In Search of a Sterile Fill

Technological developments make it easier to manufacture sterile parenterals.
Mar 02, 2010
Volume 34, Issue 3

The Bosch PreVAS filling system is completely disposable. (PHOTO IS COURTESY OF BOSCH)
More than any other dosage form, injectable drugs require a manufacturing process that ensures sterility. Problems discovered at Genzyme's (Cambridge, MA) Allston Landing, Massachusetts, facility last fall illustrated how contamination can play havoc with a drugmaker's operations. But recent developments in disposable components and isolators are helping companies protect their products and the patients who depend on them.

Fill the drug, toss the system

Disposable components are gaining currency in pharmaceutical fill operations because they can help ensure sterility and save companies time, effort, and money. "The most evolved disposable design is a complete, disposable fill set from the connection to the tank, to a filter, to the lines and hoses that go directly to the fill needle," says Jim Agalloco, president of Agalloco and Associates, lecturer about sterile processing, and member of Pharmaceutical Technology's Editorial Advisory Board. "The dream is to get something that's inexpensive enough to use once and throw away," he adds.

Until recently, pharmaceutical manufacturers had to integrate single-use elements such as tubing and fittings into reusable equipment. But in 2008, Bosch Packaging Technology North America introduced the PreVAS filling system, which is completely disposable. The system includes a supply connector, tubing, fittings, rolling-diaphragm pumps, and needles. One available version includes an eight-head filling machine, which is common in production-scale operations, and a manifold that feeds all eight pumps and needles. The PreVAS system is assembled in a cleanroom, gamma-irradiated, and double-bagged for sterility. It fills vials, cartridges, syringes, and ampuls at clinical and production scales.

The PreVAS system is the first to include a disposable positive-displacement pump, according to Jeff Jackson, North American pharmaceutical sales director at Bosch. The pump is made of polycarbonate, rather than stainless steel or ceramic, which enables it to be gamma sterilized and discarded. Because it is hard to use liquid product as a seal in plastic pumps, Bosch chose a diaphragm pump with a platinum-cured silicone seal for the PreVAS system. The pump's design and performance are the same as those of Bosch's stainless-steel diaphragm pump, which the company debuted 30 years ago. The PreVAS pump can complete 400,000 cycles with no reduction in performance, says Jackson.

The PreVAS system can perform positive-displacement filling with either a rolling-diaphragm pump or a peristaltic pump, two devices familiar to the drug industry. The PreVAS pump also can perform optical filling (i.e., using a vision sensor) and fill-by-weight, but these less-common techniques generally are used for specific applications such as cartridges. One common technique that the system cannot perform is time-pressure filling, says Jackson.

Because the pump is disposable, it does not need to be disassembled for cleaning and sterilization. The PreVAS system thus spares manufacturers much labor, reduces utility consumption, and eliminates an opportunity for operators to be exposed to hazardous materials. Like individual single-use components, the system can be dedicated to one product, thus eliminating the risk of cross contamination.

Pharmaceutical manufacturers try to minimize the number of aseptic connections they must make in their production systems. The PreVAS system requires only one aseptic connection: a link to the bulk supply. Personnel can use many different types of connectors (e.g., traditional tri-clamps, quick-connects, closed connectors) with the PreVAS system, including disposable connectors. The connectors can be made of the same materials as the PreVAS system, or they can be made of different materials, depending on the drugmaker's needs.

The PreVAS system's disposability and capacity can simplify scale-up. Many drugmakers use a single-use product path during clinical-trial fills, partly to reduce costs, and partly because they don't know what the cleaning requirements at production scale will be. Manufacturers can use the PreVAS dosing-pump system as a one-pump station for clinical fills and laboratory work. "You have the exact same fluid path all the way to production with the same performance, accuracy, and materials. Nothing needs to be changed," says Jackson.

VanRX's Raptor system performs isolated filling. (PHOTO COURTESY OF VANRX)
Agalloco acknowledges that disposable technology eliminates the need for cleaning and sterilization, and so makes product changeovers quicker, which is especially important for multiproduct facilities. Single-use systems also maximize uptime, which is a goal shared by drugmakers and contract manufacturers alike. But, he cautions, companies must verify that their products are compatible with disposable materials. He adds that normal wear could affect the components' extractables–leachables profiles.

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