The pharmaceutical industry has had to adapt to major changes and challenges over the last decade. This has been mainly driven by the fact that many of the blockbuster drugs are running out of patent, forcing the industry to focus more on R&D with greater interest towards developing biopharmaceutical products. This trend has highlighted the need for efficient, small batch, aseptic liquid processing and fill/finish operations. In addition, ever-increasing FDA demands, especially regarding cleaning validation, have forced the industry to look for more efficient and safer production technologies. The traditional filling technologies have been piston pumps and time pressure filling systems, but new challenges and more stringent validation requirements have put the focus on peristaltic filling technology.Peristaltic pumps are extremely convenient to use. They are often the preferred choice for fluid transfers in all types of environments such as in the laboratory or in the heavy chemical industry. On the other hand, piston pumps are also very popular and have proven themselves over the years, but piston pumps can have drawbacks in some applications. A piston pump is 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 re-assembled between each use. 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. When using peristaltic pumps, product only comes in direct contact with a single piece of tubing, which can easily be replaced after use. This single-use feature makes the peristaltic pump an attractive alternative to piston pumps for dispensing of biopharmaceutical injectable drugs. For the last few years, the pharmaceutical industry has been searching for ways to reduce the cost for developing and producing new drugs. The concept of the disposable or single-use production factory is becoming a reality. As a point of reference, it is important to note that while most of the existing drugs used today are chemically based, most of the promising new drugs are biopharmaceuticals which are developed in liquid form. An innovative breakthrough for making peristaltic pumps accurate occurred 21 years ago when Flexicon A/S of Denmark created the “pulsationfree” peristaltic pump. Once pulses were removed, the potential for high accuracy dispensing was made possible. Today, and five generations of improvements later, peristaltic dispensing pump accuracy rivals piston pumps down to micro fill volume
- The use of multiple rollers
- The removal of the typical peristaltic flow pulses by using offset rollers
It has been determined that the optimal configuration for a pump head design is to have two sets of six rollers, with each set of rollers offset with respect to one another. As the product is drawn by two tubes through the pump head, they merge into a single tube via a y-connector, and thereafter, the pulses add-up to cancel each other. The resulting pulsation-free flow is then controlled using a precise positioning motor and special software allowing for accurate dispensing. There is a huge selection of tubing available made of many materials and of various sizes, many of them made specifically for peristaltic pump use. Nonetheless, to allow for consistently accurate dispensing down to the micro litres, it is imperative that both the tubing and the pump head be designed to work together from the beginning and that they both must 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 good manufacturing practices requirements (cGMP). When compared to piston pumps and other dispensing technologies, peristaltic pumps offer the following benefits:
- One Pump Can Fill a Wide Range of Fill Volumes - A single peristaltic pump can fill volumes between 0.1 ml to 250 ml, simply by changing the tubing size. More than one piston pump would be required to meet a similar fill range.
- Fast Set-up and Calibration - It can take less than 5 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, since each batch is produced with new tubing that creates a new fluid path or set of contact parts. In comparison, when filling injectable drugs on a traditional piston filling line, it is not uncommon to buy dedicated piston pumps for each product in order to prevent cross-contamination between batches. Those pumps require cleaning, sterilizing and maintenance.
- Greatly Reduced Cleaning Validation - Cleaning validation is a cGMP requirement to demonstrate and document that the equipment used for processing an injectable drug is clean and free from contaminants
For a multiple-use piston pump filling system, cleaning validation typically requires two qualified resources up to four months to write-up the protocols and execute them. 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. In addition to these labor costs are other costs associated with the use of water for injection (WFI), for washing, rinsing, and for sterilization using pure steam and finally the cost of detergents and water disposal.
- Flow Control - It is very easy to adjust flow speed via 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, which can potentially damage biological products. Even valve-less piston pumps generate higher pressures, higher shear factors and, by design, inherently produce a “dead volume” with each stroke. Peristaltic pumps are valve-less and only apply low pressure to move the product.
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%.When peristaltic pumps are integrated into highspeed filling machines, an automated closed-loop weight-check weight control system assures that the fill volumes remain within tight tolerances. While piston pumps need to cycle through a recovery or suction phase between each dispensing stroke, there is no such downtime required with peristaltic pumps. Consequently, peristaltic pumps will dispense product immediately upon demand. The high-end peristaltic dispensing pumps are designed to run at high RPM to minimize fill time. They are equipped with a control system that provides an immediate response from a filling machine input signal. Therefore, 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 minutes. 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 potential 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 the micro fill volumes is to apply 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. 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. The use of peristaltic pumps and single-use tubing is also becoming more commonplace as it allows for simple fluid transfers with no cleaning and no risk of cross contamination. New drugs and, in particular, biopharmaceutical drugs are often designed for a specific population. Therefore, they are more likely to be made in relatively small batches than general application “chemical” drugs. As new drugs evolve to offer a more specific spectrum of applications, batch sizes are becoming smaller and the need for efficient product changeovers on the filling lines will become greater. Many articles about single-use technology have been written regarding efficient use of the utility and process equipment for upstream processing. Benefits of single-use technology include reduced labor, equipment and energy costs, increased plant flexibility and faster turnaround with significantly less risk of contamination. In addition to R&D, there is now a requirement for greater reliability and efficiency for the fill/finish side of mass manufacturing of biological drugs. Therefore, it is expected that single-use technology will make its way in production facilities where accurate peristaltic dispensing pumps can eventually replace pistons and other mechanical dispensing systems, potentially allowing for 100% singleuse drug manufacturing. Until now, the pharmaceutical industry has used single-use silicone tubing and fittings for peristaltic dispensing but has not been able to provide a single-use filling nozzle. In an effort to offer a complete solution to singleuse 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 ring the product directly from the product holding tank to the filling nozzle for dispensing on the filling machine— making the entire process singleuse. The pharmaceutical industry is implementing single-use technology in both the R&D laboratory and large scale production of injectable drugs. Peristaltic pumps have benefited from major technological improvements that have made them very accurate, fast, and reliable. Today, single-use peristaltic pumps offer a serious alternative to piston pumps for the production of biopharmaceutical drugs.
