Filter Membrane Resistance in Biopharma or Beverage Processes

[Joe Reckamp]

Tangential Flow Filtration Resistance in Seeq

Many pharmaceutical and beverage processes involve a filtration process where a common type of filtration is tangential flow filtration. In biopharmaceutical processing, this is commonly found in a perfusion bioreactor and in the ultrafiltration/diafiltration (UF/DF) concentrating step. Beverage processes also typically involve a UF/DF type process to remove potential contaminants or further refine the concentration of the desired beverage.

A typical tangential flow filtration set up looks like the picture below where you have an inlet stream and two outlet streams: the retentate, which did not pass through the filter and is returned to bulk inlet, and the permeate, which is typically the product stream that has been filtered.

The goal of the process is to concentrate the product while removing large contaminants that may be present by filtering them out. During the filtration process, particles can build up on the filter membrane, causing additional resistance that reduces the effectiveness of the filter and slows down the filtration process. Therefore, it is imperative to effectively clean and sanitize the filter membrane between each batch and to monitor the membrane resistance over time to determine whether the unit operation is still effective.

One method for monitoring this is through filter resistance calculations. In order to calculate the filter resistance, the following signals are required:

·        Feed Inlet Pressure

·        Retentate Pressure

·        Permeate Pressure

·        Permeate Flow Rate

If the permeate flow rate is not present, it can be calculated, by way of the Conservation of Mass using the feed and retentate flow rates, in Seeq through the Formula tool:

$FeedFlowRate = $RetentateFlowRate + $PermeateFlowRate

The first step in solving for the resistance is to calculate a variable called the Transmembrane Pressure (TMP). This is an average pressure differential, or driving force, across the filter and can be calculated by the following formula in Seeq:

($FeedInletPressure + $RetentatePressure) / 2 - $PermeatePressure

Membrane flux (J) is the amount of permeate per unit area of the filter. This can be calculated in Seeq Formula as well:

$PermeateFlowRate / MembraneArea

where MembraneArea is a value input by the user.

Membrane flux (J) and TMP are related by the Darcy Equation, which is:

J = TMP / (μ * R)

Therefore, this equation can be rearranged to calculate the resistance (R), which includes both the inherent membrane resistance and the added resistance due to fouling. The resistance can be calculated in Seeq Formula:

$TMP / ($MembraneFlux * Viscosity)

where Viscosity is a value input by the user. If the viscosity value is unknown, the value can simply be removed from the equation to be grouped with resistance since it is a constant and will not impact the analysis of monitoring the change in resistance over time.

This resistance value should be evaluated over time or multiple batches to determine whether there is any fouling occurring or inadequate cleaning or sanitization between batches. It is recommended to use the Boundaries tool in Seeq to set limits based on historical data sets. Lower membrane resistance than historical values may represent breakthrough in the filter due to quality defects in the filter membrane. Higher membrane resistance may represent fouling of the membrane over time and result in a loss of yield if additional filtration time is not included. This higher membrane resistance may signify that additional cleaning or membrane replacement is required. These deviations from the expected resistance values can be flagged using the Deviation Search tool within Seeq.