drug formulation and the mechanical aspect of the assembly, with electronics and usually software, you have more things that have to work together, increasing device complexity by an order of magnitude."

By the same token, Welch adds, whenever manufacturers start bringing electronics into the mix, the cost, size, and complexity of the device go up. In addition, they have to manage such factors as battery and shelf life. And to further complicate matters, they also face disposability and recyclability concerns to ensure that their combination products maintain a good, green profile.

On the miniaturization front, molders will have to develop expertise in micromolding and precision injection molding as part of the quest to reduce variation, Welch says. Reducing variation means achieving greater cavity-to-cavity repeatability in the injection-mold tooling and greater shot-to-shot repeatability in the molding machines themselves. "This area isn't undergoing a revolution," Welch adds, "but toolmaking equipment and injection molding machines are evolving. Thus, companies must invest in technology if they are going to be able to operate on the cutting-edge of combination products."

Engineering usability into combination products and designing for the patient will also continue to receive more and more emphasis in the years to come, Welch says. "The reason for this is that manufacturers are trying to make their devices smaller and smarter. And if you try to make things smaller and smarter and easier to use, how do you get there and still keep the device safe?"

Another major challenge facing manufacturers of combination products will be controlling costs. "Whether we're dealing with generics, an existing drug being put into a new combination-product package, or a new drug, the overall emphasis is on therapies aimed at improved patient outcomes and a reduced cost of healthcare. Thus, in the future, we will be trying to get smaller, smarter, less expensive in everything we do, and that will be challenging." --Bob Michaels