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

Anurag S. Rathore
Filtration is one of the most commonly used unit operations in the manufacturing of biopharmaceuticals. This is the second part of the fourth article in the "Elements of Biopharmaceutical Production" series. In this second segment, Manoj Menon and Frank Riske present an approach for the development and optimization of a TFF application, followed by a contribution from Jennifer Campbell and Elizabeth Goodrich reviewing key issues involved in validation of a TFF step.

Manoj K. Menon and Frank J. Riske, Genzyme Corporation

Process Development for a Tangential Flow Filtration Step Tangential flow filtration (TFF) is used extensively in the biopharmaceutical industry for harvest clarification, protein concentration and diafiltration, and viral clearance filtration. A typical TFF system is shown in Figure 1. The feed stream to be processed is recirculated across the upstream surface of the porous membrane by the recirculation pump. The flow generates a pressure difference across the membrane, with the average trans-membrane pressure (TMP) given by:

where P1 and P2 are respectively the pressure values at the inlet and outlet of the retentate stream, while P3 and P4 are pressure values at the corresponding points on the permeate side. TMP can be increased by partially closing the retentate valve (V1), which results in an increase in the retentate pressure (P2), and a corresponding increase in feed pressure (P1). Increasing recirculation flow rate raises the feed pressure (P1) and also results in an increase in the TMP.

As the fluid is forced through the membrane pores, particles retained by the membrane accumulate at the membrane surface, a phenomenon known as concentration polarization (Figure 2). The accumulated particles may form a dense particle cake or "gel layer" on the membrane surface thereby increasing resistance to flow. The high concentration of particles may also cause membrane fouling and reduce permeate flow. The shearing action of the flow across the membrane in TFF sweeps the retained particles away from the membrane surface, reducing the extent of concentration polarization and increasing the permeate flow. Increasing the shear rate (by increasing recirculation flow or reducing the channel height) can further reduce the concentration polarization (Figure 2). However, the higher shear rates cause a larger pressure-drop across the retentate channel — P1-P2 in Figure 1 becomes larger — increases the power required for recirculation, and may cause lysis of cells or denaturation of proteins. A key aspect in the design of TFF systems is choosing a recirculation flow rate that provides high product recovery at an acceptable operational performance, as characterized by step recovery, process time, pool quality, filter capacity, and minimal overall cost.

Membrane Screening Due to the complex interaction of various factors that determine performance, it is difficult to predict which membrane type will perform best for a given application. Scale-down experiments with a representative feed stream will need to be performed before the membrane choice can be made. Select candidate membranes for evaluation based on the following guidelines:

  • Limit choices to products from manufacturers with proven manufacturing expertise and reliable quality control systems.
  • Flat-sheet cassettes with open channels and wide ports are preferred for feed streams with high levels of suspended solids — for harvest clarification — or a shear-sensitive product, while modules with narrow channels and turbulence promoting screens or hollow-fiber systems are preferred for applications with low or no suspended solids — ultrafiltration for protein concentration.
  • Pick membranes with an average pore size significantly smaller than the size of the retained species in order to minimize membrane fouling by pore plugging and to ensure the retained species (in many cases your product) remains on the upstream side of the membrane.1 Test different pore sizes and select the largest possible pore size that does not result in significant fouling during the process to maximize process flux and does not allow target retained species to pass through the membrane.

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