Downstream Development

PEGylating Peptides (and Proteins)

Peptides should be promising drug candidates. But their small size makes delivery difficult and gives them an extremely short in vivo half-life. They are often cleared by the kidneys or reticuloendothelial system only minutes after being administered, and they are susceptible to degradation by proteolytic enzymes. These problems could be solved by linking them to polyethylene glycol (PEG). Repeating chains of ethylene oxide (CH2CH2O), PEG molecules can be long or short and straight or branched. PEG groups are linked to…

Industrializing Stem Cell Production

Stem cells have potential as a readily available, consistent source of many differentiated cell types. This unique property can be leveraged both for therapeutic purposes and for facilitating and improving a number of drug discovery and development processes. Large-scale, “industrialized” production of human stem cells in tightly controlled conditions will be required to deliver the quantity and quality of cells needed to support clinical trials and drug discovery development activities (Figure 1). Achieving this level of production while meeting rigorous…

Rapid and Scalable Microplate Development of a Two-Step Purification Process

    High-throughput screening and process development methods are becoming more widely used in the biopharmaceutical industry. Recent development of high-expression (high–target-titer) recombinant culture methods has enhanced the need to also develop more effective separation products, methods, and processes (1). Part of the solution would be chromatographic resins offering higher capacities and flow rates.       However, developing an optimized purification process that involves several chromatographic steps can consume significant time and samples. In addition, a purification process developed…

Improving IEX Throughput and Performance with Differentiated Chromatography Sorbents

    Optimized upstream processing and high-productivity cell culture increase not only target protein titers, but also impurity and contaminant concentrations to be removed from large volumes of feedstock. Simultaneously, biopharmaceutical drug production is increasingly driven by manufacturing cost reduction. These facts together increase the pressure on downstream processing and create an urgent need for more productive and streamlined chromatography operations. Key parameters to consider for enhanced process economics in chromatography are higher protein binding capacities at high flow rates…

Are “Land Mines” Hiding in Your Supplier Records?

    A growing trend in US Food and Drug Administration (FDA) warning letters has been citations for “no justified rationale.” Since 2004, warning letters taking companies to task for poorly documented decision-making and risk-assessment practices has more than doubled — from two in 2004 to four in 2008 and five in 2009. These citations are always in relationship to risk-based decisions: sampling (what, how often, and how much), nonconformances and corrective/preventative actions (when is “root cause” actual root cause,…

How Pore and Fibrous Interstice Structure Influence Filter Performance

    A common objective in pharmaceutical processing is the removal of solids from fluid suspensions through filtration. The usual purpose is the removal of the solid particles to a specified extent, within a given time interval, at the largest possible throughput. Attainment of those goals is managed by proper selection of filtration conditions: principally an adequate effective filtration area (EFA) as defined by filter porosity and a proper rate of flow as regulated by applied differential pressure (ΔP) over…

Process Development’s Impact on Cost of Goods Manufactured (COGM)

    Manufacturing throughput (the amount of material a plant can produce per year) is affected by process yield and plant run rate. The higher they are, the more a plant can produce per year, requiring fewer lots to meet annual demand. Although a process development team obviously determines the process yield, the team also determines the impact on the run rate of duration and potential implementation complexity of the entire train of unit operations. Thus, an optimized process maximizes…

Questioning the Downstream Bottleneck

In preparing for our October supplement on bioprocess design, BPI’s contributing editor Lorna D. McLeod spoke with Bayer Healthcare’s Harald Dinter (vice president of global biological development) and Jens Vogel (CMC development team leader and head of isolation and purification in global biological development) about the downstream bottleneck. Is it or isn’t it a real problem? Does the answer depend on your point of view? BPI: “Does a company’s downstream capacity place practical constraints on increasing production titers? Is that…

Shrinking the Costs of Bioprocess Development

Process development for large-scale bioproduction is generally more labor-intensive, time-consuming, and expensive than for comparable nonbiological processes because of the large number of individual processes and potential variables involved. To ensure the future commercial viability of biological manufacturing processes and prevent bottlenecks, it is essential to accelerate development of both upstream and downstream processing, as well as to improve process analytics. This not only reduces time and cost factors involved in design of robust bioprocessing protocols, but also reduces the…

Creation of a Well Characterized Small Scale Model for High-Throughput Process Development

    Streamlining process development has been the focus of the biotechnology industry over the past several years. To be financially viable in the current market, a company has to be competitive in all three of the following areas: quality, speed, and price (1). Attaining any two of the three attributes at a time is no longer sufficient. With new tools and technologies along with improved understanding of the cell-culture process, doing high-quality process development while reducing both cycle time…