Manufacturing

Modern Technology Transfer Strategies for Biopharmaceutical Companies

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Application of industrial biotechnology has changed dramatically over the past decade. Stainless steel process equipment has largely given way to disposable systems, facilitating easier and quicker process configurations and up-scaling. Suppliers generally made incremental advances in the quality of raw materials and consumables to ensure that those could more readily comply, “off the shelf,†with regulatory expectations. Once out-of-reach analytical equipment such as mass spectrometers and cell analyzers are becoming more common place in development laboratories, which better enables biopharmaceutical…

March 10, 2015

Improved Fluorescent Labeling Efficiency of N-Linked, High-Mannose Oligosaccharides: Using 8-Aminopyrene-1,3,6-Trisulfonic Acid (APTS) for Analysis of Glycoproteins

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Glycosylation of proteins, including monoclonal antibodies (MAbs), is recognized as important for the efficacy, immunogenicity, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) of biotherapeutics (1–6). So research and development of protein candidates is increasingly focused on the effects of glycosylation and how its pathway is affected in the Golgi system of cells involved in biosynthetic processes (7). Such attention on glycosylation has helped advance analytical technologies such as high-pH anion-exchange chromatography (HPAEC) (8); normal-phase chromatography (NP- HPLC), hydrophilic-interaction chromatography…

March 10, 2015

The Importance of the Concentration-Temperature-Viscosity Relationship for the Development of Biologics

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JIM DELILLO (WWW.FREEIMAGES.COM) Patient preference and a competitive landscape in the parenteral market have fueled the need for convenient delivery systems and a desire for less‑frequent dosing injections. Monoclonal antibodies (MAbs) often have high dose requirements, so they must be formulated at very high concentrations (1). At low concentrations, an antibody solution’s viscosity increases moderately as a function of protein concentration. But at high concentrations (>100 mg/ mL, depending on the molecule), viscosity increases exponentially (2, 3). Thus, a specification…

March 10, 2015

Characterization of Postcapture Impurity Removal Across an Adsorptive Depth Filter

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In the manufacture of monoclonal antibodies (MAbs), the first purification step following harvest clarification is normally protein A affinity chromatography because of its high selectivity for IgG and high process yield (1, 2). At this stage, a MAb is eluted from a protein A ligand at low pH and then held or adjusted to a low pH (pH ≤ 3.8) for a given amount of time before pH adjustment, usually ≥30 minutes, in a virus inactivation (VI) step targeted at…

March 10, 2015

A Multidisciplinary Approach to Manufacturing Biotherapeutics

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Optimizing antibody manufacturing processes has gone beyond the first-order goal of achieving elevated protein titers and now also focuses on understanding biologic and manufacturing process variables that define cellular machinery and protein quality. A holistic approach to biotherapeutic manufacturing incorporates several applied disciplines such as biology, engineering, process control, signal processing, and modeling to reduce the “black-box†model of cell- based protein production into an operational design space. This is in line with the US Food and Drug Administration’s quality…

March 10, 2015

Special Report: The Path to Vaccine Profitability

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Managing vaccine supply chain improvements involves a complex interaction of laboratories, other facilities, CMOs, and suppliers. Since the business of making vaccines became a commercial proposition, profitability has often been elusive. The economics are difficult: Costs of development and production, already high, are rising. Profit margins historically have been lower than those of other pharmaceutical products, in part because of the complexities of manufacturing and distributing vaccines as well as their stringent safety, testing, and quality requirements.

February 6, 2015

Affinity Capture of F(ab’)2 Fragments: Using Twin-Column Countercurrent Chromatography

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Antibody fragments are potent active drug substances (1–4). Because they lack glycosylation, they can be produced using different biological expression systems, including yeast and microbial systems as well as mammalian cells. These molecules are interesting as biopharmaceuticals because they are smaller than full-size antibodies and therefore may penetrate better into different tissues. Antibody fragments are cleared faster in biological systems because they lack the Fc antibody structural region (4). However, fragments may be conjugated to increase their size for improved…

February 6, 2015

Simulating Seal Life with Finite-Element Analysis

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Finite-element modeling is an attractive alternative to physical testing for predicting seal life, particularly when aging poses major concerns and seal replacement is expensive. For years, seal manufacturers and users alike have searched for a reliable method for predicting how long seals will last in service. Past methods for evaluating an elastomer’s potential as a static or dynamic seal use American Society for Testing and Materials (ASTM) or other standard immersion tests. These tests involve submerging a material in a…

February 6, 2015

Protein A Intermediate Wash Strategies

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Protein A affinity chromatography offers efficient monoclonal antibody (MAb) purification and is used extensively in large-scale MAb production. As is the case with most chromatography media, protein A resins often have some degree of nonspecific binding, which causes host-cell proteins (HCPs) to coelute with a MAb. To reduce nonspecific binding interactions, an intermediate wash step can be performed before product elution. Doing so can improve product purity, extend column lifetime, and potentially eliminate a subsequent polishing step. For large- scale…

February 6, 2015

The Single-Use Watering Hole: Where Innovation Needs Harmonization, Collaboration, and Standardization

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Within the past few years, the single-use technology (SUT) arena of the biopharmaceutical industry has exploded in growth. Leading organizations have predictably and understandably stampeded to the “watering hole†of single-use to drink up the advantages that disposable components offer over traditional multiuse parts and technologies. The initial value and risk-reduction results are being realized — but not without the emergence of other trade-offs. End users continue to call for standardization in emerging areas of the industry while also recognizing…

January 13, 2015