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Optimizing Unit Operations In Biopharmaceutical Manufacturing

Introduction

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.

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

Chromatography, virus filtration and tangential flow filtration (TFF) are three of the more common unit operations that can be used in the manufacture of biopharmaceuticals. In

order to provide efficient, reliable and cost-effective processes in all three unit operations, as well as guaranteeing the production of drugs that are suitable for human or animal

consumption, manufacturers must utilize a pump technology that features low-pulsation and low-shear operation even when encountering variable flow rates and pumping

pressures. A technology that meets all of those operational requirements is the Quaternary Diaphragm Pump from Quattroflow™, which also possesses the versatility to operate

effectively in a fixed stainless-steel production setup, as well as in the increasingly popular single-use manufacturing applications.

the filters become clogged or fouled. And in TFF, the main

pumping action must be low-pulsating and low-shear, lest

the material be damaged.

This white paper will examine the material-handling

challenges pertaining to flow rate and pressure in

chromatography, virus filtration and TFF processes and

illustrate why the design and operation of the quaternary

diaphragm pump – rather than other technologies such as

the lobe or peristaltic (hose) pump – makes it ideal for use

in critical biopharmaceutical-manufacturing applications.

Additionally, the paper will show how the quaternary

. If the pump

concentration may not be attained. Also, if the pumping

action produces excessive pulsation, the buffers can be

susceptible to experiencing spikes in their conductivity.

This can affect the purification level of the product as the

salt level in the buffer could be compromised.

Also, during the loading of the sample, it is not

pump’s speed (measured in RPMs).

In biopharmaceutical manufacturing, virus-filtration

systems are used to ensure the viability and safety of

the drugs that are produced through the removal of

potential contaminants from products that are created

using cell cultures. Whereas chromatography features

constant flow rates and variable pressures, the operation

of virus-filtration systems is the opposite – most virus-

filter applications use constant pressures with variable

due to the nature of the tight pores in the filtering

medium, but the flow rates will decrease as the filter’s

pores become fouled. When this happens, the flow rate

will not decrease in a linear fashion, which will adversely

affect the performance of the filter, product yield and

overall quality.

After its invention in 2000, quaternary diaphragm pump technology from Quattroflow™

quickly gained popularity as a low-pulse, low-shear option for the various unit

operations that can be used in the manufacture of biopharmaceuticals.

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Optimizing Unit Operations In Biopharmaceutical Manufacturing

Some virus filters have been designed with a flux-

. Spiking

studies for virus-filtration use a pressure vessel with a

small surface area, which can be as little as 5 cm

and

demand a pump that has low-shear and low-pulsation

operation if commercial-scale production levels are to

replicate the small-scale studies. The use of low-pulsing

recirculation loop, such as a TFF filtration system, 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 is a controlled

product leak and does 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.

increase in power required to overcome the pump’s slippage.

™

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Optimizing Unit Operations In Biopharmaceutical Manufacturing

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

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,

• If there is pulsation, an operational certainty with

The Solution

An effective solution to the operational shortcomings of

growing increasingly frustrated with the overall operation

of the pumping technologies that were commonly used in

chromatography and TFF applications.

“We were using peristaltic pumps but we found out that

these pumps were not made for TFF applications. We were

checking the marketplace looking for better pumps and

spent 80% of our time looking for pumps,” Glabiszewski

recalled. “One night I went home and I was sitting in

my car frustrated after a pump failure and asked myself a

question, ‘Which type of pump did Mother Nature invent

When the new technology was finalized in 2000, the

pair created a company that would begin producing

quaternary diaphragm pumps for use in biopharmaceutical-

manufacturing processes. As the duo’s invention grew in

popularity over the past 15 years, the technology was also

modified so that it could employ disposable plastic heads

and wetted parts to make it applicable in the burgeoning

single-use biopharmaceutical-production marketplace.

The operating principle of the quaternary diaphragm pump

most closely resembles the operation of the human heart

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

through the column, both of which are critical concerns

that require low pulsation with accurate and constant

flow rates and pressures. In TFF applications, quaternary

diaphragm pumps deliver the consistent flow control that

is essential in producing optimal filtrate yields.

In today’s evolving biopharmaceutical-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

campaign

pump chamber that has come in contact with the

fluids is disposed of

wetted parts are replaced, which eliminates elevated

maintenance costs

sterilization is not practical or possible. This represents

a significant simplification and cost reduction to the

overall process as there are no contaminated cleaning

chemical and water solutions that need to be treated

and disposed of. The costs to properly treat and

dispose the cleaning fluids can alone be the driver to

require use of single-use alternatives.