Prefill Revolution: A Market Segment on the Rise

In past decades, virtually all drugs were delivered to healthcare facilities in multidose vials. This evolved to single-dose vials, but now that is also changing. Suppliers of both vial and syringe assemblies to pharmaceutical and biotechnology companies are seeing more requests for presterilized syringe assemblies ready for single-dose, prefill lines.

BD (Becton, Dickinson and Co.; Franklin Lakes, NJ) is a global medical technology company focused on improving drug delivery. The BD Medical-Pharmaceutical Systems unit provides a variety of innovative and clinically proven prefillable drug-delivery systems to pharma companies worldwide.

Geoffrey A. Dugue, MD, medical director North America, BD Medical-Pharmaceutical Systems, explains that while the paradigm of having multidose vials has given way to single-dose vials, the procedure for drawing contents out with a syringe stayed the same. “The risk of contamination exists because you are still inserting a needle and it may have been contaminated.” Prefilled syringes from the pharmaceutical manufacturer, sterile and ready for use, may be a better solution. Each prefilled syringe contains one premeasured dose for one patient, and it is disposed of after use, eliminating the possibility of cross-contamination between patients injected with medicines pulled from vials.

To the healthcare provider, the elimination of contamination is the foremost benefit. There is also the advantage of accurate dosing. Most vaccines are not administered in hospitals. Locations can range from clinics and schools to humanitarian-aid facilities in the developing world. Prefilled syringes have the ability to reduce errors, minimize the risk of accidental contamination, and lower the amount of wasted vaccine.

“When talking about a true pandemic situation, getting the optimal amount of vaccine out efficiently is critical,” Dugue explains. “In multidose vials, a percentage of vaccine in each vial is lost. You simply cannot get every drop out of a vial. If you can save 10% over a total batch of vaccine using prefilled syringes, that could result in tens of thousands of additional doses and could be the difference between life or death in an emergency situation.”

The European pharmaceutical market has largely converted to prefilled syringes for vaccines and standard hospital medications, such as low-molecular-weight heparin (LMWH). The U.S. market is catching on to the prefilled syringe movement, but is slower in changing from multi- and single-dose vial production lines.

PHARMACEUTICAL PROVIDERS

The benefits to the end healthcare provider are very clear. But what about the pharmaceutical company? Other than happier customers, are there any solid benefits to making a change?

Every production change has a price tag. However, there are some financial benefits. For instance, Janice Fajarito, marketing manager, North America, BD Medical-Pharmaceutical Systems, says that one primary benefit pharmaceutical manufacturers enjoy with prefilled syringes is the reduced impact of overfill. Vials require a 20–24% overfill, according to USP <1151> recommendations.

“In the case of a public immunization campaign, given a specified level of bulk vaccine produced, a pharmaceutical company would be able to deliver about 20% more doses to the market when using prefilled syringes versus multidose vials,” she says. “This translates into more doses available for sale. For certain difficult-to-produce biotechnology products, this can add up to thousands of dollars per milligram of drug.”

Patrick Begley, manager, technical services for BD Medical-Pharmaceutical Systems, says that from his experience, prefilled syringe lines are equal or superior to vial lines in terms of speed. Also, the actual capital cost of the equipment is often less expensive to install and more flexible than a traditional vial line. “A vial line requires the pharmaceutical customer to prepare the components for filling and assembly,” he says. “The vial cost and rubber component washers, the depyrogenation oven, the feeding, and line integration of these linked processes are all parts of the puzzle that prepare vial components for filling,”

“With a comparable BD Hypak SCF prefilled syringe filling line, the components are delivered to the line already sterilized and ready to fill, so the pharmaceutical customer doesn’t have to do anything but fill and insert the plunger stopper. The BD Hypak acronym, SCF, stands for: Sterile, Clean, and Ready-to-Fill,” he adds.

However, even with these benefits, when a pharmaceutical company has invested significant capital into establishing a fully validated, high-speed vial-filling line, the last thing it wants to do is unplug it. The line is paid for and efficient, and the firm can accurately calculate overhead, manpower, and output.

Still, everything has a life cycle. When looking at the latest CGMP guidance documents, such as the recently revised Aseptic Processing Guidance document, an older filling line may be ready for an upgrade. If so, that would be the perfect time to evaluate a new line for prefillable syringes.

Begley says that a prefilled syringe line can reduce cost on utilities, manpower, cleanroom size (especially ISO 5 area), capital equipment, installation, validation, maintenance, and save overall floor space. A smaller footprint for the filling and stopper insertion equipment means less equipment in the ISO 5 area.

Whether starting up a new vaccine line or testing the difference between a multidose vial line and prefilled syringe line, a contract manufacturing organization (CMO) is a good way to see whether the benefits are as good as predicted. Using a CMO first, rather than setting up new filling lines in-house, offers several benefits, including testing market acceptance and product preference. Most CMOs have certified their processes on other pharmaceutical products, and customers can review their FDA status and most-recent audit information.

Although a CMO will run at a slightly higher cost per unit than what it would take to manufacture internally, it offers early market presence for a new product and provides a good base to see what is needed to configure a line in-house.

EQUIPMENT ALTERNATIVES

Today virtually every equipment manufacturer is also a system integrator. Even those that specialize in one type of equipment are typically quite capable of procuring the rest of the line for a customer, or at the very minimum, handling the line integration.

Filamatic, a Division of National Instrument LLC (Baltimore, MD), is a specialized equipment manufacturer and system integrator with a technical concentration in vial and syringe production lines. “We manufacture liquid filling and closure equipment,” Jack Grosskopf, director of engineering says. “But we integrate with all other types of equipment to create a full line specific to customer requirements.”

As a company that services both the multidose vial and prefilled syringe market, Filamatic is seeing a significant increase in interest regarding automated prefilled syringe production lines, Grosskopf notes.

Of course, when considering a change to prefill syringe lines, all options need to be considered. Companies such as the Optima Group Pharma (Green Bay, WI,) provide lines that go from high-performance to small-batch processing in both the prefill syringe and the vial/infusion bottle area. The advantage for customers is that they can choose a suitable configuration for their requirements from modularly designed standard machines.

Marc Machauer, sales manager, says that the most important thing to consider when changing process lines is to find the precise fit between needs and available technology. “Machines differ tremendously in design, and it is vitally important that the customer look for the best fit/solution for them in great detail,” he says. “Every product varies as well, and reacts differently to certain configurations. It is imperative that the machine manufacturer understand the challenges of the pharmaceutical company and caters to its needs. The machine manufacturer has to play the role of a consultant as well as a supplier and must have proven technology so that there are no surprises or special challenges.”

In the maze of equipment providers, some like Groninger USA (Charlotte, NC), have always focused on the prefill syringe market. Jorg Bengelsdorf, director of pharmaceutical projects, notes that the company is definitely seeing growth in this market, particularly in new product introductions. While Groninger’s core business is manufacturing the equipment to fill prefill syringes, the company also provides equipment that complements the process and a variety of alternatives.

“We make a very small, table-top unit that pharmaceutical manufacturers can try in-house to get familiar with the prefill without stopping what they are doing. They can learn what can be achieved with our equipment,” he says. “CMOs can find customers that will benefit from this process and then upgrade to our higher speed equipment as their customer base grows. We provide leased equipment and under some circumstances, they can even borrow equipment, test it, and if it works for them, they can buy it. If not just return it,” he adds.

While this may sound risky, in most cases the equipment is ultimately purchased because, as Bengelsdorf says, “Customers see that this is a good market. In the end it provides a safer product and it is faster and easier to use for the healthcare provider.”

ENTER THE ROBOTS

When the focus comes to moving single-prefilled syringes down the production line at high speed while maintaining safety, nothing beats a robot. ESS Technologies Inc. (Blacksburg, VA) specializes in packaging line design, manufacturing, and integration.

As a strategic relationship partner with FANUC Robotics for secondary packaging and palletizing of pharmaceuticals, and a U.S. distributor for Bergami’s line of packaging machines, ESS provides the full spectrum for every type of standard and custom solutions for moving the products through all processes to final shipping. Walt Langosch, director, sales and marketing, notes that from an equipment manufacturer’s point of view, both the primary and secondary packaging of prefilled syringes can be approached in a number of ways. Syringe filling may be accomplished using automated aseptic filling systems with the final assembly and labeling process done in a secondary packaging environment.

“Automated part feeders and robotic systems perform the assembly process while vision inspection systems safeguard quality,” he says. “This results in increased efficiency, reduces scrap, and reduces overhead while significantly reducing total cost of operation.”

Langosch says that in ESS’s experience with prefilled syringe packaging applications, handling the syringe usually represents the manufacturer’s great concern. Glass syringes are fragile and the units must be handled carefully to maintain product integrity and sterility. Robotic systems with custom-designed end effecters offer a very flexible and agile solution that carefully handles fragile syringes while maintaining the speeds needed to keep the packaging equipment operating.

COMPLETE PACKAGE

Where do you turn when you need it all? Pharmadule Inc. is a very special company based in Sweden that is focused on only one thing: building pharmaceutical process and biotech facilities in a modular way.

“We are a designer/builder. We design, build, and qualify process facilities worldwide from our facilities in Estonia,” Pär Almhem, president of Pharmadule Inc., says. “We break these process facilities down into large modules and provide everything that goes into the facility: process equipment, wiring, duct work, architectural finishing. We install all of it in our factory and we do a significant amount of testing, so that when we ship to any location, it is so complete there may be only 20% additional work to finish at the site to be up and running.”

This unique method allows the owner’s contractor to prepare the site with access roads, foundations, sewers—all the infrastructure—in parallel while Pharmadule develops the actual facility.

Almhem notes that the two areas that have been the most active recently are process facilities for prefilled syringes and aseptic vials, and biological manufacturing. “There is an increasing need for aseptic filling in general,” he says. “The focus is on biological products. There is definitely added interest in prefilled syringe lines. For example, Baxter BioPharma Solutions (BPS) won the facility of the year award in 2006 for its plant in Indiana. This was presented by ISPE and Interphex. That particular facility has both a prefill syringe line and a vial line that we built for Baxter.”

INJECTION EVOLUTION

You can’t talk about the growth of the prefilled syringe market without mentioning innovations going on in the sister injectables area and safety mechanisms for all devices; autoinjectors, injector pens, dual- and single-chamber mono-dose injectors.

Peripheral safety devices are affixed to all types of prefill injectors, whether syringes, autoinjectors, or pens.

Ypsomed AG (Burgdorf, Switzerland) is highly involved in the design, development, and manufacture of the subassemblies that make up the delivery systems for self-injected pharmaceuticals and also the associated safety mechanisms.

“Insulin injectors have evolved to what we now call “dial and inject” where the user simply dials in the dose, pushes the button, and the correct dose is delivered,” Ian Thompson, head of business development, says. “We preassemble the precision-dosing mechanics. The pharmaceutical company or contract filler assembles them with the cartridge or prefilled syringe, as applicable.”

Off-the-shelf safety pen needles, such as Ypsomed’s Clickfine AutoProtect and the BD AutoShield Pen Needles, in combination with cartridge-based pen devices, automatically cover the tip of a pen needle after use. This obviates the need to build needle safety into the pen device itself. “We also provide the disposable autoinjector technology that fits around a prefilled syringe,” Thompson adds. “If you look at the market you will see that more than 2 billion prefilled syringes are manufactured every year.”

Rexam Pharma also focuses on prefilled syringes and injection devices and safety systems. Fitted onto the syringe during the assembly process, its safety devices automatically retract the needle into a sleeve after injection. “The assembly is done at a station after the sterile filling,” Patrice Lewko, marketing director, explains.

This is a newly launched product for Rexam, and Lewko notes that it is expanding very rapidly to keep pace with the growing prefilled syringes market. “Drawing on our expertise in the autoinjector and pen area, we saw where we could use our technology to benefit other devices, and expanded into that direction, taking in the broader prefill syringe market,” Lewko says. “The market is looking for systems that will provide the most efficient protection in the easiest manner. The beauty in this type of system is that it is automatic. There is nothing the user needs to remember to do. After the injection, the needle retracts automatically into the sleeve, eliminating any risk of mishandling.”

THE BOTTOM LINE

As pharmaceutical manufacturers consider capital equipment investment, it pays to take a good look at the benefits of prefilled syringes. Prefill syringes provide solid product differentiation, end-user safety, lower manufacturing costs, higher profit margins, and the ability to provide more individual doses from each batch of vaccine or medication.

When considering adding prefill syringes to company offerings, there are many ways to test the waters before jumping in. It is only a matter of finding the one that works best for any specific pharma company.