Medical device industry suppliers and outsourcers are helping to enable the latest drug-delivery tech.Drug-eluting technologies are moving beyond stents, thanks in part to the development of polymeric hydrogels engineered to respond to a range of different physical and chemical stimuli.
Medtech innovators have figured out how to use hydrogels as components of micro-shells or nanoparticles to assist with controlled, long-term drug delivery. They’ve also figured out how to take soluble polymers integrated into the coatings for drug-coated balloon and use them as excipients to optimize short-term local drug delivery.
In nonvascular applications, specialized polymers have been used for drug release in the eye and in 3D matrices for tissue engineering and stem cell applications.
Add to that the need to encourage better compliance, and drug-delivery technology is booming. The global market, valued at about $200 billion this year, is expected to near $300 billion by 2025, according to Research & Markets.
A range of new uses are making their way through the pipeline, according to experts at suppliers and outsourcers – everything from treating glaucoma, to contraception, to helping implanted sensors and rhythm control devices work at a higher level.
And as the technology advances, future uses could include treating organs and diseases in the body beyond the vascular system, Ingolf Schult, director of business development & clinical affairs at Freudenberg Medical/Hemoteq, told Medical Design & Outsourcing.
Medtech companies are feeling increased pressure to get drug-delivery technologies to market; suppliers in turn are seeking to improve drug-eluting polymers, shepherd pharma companies through the device world and improve manufacturing capabilities to lower risk and cost and increase quality.
Here are some of the product development and technological challenges – and solutions – facing drug-delivery technology companies and the suppliers:
1. The need to determine primary modes of action
At the beginning of any conversation with a supplier, the device maker should know the primary mode of action.
“Combination products typically fall into one of two buckets,” explained James Arps, director of pharma services, ProMed Pharma. “If the device is the primary motive (mode of) action and the drug is secondary, then representatives from the device side of the FDA will usually be assigned lead the regulatory assessment, with support from [the Center for Drug Evaluation and Research]. If the drug is the primary actor, then CDER usually takes the lead.”
Combination products include steroid-eluting electrodes for cardiac pacemakers and implantable sensors. In these cases, the drug’s application could be to minimize fibrous encapsulation, Arps said.
“Simply put, you’re trying to mitigate the effect of delivering an implant into the body, how it scars over,” he told us.
Pharmaceutical experts can also infuse devices with antimicrobial or antibiotic agents to prevent infection, or with bioactive agents to encourage bone regrowth and fusion, Arps said. Or the drug might be part of an intrauterine device, an ophthalmic drug-delivery implant or subcutaneous implants.
Determining the primary mode of action determines how the FDA will manage the approval or clearance process. Arps noted that most product developers have a good sense of which path the federal safety watchdog is likely to use because “the statutes and guidances are pretty clear.”
2. Other product development challenges
There are other hurdles when it comes to developing drug-delivery products. Many are similar to what any medtech developer faces, according to Schult. Crossover issues encountered by manufacturers of some combination products – those with primary “device” and secondary “drug” functions – include increased time to market, “up to 10 years from project ideation to global roll-out,” decreased value for incremental improvements and extreme price erosion.
Arps sees additional development challenges, particularly when a pharmaceutical firm attempts to make a device, or vice versa. Pharma companies might not be familiar with the intricacies of device development; unfamiliar processes, such as managing design history files, require a learning curve.
“We try to help them as much as we can, but being more of a contract developer/manufacturer, we don’t own the design of the product, so we have to work with them closely to make sure that all happens appropriately,” he said.
Joey Glassco, global market manager at Lubrizol, said working with both pharma and medtech companies can be a challenge because “it literally is two different languages.” For example, she said, when pharma companies look at clinical trials they’re looking for parameters that have nothing to do with the parameters set by the medtech company. From a supplier standpoint, it helps to have expertise in both company’s requirements, Glassco said.
3. Knowing your polymer options
The technological challenges can be very complex, Arps said, especially making sure a drug is matched with the right polymer and release rate. Although each supplier might have a different idea of how to accomplish that, there are many similarities in how they approach the challenge.
Bruce Frank, VP of project management & operations at Lubrizol LifeSciences, explained the most common polymer options for drug delivery, including ethylene-vinyl acetates (EVA), thermoplastic urethanes (TPU), polylactic-co-glycolic acids and polycaprolactone.
The first two are biodurable, meaning they don’t degrade within the body; the second pair are biodegradable, meaning water and enzymes in the body eventually break down and absorb them. Frank also noted that silicones are increasingly used for their ancillary benefits, such as ease of manufacturing for injection molding and long-term biostability.
Lubrizol’s contract development and manufacturing services division tends to prefer TPU because it can be modified for physical and chemical properties, he said.
“We can more easily tailor the exact properties we want into the polymer to give us the drug elution profile we’re looking for. What we found really is that every drug and every drug-delivery profile can benefit from having a polymer with different physical and chemical properties.”
4. The need to build expertise
A deep knowledge base is a priority for suppliers. ProMed put a lot of effort into constructing a library of experience, according to Arps, including investments in internal R&D to evaluate materials. The company partners with suppliers to assess new materials, analyze the initial formulation development and screen and test products for clinical studies or commercial use. That knowledge base cuts down on development time, he noted, so that the company can anticipate and minimize problems, such as degradation of the drug during processing, for example.
“If you have manufacturers that have these capabilities that can plug them in on an as-needed basis and have this flexible manufacturing capability – that’s going to be critical to future planning,” noted Mark Gordon, product manager at Trelleborg Sealing Solutions Americas Healthcare & Medical. “For instance, we have subsets of materials that we can use, say for small-molecule drugs, such as liquid silicone rubbers that lend themselves toward formulation with certain active ingredients. There are different polymers that can be used, primarily silicone, but in some cases other polymers that can be used as rate-release controls. All of these things work in conjunction and need extensive data to support the product specifications.”
5. Determining release rates
There are two primary configurations for implanted release reservoirs, Gordon said. In one, a matrix, such as a silicone collar, “could be mixed with dexamethasone acetate, for example, for devices like pacemaker leads.” These drugs are designed to be effective for a short time, say six to 12 weeks, after which there’s no longer a need for them because as the surrounding tissue heals the inflammation goes down, he said.
The second set of products requires release rates that can dose the drug over months or even years. Those products, Gordon explained, require a “throttle” of some sort to control the rate of release.
6. Shelf life
Shelf life for drug delivery is also a big issue, Frank said.
“You want to get at least two years of stability and still maintain potency,” he said.
Stability tests should be run in early prototyping, he advised, and ideally should run at least one year longer than the requirements call for. He said calculating for chemical stability is a concept that is new to medical and a continuous challenge.
As the drug-delivery technology moves forward, Gordon said the drivers for better costs, higher production speeds, faster time to market, increase quality and risk reduction won’t change. But he also predicts an increased move to personalized medicine. That will mean even more pressure on suppliers for rapid development, turnaround and qualification.
“We as manufacturers will need to be able to plan for personalized medicine to provide pharmaceutical and drug related products on a more custom basis,” Gordon predicted.
Steve MacMillan took over as CEO of Hologic in 2013, drawing on his experience at medtech titans like Stryker and Johnson & Johnson. Since then, Hologic has grown into a $3 billion business.
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