Filtration

Integrity Testing of Ultrafiltration Systems for Biopharmaceutical Applications

    Ultrafiltration (UF) is a membrane-based separation technology commonly used in the biopharmaceutical industry for concentration or diafiltration of protein solutions to remove low–molecular-weight (LMW) impurities or exchange buffers. The nominal MW limit of UF membranes ranges from 1,000 Da (1 kDa) to 1,000,000 Da (1,000 kDa). A target product is retained by the membrane while lower-MW solutes or impurities pass through (1). For a target product with a smaller MW than the impurities, separation is accomplished by allowing…

Sterilizing-Grade Filter Sizing Based on Permeability

    Sterilizing filtration renders biotherapeutics free of biocontamination. In many cases, sterilizing-grade filters also reduce bioburden or facilitate closed or aseptic processing. They are used to filter active pharmaceutical ingredients (APIs), formulated bulk, cell culture media, buffer, additives, process intermediates, and so on. Such applications are often critical for ensuring a successful batch operations. Nonetheless, a significant amount of time and resources are typically not devoted to establishing filter sizing requirements for “simple” applications such as buffer filtration. Here,…

A Decade of Filtration

    Filtration is just as vital to bioprocessing as chromatography — and arguably even more so. Filters are not only used as downstream unit operations in themselves, but also in support of nearly every other step in bioprocessing. Gas or liquid filters ensure the quality of incoming air and feeds for cell culture operations, clean the circulating media in perfusion processes, aid in harvest clarification, and remove buffers from chromatographic eluate after chromatography columns. They are used in formulation…

Large-Scale, Single-Use Depth Filtration Systems

    Clarifying cell culture broth is the first downstream unit operation in an elaborate sequence of steps required to purify a biological therapeutic. A combination of centrifugation, depth filtration, or tangential-flow filtration (TFF) is used for that operation. The availability of largescale, single-use, depth filtration technology in the recent years, however, has given process developers the capability to improve and simplify downstream processes.   Clarification of Cell Culture Streams   The main purpose of clarification is to efficiently separate…

Integrity Testing of Sterilizing-Grade Filters

    Integrity testing of sterilizing-grade filters is necessary to reliably prevent damage to these sterile barriers from compromising the production of biopharmaceuticals. Documented integrity test results are essential to a manufacturing audit trail for releasing pharmaceutical products (1, 2). Accordingly, problems encountered during this testing can lead to considerable financial damages and substantial delays or even entirely prevent a production lot from being released to the market. Therefore, filter integrity testing is a critical step with high economic importance…

Retention of Highly Penetrative A. laidlawii Mycoplasma Cells

    Mycoplasma are infamous for contaminating cell culture lines at rates as high as 80% (1,2,3,4,5). For biopharmaceutical processes, the inadvertent use of contaminated culture medium or medium components can lead to contamination of an aseptic process-validation media fill or cell culture medium for a bioreactor (6,7,8,9,10,11). Thoroughly testing medium components before use is generally impractical because of the large volume of material in use. Frequently, culture media cannot be autoclaved (because of the presence of heat-sensitive components or…

Scaling Up Normal-Flow Microfiltration Processes

    Scaling up biological processes from laboratory bench to process scale is complex and requires considering a number of factors to ensure process robustness. Due to variability among raw materials and processes, most process developers use generous safety factors to ensure that their systems are not undersized. Although that method can be reduce process risk, it is inefficient. To improve process efficiency and reduce risk, we conducted a study to identify and quantify key factors that contribute to variability…

Evaluating Disposable Depth Filtration Platforms for MAb Harvest Clarification

At small to medium scales, single-use technology offers significant advantages over traditional reusable (e.g., stainless steel) manufacturing technology with regard to flexibility, cost of goods, implementation timelines, and maintenance. However, process design based on disposables does create new challenges. With traditional fed-batch processes, harvest clarification is usually achieved by centrifugation followed by depth filtration. For processes based entirely on disposables, the disc-stack centrifuge needs to be replaced by filtration alone. To extend its manufacturing capabilities and capacities, Rentschler decided to…

Streamlining Downstream Process Development

Normal-flow filtration is used throughout downstream processes for biologics including depth, sterile, and viral filtration applications. Because of its ubiquity in large-scale biomanufacturing, using the most efficient normal-flow filter media area and type can lead to significant cost savings. To determine the most effective media type and area, developers use a scaled-down process model is used in bioprocess laboratories to minimize material requirements. Constant–flow-rate filter evaluations involve direct scale-down parameters that match manufacturing-scale process conditions. This type of evaluation can…

A Framework for Selecting and Working with a Normal-Flow Filtration Supplier

The biopharmaceutical market accounts for about 20% of the total market for pharmaceuticals, but its share continues to increase because of double-digit compound annual growth rates leading to projections that by 2014 eight of the top 10 best-selling drugs will be biologics (1). The industry faces many challenges and opportunities, as Jim Davies of Lonza Biologics explained to me: “Biomanufacturers have to contend with what is at present a dynamic technical and commercial landscape. Industry consolidation continues to occur as…