Optimization, scale-up, and validation issues in Filtration of Biopharmaceuticals, Part 1 - - BioPharm International


Optimization, scale-up, and validation issues in Filtration of Biopharmaceuticals, Part 1

Filtration is one of the most commonly used unit operations in biopharmaceutical manufacturing. Available formats include direct or normal flow filtration (NFF) and cross or tangential flow filtration (TFF). These methods are used for sterilization and virus filtration, depth filtration or ultrafiltration, and diafiltration applications. Some common objectives include:

  • separation of particulates from the process stream (for example, to separate host cell components and cell debris in the upstream or midstream portion of the process or before a chromatography step to prevent particles in the feed or buffer from clogging the column)
  • separation of impurities from the process stream (for viral clearance, for sterile filtration, or for host cell protein or DNA removal by charged filters)
  • concentration of the feed stream using ultrafiltration to reduce the process stream's total volume or to reach a targeted product concentration
  • buffer exchange via the use of a diafiltration step to deliver the product to the desired buffer system before chromatography or final formulation.

This article is the fourth in the "Elements of Biopharmaceutical Production" series and will be published in two segments. In this first segment, Anurag Rathore and Alice Wang present development and scale-up of a depth filtration step, and Jerold Martin discusses development and validation issues for a viral clearance filtration step.

Anurag S. Rathore and Alice Wang, Amgen Inc.

Process Development and Scale-up for Depth Filtration The following shows the development of a robust depth filtration step for clarification.1 We wanted to design a robust and scaleable depth filtration step that could maximize product recovery (in this case, a protein expressed in Pichia pastoris) and that could handle varying % solids content in the feed stream from the preceding centrifugation step. First, we performed a screening study using various depth filters available on the market that met our manufacturing process criteria. Second, we chose filters based on the screening data; we directly and thoroughly compared those filters to determine the best performing filter. Then, we performed characterization studies on the chosen filter to ensure robust performance at scale. Finally, we scaled the filtration step up to pilot scale and compared its performance under these conditions.

FILTER SCREENING As listed in Table 1, we chose ten different filters from three manufacturers based on their suitability for manufacturing. We used disposable filter disks for filter screening experiments. We used filter format, surface areas, and recommended flow rates from the various manufacturers as guidelines for the screening study (Table 2). We designed the depth filter train in stages with a more open filter (such as Cuno 10SP, Pall Supra 80P) ahead of a tighter grade to allow for robust operation with high capacity. Some of the depth filters in Table 1, including the Millipore Millistak+A1HC, Millistak+B1HC, and the Cuno 90M08, combine sequential grades of media in one filter.

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