Challenges in Biologic Drug and Vaccine Delivery

Increased growth and competition in injectable markets, the increasing use of biologics drugs, greater global demand for vaccines, the rise in drug delivery in non-medical settings, and the heightened focus on more efficient drug administration are all driving the growth of the prefilled syringe market. Biologic drugs, both currently on the market and in development, account for a growing share of the pharmaceutical market. Due to their greater sensitivity, many of them require advanced drug delivery technologies. In addition, many of these therapies are intended for self-administration in the home, while vaccines are increasingly obtained at local drugstores from pharmacists or nurse practitioners. In both cases, convenient, safe, and efficient delivery systems are needed. At the same time, all market participants are looking to improve the cost-efficiency of biologic drug and vaccine delivery through the reduction of wasted drug product, a decrease in the time required for drug administration (to enable more time for high-value tasks), and a lessening of the risk of errors. Prefilled syringes are helping meet all of these needs.

Numerous benefits
Prefilled syringes (PFSs) offer many benefits to patients, healthcare professionals, and drug manufacturers. General benefits of prefilled syringes include dose accuracy (a fixed dose with minimum wastage), convenience (an integrated container/delivery system with no need for adding a needle or withdrawal from a vial), and compatibility with injection devices (auto-injectors, safety systems), according to Graham Reynolds, vice-president of marketing and innovation, with West Pharmaceutical Services (West).

The increased convenience of prefilled syringes compared to vial dosage forms is important. “Instead of the patient or healthcare professional having to handle needles and a disposable syringe to retrieve and administer the product from a vial, the prefilled syringe is ready to use. This convenience is also useful for patients administering at home, particularly those that have dexterity limitations,” says Donna French, senior director for device development in the Pharma Technical Development group at Genentech. Furthermore, the prefilled syringe can be incorporated into a self-injection device (such as an auto-injector) or used as a stand-alone manual injection system, sometimes with the incorporation of ergonomic enhancements to facilitate easier injection, adds Reynolds.

PFSs also offer a unit-dose ready-to-administer format that simplifies the preparation and administration of injectables by a patient or caregiver (versus, for example, a vial, which requires many more steps and ultimately the transfer of the injectable from the vial to a syringe). The time savings can mean more time on higher-value activities involving patient care or shorter patient wait times, according to Brian Lynch, program lead for health science & technology for immunizations with Becton Dickinson and Company (BD). He adds that because they are filled, labeled, and packaged by the pharmaceutical company and are unit dose and ready-to-administer, there are fewer steps involved in the preparation of PFSs and fewer opportunities for human error. “Prefilled syringes reduce dosing errors and the amount of overfill needed to account for the filling process and container variability,” adds French.

The simplicity of prefilled syringes is also ideal for the self-administration of anticoagulants following surgery, which is one of the largest applications for pre-filled syringes, Reynolds adds. Similarly, for vaccines, prefilled syringes are advantageous compared to vials given their ease of preparation, dose accuracy, and ease of use.

In addition, for drug manufacturers, prefilled syringes maximize yield and reduce cost due to lower drug overfill. “For example,” explains Christina Braden-Moore, North American marketing director for pharmaceutical systems with BD, “for a 0.5-mL vial, the USP [United States Pharmacopeial Convention] recommends 20-25% overfill. In contrast, for a 0.5-mL prefilled syringe dose, the required overfill is approximately 2%. In addition, prefilled syringes offer drug manufacturers the opportunity to enhance product differentiation and extend product life spans,” she notes. Drug manufacturers also benefit because syringes are a safer form of packaging that offer a means for higher quality manufacturing, according to Peter Soelkner, a managing director with Vetter Pharma International GmbH.

Technology advances
Currently, many drugs in development are protein therapeutics, which can be sensitive to specific surfaces (typically hydrophobic), shear forces, and the presence of silicone and tungsten in the prefilled system, according to Theresa Bankston, manager of bioanalytical and pharmaceutical development for BD. “Unfavorable interactions between the drug and device can occur, leading to loss of efficacy, increased subvisible particles (SbVPs), or undesired immune responses,” she comments.

Extractables/leachables have been another important issue for prefilled syringes. “In order to function effectively, glass syringes typically require an amount of silicone oil lubricant to be applied within the barrel. This process may be variable, and silicone oil has been shown to create aggregation with certain proteins,” Reynolds remarks. In addition to drug interactions, this variability may cause problems within an auto-injector. In extreme cases, slow or incomplete drug delivery may result.

In addition, some new protein-based drug formulations are higher in viscosity and, therefore, present different device/injection challenges. Furthermore, the integration of syringe and device, such as an auto-injector, present specific challenges when ensuring primary container integrity and accurate dose delivery.  Other concerns that have been raised in the industry include particulates and needle quality, observes French. Most of these challenges can, however, be overcome by optimizing the formulation, through proper choice of prefilled system components and with the use of new technologies.

Overcoming subvisibleparticle challenges
New coatings for both glass and plastic syringes are being developed to eliminate the need for silicone as a lubricant and reduce glass breakage, according to French. As examples, Bankston points to technologies offered by BD that include the use of new crosslinked silicone coatings on syringes and silicone-free polymeric syringes, which she says can greatly reduce silicone-related SbVPs.

Optimizing glass syringe technology
Prefilled syringes are exposed to a variety of forces and impacts from manufacturing, filling, device integration, shipping, and handling, which make them susceptible to defects, particles, and breakage, according to Braden-Moore. For instance, glass breakage can be a concern, particularly when the syringe may be incorporated into a device that exerts stresses on the syringe, according to Reynolds. The dimensional variability of glass may also present challenges for devices and must be evaluated within the combination product to ensure compatibility at extremes of tolerances, he adds.

One way to address this issue is to employ quality-by-design (QbD) methodologies during syringe manufacturing, syringe filling, and packaging to minimize the occurrence of defects, particles, and breakage, according to Braden-Moore.  Additionally, BD has developed a new glass surface ion-exchange technology that has demonstrated increased strength and durability for prefilled syringes and ensures optimal performance even under suboptimal or demanding use conditions.

Enabling sub-cutaneous injection of higher-viscosity drugs
The concentration and viscosity limits of protein-based drugs continue to pose challenges for prefilled syringe systems. These hurdles include compatibility and usability with high-concentration formulations, which are increasingly common for biopharmaceutical products, according to French. Many of the drugs are highly viscous and require higher mechanical forces for the injection, which is less than ideal for patients with dexterity limitations and can lead to syringe breakage when the drug is delivered with an auto-injector. In some cases, even dosing of 1 mL or less can be difficult to achieve, according to Braden-Moore. She notes that thin-wall needle technology from BD overcomes viscosity hurdles by optimizing the inner diameter of the needle for better flow, thereby reducing the required injection force while maintaining the same drug volume without negatively impacting the patient’s injection experience with a larger needle.

Better system performance through improved elastomers
Enhancements in glass syringes include the launch of improved elastomer plungers such as those from West, which are produced under QbD principles to help ensure improved consistency and functionality. “With increased emphasis on reducing particles, manufacturers of syringes and the constituent components continue to work on improvements to reduce the potential for particles within drug products,” says Reynolds.

New stopper and needle shield materials are also being developed or continuously improved for better drug compatibility, syringe performance, and needle quality, according to French.

The possibility of plastic
The development of polymeric, or plastic, syringe technologies has been a focus for many prefilled syringe manufacturers. “A number of plastic syringe technologies are in development and have been touted as a means to reduce the likelihood of breakage and improve product compatibility,” says French. She also notes that plastic systems offer more flexibility for novel shapes for primary containers. West is one company offering plastic syringes. “We believe such plastic prefilled syringes offer advantages in terms of break resistance, improved dimensional tolerances, consistent functionality, and the absence of silicone oil, tungsten, and adhesives,” Reynolds states. He adds that the syringes are produced under extremely clean conditions and packaged in such a way as to be compatible with established filling equipment.

Improvedmanufacturing processes
Prefilled syringe manufacturers are also tackling the various issues associated with their products by improving their manufacturing processes. For glass prefilled syringes, French notes that improvements in syringe forming, washing processes, and glue curing (for needle attachment) have reduced product quality issues with extractables/leachables. In addition, improved siliconization of prefilled syringes provides more reliable injection forces, and treatments to strengthen glass, as described previously, are also being developed to reduce the likelihood of breakage.

Because prefilled syringes are more sophisticated they require more sophisticated manufacturing processes, particularly given the increased number of transfers that take place, according to Soelkner. “Automation in the cleanrooms at Vetter is helping to minimize risk and human error, and the use of robots is becoming more commonplace as the benefits become apparent,” he notes. Separately, he points out that with increasing numbers of smaller volume, niche drugs being developed, the ability to allow for dedicated production of specific products while still maintaining efficient and flexible manufacturing facilities has been necessary. Adoption of QbD and process analytical technology for the manufacture of PFDs is also becoming more formalized and having a positive impact on quality.

Customizing drug-delivery systems to meet patient needs
On the patient side, the needs of different homecare patients who are self-injecting must be considered, according to Soelkner. “Many patients that are using PFSs have arthritis and problems with their joints and need delivery systems with broader finger flanges for self-administration,” he observes. French agrees: “One recent trend relates to the improvement of the usability of prefilled syringes for patients with dexterity issues. Specialized flanges and plungers have been developed for better ergonomics, and new needle shield designs facilitate needle shield removal.”

More work to do
“Suppliers have worked to address many of the issues with prefilled syringes by improving their manufacturing processes and materials used for the production of pre-filled syringe components.  However, many prefilled syringe systems do not yet fully meet the needs of biopharmaceutical products, and new technologies, such as plastic syringes, have not yet made inroads into the marketplace,” French says.

Early collaboration between drug and device manufacturers is essential to ensure successful combination product development without impact to timelines, according to Braden-Moore. Soelkner also asserts that to produce high-quality prefilled syringe products using the most effective processes, manufacturers must have knowledge about both production issues and patient needs, which requires extensive experience in biologics manufacturing and packaging.