Downstream Development

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Reducing Clinical-Phase Manufacturing Costs: Collaborating for Savings without Compromising Quality or Performance

In downstream purification of monoclonal antibodies (MAbs), the single greatest contributor to manufacturing costs is the expensive capture step typically based on protein A affinity chromatography. Almost since its introduction to bioprocessing, efforts have been made to reduce the cost of this step. Several alternative ligands have been promulgated as potential replacements for protein A, but they have proven difficult to adopt and scale up. Supplier companies have pushed for increases in capacity and economics, but those are always accompanied…

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Special Report: A Strategy for Cost-Effective Capture Using Agarose-Based Protein A Resins

It is well recognized that the cost of Protein A resins is substantial. If a developmental monoclonal antibody (MAb) makes it to marketing approval and manufacturing, the high cost of purification using a Protein A resin is amortized over a large number of purification cycles, and the contribution to cost of goods is reduced to acceptable levels. However, a high percentage of clinical projects will fail, and the Protein A resin will be used only for a small number of…

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Emerging Technology Trends in Biologics Development: A Contract Development and Manufacturing Perspective

For a contract development and manufacturing organization (CDMO), process development and manufacturing of recombinant proteins must be linked because of tight timelines driven by client expectations. Those are in turn driven by a need for rapid progression to clinical testing. Early in process development, the choice of raw materials needs to reflect existing supply chain and manufacturing infrastructure, but remain suitable for scaling up to meet future needs. One approach is to establish platform processes for a class of molecules…

Along with increased selectivity, mixed-mode and multimode media offer  significant potential operational cost savings by eliminating intermediate purification  steps that require additional time, materials, equipment, and personnel.

Selective and Flexible Chromatography Media: Improving Biopharmaceutical Operational Efficiencies

Continuing development in protein and peptide engineering have produced a broad range of new biological products with improved therapeutic and diagnostic potential. In the development pipeline, more than 900 biologic products target more than 100 diseases (1). Increased manufacturing complexities caused by closely related impurities and requirements to improve process efficiencies and reduce operating costs highlight the need for new approaches in protein purification. Platform-based chromatographic approaches have been successfully applied in separating and purifying monoclonal antibody (MAb) products. But…

A researcher at MilliporeSigma, the life science business of Merck KGaA, Darmstadt,  Germany, investigates the ability of tentacle ion-exchange media to  remove viruses effectively in monoclonal antibody purification processes.

Viral Clearance in Antibody Purification Using Tentacle Ion Exchangers

Manufacturers strive toward cost-effective purification of target molecules and a high level of confidence that their biologics are safe and not compromised by the presence of endogenous retrovirus-like particles or adventitious viruses (1). Reliable reduction of viral particles throughout downstream purification processes must be ensured through different techniques such as chemical treatment, filtration, and chromatography. Common monoclonal antibody (MAb) purification schemes use both cation- and anion-exchange chromatography steps (CEX, AEX). Although CEX (to remove product- and process-related impurities) is not…

determined by Jiang et al. for a hydrophobic-interaction chromatography (HIC) step used to purify an Fc fusion protein (4). This example shows the acceptable design space for protein loading and HIC resin hydrophobicity (defined in minutes of lysozyme retention time) related to high–molecular-weight content (a CQA for the product) and step yield (an important process performance attribute)

Quality By Design for Monoclonal Antibodies, Part 2: Process Design Space and Control Strategies

Process design space and control strategy are two fundamental elements of quality by design (QbD) that must be established as part of biopharmaceutical development and regulatory filings. Like all of QbD, they are interconnected and iterative. Both are based on knowledge gained during product and process development — but both need to be in place (in a potentially very limited form) when a company begins to manufacture drug substance for clinical trials. Part 1 of this discussion appears on pages…

Figure 1: The quality by design (QbD) approach aligns with product and process development stages and clinical development phases. QbD provides milestones and assessments to facilitate product development and ensure quality. (BLA = biologics license application)

Quality By Design for Monoclonal Antibodies, Part 1: Establishing the Foundations for Process Development

The quality by design (QbD) modernized approach to pharmaceutical development is intended to provide regulatory flexibility, increased development and manufacturing efficiency, and greater room to innovate as well as improve manufacturing processes within defined ranges without obtaining regulatory approval first. QbD is a systematic developmental approach that starts with a clear goal in mind and emphasizes understanding of how variability in both process and materials affects a final product (1). Historically, product quality has been assured either with end-product testing…

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Special Report on Continuous Bioprocessing: Upstream, Downstream, Ready for Prime Time?

Once an engineering curiosity and smallscale laboratory technique, continuous bioprocessing has evolved in just a few short years to a topic of intense and increasing interest to most bioprocessors. Critics point to a steep learning/adoption curve, but that is nothing new in biomanufacturing.Andrew Zydney is a distinguished professor of chemical engineering at Pennsylvania State University. He has noted these challenges facing continuous processing: commercially unproven unit operations (especially downstream), a lack of equipment robustness, sterility concerns, and uncertain development timelines…

Figure 1a: Conventional batch operation

Accelerated, Seamless Antibody Purification: Process Intensification with Continuous Disposable Technology

Process intensification through continuous manufacturing has been practiced in the chemical, petrochemical, and food industries for years and has gained much interest among biopharmaceutical manufacturers (1). Key drivers encouraging biomanufacturers of therapeutic molecules to convert batch processes into continuous operation include flexibility, productivity, cost effectiveness, and product consistency. Continuous upstream processing has been demonstrated for the manufacture of a broad range of molecules, including complex/labile proteins such as enzymes (2) and monoclonal antibodies (3). Recent publications have reported successful application…

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Prepacked Chromatography Columns: Evaluation for Use in Pilot and Large-Scale Bioprocessing

Time to market, resource requirements, cost, and flexibility are key considerations in designing purification processes suitable for manufacturing biopharmaceutical products. Over the past decade, many advances have been achieved in disposable processing systems that have allowed for increased processing at a lower cost. That is in part attributable to reductions in necessary resources, changeover costs, and cleaning-validation requirements. Large-scale, prepacked chromatography columns have recently become available for clinical and commercial manufacturing, and they represent a growing trend in the industry.…