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Advances in wearable devices have made it possible to deliver high-volume, high-viscosity biologics.
The majority of molecules in today’s drug development pipeline are biologics, driven by the shift toward personalized medicines. But despite their superior efficacy and safety profiles, biologics present multiple challenges. Biologic drugs are macromolecules that are hundreds of times the size of conventional small-molecule drugs, notes Mike Hooven, CEO of Enable Injections. “They are frequently composed of a heterogeneous mixture of more than 1300 weighty amino acids, thus, creating three main challenges for pharmaceutical companies seeking to develop the next blockbuster biologic--first, biologics are hard to make; second, they are hard to take; and third, they can be expensive,” he highlights.
A large proportion of biologics are injected, in most cases, by intravenous infusion in a hospital setting. Over the past decade, however, self-administration in a home setting has become a growing trend, driven by the increasing focus on patient centricity. Pharmaceutical companies are constantly striving to differentiate their biologic drug products from competitors through the use of innovative drug delivery devices that offer better patient experience and improved compliance, but they are faced with a number of challenges.
Most biologics present as highly viscous formulations that have to be delivered in large volumes, often beyond the capacity allowed by a prefilled syringe or an autoinjector. Also, because biologics are often used to treat chronic diseases, repeated dosing at regular intervals is required. These requirements create a demand for self-administration devices that not only provide safe and effective subcutaneous delivery of high-volume, high-viscosity drugs but also offer convenience and ease of use. As a result, large-volume wearable injectors, which are worn on the skin, have gained increasing interest within the pharmaceutical industry.
“Large-volume wearable injectors enable patient-centered, stress-free subcutaneous biologics delivery--easily, comfortably, and conveniently at home or at work,” highlights Hooven. “These devices are expected to increase patient compliance, influence outcomes positively, and generate cost savings while increasing patient satisfaction. For pharma companies, that is the bottom line in successfully navigating the outcome-based models that health systems are moving toward.” He quotes a former US Surgeon General, Dr C. Everett Koop, who famously remarked that “drugs don’t work if patients don’t take them.”
According to Hooven, cost-effectiveness analyses (CEAs) that are routinely used to determine which medical technologies offer value for money, when applied to biologic drugs, show that variable “subcutaneous delivery” is associated with lower administration costs. “Administration costs are a major cost factor for drugs delivered intravenously; these are costs that could be eliminated,” he says. “Large-volume wearable injectors deliver drugs subcutaneously at significant savings to health systems because they eliminate the costly health facility and health professional.”
“For formulation teams developing injectable biologics, the new drug-delivery technology makes development of stable, bioavailable, clinically relevant formulations easier, faster, and less costly,” Hooven adds. “It can shave months off development time, bringing differentiated products to market faster, cheaper.”
For drug developers, a wearable device can be considered if the biologic can be injected subcutaneously and safely by the patient or caregiver without the need for continuous clinical monitoring, Thomas Mayer, sales manager, Sonceboz, points out. “Typically, one would consider pairing a drug with a wearable device if the intended delivery volume exceeds values that can be administered comfortably with alternative technologies such as autoinjectors,” he explains. “The typical limit for autoinjectors is at a payload of 2.25 mL; therefore, if the required dose is above this value, one could consider moving towards a wearable system that delivers the drug over a prolonged period of time, thereby, enabling the administration of larger quantities without causing injection pain induced by volume.”
Another driver for wearable device technology is time-dependent delivery, Mayer observes. He cites Amgen’s Neulasta Onpro as an example, where the drug has to be delivered at a specific time window after chemotherapy. The on-body injector is applied to the patient’s skin after chemotherapy by the healthcare provider and it automatically delivers the biologic (pegfilgrastim) over a 45-minute period approximately 27 hours after application. The patient can remove the injector when dosing is complete.
“In such cases, the microcontroller inside a device can be programmed accordingly,” says Mayer. He notes that these advanced technologies enable pharmaceutical companies to work with drug formulations that cannot be delivered with prefilled syringes or autoinjectors due to their high viscosity or high dosing volume requirement.
Volume is obviously a key consideration when developing a wearable drug product. “For patch type devices, the volume can start at 1 mL up to 50 mL,” Mayer says. Nonetheless, he cautions that while it is possible to have more than 20 mL in a wearable device, one needs to consider that devices become larger when they have to accommodate higher payloads, and a bigger device will be less comfortable and concealable for the user.
Another crucial consideration is the primary container. “In order to make easy-to-use devices a reality, it is important that the drugs are stored in suitable primary containers,” Mayer says. Ultimately, the aim is to ensure that the stability and quality of the drug is maintained throughout its shelf life.
Graham Reynolds, vice-president and general manager, Global Biologics at West Pharmaceutical Services highlights that a wearable injection technology should be regarded as an integrated system. “It starts with an understanding of the interface between the molecule and the container and incorporates a thorough understanding of the needs of the patient, to ensure effective drug delivery and optimum patient outcomes,” he explains. He recommends partnering with a company experienced in the selection and supply of high-quality container systems for biologics, which often incorporate fluoropolymer-faced closures and polymer containers. “It is important that this consideration is not made in isolation and that the integration of the container with the device is considered early to optimize performance,” he says.
Systems currently approved on the market are either using a container that is part of the device and then loaded with drug by the user via a syringe, or one that works with a proprietary container system, observes Mayer. “We are convinced that future devices will work with proven primary containers such as cartridges and vials. This reduces the validation burden and helps pharma companies to leverage on existing fill/finish infrastructure.”
According to Reynolds, today’s advanced drug-delivery systems are complex pieces of technology that can incorporate innovative and intuitive features to potentially make it easier for patients to self-administer critical medications. This shift, however, has created an interesting challenge, he notes; while self-administration technology becomes more complex, it must easily integrate into a patient’s life. Reynolds stresses that key to this mission is providing drug-delivery systems that are:
“Medication adherence is a complicated, ever-evolving puzzle,” Reynolds says. “How patients view and use their drug delivery system is one important piece of that puzzle and can significantly impact whether they stick with prescribed treatment regimens.” But he believes that the adherence challenge can be addressed when pharmaceutical companies work collaboratively with their device partners early in the drug development process to design delivery systems that patients not only can use safely, effectively, and reliably, but want to use.
West has developed the SmartDose drug-delivery platform with extensive human factors testing and analysis to understand the interaction between the patient and the delivery system. The system adheres to the patient’s body, usually on the abdomen, allowing patients to be hands-free during administration. “The SmartDose drug-delivery platform also offers a variety of integrated solutions for delivery and containment, featuring a silicone-free Daikyo Crystal Zenith cartridge and a FluroTec-coated piston containment system,” says Reynolds. “This combination was chosen to provide an optimum system for drug containment, as well as a high-precision system that helps facilitate reliable injection performance.”
In addition, to help address barriers to adherence, West collaborated with HealthPrize Technologies to develop a connected health offering that is designed to improve and reward medication adherence with unique technologies in a gamified environment. “The West and HealthPrize offering integrates HealthPrize’s Software-as-a-Service (SaaS) medication adherence and patient engagement platform into injectable drug-delivery systems with an app that tracks and rewards patients for taking their medication,” Reynolds explains. “By leveraging connected health in chronic disease management, including incorporating apps and other systems that add positivity or ‘gamify’ treatment regimens into integrated drug delivery, patients will have new motivation for caring for themselves, in both incentive and accountability, and clinicians will be able to better monitor patient data and medication adherence.”
Sonceboz’s devices platform is unique in that it-aside from a single 6-mL container large-volume injector-provides pharma companies with novel options such as dual-cartridge injectors for combination therapies or payload extension and automatic reconstitution injectors that enable the patient to perform complex drug delivery from lyophilized drugs at home. “Although in-part still under clinical investigation, and currently administered intravenously, we see the potential use for dual-drug combinations especially in immuno-oncology, where two or more proteins are administered in combination, for example, the checkpoint-inhibitors PD1 and CTLA4,” says Mayer. Dual-drug combination could potentially also be useful in cases where co-formulation of drugs is not possible for reasons of stability.
“For automatic reconstitution, our device will be preloaded with both the lyophilized drug and the diluent stored in standard primary containers. Upon activation, the device starts a reconstitution cycle, mixing the diluent with the drug, and then injecting the reconstituted drug into the patient. This capability is a great benefit because it eliminates multiple use steps such as the external connection of the drug containers to the device, therefore, enhancing patient comfort and safety, which ultimately improves quality of life and therapeutic outcome,” he adds.
“Our three devices out of one platform design approach centers around usability for patients and compatibility with existing pharmaceutical infrastructure,” Mayer says. “Each device design builds upon proven standard containers ranging from cartridges to vials. We are partnering with experts in primary packaging and assembly to provide a streamlined integration into existing filling processed.”
Ypsomed’s large-volume patch injector, YpsoDose, allows patients to self-inject antibody-based drugs in the range of 2–10 mL. The device is not an infusion pump, which takes hours or days to administer the drug, Ian Thompson, vice-president, Business Development, Ypsomed, points out. “Instead, it is designed to be worn for up to 30 minutes during the injection,” he says, adding that for ease of use, YpsoDose comes prefilled with the drug cartridge to minimize user steps and simplify handling.
In addition, YpsoDose has a proven and robust electromechanical drive mechanism, which can be customized to a range of drug volumes, viscosities, and flowrates. The system also controls needle insertion and the needle safety mechanism, Thompson highlights. When the patch injector is attached to the skin, the device senses skin contact and needle insertion and injection is initiated by pressing a button. YpsoDose also has the functionality to communicate with the patient or caregiver via audio and visual signals before, during, and after the injection.
Pens and autoinjectors have standardized drug reservoirs, typically 3-mL cartridges and 1-mL or 2.25-mL syringes, respectively, notes Thompson. “A key aspect of YpsoDose is the careful selection of a standard drug container that interfaces with the sterile fluid path,” he says. “In close collaboration with pharma companies and specialist suppliers, Ypsomed has selected 5-mL and 10-mL cartridges with vial stopper closures that interface with the proprietary needle unit, which contains the injection needle and fluid path.”
“Right from the start we have focused on using standard drug reservoir components that have been specified in collaboration with pharma customers, glass/elastomer manufacturers, filling equipment companies, and contract fillers. This approach provides customers with an ‘open source’ drug container that facilitates the drug formulation and stability testing processes,” Thompson explains. “The integration of the cartridge system with the proprietary needle unit, skin sensing patch, and electromechanical drive as well as patient interface combine to generate a unique system that can be industrialized for a range of customers based on the same basic YpsoDose product platform.”
The patient interface and size and weight of the device need to be carefully tested with patients, Thompson asserts. “Human factors studies to date have shown that the technology is well understood and accepted by patients and that they can handle YpsoDose easily,” he says.
Enable Injections has developed the enFuse wearable platform, a disposable wearable infuser that delivers high-volume (up to 50 mL), high-viscosity drug (biological) products to the subcutaneous tissue. According to Jeannie Joughin, executive vice-president and chief commercial officer, the enFuse is smaller than other wearable devices. “The 10-mL device is about the size of an Oreo cookie,” she says, adding that the small size-to-volume ratio could be achieved because the device does not incorporate a separate rigid container closer and mechanism to extract or deliver the treatment; hence, it is more comfortable and discrete to wear under the user’s clothing.
The enFuse has the functionality for automated mixing and reconstitution of lyophilized drugs, which removes patient variability from the mixing process. The smallest possible needle size is used but it can still deliver highly viscous drugs, Joughin highlights. “Because the patient never sees the needles, injection anxiety is reduced,” she says.
Joughin explains that the platform has also been optimized to provide dosing flexibility, including a multi-vial system or syringe filling system for weight-based dosing. A unique feature is the ability of the technology to respond to each patient by adjusting the injection flow rate for minimum pain. Moreover, the device comes with a “pause” functionality. “Connectivity enables data capture via an app to aid in monitoring of patient compliance,” Joughin says, adding that the enFuse can accommodate any pharmaceutical primary container closure, hence, eliminating the need for new container closure stability studies.
Vol. 31, No. 4
When referring to this article, please cite it as A. Siew, " Wearable Injection Devices Address Delivery Challenges" BioPharm International 31 (4) 2018.