Turn Down the Fill Volume

Rising titers in biopharmaceutical processes have enabled companies to produce highly concentrated liquid drugs. As concentrations have increased, fill volumes have decreased. The lower limit of a dose has dropped from 10 mL to 0.1 mL, and even smaller volumes are needed sometimes. Drugmakers have many incentives to avoid overfilling their containers, including the scarcity, and correspondingly high cost, of certain cells and ingredients. These concerns highlight the need for techniques that can fill small volumes of product with great accuracy. Many strategies are available to the industry, but which one works best?

Bosch Packaging Technology studied the accuracy of various fill techniques and concluded that positive displacement remains the most accurate, according to Jeff Jackson, the company’s North American pharmaceutical sales director. A positive-displacement pump traps a given amount of fluid and forces it into a discharge pipe. Piston pumps, diaphragm pumps, and peristaltic pumps are different types of positive-displacement pumps, which are less sensitive to a product’s viscosity than other pumps.

The traditional method of filling is with a piston pump that incorporates an O-ring seal. “The injectable pharmaceutical requirements for clean, accurate filling changed this design to a lapped-piston design that has a piston-to-cylinder clearance of one-hundred-thousandth of an inch without an O-ring. This has been the normal method of parenteral filling for several decades,” says Jack Lysfjord, principal consultant for Lysfjord Consulting. Though accurate, these devices also are delicate. “If you drop it just slightly or damage the piston, they won’t work anymore.” They’re also expensive.

Rolling-diaphragm pumps, which were introduced later, do not exhibit the slight leakage that lapped piston pumps do. These pumps also reduce the shear effect on biological products and proteins, compared with piston pumps. They also equal the accuracy of the lapped piston pump. The rolling-diaphragm pump is one of the most accurate pumping systems available, says Jackson.

A peristaltic pump, which typically is used in clinical applications, incorporates a rotating roller or series of rollers. An operator inserts flexible tubing into the rollers, connects it to the nozzle, and feeds product into it. The rollers compress the flexible tubing and force the liquid out the discharge, thus dispensing the desired volume. Peristaltic pumps have not performed as well as other types, but their accuracy has been improving as new designs emerge. “I would say their accuracy is approaching that of piston pumps,” says Jackson.

Other filling techniques are less common, but still used for certain applications. Time-pressure filling, for example, uses air, nitrogen, or gravity to create a slight overpressure that pushes the product through an orifice. This filling method has fewer parts than other kinds, but the simplicity of design has its tradeoffs. Time-pressure technology is sensitive to product characteristics such as viscosity, says Jackson. The accuracy of time-pressure filling varies depending on fill volume. At low volumes, time-pressure filling is not as accurate as piston pumps are.

In optical filling machines such as Millipore’s (Billerica, MA) Acerta system, sensors trained on the tubing trigger a valve to shut when product reaches the desired height or fill volume. Optical filling is about as accurate as time-pressure filling, according to Jackson.

In the fill-by-weight technique, an empty vial is weighed on a scale. Next, a valve is opened to begin the fill. The valve must be closed in time so that the last drop of product does not overfill the vial. The accuracy of this technique varies, says Jackson. The weight keeps changing during the fill, so the system must stop filling, let the product settle, then read the weight to get an accurate measurement. This method is impractical for filling commercial quantities, so a company might choose to weigh one vial and use it as a guide for the others. “If you’re doing it at production speeds, fill-by-weight is probably the least accurate of any of the techniques,” says Jackson. On the other hand, the technique provides data about every container filled and allows underfilled units to be rejected.

The mass-flow technique uses a sensor built around the product dosing tube. As product flows through the tube, the sensor measures its fluid mass. Mass flow is growing in popularity in the pharmaceutical industry because the accuracy of the flowmeters has improved. “It’s pretty accurate on big fill volumes, it’s not as accurate on small fill volumes,” explains Jackson. In addition, the flowmeter must be cleaned and sterilized on the filling machine because it’s part of the fluid path.

Each filling technology is susceptible to certain product characteristics that can affect its accuracy or performance. “From my perspective, no one filling technique does everything, although the rolling-diaphragm pump is one of the better ones,” says Jackson. Current filling technology can accurately fill common dose volumes. Bosch has successfully filled 0.03-mL volumes accurately with rolling-diaphragm, piston, peristaltic, and time-pressure pumps. The company controlled fills to fractions of a drop. Drugmakers can rest assured. Apparently, it will take even higher titers and rarer products to challenge the accuracy of the filling techniques available to the industry.