Guidelines for Selecting Normal Flow Filters - Pharmaceutical Technology

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Guidelines for Selecting Normal Flow Filters
Proper selection of normal flow filters leads to increased process efficiency from early phase product development through to full-scale biopharmaceutical production.

Pharmaceutical Technology

Figure 1: The relative cost of biopharmaceutical separations. (CREDIT_PHOTO)
Normal flow filters are used widely in biopharmaceutical operations to remove colloidal material, bacteria, and viruses from growth media, buffers, and process intermediates. A modern biopharmaceutical process typically contains 40-50 normal flow filtration operations from seed culture propagation to final vial filling. As shown in Figure 1, normal flow filtration accounts for approximately one-fourth of the total cost for downstream processing. Therefore, the choice of normal flow filter(s) has a potentially large impact on the total production cost for a biotherapeutic.

Quick guide to the selection of normal flow filters
The variety of filter materials available to process development scientists is large—from depth media containing nominally-rated micron-sized filtration-matrices to validated sterile filtration membranes containing submicron-sized pores. The criteria by which one chooses the optimal filter is commonly application-specific, and it is therefore important to understand these criteria when designing experiments, analyzing data, and comparing product attributes.

In general, normal flow filtration operations can be divided into three main categories:

  • Cell culture media sterilization
  • Buffer filtration
  • Product-stream filtration.

Figure 2: Normal flow filtration in biopharmaceutical production.
Figure 2 shows a typical biopharmaceutical process and highlights where each of these filteration steps occurs.

Cell culture media sterilization

One of the first unit operations in any biopharmaceutical operation is the preparation and sterilization of cell culture media. Cell culture media are nutrient-rich, buffered solutions containing amino acids, salts, vitamins, and energy sources (e.g., glucose)—all of which are essential components for the culture of healthy cells. Over the past several decades, formulations have evolved from generic basal media supplemented with animal-derived sera, to more cell-line specific formulations that are serum-free, animal-derived component-free and chemically defined. The sterilization of these media is critical to successful cell growth and protein expression.

There are many characteristics one should look for when selecting a cell culture media filter. The following paragraphs describe some of the most important features.

Sterilizing-grade membranes. The term "sterilizing-grade filter" is defined in the FDA's document Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice (1), which describes a sterilizing-grade filter as a filter that is "validated to re-producibly remove viable microorganisms from the process stream, producing a sterile effluent." The validation of sterilizing-grade membranes is commonly performed using the procedure documented in ASTM F838-05, "Standard Test Method for Determining Bacterial Retention of Membrane Filters Utilized for Liquid Filtration" (2). To be labeled "sterilizing-grade," a filter must produce a sterile effluent when challenged with Brevundimonas diminuta (B. diminuta) at a minimum concentration of 107 colony forming units (CFU) per square centimeter (cm2 ) of membrane area. Sterile filters are nearly always constructed of one or more sheets of polymeric membrane, either in pleated or flat-sheet form.


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