Sterile Injectables Device and Packaging Trends
Mar 14, 2022PAO-02-022-NI-01
Parenteral packaging products include traditional vials and ampoules, as well as prefilled syringes, cartridges (for pen-based autoinjectors), and other ready-to-use systems. This global market is estimated to be expanding at a compound annual growth rate (CAGR) of approximately 11% and predicted to reach $18.2 billion by the end of 2024 and $19 billion by the end of 2026.1
The global injectable drug-delivery device market, which includes conventional syringes, needle-free injectors, autoinjectors, pen injectors, and dual-chamber devices (powder and liquid), is expected to grow from $15.38 billion in 2020 to $17.13 billion in 2021 at a CAGR of 11.4% and $25.79 billion in 2025 (CAGR of 10.8% from 2021 to 2025).2
The global autoinjectors market, including cartridge- and prefilled syringe–based systems, is estimated to be expanding at a CAGR of 14.9% and predicted be valued at more than $6.2 billion by 2027.3 Meanwhile, the global prefilled syringes market size is projected to expand at a CAGR if 9,0% from $5.6 billion in 2020 to $8.6 billion by 2025.4
Borosilicate type I glass is the standard glass used for pharmaceutical primary packaging, but its supply has been stressed has been constrained in recent years due to the movement in Asia to higher-quality glass packaging. Due to the need for billions of doses of COVID-19 vaccines, the situation has only worsened over the last 18 months. Challenges are expected to continue for the foreseeable future, with demand for not only borosilicate type I glass and tubular vials but plugs, stoppers, and various consumables needed to produce finished and packaged sterile injectable drug products.5
Glass and glass packaging manufacturers have been required to boost the performance of their products to allow rapid, low-temperature filling, closure, freezing, and very-low-temperature storage of mRNA vaccines. The glass must be of greater strength and have a lower coefficient of friction for its exterior surface to withstand these conditions.5
One new glass does not contain boron or sodium on the glass surface, allowing increased throughput on filling lines. Aluminosilicate glass, meanwhile, has more tensile strength and higher temperature and chemical resistance.5 New surface coatings have also been developed that provide increased durability, reduced particulate generation, and greater processing speeds. Built-in sensors for real-time monitoring of vials during fill/finish have also been introduced.9, 3 New device-forming processes are also having an impact. For instance, a new process for glass syringe formation that reduces the tungsten content is reducing issues regarding biologic drug substance degradation.6
Some sterile injectable drug manufacturers have chosen alternatives to traditional tubular glass vials, including molded glass and ready-to-use (RTU) vials, as least as backups.5 Molded glass is of higher weight and can have a nonuniform thickness but does meet GMP requirements. RTU glass vials come pre-sterilized and in appropriate secondary packaging, eliminating the need for washing and depyrogenation. They can also be of molded glass, such as those offered by SGD Pharma, and have the benefit of being available in multiple combinations of primary packaging to meet the specialized fill/finish needs of personalized medicines.
Glass manufacturers are not only investing in new manufacturing technologies but also new production capacity.5 SCHOTT, for example, is investing $1 billion for capacity expansion across all pharmaceutical packaging product groups.6 The bulk of announced borosilicate capacity investments are located in Asia and are not expected to come online for one or two years, however, and much of the glass produced will likely be consumed in that region.5 In the United States, Corning has made manufacturing investments supported by the federal government. Additional capacity expansions will likely be needed.
Given the supply issues with pharma-grade glass, interest is rising in the use of plastic for the delivery of sterile injectables.5 Improvements in molding technology, including blow-fill-seal (BFS) solutions, are accelerating this trend.
One example is the steady increase in the use of polymer syringes, which also benefit from being free of heavy metals and tungsten, particularly plastic syringes that do not require the application of silicone to the barrel to facilitate movement of the plunger.6 Hybrid syringes are also in use today that have a thin glass layer that serves as a barrier to gas and moisture ingress.
While plastic syringes can be based on forms of polyethylene and polypropylene, cyclic olefin polymers (COPs) are receiving significant attention because they offer break resistance, superior functional performance, highly reduced extractables, and a low particulate burden.6
Plastics also provide flexibility that can be beneficial in other applications related to sterile injectable drug delivery, such as small reservoir pouches for wearables and IV bags that are easy to empty.7 The flexible nature of the plastic allows for greater design flexibility to address flow and other issues for more accurate dosing, for example.
BFS solutions, meanwhile, facilitate the production of sterile injectables in unit-dose packaging in various shapes and sizes.8 BFS has been used in the food and beverage and cosmetics and personal care industries for many years.
For pharmaceutical applications, it offers advantages for the aseptic production of everything from ampoules to prefilled syringes because forming, filling, and sealing of containers occurs at the same time within a continuous ribbon of parison (melted resin), leading to reduced risk of microbial and particulate contamination.9
Figure 1: While product runs through the system, resin pellets are melted
and extruded into a continuous ribbon of parison (melted resin).9
Elimination of the human intervention required in traditional glass fill/finish operations, combined with the greater flexibility and reduced breakage concerns with plastics, are key advantages of BFS.10 In addition, the production of BFS devices involves a much simpler supply chain than the production of glass devices, as only one primary packaging material is needed, and pharmaceutical-grade resins are widely available and can be stockpiled for years.11 There are environmental benefits of the BFS process as well, including reduced energy consumption and a smaller carbon footprint.
In addition, for prefilled syringes, the needle can be attached as part of the process.9 Elimination of a separate assembly step combined with the reduced weight of the syringes adds up to reduced time and cost to reach the market. With BFS, it is also possible to operate at refrigeration temperatures (such as 4 °C), which is particularly valuable for heat-sensitive biologics and vaccines.
On the negative side, BFS requires specialized equipment and process knowledge, and it is necessary to demonstrate compatibility and stability of the drug product in the formed package, including with respect to extractables and leachables.10 Secondary containment is also required, because plastics are generally semi-permeable, potentially allowing contaminants to leach into the drug product from the environment.11
Catalent has demonstrated that, for formulated mAbs filled in both traditional glass vials and its ADVASEPT® BFS vials, BFS technology is not only a viable option for the primary packaging of biologics but also a cost-effective method for the production of unit doses of sterile injectables.10 It is possible, according to some, that BFS could enable the adoption of unit-dose parenteral drugs in low-and medium-income countries without increasing existing budgets.11
Currently, BFS is used for more than 50 injectable products.11 Meanwhile, the Consortium for the Rapid Aseptic Filling of Injectable Drugs (RAPID) is a public–private partnership dedicated to helping the United States and its allies more quickly and effectively manufacture, package, and transport injectable medicines and vaccines in a national health emergency.12 The Consortium is exploring the use of BFS and other modern drug packaging and delivery technologies to enable the rapid production of hundreds of millions of prefilled syringes.
The global market for BFS technology used in pharmaceuticals, food and beverage, cosmetics and personal care, and other applications is predicted to grow at a CAGR of 10.3% from $3.13 billion in 2020 to approximately $5.64 billion by 2026.13
One of the key patient concerns with sterile injectable drug delivery is the sensation of pain upon injection. Pain perception is influenced by many factors relating to the drug formulation, the delivery device, and the patient involved.14
The volume required, the site of injection, and the viscosity and pH of the formulation are drug-related factors, while the needle size and insertion speed are related to the device, as are the presence or lack of control and information feedback systems.14 The preference of patients for one device type of another may also influence their perception of pain. Injection speed, meanwhile, is under the control of the patient. Individuals also have varying pain tolerances, and some may find self-injection stressful, leading to increased tenseness, which can contribute to increased pain. Lack of training and/or disregard of instructions, such as warming of refrigerated drugs, can contribute to greater pain sensation as well.
Devices designed for self-administration are evolving rapidly to — where possible — address these many factors. The shape and size are designed to be ergonomic and to facilitate operation. Many devices today include visual and audible signals to indicate when patients must do something or when automated steps have been completed. Sensors indicate when device placement is correct. Needles automatically retract to prevent reuse and ensure avoidance of needle-stick injuries. Some devices offer single-step mixing and injection, while others are designed for sequential injection of two liquids. Others enable automated mixing of lyophilized powder with water for injection (WFI), avoiding potential contamination issues.
The use of demonstration devices is one approach to improving the patient self-administration experience that is not often leveraged today.15 In fact, nearly half of patients prescribed self-injection medications do not receive any in-office training, yet it is known that training leads to greater patient adherence and that more than three-quarters of patients use autoinjectors incorrectly once they are at home.
Demonstration devices replicate the self-injection experience, but without any needle or delivery of medication.15 As such, they allow patients to familiarize themselves with the self-injection process without any risk. Use of demonstration devices in human factor studies during early clinical phases could also provide invaluable insights into device design.
The rising complexity of drug formulations and the growing percentage of personalized, niche, and self-administered medicines has made legacy off-the-shelf systems, namely vials and simple syringes, appropriate on a less frequent basis. Instead, medical devices more often need to be tailored to the requirements of specific sterile injectable formulations with respect to fill volumes, injection volumes, injection times, needle requirements, container materials, and other considerations.6
There is an additional need for patient-centric designs that offer intuitive and flexible injection processes for patients without skill or training in self-administration while addressing individualized dosing needs based on body weight.16
Custom-designed reusable devices, while initially more expensive to develop, can in the longer term be cost-effective, because patients prefer more user-friendly solutions, and there is a growing preference from an environmental/sustainability perspective for reusable devices.16 In addition, production scaling of reusable devices is simpler due to the need for fewer units versus the establishment of high-volume manufacturing lines. In addition, greater design flexibility can be achieved using software-controlled electromechanical systems, affording greater usability, risk, and robustness. Small and specialized pharma companies should be wary of staying too focused on drug development and downplaying the importance of device design.
Drug developers for early-phase clinical trials will typically use vials because they allow for overfilling, which is often required. Switching to a more complex drug–device combination product, including custom-designed solutions, is often part of the development strategy today to address patient preferences (e.g., subcutaneous vs. intravenous delivery and/or autoinjectors and safety devices) or due to changes identified in early phases regarding dosing or the need outside the clinic to administer very low doses as accurately as possible in the lowest achievable volumes with minimum waste, such as is the case for flu vaccines.17
Switching to a drug–device combination product is optimally achieved before phase III trials, because at this point the delivery method, dosing pattern, and drug substance synthesis have been established.18
To achieve this switch in an effective manner requires a scientifically robust bridging strategy that includes a method for device selection and the studies necessary to demonstrates similar performance of the drug–device combination product, including bioequivalence of any new formulation (such as when switching from a lyophilized powder to a liquid in a prefilled syringe) and potential for interactions of the product with the device components.18
Volumes for subcutaneous injection have typically ranged from 1 to 2 mL, with up to 3 mL possible more recently. There is a need, however, for the delivery of larger volumes. Approaches include increasing the concentration to reduce the volume or enabling the delivery of larger volumes through device-design advances and/or modification of the subcutaneous space.19
While the use of large-bore needles and long delivery times allow high dose/volume SC deliveries, these approaches are not patient-centric.18 Fortunately, more attractive solutions have been commercialized or are in clinical evaluations. They allow for high-concentration formulations by creating suspensions in a carrier fluid and the formation of microparticles, microbeads, and crystals. Other solutions minimize intermolecular interactions to enable high-concentration formulations and are in clinical studies for the delivery of ultra-rapid-acting insulin, ultra-concentrated rapid-acting insulin, and other therapies, including antibody drugs.
Many of these drugs have high viscosities, which require increased force or time to administer. The increased force can be a significant issue for many patients and caregivers, so efforts have also been focused on designing devices that manage this issue.19 Autoinjectors have been introduced or are in development that have increased spring forces, either using traditional linear springs with added support for device components or torsion springs and regulators. Others are using different sources of force, such as compressed gas or electromechanical motors.
Other approaches involve the use of cyclo-olefin co-polymer containers, which can handle more stress, and innovative needle designs, including shortened needles, thin wall/ultra-thin wall technology, needles with tapered geometry, and side-bores. Wearable devices, meanwhile, can also enable the delivery of larger volumes over longer periods of time.
Local and transient modification of the SC space using the enzyme hyaluronidase to induce degradation of hyaluronan is also being investigated as a means for allowing the SC delivery or larger injection volumes.19
Regardless of the approach, the development of new device technologies that can enable the self-administration of high-volume and high-viscosity sterile injectable formulations can be a real differentiator in the current, highly competitive marketplace for next-generation biologics.20
Wearable injection devices, also referred to as on-body delivery systems (OBDS) or patch pumps, have the potential to enable delivery of high volumes or higher concentrations of sterile injectable drugs while minimizing patient discomfort. They can serve as a market differentiator for drug manufacturers, a cost-saving treatment approach for payers and providers, and a means of maximizing convenience for patients.21
However, wearable injectors are extremely complex drug–device combination products that pose significant development challenges. As a result, there have been few commercialized OBDS since the FDA granted approval in 2001 to Cygnus’ GlucoWatch Biographer as a prescription device for adults with diabetes, other than those designed to deliver insulin.22
One issue has been the advances made in autoinjectors for the delivery of volumes up to 3 mL. Several OBDS in development are for volumes of less than 5 mL, which could theoretically be managed with state-of-the-art autinjectors.22
There are changing market dynamics that could drive growth in demand for OBDS solutions outside of the diabetes space. In addition to the increasing need for delivery of high-volume and highly viscous biologics, some drugs require specific dose timing, such as a certain flow rate, or unusual dosing regimen, such as delivering the drug from more than one container.23
In oncology, there is potential for OBDS solutions for cancer drugs traditionally administered intravenously. The switch to SC delivery of any type, let alone through a wearable injector, will require overcoming this long-standing approach.
A few commercialized anticancer therapies have been developed for SC administration. There are also a few clinical studies evaluating SC delivery for maintenance therapies and PD-1 and PD-L1 checkpoint inhibitors initially developed as IV drugs, including Merck & Co.’s Keytruda (pembrolizumab), a globally top-selling drug. With estimated volumes of 5–20 mL, such drugs could be ideal candidates for delivery using OBDS.22
As with other self-administration approaches, OBDS eliminate the need for hospital or clinic visits, reducing the patient and clinician burden.22 They also have the potential for faster setup times and shorter delivery durations than IV administration.
Wearable injectors on the market and in development include both prefilled and reusable, refillable options.22 Some push the drug using a more traditional telescopic or bending plunger rod or via novel technologies such as battery-driven flow from a semi-flexible container.23 Others pull the drug using some sort of reciprocating piston or peristaltic or other pump. Pushing avoids bubble formation and contact of the drug with other materials. Pulling allows for more device layouts and support of different drug containers, and some pumps can be used to both fill the OBDS reservoirs and deliver the drug.
Even though there is no single strategy for wearable injectables, most pharmaceutical companies developing injectable drugs are at least evaluating OBDS, and most injectable device manufacturers have developed at least one wearable injector. Any injectable device, including OBDS, with clear advantages with respect to ease of use and other patient preferences should do well given the continued shift toward self-administration.
The global market for wearable injectors is estimated to be expanding at a CAGR of 17.2% and is predicted to reach $18.3 billion by 2028.24
As part of the trend toward increased patient centricity, many of today’s devices for the self-administration of sterile injectable drugs include digital technology.6 Sensors help patients position and use devices correctly. Smart devices allow for app-based tracking of usage, dosage, and adherence and/or send data to cloud-based systems for further analysis. These systems allow for ongoing patient–physician interactions. In addition, the data can, for instance, be used to create future therapies customized for specific patients.
The key to the incorporation of such digital technologies, particularly for disposable devices, is cost-effectiveness.6 The electronic modules must also have minimal footprints and be integrated into a single chip using appropriate sensing and communication architecture.
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