Optimization, scale-up, and validation ISSUES in FILTRATION of Biopharmaceuticals, Part II - - BioPharm International


Optimization, scale-up, and validation ISSUES in FILTRATION of Biopharmaceuticals, Part II

Figure 2. Effect of Shear Rate on Concentration Polarization in TFF
Compare the water permeability of the membrane after cleaning to the initial water permeability. The permeability typically drops 10 to 20% after the first run and levels off at 60 to 80% of the initial value after subsequent runs. A drop in the permeability of more than 40% or a continued drop in permeability after every run suggests that the cleaning procedure is not adequate.

If the initial experiment results are promising, repeat the experiment with a permeate pump to control the permeate flow 10 to 20% higher than the average permeate flow obtained in the previous experiment. Operation at constant permeate flux typically results in a higher average permeate flux and better performance compared to a constant TMP operation, since in the latter case, the high initial flux causes a large concentration polarization that may cause increased membrane fouling.

Figure 3. Effect of Membrane Type on Product Transmission
For constant permeate flux operation, the retentate side pressures (P1, P2) stay nearly constant, while the permeate side pressures (P3, P4) decrease as the operation proceeds and the membrane becomes fouled. This results in an increase in TMP over the course of the process. Perform the constant permeate flux experiment at the low and high ends of the recirculation flow recommended by the manufacturer. At higher recirculation flow rates, rise in TMP is slower due to reduced concentration polarization. Figure 4 shows the effect of recirculation flow rate on the TMP profile for a scale-down microfiltration process for cell harvest clarification. The results show TMP rises rapidly for operation at recirculation flow rates below 2.3 L/min. The overall recovery also dropped significantly for operation at recirculation flow less than 2.3 L/min due to increased membrane fouling at lower recirculation flow.

Figure 4. Effect of Recirculation Flow Rate on TMP Profile for Microfiltration of Cell Culture Harvest Using a 4 ft2 TFF Membrane
Perform similar experiments with other candidate membrane systems using the same feed stream and product loading used in the experiments above. Compare product transmission, product quality attributes, average permeate flux, recirculation flow rates, cleaning procedures, and recovery in water permeability after cleaning. The critical deciding factors are product recovery and quality. If these factors are similar for two types of membranes, consider the operational parameters. Calculate the membrane area and recirculation flow rates required at scale based on the average permeate flux, and product loading determined from the above experiments. Choose the system that requires lower capital costs — lower membrane area, and smaller system size — and lower operating costs — lower recirculation flow, more membrane cycles before replacement.

Once the membrane and operating parameters are chosen, repeat the experiments with several lots of feed material to ensure that the process is robust and produces a high quality product with overall recovery at or above the target value.

Jennifer Campbell and Elizabeth Goodrich, Millipore Corporation

Validation of a Tangential Flow Filtration Step This section describes how validation is linked back to the choices made during process development and scale-up and will highlight important validation considerations for a large-scale TFF process. The items that must be validated in a TFF process can be divided into three separate categories — process characterization, process validation, and cleaning validation. In addition, the suitability of the industrial-scale system to manufacture product must be verified. This article will highlight the important considerations within each of these four segments of a TFF validation plan.

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