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Jennifer Markarian is manufacturing editor of Pharmaceutical Technology.
Wearable and smart devices allow user-friendly subcutaneous drug delivery.
The trend to self-administered, home-based, subcutaneous drug delivery is creating a need for drug-device combination products that are easy to use correctly and designed with patients in mind. Patients may be familiar with prefilled, handheld autoinjectors or pens. Another type of device, not as familiar today but perhaps soon to see broader use, is the wearable autoinjector, which is attached to the skin to inject a larger volume dose over a matter of minutes, compared to seconds for the smaller dose of a handheld injector. The increasing use of biologics that must be delivered in larger-volume doses is creating a growing need for these larger-volume, wearable autoinjectors, which may also be called patch injectors, large-volume body injectors, on-body delivery systems, or wearable bolus injectors (WBIs).
Choosing a wearable injector rather than a handheld injector depends on the injectable volume and injection frequency, says Ian Thompson, vice-president of business development at Ypsomed Delivery Systems. “We believe the key applications for patch injectors will be in the 3–10 mL space for monthly or quarterly autoimmune or immuno-oncology therapies,” he notes. Ypsomed is developing YpsoDose as a prefilled, ready-to-use, patch injector for antibody-based drugs in the range of 3–10 mL (see Figure 1). Functional devices for testing are available, and the company is engaging in feasibility trials with pharma companies, says Thompson.
Using platform technologies that can be easily customized for multiple therapies is important for manufacturing cost-efficiency, which is particularly important for drugs that target smaller patient populations and thus have low annual quantities, notes Thompson. Ypsomed produces devices for multiple products and customers from the same tooling and equipment. In addition, the electromechanical drive system is programmable for different viscosities or fill volumes. This drive system ensures consistent flow rates, which allow reproducible injection times, and the electronic circuitry is already in place to provide connectivity. The devices are designed to hold standard, 10-mL glass cartridges that are filled in a ready-to-fill tub format.
Sorrel Medical is developing single-use, prefilled wearable injectors in configurations ranging from 1–20 mL. “The 3-mL device configuration has been fully verified and validated and is available for performing feasibility testing by our pharmaceutical partners,” says Andrei Yosef, CEO of Sorrel Medical. “The 20-mL device has working prototypes available. The other configurations are in the earlier stages and can be developed to commercialization with a partner.” Yosef notes that all the devices are based on the same pumping mechanism, with slight modifications to the outer shelling to accommodate different sized primary containers. Using a platform solution lowers risk in development and commercialization, adds Yosef.
Subcuject is developing a platform for prefilled WBIs to deliver 1–10 mL of drug using an osmotic pump, which is a fully mechanical drive, without electronics. “Osmosis can create a high drive pressure and it is, therefore, not a problem with high viscosities or high tissue back pressure, which can be a problem with electromechanical devices. The injection flow rate is around 1 mL per minute for viscosities up to more than 50 cP,” explains Jesper Roested, CEO of Subcuject. Eliminating the electronic component also eliminates the limitations of battery life in cold storage conditions and reduces the environmental impact of disposal, he says. The company is currently testing performance of functional device models, and the device is expected to be ready for regulatory development by the beginning of 2020. The WBI is designed to have low cost of goods, and assembly and filling is straightforward, says Roested. It is also designed to promote uncomplicated development at pharma companies by using a standard glass cartridge with a plunger of standard material.
The enFuse On-Body Infusor from Enable Injections, shown in Figure 2, is being developed as a device platform for volumes from 5–50 mL, says Matt Huddleston, Enable Injections executive vice-president and chief technology officer. A unique aspect of the technology is the use of a constant-pressure design using an elastomeric pump, rather than a constant-flow design using an electromechanical pump. “This design allows the enFuse to automatically adapt to the injection site back pressure, and it is hypothesized to potentially alleviate infusion site leakage and pain,” notes Huddleston. The company received a US patent in March 2018 for its expandable elastomeric bladder and infusion cannula system, and additional patent applications are pending in the United States and other countries. Apellis Pharmaceuticals is conducting human clinical trials using enFuse technology to deliver its immunotherapies, and biopharmaceutical company UCB entered a development agreement with Enable Injections in November 2018 (1).
West’s SmartDose technology platform (see Figure 3) is an on-body infusor that uses a Daikyo Crystal Zenith cartridge and a Flurotec-coated piston containment system. A combination product from Amgen for a single, monthly dose of Repatha (evolocumab) using West’s SmartDose technology was approved by FDA in July 2016 (2). In January 2019, scPharmaceuticals announced that it had completed preliminary feasibility studies of its Furoscix (furosemide) with the SmartDose Drug Delivery System and was moving forward with development in anticipation of filing a new drug application in 2020 (3). West also announced a collaboration with fill/finish provider Swissfillon, to provide bio/pharma customers with clinical fill/finish capability with the SmartDose technology (4).
Most wearable injectors are designed to use conventional primary containers. A new development program from SCHOTT is aimed at bringing design freedom to the container, which the company says can give manufacturers the ability to improve the design of wearables. Customized designs could reduce the container size to make the device more discreet, for example, or add dimensional features (e.g., a ring, bar, or notch) to the container to improve alignment and allow easier assembly or improve the connection force between the container and device, explains Tom van Ginneken, global product manager at SCHOTT. Such containers would use standardized tub-and-nest transport packaging for the filling step.
The move to self-administration at home rather than in a clinic makes communicating information to patients crucial. Devices designed for self-injection can incorporate “smart” sensors and mechanisms to communicate information from the device to the user. Furthermore, wearable injectors can be connected through the Internet, typically using near-field connectivity (NFC) or Bluetooth, to communicate information through a smart phone or other connected device to a patient or to others, such as their medical team.
On Sorrel Medical’s devices, for example, smart sensors “include air and occlusion detection, needle position, ensuring the primary container is in place, and on-body detection, in addition to a series of internal system checks,” says Yosef. In addition, Sorrel’s devices have integrated NFC and Bluetooth connectivity.
In the enFuse device, a gauge and the button mechanism give active feedback to the patient for delivery progress and end-of-delivery cues, says Huddleston. “Beyond this, an option in development for connectivity will be capable of interfacing with smartphone applications to give information such as the delivery status of the device and the patient,” he adds. “Connectivity could potentially improve patient compliance, verify proper device function, and increase patient safety by identifying possible risks.” Management of confidential patient data, however, is a challenge, and connectivity to a healthcare provider or other party can raise concerns about data privacy.
“Both pharmaceutical companies and device manufacturers are aware of the vast potential in having data from connected drug delivery devices, and how it may be utilized to benefit various patient populations,” agrees Yosef. “We believe the question of how that data will be used is one that must be had with each individual pharmaceutical partner based on the molecule, the indication, and the patient population.”
Connected devices are being developed for combination products besides wearable injectors. For example, Haselmeier is collaborating with Common Sensing to develop a smart, disposable injector pen platform. Haselmeier’s subcutaneous drug delivery injection systems for self-administration will be combined with Common Sensing’s Gocap injector monitoring technology to record the time and amount of every injector dose, along with other information, such as storage temperature, says the company (5). Initially the monitoring cap will be an add-on, replacement cap, but is intended to eventually be an integrated device, says Paul Jansen, Haselmeier advisory board member. “Initial products are expected to be focused on clinical trial use. In this environment, patients are engaged and motivated to collect data,” notes Jansen.
Connected devices are ideal tools for disease management, says Sai Shankar, vice-president, Global Digital Healthcare Systems, at Aptar Pharma, which offers both add-on and integrated connected devices for several different delivery routes. “They provide real-time analysis of dose adherence and patterns of dose administration, and they are potentially diagnostic tools to assess patient health and potential exacerbations.” Although the initial cost may be a concern, Shankar believes that the cost of connected devices will come down as increased adoption results in higher volumes. A key challenge for manufacturing connected devices is managing the need for manual assembly of early-stage, low-volume devices as well as the need for automated assembly for higher volumes, he notes. Securing the supply chain for electronic components is crucial, adds Shankar. Selecting known suppliers with medical-grade quality components, dual-sourcing components where feasible, and understanding the total cost of supply are key considerations.
Finding manufacturing efficiencies such as using automation or standard parts (e.g., electronic chip or Bluetooth module) will be important for bringing down the cost of connected products, agrees Jansen. Another challenge is ensuring the electronics and software are compliant, including testing for data security and understanding and minimizing the risk of software bugs. Managing software updates can also be a challenge. “Pharma companies should be prepared for the unique challenges of being accountable for connected products,” Jansen says.
Developers of drug-device combination products should use human factors (HF) studies to ensure that the product can be used effectively and safely and “eliminate or mitigate patient adverse events and medication errors attributable to use-related errors” (1).
“Human factors engineering (HFE) studies are not a ‘check the box’ activity to meet submission requirements,” says Stefanie Johns, Enable Injections associate director of Regulatory Affairs. “Complete response letters for drug-device combination products are most frequently a result of HFE deficiencies. It is up to the marketing application holder to demonstrate safe and effective use of the drug-device combination product by the intended users within the intended use environments. The HFE deficiencies identified by FDA during review are often related to concerns that specific use errors identified in HFE studies may lead to a potential underdose or overdose of the drug constituent part. Without demonstrating that appropriate mitigations have been put in place to resolve these types of use errors, substantial design changes to the device constituent part may be required to gain product approval.”
Failure to adequately integrate the drug and device constituent parts within the overall design and development plan for the drug-device combination product is another problem, says Johns. “The bottom line is that drug and device constituent parts cannot be developed independently or in silos; cross-functional team members from both sides must communicate frequently and transparently.”
1. Enable Injections, “Enable Injections Enters into Strategic Partnerships with UCB and Apellis Pharmaceuticals,” Press Release, Nov. 13, 2018.
2. West, “West’s SmartDose Drug Delivery Technology Platform Selected by Amgen for Pushtronex System,” Press Release, July 11, 2016.
3. scPharmaceuticals, “scPharmaceuticals Inc. Announces Development Agreement with West Pharmaceutical Services for Next-Generation FUROSCIX On-Body Infusor,” Press Release, Jan. 29, 2019.
4. West, “West and Swissfillon to Partner on an Integrated Solution for Clinical Filling of SmartDose Drug Delivery Platform,” Press Release, Feb. 6, 2019.
5. Common Sensing, “Haselmeier and Common Sensing Enter Connected Injectable Medicine Collaboration,” Press Release, May 3, 2018.
Vol. 43, No. 6
When referring to this article, please cite it as J. Markarian, “Putting Drug Delivery into Patients’ Hands,” Pharmaceutical Technology 43 (6) 2019.