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.
Conclusion
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.