Pumping Fluids in Biopharmaceutical Processing

Pump systems must be designed to meet the needs of specific processes, including preventing cross-contamination and damage due to shear forces.
Feb 02, 2017
Volume 41, Issue 2, pg 72–73

In a biopharmaceutical process, pumps are needed to move fluids (e.g., buffer, media, and water for injection) through tubing and deliver them to the process equipment. Several types of positive displacement pumps are used, including peristaltic, diaphragm, rotary lobe, and gear pumps. In hygienic or sanitary uses such as in biopharm, pumps must prevent contamination and be able to be validated. Pumps may use single-use components or, if multi-use, be designed to be easily cleaned. Pumps must be designed to meet appropriate standards for biopharmaceutical processing, such as the American Society of Mechanical Engineers (ASME) Bioprocessing Equipment (BPE) standard (1). Pharmaceutical Technology spoke with experts at manufacturers of peristaltic and diaphragm metering pumps about some of the considerations for fluid handling in biopharmaceutical manufacturing.

Diaphragm pumps

There are different types of diaphragm pumps. Air-operated double-diaphragm (AODD) pumps are used for transferring fluids from one place to another and for ultrafiltration or diafiltration, notes Gary Gaudet, technical leader of bioprocessing at LEWA-Nikkiso America. AODD pumps, however, do not have volumetric control. Diaphragm metering pumps, which have highly accurate volume control, are used in processes and for dosing. Applications include: chromatography, buffer inline dilution, homogenization, injection of fluids (e.g., liposomes) into extruders, coating operations, filling, caustic dilution, and aseptic transfer of proteins, cells, and other materials, says Gaudet.

A diaphragm pump uses the reciprocating movement of a flexible diaphragm that decompresses to draw fluid into the pump chamber and then compresses the pump chamber to push fluid out. The diaphragm separates the pump drive from the product-wetted side. This separation means that mechanical seals are not needed, which ensures product safety, simplifies maintenance, and allows the pump to run dry (i.e., without fluid) without being damaged, says Andreas Frerix, product manager Quattroflow, at PSG, a Dover company.

Multiple-use pumps have housings made from stainless steel that can be reused after cleaning in place. Multiple-use diaphragm pumps are still commonly used and are meeting customers’ needs, says Gaudet. Single-use diaphragm pumps have chambers made of plastic that have been designed for one process or batch. “After the process, they are replaced with a new chamber and the new process can begin. Single-use pump chambers save money and time by avoiding cleaning and associated cleaning validation and eliminating the risk of cross-contamination between batches or products. Single-use pumps are most valuable if products are changed frequently and fast product changeovers are needed,” says Frerix.

Peristaltic pumps

In a peristaltic pump, the fluid is contained in a single-use tube that is compressed and decompressed by a moving rotor to move the fluid. Tubing is made from biocompatible materials that meet requirements for purity, and the single-use tubing is disposed of after each process to prevent cross-contamination. Because the fluid is completely contained within the tubing and connectors, process validation is simplified, notes Russell Merritt, marketing manager at Watson-Marlow Fluid Technology Group, “Once the pumps are within a cleanroom environment and remain there, no regular cleaning and little maintenance of the pump itself is required.”

Although tubing could be treated as multi-use (i.e., cleaned and sterilized between batches), most tubing is treated as “single-use” because this ensures that no cross-contamination occurs and provides new performance for every batch, says Merritt. “The need to maintain fluid path sterility is a key consideration for handling/changing any component in the fluid path. Sterility is another advantage of single-use tubing.  The fluid path is provided assembled and sterile, which minimizes the number of connections which need to be made; each connection presents a risk of the introduction of contamination.”

Peristaltic pumps are easy to install and set-up, says Gregg E. Johnson, global senior product manager for the Cole-Parmer peristaltic pump product lines. Because they don’t need to be primed, they are flexible in where they can be installed in the fluid path, explains Johnson.

“Monitoring the tubing performance is probably the greatest concern,” says Johnson. “A catastrophic failure can cost the loss of an entire campaign, but it is easily prevented by monitoring the tube life, use of new long-life tubing materials, and a preventive maintenance program to replace or move the tubing to new position.”

Handling shear-sensitive fluids

Biopharma fluids vary in how sensitive they are to shear forces due to flow. Peptides and small proteins, for example, are relatively insensitive to shear, but mammalian cells can be very sensitive. “Even if the product is not shear-sensitive, using a low-shear [diaphragm] pump also reduces the temperature increase of the fluid and thus reduces the need for cooling (e.g., for tangential flow filtration). If the product is shear sensitive, then using a larger-sized pump helps, because the pump can be run at low speed to achieve low velocities and thus minimum shear,” explains Frerix.

Protecting fluids from damage is a complex issue that is affected by the pump as well as by the design of the entire fluid handling system, says Gaudet. For example, fluid damage can occur from squeezed flow (e.g., due to fluid exposed to crevices or dynamic seals) or from impact when flows come together as pipes join up. Shear is also created by cavitation at the gas/liquid interface. If the diameter of a pipe changes too quickly, for example, air can come out of the liquid and cause cavitation. “Gentle conveying means minimizing or avoiding these effects. The less resulting energy induced in the fluid, the better overall for the fluid. We design systems based on piping designs to ensure the operating conditions of the pump minimize shear and cavitation,” says Gaudet. “The absence of any dynamic seal in the pressure chamber of diaphragm pumps allows gentle conveying of process fluids. The only areas of possible damage are at the product valves during closing and possibly opening. One must note, however, the extremely short closing or opening times (around 1% of the total time), resulting in low integral damage potential. In comparison, the shearing effect at the plunger seal of a plunger pump or the impeller are present during the complete stroke cycle.” Gaudet adds, “Similar problems apply to other pump types (basically any rotating positive displacement, gear, rotary piston, peristaltic hose, or eccentric screw pumps).”

Peristaltic pumps are inherently low shear, which means that they will circulate or pump cell suspensions without damage, says Johnson. “The acceptable shear level for a cellular suspension typically can be determined by measuring cell viability after passing through the fluid-path system,” explains Johnson. “Excessive shear is caused in a fluid path mostly by two surfaces that are moving against each other, which is particularly evident in centrifugal, gear, or other types of rotating pumps or mixers. Tubing occlusion can still cause cell death, but it can be mitigated by reducing the pump speed and increasing the tubing diameter.”

“Peristaltic pumps ensure product cannot be damaged by high fluid velocities or contact with mechanical parts,” explains Merritt. “The achievable flow rate is determined by the bore size of the tube and the speed at which the pump is run. Fluid viscosity plays an important part in the speed at which the pump is run and the deliverable flow. Higher viscosity products require a large bore size tube, but a low running speed. In downstream processing, such as tangential flow filtration and high performance liquid chromatography, flow linearity with only trace pulsation and over a wide pressure range is the ultimate requirement. The acceptable level of shear is product dependent, and the suitability of any pump type can only be determined through specific testing. With peristaltic pumps, the pumping concept naturally provides low shear; through the correct sizing of the pump this can be kept to a minimum to maintain product integrity. General good practice to ensure low shear is to minimize fluid velocity. With peristaltic pumps, low shear is achieved through lowering the pumps operating speed and increasing the peristaltic tubing bore size.”

Trends in fluid handling

The move to continuous processing is evolving and will affect the requirements for pumps and other process equipment, says Frerix. Gaudet agrees, adding that there is a trend to have more self-contained processes, such as combining buffer dilution, clean-in-place systems, and chromatography skids rather than having separate skids. Steam-in-place systems are also being requested more than in the past, he notes.

Both multiple-use and single-use manufacturing systems are employed in biopharmaceutical manufacturing.  “Biopharm is naturally risk averse; innovations, therefore, rarely take hold overnight, and the advent of single-use continues to expand into different process areas due to the benefits offered,” says Merritt. “We will continue to see both single-use and hybrid (mixed single/multi use) processes being developed. Peristaltic technology is therefore well positioned to continue to meet customers’ requirements to provide a low-risk fluid handling solution through accurate pumping technology and high quality peristaltic tubing.”

Another trend, says Johnson, is an increase in the need for companies to be able to monitor fluid-path processes from remote locations. “The ability to monitor a process remotely allows the process to be run unattended and to notify users when they are complete, so the next campaign can be set up, which helps maintain productivity and improves efficiency.”


  1. ASME, Bioprocessing Equipment (2016), www.asme.org/products/codes-standards/bpe-2016-bioprocessing-equipment, accessed Jan. 6, 2017. 

Article Details
Pharmaceutical Technology
Vol. 41, No. 2
Pages: 72–73

When referring to this article, please cite it as J. Markarian, "Pumping Fluids in Biopharmaceutical Processing," Pharmaceutical Technology 41 (2) 2017.



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