Controlled Fluid Transfer Optimizing Unit Operations in Bio–, Pharmaceutical and Continuous Process Manufacturing

Author / Editor: Glenn Hiroyasu and Sueli Roel Backes* / Dr. Jörg Kempf

Biopharmaceutical manufacturing may come in a wide variety of forms, but every iteration of unit operation must adhere to an unbending set of operational parameters and structures if the desired outcome — a viable, contaminant-free drug suitable for human or animal administration — is to be realized. It is all about “controlled fluid transfer.”

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Process chromatography requires a pump technology that features low-pulsation and low-shear operation even when encountering variable flow rates and pumping pressures.
Process chromatography requires a pump technology that features low-pulsation and low-shear operation even when encountering variable flow rates and pumping pressures.
(Source: Quattroflow)

Three of the more common unit operations within the biopharmaceutical-manufacturing universe are chromatography, virus filtration and tangential flow filtration (TFF). In order for these unique operations to be implemented successfully, though, the operator must be aware of their specific operating characteristics. For example, chromatography requires constant fluid-flow rates during their operations, but may have varying pumping pressures.

Virus filtration, on the other hand, will feature constant pumping pressures, but flow rates will change as the filters become clogged or fouled. And in TFF, the main challenge is attempting to keep the flow rate and pressure unchanging throughout the process. All these characteristics are also fundamental for inline blending, a common process seen not only in the biopharma segment, but also in the chemical, pharmaceutical and food and beverage industries, where constant flow and pressure ensure the quality of the mixture.

While fluid transfer is taking place in any of these specific unit operations, it is important to know that the materials that are being transferred can be highly sensitive and delicate (and, in many cases, expensive), meaning that the pumping action must be low-pulsating and low-shear, lest the material be damaged. Let’s take a closer look at one of the most popular unit operations in biopharmaceutical manufacturing: chromatography.

Example: Chromatography Columns

A typical chromatography column, whether it is glass, steel or plastic, is filled with resins that are compressed in a certain format through which the feed stream product flows and purifies the product by selective adsorption to a stationary phase (resin). Chromatography columns contain complex target-product adsorbing media that need careful handling.

Some chromatography systems require buffer gradients in order to achieve purification of the proteins. Quite often more than one buffer is required, which creates the need to use two or more pumps. In this application, high- and low-salt buffers are mixed continuously and with changing ratios in order to affect the adsorption of the target molecule to the chromatography resin. Because of this, precise pumping is required to achieve the right pH/conductivity conditions for specific adsorption and high-resolution purification.

This requires a pumping technology that can produce a highly accurate flow with a high turndown ratio that can deliver low and high flow rates as the elution stage continues and ensure constant flow. Pump pulsation should also be minimized to prevent disturbance of the packed column.

In this instance, pumps that deliver low-pulsation flow characteristics will perform most reliably by decreasing the fluctuation in the variables. So, in considering the functional design of chromatography columns, the common thread in guaranteeing efficient, reliable, cost-effective operation is found in identifying and using a pump technology that is capable of producing both low-pulsation and low-shear operation despite varying flow rates and pumping pressures that are accompanied by high volumetric efficiency.

With these operational requirements in mind, over the years various pump technologies have been tested and used. Two that are among the more popular choices when positive displacement is required are lobe and peristaltic pumps. Both, however, have been found to feature operational inefficiencies that may make them insufficient for use in chromatography.

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Lobe Pumps and Peristaltic (Hose) Pumps

Since many biopharmaceutical materials are contained in a low-viscosity aqueous solution, lobe pumps may not be a good choice because slippage can occur during their operation, which can vary between 10 percent and 100 percent, depending on the system’s back pressure. Slip will also result in increased shear damage and energy consumption, and if used in a long-duration recirculation loop, there can be noticeable heat addition to the product that requires significant cooling efforts to protect the product from overheating.

Lobe pumps also have mechanical seals, which contribute to a controlled product leak and do not provide full containment unless special (and oftentimes expensive) seals and seal barriers are used. The sterility required in biopharmaceutical handling also means that no outside contaminants can be introduced into the purification process, which is something that pumps with mechanical seals cannot reliably ensure.

Additionally, the necessary contact between a lobe pump’s internal parts can lead to wear and the generation of particles that can result in product contamination. Solid particulates, such as undissolved salt crystals, can cause severe damage to the lobes, resulting in damage to the entire manufacturing batch. Lobe pumps will ultimately cost more to operate because of the increase in power required to overcome the pump’s slippage.

When Pumps Become a Danger for Sensitive Products

The main shortcoming of peristaltic pumps is also the most obvious: Their method of operation will undoubtedly produce pulsation, and, as noted, pulsation is always bad in biopharmaceutical manufacturing. Peristaltic pumps also have limited flow and pressure-handling abilities. For example, they cannot reliably produce the higher discharge pressures (such as 4 bar, or 58 psi) that are required in some fluid-handling applications.

They are also known to release some small quantity of hose material — in a process known as “spalling” — into the pumped product, which can compromise its purity. If the spalled hose material makes its way to the filter, it can foul the filter, making its operation not as efficient as it needs to be, which will also lead to contamination. Also, inconsistency of flow rate will result due to mechanical deformation of the hose during the pumping process.

In the end, the shortcomings of lobe and peristaltic pumps come down to two main things:

  • If there is shear, which is common in lobe pumps, you will damage the pumped material.
  • If there is pulsation, an operational certainty with peristaltic pumps, you won’t have even flow, and without even flow, you won’t have accurate flow.

The Solution: Quaternary Diaphragm Pump

An effective solution to the operational shortcomings of lobe and peristaltic pumps can be the quaternary diaphragm pump. The operating principle of this special type of pump most closely resembles the operation of the human heart because the four-piston diaphragm technology enables a gentle pumping action through soft “heartbeats.” This action produces four overlapping pumping strokes of the pistons that efficiently reduce pulsation since each stroke of the four diaphragms is generated by an eccentric shaft that is connected to an electric motor.

The quaternary diaphragm pump’s method of operation allows it to gently, safely and securely convey low-viscosity aqueous solutions and biopharmaceutical materials that are highly sensitive to shear forces and pulsation while being pumped. Since the four-piston design of the pump does not require any mechanical seals or wetted rotating parts, total product containment is ensured without any abrasion or particulate generation.

The pump’s method of operation also produces risk-free dry-running and self-priming capabilities with high turndown ratios. A pump technology with high turndown ratios allows for the creation of a broad flow range, which makes the pump applicable for utilization in a wide range of process applications.

With regards to specific unit operations, quaternary diaphragm pumps can be used to pack chromatography columns and then pump the biopharmaceutical material through the column, both of which are critical concerns that require low pulsation with accurate and constant flow rates and pressures.

The First Choice: Quaternary Diaphragms

In today’s evolving manufacturing processes, quaternary diaphragm pumps are also rapidly becoming a first-choice technology in increasingly popular single-use production setups. Basically, a single-use pump enables biopharmaceutical manufacturers to eliminate the cost of cleaning and validating their pumps by using a pump with a replaceable pump head. The result is not only a quicker production process, but one that delivers preferred levels of product purity and sterility with no chance for cross-batch or cross-product contamination.

Of course, not every pump technology is completely perfect for every characteristic of a specific fluid-handling application. In this instance, the design and operation of the quaternary diaphragm pump limits it to handling fluids that have a maximum viscosity of 1,000 centipoise (cPs) and that contain particulates up to 0.1 millimeter in diameter.

Keeping the Future of Pharma Flowing

The importance of biopharmaceuticals means that any and all products must meet strict demands regarding their manufacture. This includes ensuring that no damage is done to component materials.

Compared to lobe and peristaltic pumps, a better choice can be the quaternary diaphragm pump, the operation of which greatly reduces the chance that pulsation and shear will compromise the safety and effectiveness of the end product.

* * Glenn Hiroyasu is the Americas Development Manager for Quattroflow Fluid Systems, Kamp-Lintfort/Germany. Sueli Roel Backes is Business Development Manager, EMEA Hygienic for Quattroflow and PSG.