Downstream Processing

µPAC™ Microchip Chromatography: Better By Design

The boundaries of technology can be pushed significantly when insights from different fields reinforce each other. Based on in silico simulations demonstrating the importance of order on the efficiency of chromatographic separations, PharmaFluidics has combined expertise from the analytical chromatography and semiconductor chip manufacturing industries to create a new type of nanoscale liquid chromatography (LC) column. Conventional LC columns contain randomly packed beads as a stationary phase. By contrast, PharmaFluidics uses a lithographic etching process to create a perfectly ordered…

Recent Advances in Endotoxin Removal: An Upgrade to a Traditional Method and a New Adsorption Chemistry

Endotoxin contamination has been the bane of the bioprocessing industry since its inception. Endotoxins are everywhere: They are toxic and/or interfere with every type of therapeutic, diagnostic, and research product; they are indestructible within the limits of product tolerance; and they are difficult to remove (1–4). Beyond that, they interact with various biological species in ways that prevent accurate measurement (5, 6). Managing these issues has been a focus of the industry for at least half a century, yet it…

Moving DSC Downstream: Exploiting Differential Scanning Calorimetry As a Process Development Tool

The primary goal of biopharmaceutical process development is to determine what steps and conditions will maximize and optimize yields of purified product in the most reproducible, robust, and cost-efficient way. Characterized by high batch-to-batch comparability minimizing economic losses associated with batch failures, success relies on a thorough understanding of a given biological drug. Determining how its activity and stability are affected by processing and how to mitigate and control associated risks is advocated by a quality by design (QbD) approach.…

Continuous Processes: Disposables Enable the Integration of Upstream and Downstream Processing

Despite decades of advancement in characterization analytics, biotherapeutics still are largely defined by the manufacturing processes used to make them. This linking of process to clinical results (and thus to commercial success) has made the biopharmaceutical industry somewhat risk-averse when it comes to the adoption of new technologies. That desire to “derisk” biomanufacturing through better process understanding — as well as the need to adapt to uncertainties in patient population size through process flexibility — in turn drives the need…

Is Continuous Downstream Processing Becoming a Reality?

Over the past 30 years, several biopharmaceuticals have been produced by continuous cell culture processes run in a chemostat or perfusion mode. In most cases, no alternative was available to produce certain unstable molecules (1). However, downstream processing is and has remained a step-by-step batch operation. Continuous processing generally requires more process knowledge, equipment, and technological advances than do batch processes. With the maturity of bioprocessing and increasing awareness of manufacturing costs, companies are focusing on developing continuous downstream processing…

Scaling Considerations to Maximize the High-Area Advantage

Maximizing filtration-area density is a design strategy to minimize filter footprint and improve filtration process economics. Pleated membrane formats commonly are used to achieve that goal for sterilizing-grade filters operating in dead-end mode (also known as normal-flow filtration). Although high-density pleat geometries increase productivity for a device, such formats can present unique challenges. One of the most common concerns is that pleat formats can introduce flow resistance that impedes a device’s filtration efficiency, particularly for high–pleat-density geometries (1, 2). Filtration…

Current Thinking in Viral Safety: Risk Management Protects Patients

BPI’s editor in chief S. Anne Montgomery recently caught up with long-time editorial advisor Hazel Aranha (purification technologies technology expert for Sartorius Stedim Biotech, North America). They discussed a number of topics related to viral safety. Montgomery: What is the current thinking regarding virus-safety assurance in biopharmaceutical manufacturing? How is the industry preventing viral contamination? Aranha: The “holy grail” of viral safety — absolute freedom from extraneous agents or residual pathogenicity — is a myth. That said, biopharmaceutical products have…

BioPhorum Operations Group Technology Roadmapping, Part 3: Enabling Technologies and Capabilities

Although great strides have been made over the past 20 years to increase the productivity and robustness of manufacturing processes for biopharmaceuticals, the cost and complexity of their development and manufacturing remain high, especially in comparison with those of small-molecule pharmaceuticals. Process improvements are required to increase patient access while maintaining the viability of an R&D-driven biopharmaceutical industry. Facility productivity, cost of goods (CoG), and capital investment all have significant margins for improvement. Such goals can be achieved not only…

Scalable Purification of Viral Vectors for Gene Therapy: An Appraisal of Downstream Processing Approaches

Gene therapy is the transfer of genetic material to a patient’s cells to achieve a therapeutic effect. Therapeutic DNA is largely delivered using viral vector systems based on adenoviruses (Ad), adenoassociated viruses (AAV), and lentiviruses (LV). With the application of such viral vectors as clinical therapeutics growing, scalable commercial processes (particularly for purification) are being investigated and optimized to best ensure that critical quality attributes (CQAs) are retained. Herein we review viral vector purification techniques and the effect of different…

Examining Single-Use Harvest Clarification Options: A Case Study Comparing Depth-Filter Turbidities and Recoveries

Steadily increasing demand for biopharmaceutical drugs has led the industry to examine its manufacturing scales while pressuring research and development groups to produce high-yielding clones and processes. Improved media, feed supplements, bioreactor designs, and control of process parameters have helped biomanufacturers achieve multifold increases in volumetric productivity from production bioreactors. However, cell culture processes are significantly affected by their bioreactor’s ability to support cells at higher densities and sustain cultures at lower viabilities. With the implementation of a number of…