New peristaltic pump designs mean more accurate dispensing of biopharmaceuticals
Over the last decade, the pharmaceutical industry has had to adapt to major changes and challenges, driven mostly by the fact that many of the blockbuster drugs are running out of patent. The industry has had to focus more on research and development (R&D) with a greater interest toward developing biopharmaceutical products, a trend that has highlighted the need for efficient, small batch, aseptic liquid processing and fill operations. In addition, ever-increasing Food and Drug Administration (FDA) demands have forced the industry to look for more efficient and safer production technologies.
Traditional filling technologies are piston pumps and time-pressure filling systems, but new challenges and more stringent validation requirements have put the focus on peristaltic filling technology. Innovations in peristaltic pump design are already reducing the cost of bringing new drugs to market and are demonstrating changes that may be made in the way products are mass-produced.
Peristaltic pumps, which are extremely convenient to use, are often the preferred choice for fluid transfers in all types of environments, including both the laboratory and the heavy chemical industry. Piston pumps are also very popular and have proven themselves over the years. Unfortunately, piston pumps have drawbacks in some applications. For example, because piston pumps are designed with many mechanical parts such as valves and seals that are in direct contact with the product, these components—which will wear out—need to be taken apart, cleaned, and reassembled between uses. Even the high-end valveless ceramic piston pump comes into direct contact with the product. Additionally, diligent care is required to prevent damage to the piston in these extremely fragile pumps.
In peristaltic pumps, product only comes in direct contact with a single piece of tubing, which can easily be cleaned or replaced after use. This single-use feature makes the peristaltic pump an attractive alternative to piston pumps for dispensing of biopharmaceutical injectable drugs, which are quickly becoming the most promising new biopharmaceuticals.
Pulsation-Free Peristaltic
Technology
An innovation in the accuracy of peristaltic pumps occurred 21 years ago when Flexicon A/S of Denmark created the "pulsation-free" peristaltic pump. The removal of pulses made it possible to achieve high accuracy dispensing. Today, five generations of improvements later, peristaltic dispensing pump accuracy rivals piston pumps down to micro fill volumes.
Two key design features allow the peristaltic pump to dispense accurately: the use of multiple rollers and the use of offset rollers to remove the typical peristaltic flow pulses. Optimal configuration for a pump head design is two sets of six rollers, with each set of rollers offset with respect to one another. The two tubes drawing the product through the pump head merge into a single tube via a Y-connector, after which the pulses add up to cancel each other out (see Figure 1). The resulting pulsation-free flow is then controlled using a precise positioning motor and special software that ensures accurate dispensing.
A huge selection of tubing is available—made of many materials and in various sizes, many of them made specifically for peristaltic pump use. Nonetheless, to allow for consistently accurate dispensing down to microliters, it is imperative that the tubing and pump head work together from the beginning and that they both have close dimensional tolerances.
Key mechanical characteristics in the selection of peristaltic pump tubing include uniform wall thickness, consistent material hardness, and high mechanical "memory" after compression. Finally, and in consideration of dispensing injectables, the silicone tubing must be of the highest quality to meet the FDA’s current good manufacturing practices requirements (cGMP).
The Benefits
When compared to piston pumps and other dispensing technologies, peristaltic pumps offer several benefits.
• One pump can fill a wide range of fill volumes: A single peristaltic pump can fill volumes between 0.1 ml and 250 ml, with just a simple change in the tubing size. More than one piston pump would be required to meet a similar fill range.
• Fast setup and calibration: It can take less than five minutes to load the tubing, purge the system, make one calibration, and begin filling.
• Cross-contamination: Peristaltic pumps do not require cleaning when utilized for single-use dispensing, because each batch is produced with new tubing that creates a new fluid path or set of contact parts. In comparison, on a traditional piston filling line for injectable drugs, it is not uncommon to buy dedicated piston pumps for each product in order to prevent cross-contamination between batches. Those pumps require cleaning, sterilization, and maintenance.
• Greatly reduced cleaning validation: Cleaning validation is a cGMP requirement that demonstrates and documents that the equipment used for processing an injectable drug is clean and free of contaminants. For a multiple-use piston pump filling system, cleaning validation typically requires two qualified employees up to four months to write up and execute the protocols. For each subsequent production batch, cleaning in accordance with the validated procedures has to be maintained and properly documented each time throughout the drug’s commercial life. These labor costs are added to other costs associated with the use of water for injection; for washing, rinsing, and sterilization using pure steam; and, finally, for the cost of detergents and water disposal.
• Flow control: It is easy to adjust flow speed with the peristaltic pump interface in order to prevent foaming or splashing of the product. It is also possible to adjust how fast the fill speed is reached using the ramp-up and ramp-down feature. This is helpful in optimizing overall fill time to permit greater throughput from the filling machine.
• Gentle handling for shear-sensitive products: The valve system in the piston pump generates high-speed flow through small orifices, potentially damaging biological products. Even valveless piston pumps generate higher pressures and higher shear factors and produce, by design, a "dead volume" with each stroke. Peristaltic pumps are valveless and apply only low pressure to move the product.
• Better accuracy: The typical industry standard for fill volume accuracy is ±0.5%. Peristaltic dispensing pumps meet this requirement for fill volumes as small as 0.5 ml. Below that fill volume, accuracy can be as good as ±1% (see Figure 2, p. 35). When peristaltic pumps are integrated into high-speed filling machines, an automated closed-loop weight-check system assures that fill volumes remain within tight tolerances.
• Fill time: While piston pumps need to cycle through a recovery or suction phase between each dispensing stroke, peristaltic pumps require no such downtime. Consequently, peristaltic pumps dispense product upon demand. High-end peristaltic dispensing pumps are designed to run at high revolutions per minute to minimize fill time (see Figure 3, above). This feature, along with a control system that provides an immediate response from a filling machine input signal, means that using a peristaltic dispensing pump instead of a piston pump will not slow down the filling process. It is now commonplace to have high-speed filling lines with peristaltic pumps that fill at rates over 400 bottles per minute.
• Viscosity limitations: Peristaltic pumps have limiting capabilities for dispensing viscous products. In general, a product with the viscosity of olive oil can be dispensed using peristaltic pumps. Slightly higher viscous products will also work but may exhibit loss in accuracy and flow rate. While piston pumps have the capacity to generate significantly greater pressure for dispensing more viscous products, high-end peristaltic dispensing pumps do not. In fact, one of the underlying principles in achieving accurate peristaltic dispensing down to micro fill volumes is the application of very little pressure on the tubing. When used for micro filling, peristaltic pumps are calibrated to provide no more than approximately 1.3 bar of pressure.
Single-Use Bioprocessing
In recent years, biotech companies have embraced single-use technology, an efficient method for developing and bringing new drugs to market. Single-use process components such as small reactors, filters, mixers, and fluid handling bags have been available for the last few years. Peristaltic pumps and single-use tubing are also becoming more commonplace because they allow for simple fluid transfers with no cleaning and no risk of cross contamination.
New drugs, biopharmaceuticals in particular, are often designed for a specific population. Therefore, they are more likely to be made in relatively small batches than are general application "chemical" drugs.
As new drugs evolve to offer a more specific spectrum of applications, batch sizes are shrinking, increasing the need for efficient product changeovers on the filling lines. Benefits of single-use technology include reduced labor, equipment, and energy costs, increased plant flexibility, and faster turnaround with significantly less risk of contamination.
Just as with R&D, the fill/finish side of biological drug mass manufacturing now requires greater reliability and efficiency. Therefore, it is expected that single-use technology will make its way into production facilities where accurate peristaltic dispensing pumps can eventually replace pistons and other mechanical dispensing systems, potentially allowing for 100% single-use drug manufacturing.
Until now, the pharmaceutical industry has used single-use silicone tubing and fittings for peristaltic dispensing but has not had access a single-use filling nozzle. In an effort to offer a tool for single-use aseptic filling, Flexicon developed a plastic nozzle for single-use applications. It is now possible to purchase single-use ready-to-use tubing set assemblies. These sets include the required pharmaceutical-grade silicone tubing, connectors, and single-use filling nozzles. The assembly is double bagged and gamma irradiated and includes a complete validation package.
Various single-use tubing set configurations are available. These may include a sterile filter, septic quick-connect fittings, and a pre-filled product bag. In most cases, tubing and connectors bring the product directly from the product holding tank to the filling nozzle for dispensing on the filling machine—making the entire process single use.
Lambert is manager of the biopharmaceutical division at Watson-Marlow Pumps Group. For more information, e-mail support@wmbpumps.com or call (802) 657-3232.
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Biopharmaceutical products processing conventional of instruments. Biopharmaceutical systems as well as disposable, single-use systems. Biopharmaceutical products are manufacture and provide to suppliers around the globe.
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