Single-use technology has arguably been the biggest “story” of the past 10 years in bioprocessing. And for many people, implementation of disposable elements began soon after the turn of the century with a bioreactor (1, 2), first developed by Wave Biotech in 1996, now a mainstay of many upstream process development laboratories and sold by GE Healthcare. BPI identified the significance of such technologies early on, making them the subject of a supplement in its second year. By the fourth…
Downstream Development
A Decade of Processing
About halfway through our first decade in publication, we became well acquainted with a new buzzword phrase in the biopharmaceutical industry: downstream bottleneck (1). This followed on the heels of a manufacturing capacity crunch that had been forecast shortly before BPI made its debut. Thanks to herculean efforts by upstream process and cell-line engineers, that crunch didn’t pan out. In its place, however, high-titer production moved the pressure downstream. Now separation and purification engineers were tasked with handling…
A Decade of Harvesting Methods
The preliminary separation of a protein of interest from a reactor “soup†of process impurities (e.g., cell debris, colloids, lipids) is the first step in a downstream process. It is also a primary step that introduces a significant risk of product degradation, bioburden concerns, or process errors, especially if a harvest method is not a good “fit†with a newly designed bioreactor (e.g., single-use) or fermentation vessel. In 2003, BPI’s first year, industry concerns revolved around potential capacity…
A Decade of Process Development
Our “manufacturing †theme could be considered a sort of catch-all, encompassing much of what BioProcess International covers. You could argue that “the whole development process†is all about manufacturing biotherapeutics. But we instead consider this “pillar†of bioprocessing to include everything that isn’t strictly “upstream†(production) or “downstream†(processing) of biomolecules. Facility and supply-chain isssues come into play here, as do formulation and fill–finish (and of course, outsourcing). We discuss quality systems and their associated analytics in…
A Decade of Product Development
In 2004, the United States Food and Drug Administration (FDA) transferred regulation of many highly purified, “well-characterized†biopharmaceutical proteins from the Center for Biologics Evaluation and Research (CBER) to the Center for Drug Evaluation and Research (CDER), which until then had primarily regulated only synthetic, small-molecule drugs and chemical substances. The most novel/complex and the less-characterized biologics remained within CBER’s jurisdiction. This change complicated BPI’s mission somewhat. When the magazine was founded, we responded to questions from advertisers…
Approaches to Debottlenecking and Process Optimization
Two major challenges associated with optimizing biomanufacturing operations remain unresolved. The first is variability: how to understand and improve manufacturing with significant variation in process times throughout all unit operations. The second is complexity: modern biomanufacturing facilities are complex and interconnected, with piping segments, transfer panels, and valve arrays, as well as water for injection (WFI) and other shared resource constraints. That complexity is becoming even greater with the need for process standardization and processing of higher (and…
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…
An Emerging Answer to the Downstream Bottleneck
Biotechnology companies have invested billions of US dollars in new manufacturing infrastructure, expanding the industry’s total mammalian cell culture production capacity from 670,000 L in 2002 to 2,550,000 L in 2010 (Figure 1) (1). This capacity expansion is estimated to have cost the industry about $20 billion (Figure 2) (1). Figure 1: Macroporous structure of Natrix chromatography media (see () Figure 1: () Figure 2: () That production capacity (and the investment it represents) is…
Key Downstream Problems Decline While Industry Continues to Demand New Technologies
Downstream problems for biomanufacturers finally appear to be lessening. Over the past six years, demand for better purification has topped the list of biomanufacturing areas in need of improvement. This year, however, it appears that purification woes — though still a hot topic — are cooling off. After seven years of measuring the impact on capacity of specific biomanufacturing operations, preliminary data from BioPlan Associates’ ninth annual survey shows that activities associated with both optimizing internal downstream processes (DSPs) and…
Streamlining Cell Therapy Manufacture
The cell therapy industry (CTI) is no longer a cottage industry; it is a distinct and sustainable component of the global healthcare sector (1). Today, CTI prospects are strong, with annual revenues exceeding US$1 billion/year, supported by improving investor sentiment and public support (1,–3). The next phase of CTI growth — toward a multibillion-dollar global industry — will depend on the biomanufacturing community innovating to meet growing market demands and providing products at affordable costs to healthcare payers.…