Drug Delivery

The Ins and Outs of Prefilled Syringes

Pharmaceutical companies are realizing the benefits of prefilled syringes

and are exploring their use for a variety of drug products.

by Jenevieve Blair Polin, Contributing Editor

Image
demonstrating
the one-
handed
operation
needed for the
Ultrasafe
Passive
Delivery
System
courtesy
Safety Syringes
Inc.

Within months, the number-one-selling low-molecular-weight heparin in the world,

Lovenox (enoxaparin sodium injection), will be available in prefilled syringes
equipped with a needle-safety device and a sharper needle. Gerhard Mayer, PhD, is
director of marketing and business development for Becton Dickinson
Pharmaceutical Systems (BD; Franklin Lakes, NJ), which supplies the prefillable BD
Hypak syringes and the safety device to the drug’s manufacturer, Aventis
(Bridgewater, NJ), and manufactures most of the prefillable syringes used
worldwide. He says this launch is just the tip of the iceberg for prefilled syringes. He
and the other experts interviewed for this article agree that the U.S. market for
prefilled syringes has been growing at a rate of about 20% a year for at least 5
years.

PREFILLED SYRINGES VERSUS VIALS

Prefilled syringes offer several advantages over traditional packaging in vials.

Ease of use. Use of a prefilled syringe eliminates several steps that are required
before use of a drug in a vial. If the drug is lyophilized, one of these steps is
reconstitution.

Elimination of dosing errors. Prefilled syringes contain the exact deliverable dose
desired. Pharmaceutical manufacturers overfill vials by up to 25%, especially if the
desired dose is very small, to ensure that the user may withdraw the desired dose.
This overfill of vials allows the possibility of dosing errors that are eliminated with
prefilled syringes.

Increased drug supply and reduced waste. Elimination of the need to overfill
reduces waste of product. This is a godsend for manufacturers of product that is in
short supply, such as some vaccines. This is also true for product that is extremely
costly to manufacture, such as biotech drugs.

PRODUCTS IN PREFILLED SYRINGES

Prefilled syringes accommodate volumes that typically range from 0.25 to 5.0 ml.
They are therefore best suited to products administered by subcutaneous or
intramuscular injection. Three categories account for the bulk of prefilled syringes:
antithrombotics, vaccines, and biotech drugs.

Antithrombotics. Lovenox belongs to the class of drugs known as antithrombotics,

which account for about 40% of all prefilled syringes available globally, estimates
Erik Miller, director of marketing for Safety Syringes Inc. (SSI; Carlsbad, CA). This
class also includes Arixtra (Organon Sanofi-Synthelabo, West Orange, NJ), and
Fragmin (Pharmacia Corp., Kalamazoo, MI). Vetter Pharma-Fertigung (Ravensburg,
Germany) fills the Fragmin prefilled syringes, which are supplied integrated with the
UltraSafe Passive Delivery System manufactured by SSI.

Vaccines. Vaccines are also increasingly marketed in prefilled syringes. While

elimination of overfill is one factor driving the switch to the prefilled syringe,
another is the removal of preservative thimerosol from vaccine formulations. With
the removal of the preservative, says BD’s Mayer, “a move from a 10- or 15-dose
vial to a single-dose prefilled syringe makes a lot of sense.”
Home-use products. Home use is also contributing to the growth in this market
sector. “I would say home use is growing faster just because there are some terrific
new therapies,” says Mayer. Many drugs for long-term treatment of chronic
disorders, including treatments for rheumatoid arthritis and growth hormones, are
good candidates for self-injection. Ease of use is paramount for products designed
for patient administration.

One such drug is Copaxone, a treatment for multiple sclerosis marketed by Teva
Pharmaceutical Industries Ltd. Teva originally marketed Copaxone as a lyophilized
powder that patients had to reconstitute before administration. Then in spring 2002,
Teva launched a liquid form (20 mg glatiramer acetate and 40 mg mannitol) in a
prefilled BD Hypak syringe. The company previously supplied 32 vials of the
powdered product as a 30-day supply to allow for reconstitution problems. With the
prefilled syringes, the possibility of error is dramatically reduced, so this waste is
unnecessary. Teva now need only supply 30 prefilled syringes as a 30-day supply,
and the cost to the patient is unchanged.

DRUG COMPATIBILITY OF COMPONENTS

Prefilled
syringes, such
as these from
Baxter
Pharmaceutical
Solutions, help
ensure
accurate
dosing.

Switching to a prefilled syringe presents some challenges for packaging engineers.

In a prefilled syringe, a drug comes into contact with materials it does not
encounter in a vial.

Silicone. Lubricity is of limited importance in a stopper for a vial. Just enough

lubricity is needed to allow high-speed automated filling and closing equipment to
position the stoppers in the vials, explains Don McMillan, vice president of
marketing for the Americas region for West Pharmaceutical Services Inc. (Lionville,
PA). The company manufactures elastomeric components for vials and syringes. In
syringes, however, lubricity is essential for the proper functioning of the device
when it is eventually used. “Whether used a few days or years after its
manufacture, the plunger must move smoothly and easily,” McMillan emphasizes.
Silicone is often the agent used to ensure lubricity.

“A vial has no silicone in it, and a vial stopper generally has no silicone on it,”
explains Jeffrey Turns, senior vice president of Vetter Pharma Turm. “But when you
go into a prefilled syringe, the drug is going to see some silicone. You have to ask,
how much can the drug stand? How long does the drug stay stable? Does the drug
aggregate? Does the drug change?”

Vetter, he adds, can vary the amount and type of silicone in a custom syringe for a
client. To do so, the company uses a proprietary striping system. This system
applies thin stripes of silicone onto the glass, which reduces the overall amount of
silicone in the system.
“Silicone levels have been drastically reduced in syringes. As pharmaceutical
companies look to minimize contact of silicone with their drug, you see a lot less
particulate and cleaner systems,” BD’s Mayer says. BD manufactures a nonreusable
prefilled injection device, the BD Uniject, with an elastomer- and silicone-free drug
reservoir, which Mayer says reduces levels of particulate in the drug.

Elastomers. When it comes to elastomers, the most desirable option, says West’s
McMillan, is to use the same formulation for the components in a prefilled syringe as
was used for the vial stopper in the drug’s previous packaging. If that’s not possible,
he says, West analyzes the drug product and suggests a possible formulation or
develops a custom solution.
Proteins may potentially interact with elastomeric components over a drug’s long
shelf life. It’s a challenge to combat this possibility, says McMillan. For a lot of the
protein and peptide products, West laminates FluroTec, a conformable fluoropolymer
film, onto the surface of the elastomeric components. This coating reduces protein
adsorption and minimizes interaction between the drug and the closure.

Synthetics are replacing natural rubber, particularly latex, in elastomeric

components, but McMillan warns that not all synthetics are suitable. The moisture
vapor transmission and oxygen transmission rates of thermoplastic elastomers
(TPEs), he says, exceed the rates needed for packaging of drug products.
Lyophilized drugs are of course sensitive to moisture, and many drugs in liquid
formulations are sensitive to oxygen. Therefore, for a vial stopper or a prefilled
syringe plunger, currently available TPE formulations are not suitable, McMillan
says. West is developing custom formulations of TPEs in which these properties are
improved. “We’re very close to going to commercialization with a couple of products
for a couple of pilot customers. It might be widely available in the next two to four
years,” McMillan predicts.

Metals. “Some proteins may be averse to needles,” says Mayer. “In rare
circumstances, they may not like the amount of steel or carbon that is in the needle
itself. Although that’s not a lot of contact surface, it could set some of these things
off.”
Manufacturers have therefore developed sophisticated closure systems employing a
barrier between a preattached needle and the prefilled drug. Many prefilled syringes
have no preattached needle and instead have a luer-lock closure.
OPTIONS FOR LYOPHILIZED DRUGS AND POWDERS

Making the transition from a lyophilized drug that requires reconstitution to a ready-
to-use liquid formulation is the fondest wish of many pharmaceutical manufacturers,
says Turns. This goal, however, is often hard to attain. “I talked to people in 1990
who thought they would have a liquid formulation in a year or two, and they still
don’t,” he says.

Dual-chambered syringe. To extend the advantages of a prefilled syringe to

manufacturers of lyophi-lized drugs, Vetter Pharma-Fertigung offers the Vetter Lyo-
Ject dual-chambered syringe.

This system is a glass-barreled syringe with a stopper in the middle to serve as a

barrier between the two chambers. Vetter lyophilizes the drug in the syringe itself
and seals that chamber while the syringe is still in the lyophilizer. Filling equipment
then dispenses the diluent into the remaining volume of the syringe and adds
another stopper. On the distal portion is a screw-taper plunger rod that goes
through the finger rest. As the user advances the plunger, it puts pressure on the
diluent. The diluent then moves the center stopper into a bypass in the side of the
glass. That movement allows the diluent to escape to the front chamber and
reconstitute the lyophilized product.

“Some of these drugs may be administered in the emergency setting to patients

who have had myocardial infarction,” says Turns, “so time is of the essence.” The
prefilled syringe allows faster administration.

Two manufacturers of leuprolide acetate for depot suspension (Lupron, Eligard)

employ variants of the dual-chambered syringe. This drug inhibits growth in certain
hormone-dependent tumors. The new formulations, given once every four months,
replace daily subcutaneous injections.

TAP Pharmaceutical Products Inc. (Lake Forest, IL) offers Lupron Depot– four month
30 mg (leuprolide acetate for depot suspension) in a prefilled dual-chamber syringe.
One chamber contains lyophilized microspheres that, when reconstituted with
diluent, become a suspension for intramuscular injection once every four months.
 The
combination of
West’s
Clip’n’Ject
connector
mechanism, a
vial, and the
prefilled
diluent syringe
helps patients
reconstitute
drugs easily
and accurately.

For Eligard, Sanofi-Synthelabo Inc., the U.S. subsidiary of Sanofi-Synthelabo (Paris),

uses the Atrigel drug-delivery system developed by Atrix Laboratories Inc. (Fort
Collins, CO). Atrigel consists of biodegradable polymers that are mixed with the
active drug and injected subcutaneously, then solidify. Sanofi-Synthelabo supplies
this product in two syringes. One contains leuprolide acetate powder; the other is
prefilled with the Atrigel polymer matrix. Before use, the user mates the two
syringes, dispenses the polymer into the powder, and depresses the plungers
sequentially for 45 seconds to obtain a uniform suspension. The user then draws all
the suspension into one syringe and administers it subcutaneously.

Mike Duncan, vice president of technical operations for Atrix, describes the
engineering challenges of this unique design. The male syringe, he says, is a stock
BD Sterifill plastic prefill system with a male luer lock. “We needed to custom
manufacture a female luer lock that would mate perfectly and not leak in the mixing
process,” he says. The two syringes had to be made of the same resins.

“Furthermore,” he adds, “the polymer delivery system is terminally sterilized by

gamma irradiation, so it also had to be gamma resistant. The mixing cycle involves
30 to 60 sequential plunger actuations, so we had to ensure that the product
couldn’t leak back behind the plunger tips. It had to be a very tight feel on both the
coupling and the back side.”
Prefilled diluent syringes. While dual-chambered syringe or dual-syringe delivery
systems are elegant, they are not compatible with many lyophilized drugs. Alisa
Wright is vice president of business affairs for Baxter Pharmaceutical Solutions
(Bloomington, IN), the largest contract manufacturer of prefilled syringes in North
America. “There are limitations on what you can do with most lyophilized product,
“she says. “Most of the products that we freeze-dry must be put in a vial due to the
volume of liquid filled and the corresponding lyophilized plug size but also to get the
best freeze-drying characteristics, which in turn yields longer stability.” For these
products, another option—the prefilled diluent syringe—offers some of the
advantages of a prefilled syringe. Baxter and Vetter both offer prefilled diluent
syringes.

West currently offers Clip’n’Ject, a reconstitution system consisting of a prefilled

diluent syringe packaged with the drug vial, containing the lyophilized or dry
powder drug.

Prefilled diluent syringes reduce the possibility that the customer will inadvertently
use the wrong diluent or the wrong volume of diluent. “This cuts down on a lot of
the handling errors that could occur,” Wright says. “Such handling errors may result
in the loss of an entire vial or the patient getting the wrong dose or, the worst case,
getting way more than they should have received. It’s not about manufacturing
costs. It’s about safety.”

NEEDLE-SAFETY DEVICES

Many prefilled syringes just coming to market are sporting the latest accessory: a
needle-safety device. The OSHA Needle Stick Safety and Prevention Act, enacted in
2000, gave an initial boost to sales of needle-safety devices, but home use of
prefilled syringes is another impetus.

The idea is false that needle safety is not an issue for patients that self-administer
injections using prefilled syringes. As Baxter’s Wright points out, patients who self-
administer treatments for chronic conditions may carry syringes with them to use
when they are away from home—at work, at restaurants, at hotels, in the mall—
locations where there are no sharps containers and where the trash is handled by
others. Even at home, patients are concerned about possible risk to children in the
household. Therefore, the demand is growing for needle-safety devices not only on
products destined for administration in OSHA-regulated hospitals or clinics but also
on those marketed for home use.

SSI, which introduced the manually activated UltraSafe Needle Guard in 1999, now
offers a passively activated design, the UltraSafe Passive Delivery System, which is
integrated with Pharmacia’s Fragmin. (The integrated UltraSafe/Fragmin product has
been on the U.S. market since August 2002). SSI offers the UltraSafe Passive
Delivery System to other users and can accommodate a broad range of syringe
sizes and staked or luer lock/slip needle configurations.

“We believe that the UltraSafe Passive Delivery System offers the highest level of
compliance,” SSI’s Miller says, “because as long as the clinician administers the full
dose of product, he or she can be assured of safety guard activation with no thought
or further action required. When the plunger bottoms out, the syringe slides back
into the body of the device, and the needle is covered by the guard portion of the
device. Our market research supports the belief that clinicians want needle safety
and ease of use. The UltraSafe Passive Delivery System maintains current
technique, thus it is familiar and requires little or no training.” SSI’s current
customer base includes Abbott, Amgen, Bayer, Pharmacia, and Ortho. The UltraSafe
Passive Delivery System will be integrated with a European pharmaceutical prefilled
syringe and launched in 2003.”

BD supplies the BD Preventis safety device that Aventis is using on Lovenox prefilled
syringes, the largest-selling prefill therapy in the United States. The company offers
BD Preventis as a stock item for use with BD Hypak prefilled syringes. BD designed
and manufactured both the syringe and safety device, ensuring that they work
together optimally as a system, both for the pharmaceutical company’s processing
needs and for end-user safety and ease of use.

West offers a captured-needle version of its Clip’n’Ject prefilled diluent syringe. In

this design, a safety device that contains the syringe mates to the vial. When the
user withdraws the syringe after reconstituting the drug and drawing it back into
the syringe, the needle remains shrouded within the safety device. The user may
then attach a new needle for drug administration.

Increased
demand for the
BD Hypak
syringe drove
BD to open a
new facility.
In January of this year, TAP announced the availability of Lupron Depot packaged
with an integrated needle-safety device, the LuproLoc. Specialized Health Products
International (SHPI; Bountiful, UT), a manufacturer of needle-safety devices, custom
engineered this device for TAP. Mark Ferguson, SHPI’s director of product
development, says the device is a modification of SHPI’s FlexLoc design, a manually
activated folding plastic needle-safety shield that is advanced over the needle by
the user following the use of the syringe. The company’s safety needle devices for
prefilled syringes are suitable for virtually any syringe, particularly custom syringes
with or without stakes needles.

Dennis Kim, TAP’s manager of packaging development, says the syringes are
manufactured, sterilized, and filled in Japan. Secondary packaging and primary
labeling, however, occur in the United States. It is during this secondary operation
that the LuproLoc is integrated with the syringe. Ensuring that the devices could be
attached without compromising product sterility was essential, as was developing a
design that would work with the existing syringe.

“We were unable to use a snap fit, because that would have required us to change
the syringe,” Ferguson relates, “so we opted for a spin welding process.” TAP added
a rotary table that incorporates a spin welder (Branson Ultrasonic Corp., Applied
Technologies Group, Danbury, CT) into the packaging line.

Choosing a material for the safety device was not easy, either. “We needed to find a
resin that had a low melt index and good injection-molding properties and was
compatible with the resin of the syringe hub,” Kim says. “Fortunately, Branson and
SHPI had experience in this area.”

EXPANDING CAPACITY

Many suppliers are adding capacity to accommodate market growth.

Wright says Baxter currently has about 120 to 130 million units of capacity and is
expanding that significantly. By the end of the year, she says, Baxter will have three
high-speed syringe fillers in operation.

Turns says Vetter, which is an FDA-approved site for prefilling syringes in

Ravensburg, Germany, commissioned its latest two filling suites just this year, which
added approximately 75 to 80 million units. “With what we have in place, we can
make around 300
million pieces a year. Just last month we began construction in a third facility to be
completed and making FDA-approvable product in 2007,” he adds.

BD just built a new BD Hypak facility, located in Columbus, NE. “We have two other
large plants: one in France, one in Mexico,” Mayer says. “These plants, using the
same manufacturing technologies, can operate virtually independent of one another
and are designed to meet world demand from multiple locations.”