Biopharmaceutical manufacturing may come in a wide variety of forms, but each iteration of unit operation needs to align with a strict amount of operational parameters and structures in order to create the ideal product: a viable drug which is free from contaminants and appropriate to use on humans or animals.
Chromatography, virus filtration, and tangential flow filtration (TFF), are the three most frequently used unit operations within biopharmaceutical manufacturing. Each of these specific methods has operating features that are unique, which makes it crucial for the operator to be aware of them.
Chromatography, as an example, needs consistent fluid-flow rates while in operation, but it could have various pumping pressures.
Whereas virus filtration will have consistent pumping pressures, but the fluid-flow rates are variable when the filters become congested or dirty. In TFF, the operator must try to keep both the flow rate and pressure consistent throughout the method.
It is crucial to consider that while fluid transfer is undertaken in all of these particular unit operations, the materials that are being conveyed can be very delicate and easily harmed (and, oftentimes, are more costly). To avoid harming the material, the pumping action must be low-shear and low-pulsating.
This article details the problems encountered with material handling around flow rate and pressure in TFF, virus filtration and chromatography unit operations.
This is outlined to detail how the process and design of the quaternary diaphragm pump, as opposed to other methods, such as the peristaltic (hose) pump or the lobe pump, is most compatible with manufacturing applications in biopharmaceuticals.
Further to this, this article will illustrate how the quaternary diaphragm pump can constantly operate in a set stainless-steel production process or in the more frequently used single-use mode of application, making it capable of optimizing biopharmaceutical-manufacturing operational expenses, changeover and downtime.
The Unit Operations
Firstly, there are three most frequently used unit operations in biopharmaceutical manufacturing, which are detailed more closely below:
A common chromatography column, whether it is made from plastic, glass or steel, contains resins that are fixed into a particular shape where the feed stream product runs and cleanses the product by selective adsorption to a stationary phase (resin).
Chromatography columns are created with complicated media that specifically adsorbs the target product and need to be handled delicately. A Protein A resin, for example, can cost up to $10,000 per liter, which means it is critical to feed the resin with care.
A few of the chromatography systems do need gradients for buffer to allow for protein purification. Buffers are compounds that are defended against variables in their pH level when small amounts of bases or acids are added. As an example, buffering salts have a large pH range that can make the pH level of the material used consistent.
More often than not, more than one buffer is needed. This means that more than two pumps will also be necessary. In this method, both high and low salt buffers are combined consistently and with variable ratios as a means to affect the adsorption of the target molecule to the resin in the chromatography.
Due to this, accurate pumping is necessary to create the correct pH or conductivity environment for particular adsorption and high-resolution purification. Such as, a Buffer A and Buffer B can both be utilized to make a gradient that begins as a low-salt buffer and ends as a high-salt buffer in a linear manner.
Particularly, the method will start with Buffer A creating 95% of the flow and Buffer B creating the other 5%. During the operation, the flow rates of Buffer A and Buffer B will diminish and get larger in a linear fashion (90% for A and 10% for B, 75% for A and 25% for B, through to 5% for A and 95% for B).1
The process needs a pumping technology that can create a very precise flow and a high turndown ratio that can produce both lower and higher flow rates when the elution stage continues. The pulsation of the pump should be lessened to reduce disturbance of the packed column.2
If the pump cannot meet the specifications, the successful buffer concentration might not be created. Moreover, if the pumping action pulses excessively, then the buffers can have spikes in their conductivity.
Excessive pumping action can also affect the degree of purification in the product because the salt level in the buffer could be changed. When the loading of the sample is taking place, it is also common for there to be an increase in the operating system’s back pressure.
Pumps that are not susceptible to slipping offer positives in these instances as the flow rate will remain constant, and the stability of the linear velocity will not be compromised. Simply put, a pump with minimal slip will have a more easily controlled flow rate that will need only incremental adjustments to the pump’s speed (measured in RPMs).
In the manufacture of biopharmaceuticals, systems for virus filtration are utilized to make sure that the safety and viability of the drugs are not compromised. This is a result of possible contaminants being taken away from products created from cell cultures.
Where chromatography is characterized with consistent flow rates and changing pressure states, virus filtration operation systems are the opposite. Most virus filtration applications utilize consistent pressure rates, with variable flow rates. There may be a need to make the operation’s flow rate greater or lesser resting on the need to create consistent pressure rates.
As mentioned, the flows change as the virus filter becomes clogged. Most typical virus-filtration systems run at a constant pressure, for example, 2 bar (29 psi), as a result 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.
Some virus filtration systems have been created with a flux-decay range of up to 90% of the beginning flux rate. This needs a pump with a greater turndown ratio and one which creates less pulsation within the fluid of the pump.
The observation of viral clearance methods needs a display of the equivalence of scalability from bench to manufacturing scale. 3 Spiking studies for virus filtration operations utilize a pressure vessel with a smaller surface area.
The surface area can be as small as 5 cm² and needs a pump that has low shear and a smaller amount of pulsation if initial studies are to be upscaled into commercial-level production with the same outcome.
The utilization of pumps that are low pulsating in these events ensures that the pressure environment during the validation of each filter is not outside of the range of validation.
Tangential Flow Filtration (TFF)
Otherwise known as cross-flow filtration, in TFF the biologic feed stream flows tangentially across the membrane of the filter at a positive pressure. As it flows by the membrane, the amount of the feed stream that is lesser than the pore size within it passes through.
This unit operation varies from what is known as normal-flow (NFF), or ‘dead-end’ filtration. NFF is where the whole feed flows through the filter membrane, where the size of the pores decide which amount of the feed can pass through, and which will remain unchanged.
TFF also differs from NFF in applications that are biologic due to the tangential motion of the fluid by the membrane. This reduces the chances of molecules becoming built up in a tight gel layer on the surface of the membrane.
The above method creates a TFF process that can function consistently with high protein concentrations in comparison, and less fouling or binding in the filter.
In order to upscale a TFF process, there are two variables that must be taken care of. Recirculation (cross-flow) is needed in order to lessen the forming of the gel layer and pressure as the driving force to lead the permeate through the membrane.
The rate of recirculation must work in combination with the pressure (also known as the trans-membrane pressure, or TMP, which is the average amount of pressure against the membrane).
The maintenance of a consistent TMP is highly important as if it is too great, then it can create a layer of gel that will not be taken away by recirculation. If it is too small, then this can create low flux that will lessen the productivity of the process.
In this example, the most reliable pumps utilized are those that create a low pulsation of the flow rate as they would decrease the chances of variables changing too much in operation.
To conclude, when observing the functioning design of chromatography columns, TFF systems and virus filtration systems, they all depend on quick, trustworthy and cost-effective operation. This can be achieved by finding and utilizing a pump technology that can create low-pulsation and low-shear operations, even in the light of variable flow rates and pressure pumps.
References and Further Reading
- L. Hagel, G. Jagschies and G. Sofer, Handbook of Process Chromatography: Development, Manufacturing, Validation and Economics, 1997
- H. Aranha and S. Forbes, “Viral Clearance Strategies for Biopharmaceutical Safety” Pharmaceutical Technology, June 2001
The Quattroflow story dates back to the 1990s. One of the founders was working in the filtration technology sector, when he was in need of a pump to produce a protein solution. Together with the second company founder, an electrical-system specialist, they developed a diaphragm pump with four smooth-action pistons.
The start of the company was in the year 2000 using the location of the existing electrical-installation company. At the beginning of 2004 they relocated to more comfortable premises.
In 2012 PSG, a business unit operating within the Fluid Solutions platform of Dover’s Engineered Systems, a segment of Dover Corporation (NYSE: DOV), acquired Quattroflow. Quattroflow products are integrated into the German PSG operating company of Almatec, Duisburg.
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