SPECIAL FEATURE – Injection Devices: Designing in Sustainability, Usability & Digitization for Patient Compliance
The global injectable drug delivery market could reach more than $1 trillion by 2030, fueled by the prevalence of life-threatening diseases, the development of smart wearable devices, and the Internet of Things (IoT), which makes it possible to collect valuable data directly from injection devices.1 Prefilled syringes, autoinjectors, and pen injectors are all expected to become more popular as pharma companies seek alternatives to oral dosage regimens and deliver long-acting drugs in an effort to improve patient compliance.
Drug and device developers do face a bit of an uphill battle as they tackle challenges related to delivering viscous and large-volume biologics, preserving the integrity of sensitive formulations, regulatory issues, and manufacturing scalability. “Intravenous therapies are often cost-intensive and require certain patient compliance to achieve cost-benefit targets,” says Markus Hörburger, Product & Service Manager at Vetter. “To simplify adherence and patient convenience, many companies with products that fit this profile are reformulating their therapies for subcutaneous delivery. While that step has upsides for patients and drug owners, it can present some significant technical challenges for current injection device formats.”
Cecile Gross, Global Category Manager, Parenteral at Nemera agrees: “A user-friendly device for a seamless delivery fosters patient acceptance. But high-viscous biologics increase administration challenges as it is related to a patient’s pain perception. We need to make sure that subcutaneous administration is not painful to increase compliance and adherence.”
Viscous and/or large-dose products require devices configured to manage much higher delivery-related forces, extended injection times, or both. Meeting those specific requirements can mean extensive device customization, additional development and QA processes, and numerous other cost- and time-intensive investments. Mr. Hörburger says: “Drug owners need to consider these factors as early as possible in their therapy’s path to a combination product format.”
Experts say another consideration is smart or connected devices that play a key part in patient adherence. The challenge is embedding the technology to be as user friendly as possible. “Digital health adoption requires the addition of connectivity without adding complexity to the devices, all in an effort to manage disease and treatment,” says Ms. Gross.
And there also exists a balancing act between usability and sustainability. Developers face the challenge of growing concerns over the disposability as many devices are intended for single-use and need to be discarded after use.2 Efforts are being made to ensure reusability and recyclability into the device design.
“While sustainability is a growing priority across the biopharma industry, disposable injection devices present a direct challenge to this greater goal,” says Mr. Hörburger.
This exclusive annual report from Drug Development & Delivery highlights how leading device and drug companies are working to address the challenges of usability, sustainability, and technology to increase patient compliance.
In the pharmaceutical industry, the safety and efficacy of injectable drugs are paramount. One of the leading causes of recalls by the FDA for injectable drugs is particulate contamination, which can lead to adverse reactions. As the industry evolves and regulatory standards become more stringent, manufacturers are under increasing pressure to ensure the particulate cleanliness and safety of their products. Furthermore, with the prevalence of biologics and biosimilars in development pipelines, it is primordial for drug manufacturers to reduce their development risks and select a partner that will accelerate their access to the market, says Estelle Verger, Business Development Senior Manager, Aptar Pharma.
The recent revision of Annex 1 by the European Medicines Agency’s Good Manufacturing Practices (EMA GMP) has further underscored the importance of contamination control. This revision mandates that manufacturers not only have a robust contamination control strategy in place for their operations, but also extends this requirement to their upstream supply chain.
As a leading manufacturer of closure components, Aptar Pharma developed PremiumFill® – a state-of-the-art solution in the realm of elastomeric closure components for injectable drugs, she says.
“Manufactured in ISO-classified cleanrooms and utilizing state-of-robotization, PremiumFill vial stoppers and syringe plungers offer improved specifications on particulate, fiber contamination, and overall product quality,” she says. “This ensures that patients receive injectable drugs that are both safe and effective by minimizing the risk of contamination. This also supports pharma customers in demonstrating the implementation of a comprehensive Contamination Control Strategy in compliance with Annex 1 revision. Additionally, PremiumFill can significantly reduce scrap rate on fill-finish lines, leading to cost savings and increased production efficiency.”
A recent case study, conducted by a leading injectables manufacturer, showcased the tangible operational benefits of PremiumFill. Upon integrating PremiumFill into their filling operations, the manufacturer reported a decrease in scrap rate by more than 20%, without requiring any process adaptation, explains Ms. Verger. “A deeper dive into the data revealed that the primary contributors to this reduction were related to fiber contamination and staining of the elastomer – both of which are comprised in PremiumFill’s enhanced specification,” she says.
To further improve their operation and fully leverage the advantages of PremiumFill, drug manufacturers can choose Aptar Pharma’s Ready-to-Use (RTU) gamma-sterilized components. In addition to guaranteeing sterility at the point of use, thus meeting Annex 1 revision guideline for sterility assurance, Aptar Pharma RTU products are packaged in bags without Tyvek, which is a known source of fiber/particle contamination, Ms. Verger explains. Furthermore, PremiumFill product can be packaged in Rapid Transfer Portbags (RTP) that connect directly onto filling lines’ isolators to limit the risk of particulate contamination and facilitate compliance to Annex 1 revision regarding contamination control.
She says: “As the pharmaceutical industry grapples with the dual challenges of ensuring patient safety and complying with evolving regulatory standards, Aptar Pharma’s range of solutions help customers achieve operational efficiency and meet ever-increasing regulatory standards.”
BD regularly conducts a combination of primary market research, human factors, and clinical research studies to understand the patient experience, and applies these insights to injection device design and combination product development. BD is focused on high growth areas such as obesity and diabetes, as well as other leading chronic diseases. “We aim to apply BD’s organizational insights on patient experience, together with our injection expertise, to support treatment of chronic disease and transition to new care settings while positively impacting patients,” says Beth McBride DiLauri, Director, Portfolio Marketing, BD Medical-Pharmaceutical Systems.
BD recognizes patient experience can impact adherence and treatment outcomes. With its BD LibertasTM Wearable Injector (still in development) program as an example, the goal is to enable transition of care to new settings by shifting from intravenous (IV) to subcutaneous (SC) delivery. To de-risk that transition, BD conducted patient and pharma interviews as well as multiple generative and formative human factors studies in an iterative cycle to inform usability and patient experience with a wearable combination product. BD also conducted its own clinical study of the BD Libertas Wearable Injector. This study assessed key parameters, including subject tolerability and device acceptability that can impact patient experience. Amongst the findings was the confirmation that 100% of subjects were likely to use the BD Libertas Wearable Injector, if prescribed.3 “We see this as a leading indicator of positive patient experience and compliance,” she says.
In addition to the patient experience, BD recognizes that there are multiple key decision criteria that inform pharma’s choice when selecting the optimal device for a given combination product. BD Medical-Pharmaceutical Systems provides a broad portfolio of parenteral drug delivery systems, including glass and plastic prefillable syringes, safety and shielding systems, and advanced drug delivery systems, including pens, autoinjectors, wearable and on-body injectors. The company also offers a range of combination product development testing services.
One pharmaceutical company approached BD for support after facing significant challenges in the market related to needle-shield removal and syringe flange breakage, seemingly driven by the interface between their chosen primary container and secondary devices, explains Ms. McBride DiLauri. “Leveraging our extensive expertise and a solution consisting of a fully integrated prefilled syringe and disposable autoinjector, coupled with robust supportive data, BD helped the customer address the issues they were facing, leading to a successful filing and regulatory approval for their new combination product.”
BD Libertas Wearable Injector is a product in development; some statements are forward-looking and subject to a variety of risks and uncertainties. BD Libertas Wearable Injector is a device component intended for drug-device combination products and not subject to FDA 510(k) clearance or separate EU CE marked certification.
Catalent is focused on the assembly and packaging of delivery devices to meet its customers’ requirements, thereby supporting the needs of its patients. The company partners with its customers to provide the equipment that is necessary for assembling prefilled syringes into devices. It also provides assembly services both for customized devices as well as for the majority of pre-designed autoinjectors and safety devices.
“When pharma companies come to Catalent for assembly services, they usually rely on its expertise to help guide them through the device-selection process for their therapies,” explains Brian Galliher, Principal Engineer, Catalent Biologics. “Catalent’s experience is based on many years of assembling multiple types of devices for different therapies, and ensuring that the assembly equipment are compatible with patient needs.”
One particular customer posed a unique challenge for Catalent with a therapy that required a treatment volume of 2mL. The original size of the syringe administering this dosage was 1mL, requiring the patient to administer two injections for each treatment, describes Mr. Galliher. “The Catalent team worked diligently with this customer to qualify a 2mL autoinjector, which allowed the patient to reduce the number of injections, increase their safety, and improve the ease of use and overall patient compliance.”
As injectable therapies become more complex, greater challenges arise in delivering these injectables to provide patients and healthcare providers a user-friendly experience. “A syringe with a pre-attached needle (“staked needle”) is the gold standard in our industry, vastly preferred compared to the alternative of requiring the user to attach the needle at the time of use,” says Laxman M. Halleppanavar, Head of Portfolio Strategy and Management, Credence MedSystems, Inc. “There are significant usability benefits resulting from the use of a pre-attached needle, including reduced likelihood of user error in attaching the needle, fewer user steps and shorter preparation time, and compatibility with autoinjectors for device-assisted injections.”
However, there are circumstances that have traditionally prevented use of a pre-attached needle. Drug formulations that either include suspensions and viscous solutions with the propensity to clog a needle or demonstrate incompatibility with steel or tungsten have prevented use of a pre-attached needle because the needle is in contact with the drug during storage. Without the use of a staked-needle syringe, compatibility with autoinjectors becomes limited. The end-user’s experience is therefore negatively affected, which is especially problematic with the ongoing trend wherein delivery of medications moves from formal healthcare settings to administration at home.
Credence MedSystems focuses on identifying problems and bringing innovative design and development to solve these problems and enhance the end-user experience. “The Credence Isolation ValveTM technology solution enables all the end-user benefits of a pre-attached needle to be realized even with drug formulations that pose needle-clogging risk,” he says. The Credence Isolation Valve prevents the drug from migrating into the needle lumen during storage, therefore eliminating the needle-clogging risk. When the user or autoinjector applies appropriate pressure, the valve opens, allowing the drug to travel through the needle into the injection site. The Credence Isolation Valve is pre-mounted into a standard staked-needle syringe prior to filling and the syringe arrives to the filling suite pre-sterilized and ready for filling. Because of the valve’s low profile, typical fill volumes can be achieved for any specific syringe barrel size.
For drugs where compatibility with steel or tungsten is the problem, Credence offers the Stainless Steel-Free Companion syringe. The Credence (SSF) Companion Syringe™ is a derivative of Credence’s Dual Chamber SyringeTM platform, utilizing a front stopper to completely isolate the drug product from any exposure to the needle during storage. “Therefore, despite the formulation challenges, the user still benefits from a pre-attached needle as well as all of the demonstrated usability enhancements that come along with Credence’s Companion® needle-retraction technology,” says Mr. Halleppanavar. At the end of the injection, the user feels and hears an end-of-dose cue in the form of a click, and then the needle retracts into the syringe, preventing accidental needlestick and syringe reuse.
He concludes: “With the end-user in mind and an openness to implementing new approaches, Credence is enabling the gold standard of a pre-attached needle to be employed even with challenging drug formulations. This, combined with autoinjector-assisted injections and Credence’s needle-retraction technology, provides user enhancements to healthcare professionals and self-injecting patients.”
The global injection device market is driven by increasing prevalence of chronic diseases, technological advancements in self-administration, higher occurrences of needlestick injuries coupled with a rise of biologic drug products. All these factors are leading to a rise in the overall use of combination product devices such as prefilled syringes and autoinjectors for drug delivery. Industry has observed a dramatic shift away from the use of glass vials and single-use syringes to prefilled syringes, pens or autoinjectors. The ease of drug administration with these devices has increased patient compliance, which ultimately has been the ‘end-goal’ for these devices.
Not only are the devices evolving, so are the drug products themselves, points out Aaron Liss, Director of Sales & Marketing, DDL, Inc. For instance, pharmaceutical companies are deploying drug mechanisms such as nanoparticles and microspheres in drug suspensions to enhance targeted delivery and control the release of APIs post injection.
DDL is focused on the safety testing of the devices and performing various services for combination product companies. These unique devices (prefilled syringes, autoinjectors, pen injectors) have very specific FDA requirements that are outlined in various guidance documents and standards. One of the rapidly growing and evolving safety tests for injectable devices is Container Closure Integrity (CCI) testing utilizing deterministic methods governed by USP <1207>. CCI refers to the ability of a primary container closure system to maintain product integrity and prevent contamination or leakage.
Historically, combination product companies performed sterility and/or probabilistic ingress methods to evaluate this critical endpoint for regulatory submission. “Unfortunately, sterility and ingress methods have presented inherent issues for the life science industry,” says Mr. Liss. “For instance, sterility and microbial ingress rely on microorganisms and the absence of microbial growth as the ‘indicator’ for a passing result.”
However, false positives and false negatives can easily occur when performing sterility and microbial ingress methods. False positives can result in huge, negative financial impacts for companies if they are not able to invalidate the result and instead are left with no other option than to scrap the lot of product. False negatives hold higher risks because this outcome can result in adverse patient safety events and product recalls. Dye ingress has the challenge of subjectivity when performing it qualitatively by visual inspection. Dye ingress methods are better suited for gross leak detection during a full package validation under ISO 11607, he says.
For these reasons, industry experts began creating and drafting deterministic methods for CCI testing. The four primary CCI deterministic tests include helium mass spectrometry, high-voltage leak detection, vacuum decay, and laser headspace analysis.
These methods do not use biological systems such as microorganisms. Conversely, deterministic CCI methods use highly sensitive analytical equipment to detect leaks down to 1mm, depending on the method. “Deterministic CCI methods do not present the same inherent issues as sterility and ingress methods,” says Mr. Liss. “In addition, the limit of detection for deterministic CCI methods are much more sensitive and reliable once your method is validated.”
Duoject Medical Systems: Safer Self-Administration of Reconstituted Injectables
Duoject has a long-standing expertise in the design and development of injection devices, drug reconstitution systems, safety features, and ergonomics. As a result, the company has been concentrating its efforts on two avenues in recent months. The first area of focus is to create systems that will make it simpler to reconstitute drugs, while the second involves combining drug reconstitution and injection into the same device. Both of these can make it easier to prepare and administer drugs safely at home, explains William G. Fortina, Business Development Director, Duoject Medical Systems. “Additionally, even though these devices are likely to cost more than conventional vial or syringe formats, they will reduce the overall cost of healthcare because they would remove the need for hospital visits or medical assistance. Patients can access more complex products from the convenience of their own homes while saving time thanks to the development of such integrated and user-friendly devices.”
Custom drug delivery systems for clients are a specialty of Duoject Medical Systems. For novel, difficult therapies, custom systems are typically required. The company’s engineering team prides itself on working with difficult drug requirements (like large volumes, high viscosity, temperature sensitivity, etc.) while making sure the systems are user-friendly, error-proof, and safe. “To keep the cost of filling and sterilization processes competitive, we frequently advise clients to use common primary containers like vials, cartridges, and syringes,” says Mr. Fortina. “To achieve the desired outcome, we then create administration or reconstitution systems around these standard containers.”
Reusable systems for injectable medications present challenges, the main one being sterility requirements. Guaranteeing sterility for a single-use injection device is one thing; guaranteeing sterility for multiple use is much more challenging. Reusable injection systems face additional difficulties due to the possibility of needlestick injuries and cross-contamination. To avoid safety and regulatory challenges, he says most of Duoject’s clients choose to steer clear of reusable injection systems.
One notable exception is the use of injection pens, which are commonly used for insulin treatments. Building on this widespread adoption, Duoject has developed a single-use drug reconstitution device called PENPREP EVO. This single-use drug reconstitution device enables users to perform drug reconstitution from a vial and fill a standard 3mL cartridge with the admixture, then subsequently use it with a pen injector of their choice. This allows patients to use their injection device multiple times for ongoing medical care.
In recent months, several clients have approached Duoject to find solutions that combine drug reconstitution and injection in a single device. “There are many advantages to combining these two processes into a secure, user-friendly standalone device,” says Mr. Fortina. “Healthcare professionals would save time on drug reconstitution and administration in hospital settings. Risks from needlestick injuries and dosing mistakes would also decrease. Patients may be able to self-medicate at home thanks to such systems. Benefits in this scenario include time savings (no trip to the clinic is necessary), the ability to complete the task at home without the assistance of a healthcare professional (user-friendly device operation), and possibly improved treatment adherence.”
Enable Injections: Mechanical On-Body Delivery System
Enable Injections’ mission is to improve the patient experience. From the beginning, by designing with the patient in mind, the enFuse drug delivery system has been developed to allow medications to be delivered with a hidden needle, greater flexibility for the patient and provider, and permit mobility during administration. A study published in the past year reports: “This wearable drug delivery device simplifies drug administration and could help address some of the challenges associated with self-injection, such as complicated infusion preparation, needle phobia, and concerns about pain.”4
The enFuse is the first purely mechanical on-body delivery system, which operates silently without a motor or battery. enFuse utilizes elastomeric technology to deliver a low-pressure injection, which may confer potential clinical benefits. In addition, enFuse utilizes the original container closure for the drug rather than a prefilled cartridge. At the time of use, the user inserts the original vial into the Vial Transfer system and the contents transfer completely without further user input.
Patient-centric features include a small, hidden needle, which has the potential to positively impact patient compliance, says Jennifer Estep, Senior Director, Global Marketing & Commercial Strategy. enFuse allows for mobility and flexibility during administration. As the study stated: “Wearable drug-delivery systems have emerged as useful tools for optimal management of chronic diseases because they provide advantages over conventional subcutaneous drug delivery, including real-time drug regulation, and improvements in patient adherence and quality of life.”
Additionally, patients in the study stated unanimous preference for enFuse, due to ease-of-use, increased mobility during infusion, reduced setup time, and reduced pain at the injection site. And, 95% of surveyed patients indicated a preference to switch to enFuse in the future.4
One prohibitive factor for patients is the size of a large-volume wearable delivery device. For patients to use an on-body injector, the device must be easy to use and easy to learn, and be comfortable and easy to handle, especially for those who have dexterity and mobility challenges. The size of a device grows quickly when pumps, batteries, and traditional vials or cartridges have to be incorporated. The larger the device, the heavier it becomes, and the more difficult it can be to ensure it remains adhered to a patient’s skin at the intended location for the duration of the injection, explains Jenn Beeson, Communications Lead at Enable Injections. “A lighter, less bulky delivery device, such as enFuse with its elastomeric technology, allows the patient to have a more comfortable experience,” she says. “In addition, a more discreet delivery device permits the user to go about their normal activities as they wear the injector.”
The enFuse delivery system can administer 5-25mL with a single device, giving pharma companies the option to administer higher volumes subcutaneously. However, due to the complexity of biologic drug formulations, sometimes a higher volume of drug is needed. Ms. Estep says the range of volume offered by enFuse reduces formulation constraints and adds flexibility to dose-finding studies. “Using a large-volume, on-body delivery system, such as the enFuse, may allow a direct conversion from an IV to a SC formulation, eliminating the task of increasing concentrating and enabling faster entry into the clinic,” she says.
Flex looks to partner with customers to improve the user experience and patient outcomes. To do that effectively, it is critical to include a significant focus on HMI – the way that users interact with and experience devices. “The importance of HMI in injection device development cannot be overstated,” says Jennifer Samproni, Chief Technology Officer, Health Solutions, Flex. “As the world becomes more digital and connected, and as the point of care for more patients shifts increasingly toward the home, injection device manufacturers are responsible for ensuring that their products are innovative, efficient, and user-friendly. By focusing on the needs and experience of the full spectrum of end users, and making HMI a priority in injection device design, we can improve patient care, enhance user experience, and ultimately save lives.”
Flex develops injection pens, wearable injectors and pumps, and autoinjectors. One is the Smart Syringe 2.0 platform, which automates data collection for clinical trials, is made from recycled resins and recyclable, and is compatible with existing syringe packages. The other is a voice-controlled autoinjector demonstrator designed to enhance the dose-delivery user experience. The new device pairs with a smartphone app, which guides the user with step-by-step instructions.
“The autoinjector’s HMI design, which provides prompts when needed and allows voice activation to “start” and “stop” the injection directly, addresses users’ issues with pressing buttons on autoinjector devices,” she explains. “By focusing on elegant, user-friendly HMI solutions, we can provide more intuitive and user-friendly experiences for patients who require ongoing management of chronic conditions.”
While improving outcomes and patient experience are important elements for companies to consider, they are not the only ones. Healthcare companies are under increasing pressure to achieve sustainability goals, says Ms. Samproni. The smart autoinjector design platform was designed to enable MedTech and pharmaceutical companies to accelerate time-to-market, reduce costs, and boost reliability while ensuring patient compliance and sustainability needs. The smart autoinjector platform uses numerous eco-smart designs, such as:
- Long-life rechargeable batteries instead of disposable non-rechargeable batteries;
- Secure remote upgrades for firmware on the autoinjector platform;
- Smaller subsystems and PCBA systems that use fewer materials lowers the overall CO2 emissions; and
- Easy disassembly, better-enabling repair, refurbishment, or parts separation for reusing, recycling, or disposal
The design adheres to DfE guidelines and principles by minimizing welding and gluing of internal products during the assembly and manufacturing process, which results in benefits even at the end-of-life stage. Because of the lower contamination of materials being recycled, the design continues contributing to lower waste targets, she says.
Along with eco-smart design considerations, a cradle-to-gate lifecycle assessment is performed to evaluate environmental impacts based on:
- CO2 emissions
- Energy and water consumption
- Recycling rate (percentage of material recycled)
- Recovery rate (percentage of material used to generate energy when the product reaches the end of life)
“By prescribing to DfE guidelines with the autoinjector platform, Flex is enabling an eco-smart circular production model that ultimately reduces waste and generates higher values from resources,” says Ms. Samproni. “These processes are vital as more industries, especially healthcare, continue to move towards sustainable devices that contribute to environmentally focused goals without compromising device reliability and patient safety.”
Reusable injection devices designed to accept prefilled syringes or drug cartridges are improving adherence and treatment outcomes through innovative designs. As these therapy-specific designs are developed, many utilize microcomponents with unique features requiring complex assembly. According to John Wuschner, Vice President Engineering at Kahle Automation, getting these designs from small batch to high-volume production quantities benefits from automation for three main reasons:
Efficient Speed: High volume by definition would make this reason obvious, but the assembly of injection devices requires more than just going faster, it requires a higher level of complexity. Feeding of the components without causing damage is critical here when one considers that disposable needle assemblies are produced at speeds of over 1,300ppm. Ensuring the sharp stays sharp and the functionality of the device is maintained all the way to the customer is challenging at these speeds. “Even the reusable pen injectors themselves with their intricate settable dosage dials have to be carefully threaded together at speeds of 400ppm,” says Mr. Wuschner.
Consistency: Automated processes are designed to mitigate the risks of assembly by having six-sigma process capability proven in advance of application to the line. By so doing, not only is the probability of rejects reduced, but also the key performance indicators of the product can be managed to generate results that perform equivalently lot to lot. Performance consistency in the device translates to shorter learning curves and leads to greater adherence by the patient, he says.
Quality: While process control is paramount, automated systems also benefit from an array of quality controls that can also be integrated at these high speeds. Needle tip geometry can be inspected through computer vision inspection of the tip, functional tests can be performed to ensure patency of the fluid path or proper actuation forces, and even cosmetic indicators can be used to verify that components were manufactured to critical specifications or that the proper components are being assembled in cases where one line produces several variants of a product family.
If identified, a rejected component (or partial assembly) can be segregated from further operations (reducing wasted components) and placed in a controlled container to avoid mixing rejects with valid product. Data can be automatically collected to identify where the defect occurred and cataloged by position, process, etc. to allow trending and data analysis to be performed. This aids root-cause analysis and helps prioritize the continuous improvement process for the line. Coupled with a SCADA system, this data can be automatically delivered to factory support personnel via production monitors and even triggered as alerts on smartphones based on thresholds customized by the user. Products can also be labeled or marked/tagged with lot control features during production or even serialized. In the event of a major non-conformance at later stages, these features allow for easier segregation of suspect product from valid product.
“These three motives for automation together form a foundation for efficient production of devices which, in concert with the device design, help enhance the patient experience through consistency and high reliability while also reducing the overall unit cost,” says Mr. Wuschner.
Patients are at the heart of development and integrated in product design as early as possible at Nemera. Cecile Gross, Global Category Manager, Parenteral, at Nemera, says this engagement allows a better understanding of patient pain points and enables the company to adapt devices to meet their unmet needs.
One of Nemera’s key focuses is its on-body injector platform, SymbiozeTM, to administer complex, large-volume drugs such as mAbs with an adjustable flowrate to fit patient and drug administration profiles. The reusable injection device couples a reusable electronic part with a disposable one; the latter contains the prefilled drug cartridge. “This systems reduces the number of steps for the user and risk of misuse,” says Ms. Gross.
Nemera also offers Safe’n’Sound®, which is intended for novice users as well as patients with dexterity issues. In order to help them manage the removal of the needle cap, Nemera has developed an overcap, an intuitive Rigid Needle Shield remover. Nemera can also offer a “look and feel” customization option, including color coding and biomaterials for a ‘soft touch.’
Finally, PenOne is a disposable, fixed-dose, spring-assisted pen injector platform, which has been marketed across different countries for a variety of applications, including osteoporosis. Ms. Gross says: “As this platform has been developed with patients in mind, it is equipped with an automatic and ergonomic side release button, which allows patients to stabilize their hand during self-administration, enabling the injection of the complete dose. There is no extendable push button at the top of the pen, leading to an adequate total length of the pen. And the fixed dose means there is no risk of under- and over-dosing.” A dose-counter shows how many doses are left in the pen.
She adds that all of Nemera’s devices and capabilities are offered to its pharma partners in a holistic way, starting from front-end development. That includes, but not limited to: the patient journey; technology screening and evaluation; device development and pre-clinical supply; and connected device UI/UX design.
Sustainability is a key area that has grown significantly in importance for many pharmaceutical companies in the past few years. Owen Mumford shares this focus as well as the drive to net zero via Science Based Targets. They are B Corp-certified and have recently developed a new UK manufacturing site built to BREEAM standards.
“In line with these activities, we are also developing a reusable autoinjector that is a companion device for our 1mL UniSafe® safety syringe,” explains Michael Earl, Director of Pharmaceutical Services, Owen Mumford Pharmaceutical Services. Weighing only 5g, the safety syringe is the only disposable element. With a two-year shelf life, the autoinjector has a mechanical design and ensures that the drug can always be delivered to the patient. The device features an LED indicator that shows both dose progression and completion, as well as audible prompts to guide the patient and provide reassurance of successful drug delivery. A lifetime battery supports the user interface so no charging or docking is required, helping to reduce complexity for the user.
The UniSafe autoinjector has built-in connectivity for data exchange between the patient and the healthcare provider, allowing patients to schedule and track their injection regimen to improve medication adherence. Data transfer is via automatic Bluetooth® communication that is initiated when the shroud is pressed onto the injection site, so there are no additional user steps. The device can be used with a smartphone app to provide the patient with information and alerts related to their treatment, Mr. Earl says.
He goes on to explain that changes in formulation are an inherent part of injectable drug development from the early stages through clinical trials and into post-commercialization and lifecycle management. These changes in both volume and viscosity can impact the selection and design of devices for subcutaneous drug delivery.
“At Owen Mumford Pharmaceutical Services, we have created Aidaptus® a single-use autoinjector that provides flexibility for formulation changes in a single device,” he says. Aidaptus can be used with both 1mL and 2.25mL prefilled syringes in the same compact base device with minimal change parts. There is also a choice of springs to allow delivery of a range of viscosities. In addition, using novel auto-adjust plunger technology, the device automatically adapts to different fill volumes during final assembly. Using the same device for variations in formulation helps to streamline documentation, simplifies regulatory filing, and may reduce the requirement for human factors testing. The benefits from an operations perspective are a reduction in SKUs and complexity in supply chain, and in terms of capacity upscale, the same equipment can be used for final assembly. Owen Mumford is collaborating with Stevanato Group for Aidaptus using their combined experience and capabilities to manage the commercial scale up of the device.
Making significant improvements to the 2-step disposable mechanical devices that dominate the autoinjector market is challenging. But there are growing opportunities for reusable devices, especially electromechanical versions that combine the benefits of size, simplicity, and ease of use associated with disposable mechanical devices, with superior visual and audible feedback throughout the injection process and at end of dose.
In addition to reusable autoinjectors employing prefilled syringes with staked needles being used to deliver liquid stable drugs, electromechanical devices can improve patient experience in the preparation and delivery of lyophilized drugs from dual-chamber cartridges. “The need for patients to reconstitute these drugs before use is a significant disadvantage for medication self-administration,” says Tony Bedford, Commercial Director at Phillips-Medisize. “But lyophilized formulation is increasing as it can reduce or eliminate the need for cold chain storage and transportation of biological drugs, which otherwise adds considerably to their carbon footprint.”
He says the recent approval of the Skytrofa autoinjector is a good example of how an electromechanical autoinjector can improve patient experience, and we see growing interest in this format. This autoinjector, designed and built by Phillips-Medisize with a partner company, was developed to deliver Skytrofa (lonapegsomatropin-tcgd), a human growth hormone administered weekly and indicated for the treatment of pediatric growth failure due to inadequate secretion of endogenous growth hormone. Compared to the daily injections required for most other growth hormones, patients on Skytrofa required 86% fewer injection days per year. “The benefits it offers around guidance and support during preparation and administration of the drug have been recognized by several design and innovation awards,” says Mr. Bedford.
Patient compliance relies on minimal user burden and clear feedback to reduce user errors. Phillips-Medisize’s Aria reusable autoinjector provides a familiar configuration for established single-use autoinjector users and a non-intimidating experience for naïve patients, explains Iain Simpson, Commercial Director, Phillips-Medisize. He says: “Drugs requiring frequent injection can increase associated wastage, especially when using a more user-centric device than a prefilled syringe. Reusable devices reduce wastage considerably. During development we performed a full lifecycle analysis that showed reductions of over 50% of the amount of device-related waste compared to disposable autoinjectors.”
Mr. Bedford adds: “Data from existing electronic autoinjectors shows adherence can be improved through their use, leading to better medication outcomes. Furthermore, wireless connectivity and companion digital services can enable better patient support via an app or remote healthcare professional support using real-time use data. Development of digitally-mediated behavioral change techniques is showing promise in addressing medication nonadherence and we expect this trend to continue.”
Replicating the user experience of a predicate device also supports compliance with generic or biosimilar drugs. Phillips-Medsize’s Envoi disposable pen injector provides biotech companies with a cost-effective entry into the generic insulin and GLP1 markets, improved by shorter travel of the activation button, making the device easier to use for large doses or by patients with smaller hands.
Both gentleman see a move towards less frequent administration enabled by the formulation of complex high-concentration biologics with larger viscosities and volumes than previously delivered, but without the need for larger volume delivery systems such as patch pumps. “Electromechanical devices can generate the larger forces required to deliver these drugs, without concern for spring-based devices stalling or inconsistent delivery times impacting patient satisfaction and compliance,” says Mr. Bedford.
Phillips-Medisize is collaborating with a pharma customer to deliver a highly viscous drug that could only be delivered using a mechanical autoinjector or prefilled syringe with a much larger needle. Another customer is looking at partial dosing from a prefilled syringe to increase dosing flexibility, enabling dose titration and a reduced number of SKUs required to support weight-based dosing. Partial dosing might also offer benefits in clinical development where flexible dosing can support dose ranging studies, says Dr. Simpson.
Portal Instruments: PFS Addresses Variety of Injection Challenges
Critical factors in patient comfort and compliance are injection duration and pain. As the market evolves and high-volume and viscous formulations become more prevalent, Portal Instrument’s PRIME device is designed to adapt to those changes while still prioritizing the patient’s well-being, explains Dr. Patrick Anquetil, PHD, MBA, CEO of Portal Instruments. This is encouraged by findings from early clinical saline studies, which demonstrated the PRIME device is notably less painful for self-injection when compared to a 27-gauge prefilled syringe and needle.5
PRIME is a needle-free injection device targeting subcutaneous delivery of 1mL via a hair-sized jet in approximately 0.3 seconds. The device can accommodate a range of viscosities and concentrations while maintaining the same injection duration (~0.3 seconds). He says PRIME addresses injection challenges that arise with needle fear, injection pain, and high viscosity therapies that are often found in patients with long-term injection regimens, including, but not limited to, the areas of rheumatology, gastroenterology, endocrinology, and dermatology.
“Portal Instruments has revolutionized the idea of patient compliance through our needle-free technology,” says Dr. Anquetil. “A patient-centric design coupled with cloud connectivity for real-time tracking and reminders, the device aims to foster adherence to treatment by facilitating communication with healthcare providers. The device’s compatibility with standard pharmaceutical processes and data collection features can empower patients and their care team with insights, driving informed decisions and optimizing treatment outcomes.”
While Portal’s primary innovation revolves around needle-free administration of biologics, patient-centered design inherently aligns with environmental sustainability. PRIME is designed to be recycled after its four-year use life, and the needle-free cartridge can be disposed of in the household trash, eliminating biohazardous sharps waste.
“Incorporating the concept of reusability into the device’s design can provide stability and comfort to the patient as they manage their long-term injection regimens, potentially positively impacting medication adherence,” says Dr. Anquetil. “As new iterations of the device are developed, we focus on ease-of-use incorporating patient and healthcare provider feedback. Through rigorous human factor studies and interviews with disease-specific patient groups and healthcare providers, the device’s design considers various patient challenges (e.g., loss of dexterity).” He adds that recent clinical study results further support Portal’s efforts, with the majority (70%) of subjects selecting PRIME to be much easier or somewhat easier to use than a prefilled syringe and needle.5
For many pharmaceutical companies, developing autoinjectors capable of delivering a highly viscous drug poses a significant challenge. PRIME’s computer-driven technology is designed to allow viscous medications (up to 120cP) to be injected within approximately 0.3 seconds, including repeat injections with a full battery charge. Most notably, the device has been designed to administer medication from the prefilled cartridge either shortly after being taken out of the refrigerator when the drug is most viscous, or even after a longer interval (e.g., 30 minutes), with no change in the injection time. Dr. Anquetil says: “This addresses the consequences that can arise because of prolonged injection durations (e.g., early device removal) and is a game changer for pharmaceutical companies aiming to reformulate their therapies. When a typical autoinjector’s mechanisms fail to accommodate the drug formulation without increasing injection times and larger spring forces, we have provided the needle-free reusable alternative.”
For the past 30-plus years, autoinjectors have enabled patients to take their injectable treatments outside of the healthcare setting. With the pandemic further facilitating a detachment between patients and healthcare practitioners, demands for connected technologies that support at-home care continue to rise. Managing the expectations of patients, healthcare practitioners, policymakers, and payers has therefore become a central issue when developing new digital technologies for home-based treatments.
As with introducing any new technology to the market, there are multiple, sometimes divergent, but always complex, macroenvironmental influences that need to be managed. For self-injection devices in particular, the power of digital health through connecting and digitalizing new or existing treatment modalities is yet to be uncovered, despite the numerous efforts put forth by device and pharmaceutical companies alike.
“The gap between conceptual testing and generating real-world value often impedes innovation,” says Nils Weber, Global Head of Emerging Technologies and Digital Health at SHL Medical. “Therefore, new connected autoinjector solutions should safeguard the same ease of use for patients while also ensuring manufacturability, circumventing potential regulatory roadblocks, as well as offering real value to improving treatment adherence and outcomes.”
To this end, SHL Medical has developed a collaborative Innovation Partnership framework, allowing SHL and its pharmaceutical and biotechnology partners to co-develop solutions through an agile approach. This allows SHL and drug companies to refine product design through an incremental innovation model, ensuring that new solutions cause minimum disruption to the patient as well as the bio/pharmaceutical company marketing the combination product. Driven by its experience with commercializing over three dozen autoinjectors worldwide, including 17 combination product projects from the Molly® modular platform technology, SHL developed the Molly Connected Cap, a compact, retrofittable autoinjector cap add-on that records and transmits data about patients’ use of the product. Upon removal from the Molly device, the Connected Cap becomes active, allowing timestamped data to be relayed through a smart data transmission hub and to the cloud, which provides audio and visual cues to patients on the timing of forthcoming injections. The connection is made via Bluetooth® Low Energy beacon to facilitate seamless data transfer, which means that pairing is not required, and that the patient’s usual injection process is unchanged. An accompanying demonstration software, accessed via either a mobile app or web browser, has also been developed to further provide patients with an assistive interface to their Molly autoinjector, delivering injection reminders, injection history, and scheduled injection information. The Connected Cap was also designed with easily detachable batteries and electronics to support recycling and take-back programs.
Combined with a smart data transmission hub, an app, and cloud technology, the Molly Connected Cap is part of a therapeutics platform that can provide patients with a standalone solution for managing their self-injections, reducing the need for frequent clinic visits, and empowering patients to take control of their treatment, says Mr. Weber. The platform also enables healthcare practitioners to monitor patient adherence remotely and intervene when necessary. With the data collected, care providers and contract research organizations also have the opportunity to review patients’ injection histories, identify any deviations or missed doses, and provide timely support or adjustments to treatment plans.
“The Connected Cap platform has the potential to improve the personalization and efficiency of healthcare delivery, reduce the burden on healthcare practitioners, and enable a higher level of self-efficacy and engagement among patients,” explains Mr. Weber. “With several dozen ready-to-use autoinjectors already commercialized for patient use, the addition of a supplemental connected add-on can help pharma and biotech companies reap the benefits of digital health without significant change to their autoinjector products.”
Stevanato Group is constantly investing in a portfolio of injection devices to meet the needs of patients and pharma companies. Each patient therapy requires a unique solution, and that’s why the company has three very different products in its portfolio – the Alina® pen injector, the Aidaptus® autoinjector, and the VertivaTM on-body delivery system platform.
“Each of the devices serves a different purpose,” says Adam Stops, Head of Product Management for Drug Delivery Systems, Stevanato Group. “They are each tailored to a specific patient need, population demographic, reimbursement model, and so on – all the different aspects of the healthcare industry.”
Stevanato Group also provides contract manufacturing organization (CMO) services to pharma companies to support injection device projects. “Our unique approach as a one-stop-shop provider means we can cover the entire product lifecycle, from concept definition to industrial delivery and final packaging – for faster time to market and reduced total cost of ownership,” he adds.
Alina is a user-friendly disposable pen injector platform for diabetes and obesity care. It is designed for daily or weekly variable and multi-dose treatments and includes an easy-to-dial dosing mechanism, for patient comfort. Visual, audible, and tactile feedback helps ensure correct dose setting and injection.
Aidaptus is a two-step, single-use autoinjector for treating rheumatoid arthritis and cancer. Its versatile design can accommodate both 1mL and 2.25mL prefilled glass syringes in the same base device – so injections can be daily, weekly, monthly, or quarterly. And it can handle a variety of drug viscosities, making it suitable for a range of treatments, including monoclonal antibodies (mAb) and small-molecule drugs.
The Vertiva on-body delivery system platform combines a single-use pod with a prefilled and preloaded cartridge and a multi-use smart controller. It can deliver basal doses with micro-precision or full-content bolus injections, making it suitable for a variety of therapies to treat conditions ranging from cardiovascular and metabolic disorders to cancer and autoimmune diseases.
“mAb treatment is increasingly moving from intravenous injections in hospitals to subcutaneous treatment in the home,” says Mr Stops. “But many of these injections are still fairly large volume – above 3mL – so Vertiva is designed to serve that patient population. The fact that the cartridge is prefilled with the drug and preloaded in the pod also reduces the number of use steps for patients.”
Additionally, Vertiva is designed to strike a balance between reusability and sustainability – and simplicity for patients. The pod with the needle and drug is single-use – but the smart controller containing the electronics can be used multiple times. “The pod just snaps onto the controller using magnetic coupling,” says Mr. Stops. “Simplicity for the patient helps with compliance – and even someone with arthritis in their hands can easily put the Vertiva device together. Our aim with all these devices is to keep things simple for patients to use – as that really helps to encourage compliance.”
There is a growing focus on end-user convenience and devices that support it. Formats like autoinjectors and injector pens offer a range of advantages for patients, from convenient multi-dosing for GLP1 products to easy handling for arthritic patients with compromised manual dexterity. So it’s no surprise that self-injected therapies like these are increasingly in demand. But while CDMOs are eager to meet that demand, they’ve also focused on a closely related challenge: mitigating the environmental impact of these popular devices.
“Eventually, reusable or semi-usable formats will likely become the sustainable gold-standard solution, and these technologies are already being considered and developed,” says Markus Hörburger, Product & Service Manager at Vetter. “But while disposable devices are still the industry standard, there’s much Vetter can and should do to make today’s autoinjector- and pen-based therapies more sustainable overall.”
Rather than focus solely on the devices themselves, Vetter has zeroed in on secondary packaging as an initial opportunity to mitigate the environmental impact of current combination products. Its current capabilities already include a range of alternative packaging materials and sustainable all-paper carton configurations. “Like other CDMOs, Vetter ultimately hopes to see our industry deliver truly viable solutions for sustainable injection technology,” says Mr. Hörburger. “But in the meantime, our focus is on immediately impactful strategies that help us responsibly steward natural resources – while still meeting global demand for a new generation of combination products.”
Wirthwein Medical’s concept and strategy for injection devices focus on supply security, reliability, and ease-of-use for customers, particularly during global crises and disrupted supply chains, which take into account the principle of sustainability, as emissions for unnecessary transport or additional packaging material should be avoided, explains Dr. Thomas Jakob, Managing Director at Wirthwein Medical.
The company’s WIM Ject® ready-to-fill system consists of a syringe with Luer-Lock connection to guarantee a secure connection to standard injection needle and adapter systems. The syringe is specially coated to optimize the gliding and barrier properties and closed with a tip cap. The product is packed in a tub/nest system and then sterilized. All components are based on the ISO 11040 standard and are compatible with almost all existing filling systems in the pharmaceutical industry.
In addition to the syringe system, plungers and piston rods are also offered in various colors. Should customers require individually adapted accessories in terms of design or color, Wirthwein Medical can fulfill their requests and complete the customer portfolio as required. The company is also developing for special applications such as low-temperature applications for mRNA therapies.
“We are investing in the newest technologies, always with a focus on the highest quality,” says Christoph Merhold, Head of Program Management at Wirthwein Medical. “All our developments are focused on improving patient health.”
In tandem with the growing market share of biologic formulations, where higher volumes may be required to deliver the desired effect, the door has been opened to the self-administration of a wider range of biologic therapies via subcutaneous injection for applications that would previously have required multiple injections or intravenous delivery within a clinical setting. Earlier this year, West announced the expansion of its Crystal Zenith® (CZ) component portfolio to now include a 2.25mL insert needle (IN) prefillable syringe system. CZ is a cyclic olefin polymer (COP) that presents a sterile containment solution for protection of sensitive molecules and mitigates the risk of breakage, more commonly associated with glass. The elastomeric FlurotecTM plunger used in the CZ PFS system is coated with a barrier film, which reduces the risk of leachables from the elastomer and prevents absorption of the drug formulation. The film also avoids the need for additional silicone oil to be used for syringe functionality, thereby dramatically reducing exposure to a key source of protein aggregation.
The 2.25mL volume offering is an extension to the CZ 1mL IN syringe system that is currently used in the primary packaging for multiple approved drug products. “As more biologic drugs are formulated to support subcutaneous self-administration, they are often at larger volumes (>1mL) and at higher viscosities,” says Victoria Morgan, Director, Segment Marketing, Biologics at West Pharmaceutical Services Inc. “As market traction on larger dose injections grows, the new CZ 2.25mL IN Syringe System will help pharmaceutical companies bring their product to patients in the most user-centric model possible.”
Modern biologics, such as proteins and monoclonal antibodies, exert demanding requirements on their containment system, which can be difficult to navigate if a platform approach to packaging has been used in the past. A pharmaceutical partner of West picked their platform glass syringe system to package their new biologic drug in development, yet subsequent time pulls of stability samples showed the drug was silicone sensitive which, in turn, made the drug unstable. Analytical testing showed the presence of both visible silicone and protein in the drug product forcing the formulation team to reassess the primary packaging system. The biologic molecule required a prefilled syringe system with as low silicone oil as possible to maintain drug stability, which included both the syringe barrel and drug facing surface of the plunger. In addition, the new containment system was expected to perform as well as a glass system with respect to functionality, which includes break loose, extrusion and gliding forces, injection force, rigid needle shield (RNS) removal force, and container closure integrity. These were critical performance factors as the prefilled syringe system would be used within an autoinjector for the final drug delivery system.
“By using the CZ 2.25mL IN syringe system, West’s partner was able to provide a safe and reliable containment solution to protect the customer’s modern biologic, all the way to administration,” she says. “The drug was stable in the CZ syringe system, and our customer was able to show better results for sub-visible particles with CZ than with glass and other polymers.” The CZ syringe met USP < 1207 > for Container Closure Integrity. Functionality expectations of the syringe system were met, despite the absence of intentionally added silicone oil or other lubricants and no syringe breakage was exhibited. The partner shares: “West & Daikyo have addressed key market needs with the development of silicone oil-free (no silicone was added for functionality) tungsten-free CZ polymer pre-fillable syringe system offering, incorporating a Flurotec plunger. CZ, a cyclic olefin polymer, is a clear, biocompatible material that overcame drug-specific problems associated with glass.”
Ypsomed: Catering to Larger Volumes & Fewer Injections
The self-injection market is not only growing rapidly with many new mAb-based therapies, but it is becoming more complex as injections are dosed less frequently using larger injectable volumes. Ypsomed has recently performed handling studies summarizing whether and how patient characteristics and treatment attributes influence the decision to use prefilled handheld autoinjectors or large-volume patch injectors.6 “Performing such studies is essential to understanding patient preferences and to guide further development of Ypsomed’s large-volume injection platforms,” says Ian Thompson, Vice President, Account & Business Development at Ypsomed.
The company has built up a broad portfolio of autoinjectors and patch injectors based on the YpsoMate and YpsoDose devices. All of these devices are prefilled and preassembled to ensure convenience and ease of use for the patient. Over 15 versions of the YpsoMate 1mL and YpsoMate 2.25mL autoinjectors have been launched by pharma customers for treating autoimmune diseases (i.e., RA, MS, asthma, and psoriasis) as well as for treating migraine, osteoporosis and, most recently, for cardiovascular disease. “They are all contributing to improving patient compliance for a range of patients,” says Mr. Thompson.
Ypsomed developed the YpsoMate 2.25 Pro with constant spring force for more viscous injectables. He says: “Although the majority of ongoing autoinjector projects are for lower viscosities, Ypsomed has a number of ongoing customization and industrialization projects for the YpsoMate 2.25 Pro and is expanding the automated manufacturing infrastructure for future launches.”
Additionally, Ypsomed supplies reusable insulin pens. While Mr. Thompson says reusable injection devices are not as convenient, as safe, or as easy-to-use as prefilled systems, they do allow the opportunity of lowering therapy costs (e.g. for insulin) and the possibility to incorporate electronics and connectivity to be integrated into therapy management systems. In fact, he says there is room for improvement to develop devices for all injectables. “The market for injection devices is growing significantly and typically the same devices are used for originators as well as biosimilars. The main innovations are focused on originator drugs being developed for larger volume, less frequently injected originator drugs.”
- Pharma and healthcare—Injectable drug delivery market,” Reports and Data, Tech. Rep. RND_001382, Apr. 2023. [Online]. Available: https://www.reportsanddata.com/report-detail/injectable-drug-delivery-market
- Demand for Global Injectable Drug Delivery Devices Market Size, Facts & Factors, Jan. 16, 2023, https://www.globenewswire.com/en/news-release/2023/01/16/2589209/0/en/Demand-for-Global-Injectable-Drug-Delivery-Devices-Market-Size-to-Surpass-USD-1683-Billion-by-2030-Exhibit-a-CAGR-of-10-25-Injectable-Drug-Delivery-Devices-Industry-Trends-Share-Gr.html.
- Woodley WD, Yue W, Morel DR, Lainesse A, Pettis RJ, Bolick NG. Clinical Evaluation of an Investigational 5 mL Wearable Injector in Healthy Human Subjects. Clin Transl Sci. 2021;14(3):859-869. doi:10.1111/cts.12946.
- Wasserman RL, et al. Systemic IgG exposure and safety in patients with primary immunodeficiency: a randomized crossover study comparing a novel investigational wearable infusor versus the Crono Pump. Immunotherapy. 2022 Nov;14(16):1315-1328.
- Kelley, E Lynne et al. “Advances in subcutaneous injections: PRECISE II: a study of safety and subject preference for an innovative needle-free injection system.” Drug delivery vol. 28,1 (2021): 1915-1922.
- Understanding patient preferences for handheld autoinjectors versus wearable large-volume injectors, Schneider A. et al, Expert Opin Drug Deliv, 2023, Vol 20(2), pp 273–283).
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