Changes in the biopharmaceutical industry have given rise to new pressures and considerations for how drug manufacturers make packaging decisions. Manufacturers are faced with increased scrutiny by the FDA, which has shown that the high cost of drugs has been related to low manufacturing efficiencies caused by rejected products. While prefillable syringes have frequently been considered in both vaccine manufacturing and the biopharmaceutical industry, the market has also begun a trend toward home-use, patient administered delivery of drugs used to treat chronic conditions (e.g., multiple sclerosis and rheumatoid arthritis). These factors, coupled with the evolving regulatory environment of ensuring drug quality to meet patient needs, have raised demands for reliable and safe delivery of drug products.
Prefillable syringe systems can enhance drug product delivery by providing convenient, premixed, sterile, fixed dosages to the patient. The use of high-quality components will facilitate efficient manufacturing processes that may result in a reliable supply of drug products.
Enhancing Component Quality
Pistons for prefilled syringe systems can be coated with a fluoropolymer film that can increase lubricity and serve as a barrier between the drug and the elastomer, reducing the potential for leachables. The phenomena of chemicals migrating from the elastomers into the drug product is known as leachables, but the reverse process of the drug product adsorbing onto the piston can occur. Other concerns related to chemical migration include interaction products and degradation products, both which have the potential to cause harm to a patient.
With the development of novel materials, including cyclic olefin polymers such as Daikyo Crystal Zenith®, manufacturers can now offer a high-quality, transparent, break-resistant material that is more inert than glass, is scratch resistant and, unlike glass, does not flake, which reduces particulate contamination from the syringe container. These components also can be stored and shipped at low temperature, which is a common requirement of many biologics.
To answer demands for improved manufacturing processes, the drug industry has moved toward ready-to-sterilize (RS) and ready-to-use (RU) components for prefillable syringe systems. These components are washed and sterilized (RU components) prior to delivery to the drug manufacturer, thereby reducing the risk of introducing microbiological contamination to the drug product during final packaging. The risk of product rejects can be mitigated through the use of RU components along with verification of components defects. The verification of defect-free components can be achieved by employing an automated vision system to inspect each component prior to shipping. An example is West’s EnvisionTM vision inspection system, which further enhances the efficiency of the manufacturing process.
Biologic Drugs and Overfill
Because biologics are often expensive, manufacturers are seeking new ways to minimize waste. Prefillable syringes, with their premeasured dose, have the advantage of reducing dosing errors and potentially saving manufacturers money. Unlike single- or multi-dose vials that may be overfilled by as much as 30 percent to ensure adequate withdrawal, a prefillable syringe can virtually eliminate the need for excess overfill, thus conserving expensive drug product. This is important where manufacturing and product costs are high and bulk manufacturing capacity is limited.
Additionally, there is some degree of variability when removing drug product from a vial with a conventional disposable needle and syringe. With a prefillable syringe system, the very nature of its design removes the withdrawal step and delivers drug product directly to the patient, which results in a more accurate dose of the drug with less exposure to needles.
Another safety aspect of drug delivery is the potential for inadvertent needlestick injuries. To mitigate the risk of needlestick injuries, patients and health care workers may choose to use a passive needle safety system with a prefilled syringe, such as West’s NovaGuard® safety needle system. With NovaGuard, a plastic shield surrounds the needle before the injection is given, leaving only the needle tip exposed for injection site orientation. The protective shield is activated upon injection and extends forward to cover the needle fully as it is withdrawn. Such systems can help reduce dangerous injuries from needles during the injection and disposal processes.
Benefits of Cyclic Olefin Polymers
Glass prefilled syringes still dominate the market despite their limitations, including safety and performance issues that may directly affect patients and caregivers. Switching from a glass prefillable to a cyclic olefin polymer molded prefillable syringe can reduce the variability and breakage issues associated with glass as well as reduce the need for silicone oil, another potential source of drug product contamination.
With a prefilled syringe system using a Crystal Zenith resin syringe barrel and piston coated with a fluoropolymer barrier film such as Flurotec®, superior and consistent break loose and extrusion forces can be achieved without the use of silicone oil as a lubricant. The film is molded to the surface of the piston and provides a barrier against constituents from the elastomer leaching into the drug product. Another benefit of a silicone-free system is the reduced risk of silicone-induced protein aggregation.
In addition, since a Crystal Zenith barrel is manufactured using injection molding technology, the dimensional tolerances are very tight, which helps to assure consistent functionality (e.g., break loose and extrusion) and minimize the risk of non-fit with secondary devices such as auto-injectors.
Cyclic olefin syringe systems, which have been used in key markets for some time, continue to gain strong acceptance from pharmaceutical and biotech drug makers.
The benefits of Crystal Zenith cyclic olefin polymer syringes offer a clear advantage over traditional glass syringes:
- Durability: Crystal Zenith offers high break-resistance and consistent break loose and glide force, as well as excellent low-temperature characteristics.
- Low Risk of Reactivity: Crystal Zenith is silicone-free and offers low exposure to extractables and leachables as well as low particulate levels, minimum levels of adsorption and absorption, and improved drainability
- Visibility: Crystal Zenith has high transparency.
Overcoming Variability in Glass Syringes
As the industry trends toward the use of prefillable syringe systems, which are often used in devices or delivery systems to aid with the increased need for injection in the home setting, Crystal Zenith resin is an ideal solution. Because of flexibility in molding, these polymers can be used in a variety of drug delivery systems including auto-injectors and custom cartridges.
When comparing glass to plastic syringe barrels, the limitations are easy to distinguish. Glass is a formed product. To create the component, the glass is heated and mandrels are used to form the syringe’s overall length, nose or tip and flanges. These actions create dimensional variability. When the syringe is used manually, such variability is overcome by the human user, but with delivery devices such as auto-injectors, the device itself must overcome the variability. Since the device cannot judge the pressure required to do so, failures – including incomplete injections or incorrect needle depth upon injection – may occur. In contrast, a plastic component is molded. This process creates dimensional tolerances that are consistent and tighter than in a glass product.
For example, the West ConfiDose® disposable auto-injector system has been designed to overcome much of the inherent variability with a variety of glass syringes, including dimensional variability and variable lubrication. Novel design of the force mechanisms and location on the front-end of the syringe allow higher forces to be used, enabling consistent delivery of drugs, even those with higher viscosities, a consistency common for biopharmaceutical drugs
Impact of Silicone Oil on Delivery
Silicone is currently used on the inside of the glass barrel to provide lubricity. During the manufacturing process, the silicone may be applied unevenly, particularly toward the bottom of the syringe, which is less accessible to the siliconization process. Overtime, the silicone may become uneven. Such issues can create higher break-loose force or glide force variability, particularly at the end stroke of the piston, resulting in an incomplete injection, especially when the syringe is used in a delivery device such as an auto-injector. In extreme cases, the syringe may “stall” before the end of the stroke, and the full drug dose may not be delivered.
Mitigating Risk for Protein Aggregation
Many biotech drugs are highly sensitive to both silicone and tungsten. As mentioned, silicone is used to add lubricity to the syringe barrel in glass syringes. Tungsten originates from the tungsten pin used in the glass barrel forming process. Should tungsten contaminate a protein product, aggregation can occur, resulting in rejected product. Also, glues and adhesives are used to hold the needle in place once it has been staked into the syringe. These potential sources of leachables can contribute to the rejection of contaminated drug product. The use of Crystal Zenith resin syringe barrels can minimize exposure to potential leachables, protecting the drug product and enabling a reliable drug product supply.
In a true benefit over the glass prefilled syringes, a Crystal Zenith barrel can be molded around a needle, eliminating the need for tungsten pins, glues and adhesives. This in turn minimizes the exposure to leachables and offers manufacturers an option to provide additional protection for the drug product.
The prefillable syringe market in the US is expanding rapidly, and drug manufacturers are facing increasing pressures as new generations of biopharmaceutical drugs enter the market. Cyclic olefin products such as Crystal Zenith offer an attractive alternative to glass which, while being the industry standard for many years, has limitations in precision of dose delivery and poses contamination and other risks for biopharmaceuticals. Cyclic olefin prefillable syringe solutions minimize drug product waste that can occur due to excessive vial overfills or loss due to breakage and provide for silicone free-systems that reduce the risk of protein aggregation. Together with fluoropolymer film coated pistons in a ready-to-use format, cyclic olefin prefilled components present benefits that are gaining attention from manufacturers who seek new answers to efficiency, drug delivery and administration challenges.
About the Author
Tibor Hlobik has worked within the pharmaceutical packaging industry for over twenty years in research and development, quality, technical and marketing roles primarily at West. He has extensive experience and overall expertise with vial/closure and prefillable syringe packaging systems. Currently, he is responsible for supporting business development efforts, and for defining new products and executing strategies for West’s Prefillable Syringe technology platform.
Daikyo Crystal Zenith® and Flurotec® are registered trademarks of Daikyo Seiko, Ltd.
Daikyo Crystal Zenith® and Flurotec® technologies are licensed from Daikyo Seiko, Ltd.
ConfiDose, NovaGuard and Envision are trademarks or registered trademarks of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.