SPECIAL FEATURE – PFS & Parenteral Drug Delivery: Self-Injection is Very Much the “New Normal”
Covid-19 fast tracked the healthcare industry’s growing acceptance of patient self-injection, enabling patients to continue treatment outside of hospital environments and within outpatient facilities and home-care settings. And prefilled syringes (PFS) represent the fastest-growing self-injection segment. In 2021, the global prefilled syringes market was valued at $5.8 billion. Overall, the market is expected to grow to $12.7 billion by 2028.1
“Self-administration of injectable drug products via pen injector, autoinjector or prefilled syringe has been a growing market trend predating the occurrence of the COVID-19 pandemic,” says Eric Lee, Business Development Director, Novocol. “Following COVID, it is anticipated that self-administered injectables will continue to rise as a result of the development of novel therapeutics, biosimilars, and differentiation of existing marketed injectable products. This trend will lead to improved patient convenience while reducing the burden on healthcare systems and practitioners.”
Ziv Cahani, Vice President Business Development and Marketing at DALI Medical, agrees. The industry is well-positioned to keep pace, as there is a growing variety of solutions already available for injectable drug delivery in home settings, and many more in development. These include safety needles and safety syringes, connected injectable delivery devices, and advanced platforms for managing and analyzing compliance. Additionally, device manufacturers are developing unique solutions specifically designed for self-injection – which is very much the “new normal.”
As COVID continues to impact the research and development focus across the globe and the desire to achieve a new normal, August Bioservices expects innovators to invest further in therapies that take advantage of the ready-to-use format. “We know from decades of experience that there has long been a preference for ready-to-use” products, as they are more user-friendly, can help to save time and can help to reduce the risk of medication errors,” says Ryan Downey, Director of Customer Operations, Commercial Development, August Bioservices.
As an example, BD Medical – Pharmaceutical Systems is investing $1.2 billion over a 4-year period to expand and upgrade manufacturing capacity and technology for PFS and advanced drug delivery systems across its six global manufacturing locations, and will add a new manufacturing facility in Spain. The investment is also funding capacity expansion, new product innovations, manufacturing technology enhancements, and business continuity improvements across the existing BD network. “These initiatives are all designed to maximize supply and reduce risk for pharmaceutical companies that rely on ready-to-fill syringes for their injectable drugs – including complex biologics, vaccines, and small molecules,” says Marie-Liesse Le Corfec, Head of Global Portfolio Marketing, BD Medical – Pharmaceutical Systems.
This exclusive Drug Development & Delivery annual report showcases how leading CDMOs and drug delivery developers are responding to this and other market trends to create ergonomic technologies that are patient friendly, easy to use, reduce needle anxiety, and feature improved packaging materials.
With six automated aseptic filling lines, Ajinomoto Bio-Pharma fills clinical and commercial drug products into vials, syringes or cartridges. But before a client’s drug product makes its way to the filling line, there is a tremendous amount of work, focus, and preparation for the aseptic fill. “The operations team cleans, validates, prepares, and plans for the formulation, sterile filtration, and fill of life-saving products,” says Roland Kim, Manager, Drug Product Manufacturing, Ajinomoto Bio-Pharma Services. “In addition, the quality team inspects and tests the aseptic environment in preparation for the fill.”
Aji Bio-Pharma has invested and expanded services with the addition of a multi-purpose filling line for clients needing a quick timeline for scheduling, as well as flexibility in the configuration with the option to fill into vials, syringes or cartridges, expains Mr. Kim. “In addition, we are continuing to offer virtual solutions to help our clients across the globe that may still have travel restrictions or difficulties. These include remote suite viewing, secure document sharing, and remote audits.”
Another difficulty Aji Bio-Pharma has witnessed revolves around supply chain issues, especially with sourcing components. Mr. Kim describes how a large syringe client contacted Ajinomoto Bio-Pharma Services regarding a project with components and fill volumes out of normal operating ranges. “Our drug product subject matter experts were presented with a challenge to order new change parts, create a new fill curve, and validate the process within a timeline that would meet the client’s needs,” he says. “A cross-functional approach was taken to produce a robust and repeatable process for the client’s campaign. Being able to fill syringes that are lighter material and have a wider OVS tip versus the barrel’s outer diameter, and 50% less fill volume, was a success for Aji Bio-Pharma in helping our client achieve its goal.”
ApiJect works with pharmaceutical and biotech companies to fill/finish their injectable drug products into single-dose, prefilled injectors in a highly efficient and scalable way. This is achieved by first designing a Blow-Fill-Seal (BFS) Container that is customized to the specific drug product. Then, a prototype BFS-based prefilled injector is manufactured, tested for performance, and rapidly iterated until the pharma company is satisfied with the results, explains Josh Myers, Senior Director, Supply Chain, ApiJect Systems, Corp. Finally, the ApiJect team helps the pharma company either set up the necessary BFS manufacturing line in their facility or connect them with a contract manufacturer that has the necessary BFS experience and equipment.
ApiJect primarily addresses three major challenges in the US and global injectables fill/finish market.
- Scalability with Efficiency: “Prefilled syringes can be time-consuming to fill/finish and costly to manufacture compared to traditional vials and disposable syringes,” says Mr. Myers. “A high-capacity BFS production line fill/finishes up to 25 prefilled single doses every 3-7 seconds.”
- Flexibility: Traditional parenterals packaging is often confined to existing container sizes and shapes, which can only be manufactured and filled/finished by dedicated plants and equipment that can take years to establish, explains Mr. Myers. “BFS machines leverage molds that can be custom designed and rapidly changed out to produce a variety of shapes and sizes to meet requirements of a broad range of sterile liquids.”
- Compact Supply Chain: BFS-based injectors made on the ApiJect Platform have two primary raw materials (stainless steel for needles, pharmaceutical-grade plastic resin for containers and attachable components). “And the entire fill/finish process, including the primary container manufacturing, can be done under one roof,” explains Mr. Myers. “This short, resilient supply chain enables on-shoring and reliable production.”
As of this time, any device made on the ApiJect Platform has not been cleared by the FDA or other regulatory body. However, the scale, compact supply chain, and flexibility of the ApiJect Platform were outlined in a coordinated project with the US Department of Defense and Department of Health and Human Services in 2020 as part of America’s initial response to COVID-19, descrbes Mr. Myers. “ApiJect and related partners were able to upgrade three existing BFS lines at The Ritedose Corporation within 7 months to be capable of filling and finishing up to 45 million prefilled injectors a month with potential COVID-19 vaccine.”
He adds that while this capacity has not been utilized to date thanks to the success of more traditional domestic fill/finish supply chains, it proved the scale and efficiency enabled by the ApiJect platform, which has led to increased coordination with pharmaceutical, biotech, and contract manufacturing companies. This includes a recently announced project with Fareva to establish three similar-capacity BFS lines at one of its facilities in France for vaccine fill/finish.
Primary packaging plays a critical role in the development and delivery of every injectable drug and offers many opportunities to meet evolving market expectations. Thus, primary packaging manufacturers have been improving their processes and are working with material sciences to develop innovative solutions, such as rubber components laminated with fluorinated films (i.e. ETFE). “While Halobutyl formulations are specifically designed to limit their chemical interaction with therapeutics, ETFE films form an additional barrier that further reduces the transfer of extractables and leachables into the drug product,” says Claire Raynal-Olive, Vice President of Business Development for Aptar Pharma. “Coated components help drug developers meet the stringent requirements of regulatory agencies and reach the market faster.”
Additionally, as the demand for self-injection increases, primary packaging manufacturers must also guarantee that the functional performance of their components (such as the activation and gliding forces) is congruent with patients’ capabilities or autoinjector integration. “Such functional requirements are further emphasized as drug developers work toward reducing the frequency of injection for improving patient compliance and comfort,” she says. “Functionality issues can be avoided by selecting premium components designed to deliver consistent performance, whether for manual injection or autoinjector integration.”
Finally, accelerating time to market while optimizing and derisking operations is of key importance for pharma companies that may also rely on contract manufacturing organizations for performing the final filling steps. Primary packaging’s functionality can be a source of risk for compatibility with filling lines, and therefore a potential barrier to efficient industrialization. “Aptar Pharma’s PremiumCoat® is compatible with both vent tube and vacuum technologies, enabling operational flexibility while facilitating the choice of primary packaging and CMO for pharma partners,” Ms. Raynal-Olive says. “PremiumCoat 1mlL and 1-3mL plungers help derisk the primary packaging selection process so that our pharma partners can focus on their drug development.”
August Bioservices: One-Stop-Shop Fill/Finish
August Bioservices develops and commercializes sterile injectable products. An integrated scientific and manufacturing team are on site and under one roof, making the company a one-stop-shop for clients in early drug development through clinical trials and commercial launch, says Ryan Downey, Director of Customer Operations, Commercial Development, August Bioservices.
Additionally, he says the company offers a flexible fill/finish platform that accommodates a range of prefilled syringe sizes, up to 60mL. “Our fill/finish capability, combined with an on-site analytical services platform that includes extractables and leachables, allows August to accelerate the understanding of compatibility for new drug products, evolving primary container designs, and materials of construction.”
A recent expansion will enable August to offer drug development and manufacturing capacity later this year and into 2023, comments Mr. Downey. “Availability of capacity continues to be challenging for innovators attempting to address unmet medical needs, including COVID-related therapies. This is particularly difficult for companies who are seeking small- to mid-size batch scale and/or have complex formulation and manufacturing requirements.”
Since 2010, BD Medical – Pharmaceutical Systems has conducted more than 80 human factors studies to ensure usability of its drug delivery solutions. Its portfolio features prefilled syringes for administration of injectable or nasal vaccines, as well as integrated devices and systems that can deliver biologics across a range of volume and viscosity levels for treating chronic conditions. The company is also focused on finding solutions for sequentially injecting two liquids with a single plunger push. In fact, BD filed a patent for a system made of a regular robust prefilled syringe that enables such sequential injection thanks to a redesign of a plunger stopper – involving no costly or fragile by-pass system, says Marie-Liesse Le Corfec, Head of Global Portfolio Marketing, BD Medical – Pharmaceutical Systems.
BD also believes connectivity is the future of drug delivery devices and is developing a connected product capable of capturing and transmitting injection-related data. The device will be an optional upgrade of the BD Ultrasafe Plus™ Passive Needle Guard and is intended to support decentralized and hybrid clinical trials. “The product will address patient needs, CROs, and study sponsors for a safe, easy-to-use self-injection device that automatically captures reliable, high-quality, and time-stamped data about the injection event from the patient (who may be self-injecting remotely) to the trial’s selected electronic platforms,” says Ms. Le Corfec.
BD recently teamed up with industry-leading partners in tagging and traceability technologies to develop syringe-specific traceability solutions integrating in broader Pharma 4.0. systems. “By supporting anti-mixupcontrols, reconciliation or root-cause analysis, monitoring of time out of the cold chain, and manufacturing data integration into machine learning systems, this solution is meant to assist increasingly stringent manufacturing lines quality controls and audits while enhancing productivity,” she says.
The company has also partnered with pharmaceutical and biotech companies to develop and produce innovations that enable new drug delivery needs. One biotech company developed a case study on how early collaboration, including needs and information sharing, can give the innovation timeline an earlier start and lead to initial launch readiness in the desired device configuration, working with BD specifically on co-development of the BD Neopak™ XtraFlow™ Glass Prefillable Syringe.
Ms. Le Corfec says: “This early-stage collaboration helped BD develop the right product to meet the drug’s needs (higher viscosity, larger volumes, reduced needle anxiety, a single dose that’s easy to inject, and well tolerated by patients). This avoided the need to add an additional loop in the design process to adjust to unmet needs. This process also gave the biotech confidence in the technology early on, as they were involved in the design process.”
As Credence MedSystems scales its manufacturing capacity for its Companion® and Dual Chamber product lines, John A. Merhige, Chief Commercial Officer, Credence MedSystems, Inc., says pharma companies are provided improvements in usability, safety, waste-reduction, sustainability, and operational efficiency – without having to reengineer processes or introduce undue risk.
Credence recently announced a successful $39.9 million funding round that included strategic investments from Novartis and Molex Ventures, as well as a strategic collaboration with Phillips-Medisize, a Molex company. Those collaborations have contributed to Credence’s implementation of a flexible clinical manufacturing line that will produce up to 500,000 units per year of various configurations of the Companion and Dual Chamber product lines. Expected to be up and running later this year, this manufacturing capability will enable Credence to supply sufficient volumes to support development efforts, including stability studies and machine evaluations, as well as for human-use production for clinical study supply and eventually smaller volume commercial applications, explains Mr. Merhige.
The Credence Companion provides pharma manufacturers and their end users end-of-dose cues and automatic needle retraction. “User studies performed by Credence and its pharma customers document high user preference for the Companion while the integrated approach improves operational efficiency for pharma manufacturers by eliminating secondary assembly processes and the associated waste and cost,” he explains. “In addition, Companion’s streamlined design prevents premature activation of the safety mechanism, again eliminating waste and addressing regulatory concerns, and achieves a less impactful environmental footprint. Compared to conventional safety approaches, Companion uses 38% of the plastic, reduces the weight of added components by 58%, and occupies 33% of the volume post-use, helping pharma achieve corporate sustainability goals.”
The Credence Dual Chamber Reconstitution Syringe simplifies the delivery of complex drug products, enabling less experienced users to safely and correctly administer medication. “As delivery of injectables moves from formal healthcare settings to the home, pharma developers face the challenges of achieving liquid-stable formulations.”
The Dual Chamber system maintains separation of components during storage, offering a safe and friendly experience, he adds. “Simplified mixing and injection, combined with passive needlestick protection, minimizes time, complexity, and risk of dosing errors and contamination, while improving safety and usability.”
Additionally, the platform employs the use of conventional commercially available syringe barrels and stoppers, allowing use of syringes ranging from 1mL to 20mL, glass or plastic barrels, and pre-attached needles or luer lock needleless front ends.
DALI Medical offers a range of advanced injectable drug delivery devices and service development solutions from concept to commercialization. Its safety-engineered, patient-centric approach provides enhanced safety and ease of use for commercial trials and commercial drugs, explains Ziv Cahani, Vice President Business Development and Marketing at DALI.
DALI Medical’s SAN (Safe Auto Needle) drug delivery devices increase safety, ease-of-use, and convenience, with features such as automatic needle insertion, passive automatic sharps protection, a fully hidden needle along the whole injection process, and manual control of injection speed, Mr. Cahani explains. Additionally, the SAN-L is a passive safety and automatic needle-insertion device compatible with luer lock syringes, while the SAN-P is an automatic needle-insertion safety syringe for staked needle prefilled syringes.
Dual-chamber syringes can be integrated with DALI’s SAN passive safety needles. Mr. Cahani says that one European pharmaceutical company has selected a DALI dual-chamber syringe for a new drug, and the product is expected to be launched in 2023.
“Our dual-chamber syringes, primarily targeted to healthcare professionals, and dual-chamber pens, offer highly intuitive usability that are ideal for self-injection,” he says. Both solutions are available in a choice of configurations, enabling drug manufacturers to fit the syringe or pen to their specific drug and patients’ preferences. For example, one of DALI’s dual-chamber syringes is specially designed to ensure correct mixing of the two components.
DALI’s SAN-Light single-use passive safety needle is being used by UK-based ADVANZ PHARMA for its Mytolac®/Myrelez®, a generic Lanreotide drug product launched in 2021. SAN-Light is connected to a prefilled syringe.
DALI also offers injection connectivity. The DALI SYNNECT connected injection solution incorporates sensing and connectivity technologies to accurately measure the administered drug’s data and transmit it, enabling remote healthcare monitoring.
Even prior to Covid-19, a constant challenge associated with moving care to the home has been in maintaining patient compliance and adherence to treatment regimens and ensuring quality healthcare outcomes. As a result of the growing need for homecare solutions, the need for patient-centric self-administration devices has become a priority.
Additionally, new biologic-based drugs will be brought to market in the next decade, believes Dr. Andrei Yosef, General Manager of Pharmaceutical Solutions at Eitan Medical. “While introducing significant therapeutic benefits, their associated drug delivery challenges need to be addressed,” he says. “With higher viscosities and larger volumes than chemically synthesized drugs, many of these biologic medications are expected to require an alternative delivery system to traditional hand-held injectors, limited to 1-2mL of liquid.”
In parallel, some of these biologics are expected to launch in lyophilized form, requiring drug reconstitution prior to administration. This adds another level of complexity to the administration process and poses an additional barrier to self-administration.
Device solutions addressing both the shift to homecare, together with the challenges described above, include infusion pumps, reconstitution systems, dual-chamber syringes, wearable injectors, and more. However, for lyophilized biologics requiring dosages of above 2mL, a wearable drug delivery device that allows for reconstitution prior to administration would be ideal, says Dr. Yosef.
Eitan Medical’s Sorrel™ wearable drug delivery platform features a variety of configurations based on a patented pumping mechanism and UV technology. The device is designed for easy and efficient subcutaneous, self-administration of large-volume and high-viscosity medications for use in homecare environments, he explains. “Eitan Medical is working to further expand the Sorrel offering to lyophilized medications, allowing the drug reconstitution process to occur inside the Sorrel device. By simplifying the reconstitution process, which currently is very cumbersome and generally involves multiple accessories, patient compliance and adherence to medication regimen may be better positioned for success.”
He continues: “Furthermore, as pharmaceutical companies usually require long lead times to transition their drug product from one primary container to another, the Sorrel device’s primary container agnostic feature offers quick turnaround times for development of one primary container-based device to the next, skipping the lengthy transition process, and conforming to the primary container of Eitan Medical’s pharma partner’s choice. This allows pharmaceutical companies to go to clinic faster with the primary container they generally have available. By providing a wearable solution adaptable to multiple dosage forms, in a ready-to-use, prefilled and pre-loaded device, the Sorrel platform offers both a patient-centric and pharma partner-focused solution to the drug delivery market needs.”
Emergent CDMO offers a comprehensive range of drug product formulation and aseptic filling in vials and prefilled syringes, in various configurations, to address both viral and non-viral manufacturing needs – from early-stage clinical to late-stage commercial products. Emergent also offers cGMP lyophilization in conjunction with its fill/finish capabilities. “We can support biopharma innovators’ needs for a range of platforms and technologies, including mammalian, viral, plasma protein-based biotherapeutics, and vaccines,” says Nithin Stephen, Director, Commercial Development – Drug Product, Emergent. “We have experience working with viruses – recombinant, live, and live-attenuated – for the development and manufacture of vaccines and therapeutics.”
Emergent has been enhancing its drug product aseptic fill/finish capacity and capabilities at several sites. New flexible fill lines offer aseptic fill/finish processing, which allows for more product batches in smaller quantities, while addressing regulatory uncertainties, Mr. Stephen explains. This year, the Camden facility (drug product manufacturing site in Baltimore, MD) began manufacturing operations with a groninger® FlexPro 50, which provides sterility with minimal line interventions and interruptions through the utilization of isolator-based technology for aseptic processing of ready-to-use (RTU) pre-sterilized syringes, cartridges, and vials. The line can support liquid or lyophilized products.
A viral drug product facility in Rockville, MD, is currently undergoing a 58,000-sq. ft. expansion, which includes a state-of-the-art high-speed fill/finish line, the groninger INTEGRA, with fully integrated isolator technology, Biosafety Level 2 (BSL2) capabilities, and an automated inspection, labeling, and packaging line. Mr. Stephen says this will enhance Emergent’s capabilities in large-scale fill/finish manufacturing of viral biotherapeutics and vaccines.
Finally, a development and manufacturing site in Winnipeg, Manitoba, Canada, houses a Vanrx® SA25 Aseptic Filling Workcell, providing sterility assurance through a fully automated vial handling, filling, and stoppering process, designed to minimize line losses. “The Vanrx utilizes closed, robotic technology to support the production of non-viral next-generation therapies,” he says. “Its flexible design base makes the Vanrx ideal for supporting high-value, small-batch size medicines.”
Emergent recently supported a pharma client in achieving a successful prefilled syringe/parenteral program by expediting and solving challenges during the tech transfer process for a small-scale mRNA drug with minimal unfrozen hold time. The client asked for two fills to be completed within two months from the project kick-off, requiring Emergent to complete filling and packaging activities on the Vanrx Aseptic Filling machine within one month of project initiation. The client stressed the importance of freezing their product within 48 hours of starting formulation, which was key to the success of their therapy, Mr. Stephen explains. “Our Manufacturing Science & Technology, fill, and packaging teams worked together to successful complete the engineering and GMP fills on time. Of note, the formulation, filling, inspection, packaging, and freezing process were completed within seven hours during the engineering fill. Similarly, the GMP fill was completed within 29 hours, which allowed the product to be released on time to support toxicological and clinical studies, helping the client achieve their tight turnaround time.”
Gerresheimer is a solution provider for drug packaging and drug delivery systems for the injectables/parenteral market. Its portfolio includes glass and plastic vials and syringes, as well as drug delivery devices and autoinjectors. Its core competency is in fully automatic large-series production and in the manual and semi-automatic small series production of complex and technically sophisticated drug delivery systems.
“This broad portfolio enables us to offer customers a solution that really fits their active ingredient,” says Stefan Verheyden, Global VP Gx Biological Solutions at Gerresheimer.
Gerresheimer recently introduced a digital tool that guides users intuitively through six targeted questions about specific characteristics of their pharmaceutical product that needs to be packaged, before offering a selection of appropriate solutions from the company portfolio. Mr. Verheyden explains that the guide uses a proprietary algorithm to filter through more than 1,500 pharmaceutical products based on the information provided by the user.
Some of Gerresheimer’s products are:
- Gx InnoSafe syringe with an integrated passive safety system to prevent unintentional needlestick, as the needle is fixed in a sleeve after use. A special feature of the Gx InnoSafe syringe is that it can be processed on all existing filling lines without any additional preparation or assembly steps.
- Gx RTF ClearJect – prefillable polymer syringes are made of high performance Cyclic Olefin Polymer, making it suitable for use as primary packaging for sophisticated medications, especially for sensitive biologicals, biosimilars, and biobetters, but also e.g. hyaluronic acid applications. The dead volume in the polymer syringe is also minimized, reducing overall waste of costly drugs.
- SensAIR is an on-body drug delivery system that can deliver drugs of higher viscosity, such as monoclonal antibodies (mAb).
- Gx RTF injection vials are made from Type I borosilicate glass and meet all current requirements of the applicable ISO standards and pharmacopeias (USP and Ph. Eur.). They are manufactured in accordance with cGMP, washed in a cleanroom, packed in trays or in nests and tub, and sterilized.
- Type II glass is a form of soda-lime glass, also called soda-lime-silica glass. Type II glass is subject to a special internal surface treatment process that makes its surface less prone to leaching caused by alkaline solutions and is a possible option for most parenteral drugs.
Haselmeier™, the drug delivery device business division of medmix, designs, develops, and manufactures advanced drug delivery systems, such as pen injectors and autoinjectors, that are convenient and can be dosed with precision. Haselmeier has developed a range of ready-to-use platform devices for use with both cartridge and prefilled syringe primary packages. Its D-Flex™, D-Vario™, Re-Vario™ and new autoinjector systems are all meant for self-administration.
Haselmeier has also expanded its services to include pharmaceutical packaging to provide an integrated system for the delivery of finished combination products. Additional capability and capacity have been added in a new regional facility in the United States to reduce transport requirements for drug products manufactured in America. “These fully developed platforms, such as D-Flex, allow for a more rapid development program for devices. This can then be used across multiple indications, simplifying both the development schedule and supply chain,” says Terry O’Hagan, General Manager at Haselmeier.
In addition to improving self-administration, Haselmeier is focused on reconstitution. Mr. O’Hagan explains that new biologics drugs tend to be less stable in a liquid formulation, driving an increased need for dual-chamber systems where the drug needs to be reconstituted prior to injection by the patient. These systems tend to be more complex to use for a patient, requiring more steps to get the treatment ready for administration. “While Haselmeier has a range of reusable devices compatible with dual-chamber cartridges, one specific customer needed a disposable pen solution, which included an integrated reconstitution system with multiple dose volumes available to the patient,” he says. “Each device would then only deliver a single dose.”
Haselmeier leveraged its D-Flex disposable pen technology, integrating an in-pen reconstitution system to create the needed device. Each pen has four distinct doses available for patient selection based on the volume requirements. “We will leverage our expanded assembly capability and deliver the finished device to the customer’s packaging facility,” Mr. O’Hagan says. “This solution provided the needed device functionality while consolidating the supply chain for global distribution.”
Medical Engineering Technologies delivers combination device batch release and design validation testing. “There is a lot of physical, chemical, and stability testing to be done, whether for a clinical trial or direct regulatory submissions,” says Mark Turner, Managing Director and President of Medical Engineering Technologies Ltd. “Developers of new formulations and devices need confidence when they make these submissions. You don’t want delays and repeats at the end of your project. So, the test programs and protocols need to be well designed and executed while working against the clock.”
As a testing company, Medical Engineering Technologies has seen a variety of multi-chamber devices. But Mr. Turner says they do pose some validation challenges. In particular, it is hard to measure leaks between chambers and the efficiency of mixing when the dose is activated. Interactions between the drug and container can also be complicated by the migration of materials. “We are developing tests to detect any stopper movement in storage or transport (particularly air transport), any premature mixing, and to assess the mixing efficiency as part of the dose accuracy testing,” Mr. Turner says.
One particularly thorny issue is the Reference Listed Drug (RLD) comparison. This is meant to show that a biosimilar is equivalent to an RLD in all ways, including the physical characteristics of the delivery device. He says: “Any test program will always require deep thought about how to minimize the number of RLD samples required for testing.”
Meridian Medical Technologies is an integrated CDMO that takes complex sterile products from concept through industrialization to commercialization, offering both parenteral sterile filling and autoinjector manufacturing. “Every aspect of parenteral manufacturing is complex,” says John Wilmot, Senior Director, Biomedical Technology Lead, Meridian Medical Technologies. “They include essential performance requirements for combination products, reliable and consistent assembly, aseptic sterile filling of proprietary drug containers, manufacturing, and managing the vertically integrated supply chain.”
Meridian has developed a technology platform that offers a drug delivery system that separates the drug API in a dry format from the solvent/diluent, and fully and automatically combines them during injection for optimal delivery, he explains. “We’re looking into further developing this platform for freeze-dried products, which would add value for companies to apply this simplicity to biologicals, biosimilars or similar stability-sensitive molecules.”
Meridian applies Human Performance through Human Factors to develop and enhance its manufacturing processes and make them as seamless and efficient as possible, Mr. Wilmot says.
Mitsubishi Gas Chemical (MGC) provides a multilayer plastic vial and syringe called OXYCAPT™. The product features an oxygen and ultraviolet barrier, high-break resistance, wide pH range tolerance, very low extractables, cryogenic-temperative resistance, and more.
MGC has also been developing staked-needle syringes. Equipment installed last year has been undergoing validation studies and will start supplying samples by the end of this year, says Tomohiro Suzuki, Associate General Manager of MGC.
MGC is also developing customized syringes. “As customizability is one of the plastic’s features, MGC can help pharmaceutical or medical device companies achieve their successes,” says Mr. Suzuki.
“With the rise of biologic and biosimilar formulations, and the increasing trend in self-administration due to the switch from intravenous to subcutaneous, a drug delivery device must be simultaneously robust and easy-to-use, as well as economically viable,” says Cecile Gross – Global Category Manager, Parenteral, Nemera. “Nemera’s offerings address the challenge of designing complex devices aimed at simple care. To accommodate a range of applications, a platform approach is a must.”
The new Symbioze platform, for example, is designed to adjust to any pathology, targeted patient population, and drug posology according to therapy indications, she explains. Symbioze comprises a reusable main unit and a disposable prefilled drug container module. “It offers an ideal balance between the need to deliver advanced and complex formulations at high volumes,” says Ms. Gross. “It is the perfect combination between design robustness, ease of use, connectivity, and sustainability for a seamless and enhanced injection experience.”
Nemera’s other product lines are all offered through a platform approach. For example, Safe’n’Sound® is a highly customizable passive safety device available in 1mL and 2.25mL formats, suitable for both skilled and lay users, to enhance the injection experience. It can integrate color, material or even overcap customization, as well as a Rigid Needle Shield (RNS) puller to help with device handling, particularly for patient populations with dexterity issues.
Nemera also offers four platforms of reusable and disposable pen devices that are adaptable to treat various pathologies and are also customizable. Audrey Chandra – Category Project Manager at Nemera, explains how the reusable pen platform, Pendura AD, has been commercialized with several market references to treat different pathologies, including diabetes. Pendura AD offers automatic delivery with spring-driven movement, and an easily triggered side button actuator to allow the user’s hand to be stabilized during injection time. In addition, the dial-back possibility prevents loss of insulin, and changing the cartridge is easy to perform, she describes.
Novocol Pharma is a CDMO specializing in turnkey sterile cartridge development, manufacturing, testing, and combination product assembly services. With more than 40 years of experience filling sterile injectable cartridges, Novocol is positioned to support cartridge-based programs. “The cartridge format is commonly integrated in a combination drug device product with a history of applications, including chronic diseases such as diabetes and emergency lifesaving applications such as anaphylaxis,” says Eric Lee, Business Development Director, Novocol.
In response to growing customer and market demands, Novocol has invested in additional aseptic fill/finish and pen injector device assembly capacity. In fact, more than 50% of Novocol’s programs are paired with a pen injector device. To support clinical and registration phase customers with a cartridge-based pen injector device, Novocol now offers device assembly services using an automated pilot-scale device assembly machine. The device assembly machine was installed and qualified in 2021 with capabilities to meet the specifications for market-leading press-fit style pen injectors.
In addition, Novocol has invested in 100% increased capacity in aseptic cartridge filling, which will be fully operational in the second half of 2023. This new line will offer similarities to the existing aseptic cartridge filling lines in terms of custom siliconization, precise plunger insertion depth controls, filling capability, and highly-potent API handling capabilities, allowing for ease of line transfer and risk mitigation for new and existing customers alike. “With these investments in place, Novocol is well-positioned to support the growing demand for cartridge-based combination products,” says Mr. Lee.
Intravenous novel targeted therapies, cancer treatment, and biologic drugs that were traditionally administered in hospitals are now benefiting from advances in formulation technology, enabling simpler and easier subcutaneous administration. There is also a well-documented trend towards reducing dosing frequency with longer acting injectables. These advances mean many targeted therapies and precision medicines can be potentially self-administered by subcutaneous injection at home. However, there are still viscosity and volume challenges that cannot be met with standard glass-based autoinjector systems.
Oval Medical is addressing this with the ArQ-Bios autoinjector platform, which features a modular capability to enable customization that works for both the patient and the formulation, ensuring patients can self-administer medicines outside of a healthcare setting,” explains Barbara Lead, CEO of Oval Medical. ArQ-Bios is a high power, single-use modular autoinjector platform with the ability to deliver challenging high viscosity or large-volume dose options for subcutaneous delivery. This allows flexibility for formulation development, early engagement with the device, and reducing risk and time to the market.”
Low- to medium-viscosity formulations under 100 cp can be delivered up to 10mL and high/ultra-high viscosities up to 10,000 cp can be delivered between 0.5-3mL. At a viscosity of 1000 cP formulation, ArQ-Bios can deliver 1mL through a 25G needle in less than 5 seconds. She says: “Owning and manufacturing the primary drug container allows integrated devices to be designed for patient needs.”
ArQ Bios incorporates a proprietary hydraulic valve release mechanism that enables quiet and gentle activation of the device, even when the drug is pressurized at 300 bar. These features make ArQ-Bios an enabling technology for high-viscosity or large-volume applications.
Also proprietary is Oval’s patented “cup seal and foil” technology, which is built around a high-pressure cyclic olefin co-polymer primary drug container. “The container can safely tolerate significantly higher pressure than glass, allows stronger springs, and enables the device to generate higher pressures than other market offerings,” Ms. Lead says. “The design aims for a superior patient experience and reduced ‘wet’ injections due to highly consistent drug delivery times, independent of product age or manufacturing tolerances.”
Owen Mumford Pharmaceutical Services introduced what it claims was the first autoinjector, Autoject 1, back in the mid-1980s. Since then, the company has produced autoinjectors in a variety of designs for multiple pharma companies. In the last year, Owen Mumford launched the disposable autoinjector platform, Aidaptus®, a two-step, easy-to-use small and discreet option for the patient to integrate into their regular routine. The needle is automatically deployed following depression of Aidaptus onto the selected injection site. The drug is then delivered in a separate phase controlled by a second delivery spring in the device. “This design helps to provide a consistent injection experience and also minimizes syringe breakage that may occur with high force springs,” says Michael Earl, Director of Pharmaceutical Services.
Aidaptus is available in two base design options: a transparent body with an overwrap that can be printed and branded as required, or an opaque body with color customization choices. There also are options for window size in both designs either as a cut-out in the overwrap or different size molded windows in the opaque version. Both allow the window to be tailored to the required drug fill volume.
During development phases, through clinical trials and commercialization, parenteral drug formulations can go through a variety of iterative changes. This can pose problems when the drug requires a device, such as an autoinjector for delivery, as they are typically designed to deliver a set volume. Therefore, changes in fill volume or syringe size normally require design changes in the actual device and the associated validation processes and regulatory approvals. This can create complexity and risk in the development process. “At Owen Mumford Pharmaceutical Services, we looked to address this problem by creating a self-adjusting plunger in our Aidaptus disposable autoinjector,” he explains. The plunger automatically adjusts to differing fill volumes and stopper positions, but also creates a critical gap between plunger and stopper to allow only a restricted level of rearward movement by the stopper. This ensures that container closure integrity is maintained during pressure changes that may occur during the supply chain and during patient use.
Aidaptus can accommodate both 1mL and 2.25mL prefilled syringes in the same base device, requiring minimal change parts. This means that the small size of the autoinjector, 165mm high and 18mm wide, is maintained irrespective of the syringe size, Mr. Earl explains.
As there can be changes in volume during drug development there can also be challenges with viscosity, particularly with higher viscosity formulations typically found with biologics. Aidaptus offers a choice of high and low power springs to adapt to varying viscosity drugs while helping to keep drug delivery time within an acceptable range for the patient. Aidaptus has been designed with the two sub-assemblies that fit together after the syringe insertion; the self-adjusting plunger then automatically moves into place to ensure an easier final assembly.
Recipharm designs, develops, and manufactures injectable drug delivery devices to the global parenteral market, offering a range of autoinjectors, assisted syringes, mixing systems, and other injectable technologies. One challenge these technologies address is delivery of high-viscosity formulations. For example, the Viscala® technology platform features the proprietary VapourSoft® delivery system for delivering highly viscous formulations from standard primary packaging by amplifying the force/pressure applied. “Using this technology, formulations with viscosities of up to several thousand centipoise (cps) can be delivered using fine needle gauges, increasing possibilities for our pharma company partners and putting patient comfort at the forefront,” says Gemma Wood, Innovation Manager at Recipharm.
She describes how a customer approached Recipharm with a highly viscous formulation for delivery by autoinjector. The formulation reduced the dosing frequency required for the drug product, improving quality of life for patients and reducing overall healthcare costs, she says.
“The high viscosity of the formulation meant that it could not be delivered using standard autoinjector technologies and the customer did not want to use large gauge needles because of the impact on patient comfort and compliance. To address this issue, we developed an innovative, new autoinjector with force amplification that enables the highly viscous formulation to be delivered simply, easily, and with patient comfort in mind by using the finest needle possible.”
Ms. Wood adds that Recipharm platforms also solve challenges such as the delivery of large volumes, and re-suspension prior to delivery. She specifically points to the Lila® technology platform, a combination valve and primary pack stopper. Lila Duo enables two liquid drug products to be filled into a single primary pack, keeping the two products completely separate until the point of administration and allowing them to be delivered sequentially from a single syringe. Lila Mix enables the products to be mixed or re-suspended immediately before delivery takes place.
Societal CDMO provides preformulation, formulation development, and fill/finish services across a range of parenteral product types, technologies, and phases of drug development. Societal’s experience includes small molecules, and biologics (proteins, peptides, monoclonal antibodies, RNA, and pegylated molecules).
According to Robert Giannini, Vice President, Innovation, Societal CDMO, the company’s formulation development and manufacturing team has been able to:
- Create a completely non-aqueous formula of an insoluble compound, which upon dilution with saline, provides sufficient time for the product to be administered without precipitation;
- Stabilize and subsequently manufacture clinical trial supplies of lyophilized product for highly labile pegylated molecules and mRNA/siRNA therapeutics; and
- Create a nanoparticulate form for an extended-release (up to 3 months) intramuscular injection.
Some of Societal’s offerings include:
- Aseptic fill and lyophilization of true solutions: True solutions in vials prepared by sterile filtration (from small batches of 1 Liter or less to up to 500L for clinical materials, up to ~10,000 vials per shift, 2mL to 50mL vials, Phase I/II) with 100% weight check and with or without Nitrogen overlay; and Sterile lyophilization (from small batches of 100 to 1000 vials for clinical materials, up to ~9,000 vials per load at the 10mL vial size, the number of vials per load varies with vial size from 2mL to 50mL, Phase I/II). Controlled nucleation technology is available.
- Microspheres/nanoparticles for injection for terminally sterilized product: Prepared by solvent emulsification followed by solvent removal, size segregation, and lyophilization (small batches of about 50g to 500g of finished microspheres corresponding to about 100 to 1000 vials, Phase I/II); prepared by ball milling with surfactants followed by lyophilization or aseptic filling into vials (small batches of about 50g to 500g of finished microspheres corresponding to about 100 to 1000 vials, Phase I/II).
Stevanato Group provides a full range of products and services for injectables, supporting several therapeutic areas, with a variety of prefillable syringe systems to cater to different drug formulations and applications. A good example is biologics, explains Silvia Gallina, Product Management Specialist, Syringe Platform, Stevanato Group. “Because most biologics’ primary administration route remains parenteral, with a significant increase of the subcutaneous type, PFSs have gained strong acceptance as the preferred delivery system.”
Stevanato Group’s Nexa® product lines, for example, have been designed specifically to meet the requirements of high-viscous formulations and drugs sensitive to specific elements, such as tungsten. In addition, SG Nexa can be easily integrated into manual active and passive needle safety systems and automatic drug delivery devices, such as spring-based autoinjectors.
With a growing trend towards biologic drug products, Stevanato Group’s focus is on mitigating drug container stability risk for such drugs, which have higher chemical sensitivity, lower stability, and strong fluid dynamic characteristics (i.e., high viscosity). “Most parenteral packaging components require surface treatment or lubrication to improve their processability and functionality,” she says. “Silicone oil is often used, but it can result in some unwelcome interactions with highly sensitive drug formulations. Specifically, silicone migration can lead to the accumulation of sub-visible particles, which may cause non-compliance with pharmacopeias and potentially registration failure as product safety and efficacy are compromised. In addition, a protein can adsorb at the silicone oil interface and lead, over time, to protein denaturation.”
Furthermore, she says excipients used in formulations can negatively affect different container materials and lubricants. The performance of autoinjectors could be compromised as it could lead to variations in glide force and an incomplete dose being delivered. In addition, silicone droplet accumulation or migration may result in a higher reject rate during the final product release, which will have an impact on productivity and the total cost of ownership.
Stevanato Group developed its Alba® platform with new coating technology. “A cross-linked silicone chain leads to improved layer structure using covalent bonds, increasing the connection force between the silicone and glass while retaining lubrication performance,” Ms. Gallina says. “A thin, permanent silicone coating is created, reducing sub-visible particles release.”
Terumo Pharmaceutical Solutions (TPS) designs, develops, manufactures, supplies, and manages projects associated with polymer-prefillable syringes and injection devices. TPS products and services are focused on injectable drugs that include syringes, hypodermic needles, infusion sets, and CDMO fill/finish services.
“Compared to a vial, a prefilled syringe can reduce the number of steps to administer injectable drug and help avoid dosage errors,” says Katsuyuki Takeuchi, Associate Product Manager of Terumo Pharmaceutical Solutions. “PFS are specifically designed to meet the stringent requirements of certain applications such as ophthalmic, biologics, and dermal fillers.
Terumo also has an industry-wide network to integrate PFS into drug delivery devices like autoinjectors and safety devices. Terumo has capabilities and expertise to offer customized solutions to meet challenges of a particular drug or therapeutic area.
Terumo has been working on ophthalmic drug PFS development programs with customers. “There is an increasing number of patients that require ophthalmic drugs administered by intravitreal injection, triggered by the rapidly aging global population,” says Mr. Takeuchi. “These ophthalmic drugs are administered by intravitreal injection, however, there are still several unmet challenges to design a prefilled syringe for safe administration of ophthalmic drugs.”
For example, he says, it is known that silicone oil could be deposited in the eye’s vitreous body after repeated injections and cannot be evacuated. It is also a challenge to precisely deliver a dose as low as 50μl, which is the typical administration volume for currently available ophthalmic drugs.
“We are helping our customers to solve these challenges with solutions such as our proprietary silicone oil-free technology as well as precisely molded polymer prefillable syringes,” Mr. Takeuchi says.
Vetter is a family-owned, globally operating CDMO with services that range from early-stage development support, including clinical manufacturing, to commercial supply and numerous packaging solutions for vials, syringes, and cartridges. Vetter supports pharmaceutical and biotech companies in the development phases, in the filling of small- to large-scale batches, and in the packaging of their complex compounds. Approximately 80% of the compounds it handles are biologics. In the field of clinical manufacturing, Vetter offers process development, clinical trial manufacturing, technology transfer, regulatory support, and analytical services. For commercial manufacturing, services include fill/finish, regulatory support, analytical services, and life cycle management. Both primary and secondary packaging, as well as device assembly, are realized.
Vetter offers dual-chamber systems in its service portfolio: Vetter Lyo-Ject® dual-chamber syringe as well as V-LK® dual-chamber cartridge. Both systems are suitable for sensitive compounds. “Our patented syringe and cartridge technologies allow a freeze-dried API and a diluent to be prefilled and stored separately for easy reconstitution prior to administration,” explains Carsten Press, Senior Vice President Key Account Management, Supply Chain Management and Marketing, Vetter Pharma International GmbH.
Mr. Press adds that the dual-chamber systems combine multi-faceted advantages. For the biopharma company, they offer low residual volume and reduced API loss with a faster time-to-market. The dual-chamber cartridge is also compatible with multiple pen systems. Both systems offer high product security and extend storage periods for sensitive drugs.
“Through their design, dual-chamber systems afford improved shelf life and options for life cycle management,” he says. “For patients, dual-chamber systems offer a safe, comfortable, and user-friendly design that allows for precise dosing every time with a reduced potential risk of needle injury as well as a lower risk of contamination compared to the use of vials. Our closure systems also make them tamper-evident. And, because they have prefilled substances in both chambers, reconstitution errors are significantly reduced.”
- Packaging self-administered injectables and infusibles for better patient outcomes, Packaging Europe, April 7, 2022, https://packagingeurope.com/comment/packaging-self-administered-injectables-and-infusibles-for-better-patient-outcomes/8088.article.
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