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.

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