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Novel Lipid Delivery Mechanism of Cell-Ess Increases Higher Order Glycoforms and the Consistency of Glycan Patterns on Monoclonal Antibodies Produced by CHO Cells

by Adam Elhofy, PhD and Justin A. Beller, PhD
Volume 16, Open Access (October 2017)

Glycosolation drives protein quality and therapeutic benefits in protein-based therapies. Recently, there has been a push in the pharmaceutical industry to improve the consistency and quality of the glycan patterns on therapeutic proteins like monoclonal antibodies. Post-translational modification begins in the endoplasmic reticulum but is finished in the Golgi where more complex glycans are added. In this study, the addition of lipids via a novel mechanism provided by the medium supplement, Cell-Ess®, improves the consistency in glycan patterns so that they are more reproducible between product batches. The effect of media supplementation with Cell-Ess on the variation of glycan patterns was measured in two different media formulations across two separate experiments. Supplementation with Cell-Ess resulted in a statistically significant reduction in the variation of glycoforms when measured by the standard error of the mean. In addition, to improved consistency, there were increased higher glycoforms or galactosylation. There was also significantly more total galactosylation and significantly fewer lower glycoforms for antibodies produced by CHO cells supplemented with Cell-Ess. These data taken together suggest that the addition of lipids via Cell-Ess results in a more functional Golgi and an associated improvement of protein quality and consistency...

Elhofy A, Beller JA. Novel lipid delivery mechanism of Cell-Ess increases higher order glycoforms and the consistency of glycan patterns on monoclonal antibodies produced by CHO cells. BioProcess J, 2017; 16.

Posted online October 2, 2017.

Analyzing and Managing Biopharmaceutical Risks by Building a System Risk Structure (SRS) for Modeling the Flow of Threats Through a Network of Manufacturing Processes

by Mark F. Witcher, PhD
Volume 16, Open Access (September 2017)

Biopharmaceutical manufacturing process risks can be described as a network of processes that may include some combination of unit operations, equipment, instruments, control systems, procedures, and personnel practices. The system’s risks can be modelled by a system risk structure (SRS) that describes how threats originate and flow through the network to result in negative consequences (risks). The SRS is a quality risk management (QRM) tool a team of subject matter experts can use to prospectively identify and evaluate a wide variety of risks over the product’s entire development and manufacturing lifecycle. Based on the understanding developed from an SRS analysis, control strategies can be developed by modifying or adding new processes to mitigate the threats, thus reducing the likelihood of the risk consequence being realized. The SRS tool extends the ICH Q9 QRM approach described in a series of articles. Two examples are used to demonstrate how an SRS can be assembled and then used to prospectively identify, understand, and reduce significant risks by controlling the source and flow of threats within the systems described...

Witcher MF. Analyzing and managing biopharmaceutical risks by building a system risk structure (SRS) for modeling the flow of threats through a network of manufacturing processes. BioProcess J, 2017; 16.

Posted online September 25, 2017.


Pondering Different Scales of Knowledge

by Verne A. Luckow, PhD, JD
Volume 16, Open Access (September 2017)

I am not particularly spiritual. But as the shadow of the moon began to approach on August 21, 2017, I started to think about the limits of my knowledge of the solar system, galaxies, and beyond, compared to my focus for decades on smaller objects, such as molecules, cells, and tissues. A week later, Hurricane Harvey developed rapidly and lingered over southeast Texas, dumping over 50 inches of rain in some locations, causing widespread flooding, releasing sewage and toxic chemicals into the water, and triggering outbreaks of mold. Hurricane Irma, on its path through the Caribbean and up the western coast of Florida, devastated vegetation, buildings, and power lines, with intense winds that once peaked at 185 mph...

Luckow VA. Opinion: pondering different scales of knowledge. BioProcess J, 2017; 16.

Posted online September 21, 2017.

Demonstration of Porcine Circovirus Type 2 Inactivation by the Low pH Step of the Trypsin Manufacturing Process Using a New Infectivity Assay

by Tara Tagmyer, PhD and Kathryn Martin Remington, PhD
Volume 16, Open Access (September 2017)

Porcine circoviruses (PCVs) are small (17 nm) non-enveloped viruses with a covalently closed, circular, single-stranded DNA genome. PCV type 1 (PCV-1) and PCV type 2 (PCV-2) belong to the circovirus genus within the Circoviridae family. PCV-1 was originally isolated as a contaminant of porcine kidney (PK15) cells, and although it was found to be widely distributed in domestic swine in both North America and Europe, no correlation to any porcine disease or disorder has been established. PCV-2, however, has been found to be associated with several disease syndromes in pigs. For manufacturers of biologics utilizing porcine tissue or porcine tissue-derived materials, PCVs represent a contamination risk. In fact, an independent academic laboratory detected PCV-1 in a live attenuated rotavirus vaccine using metagenomic analysis and a PCV-1-specific polymerase chain reaction (PCR). While this study did not detect PCV-1 or PCV-2 nucleic acid in rotavirus vaccine from a second manufacturer, subsequent testing by the manufacturer revealed low levels of both PCV-1 and PCV-2 DNA. The source of the PCV nucleic acid contaminating both vaccines was determined to be porcine pancreas-derived trypsin used in the manufacture of the vaccines. The manufacturer of the rotavirus vaccine that was initially found to contain PCV sequences determined that their cell banks and virus seeds were contaminated with the viral sequences. The strong safety record of both vaccines and the benefits of vaccination against rotavirus convinced both the United States Food and Drug Administration (US FDA) and the European Medicines Agency (EMA) to permit their continued use...

Tagmyer T, Remington KM. Demonstration of porcine circovirus type 2 inactivation by the low pH step of the trypsin manufacturing process using a new infectivity assay. BioProcess J, 2017; 16.

Posted online September 18, 2017.

Inactivation of Adventitious Agents by UVC Irradiation in a Plant-Based Influenza Vaccine Production Process

by Todd L. Talarico, Kevin Williams, Timothy Yeh, Bruno Pancorbo, Mélanie Bérubé, Michael Murphy, and Michèle Dargis
Volume 16, Issue 1 (Spring 2017)

Biologics are often produced in or derived from matrices that harbor the potential for introduction of adventitious agents to the drug product. This potential is not strictly theoretical, as viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), porcine circovirus (PCV), and minute virus of mice (MVM) have been detected in biological products in the past. From a regulatory and safety perspective, assurance that adventitious agents are not present in the drug product is a critical measure of product quality. Guidelines for assuring safety, with respect to adventitious agents in blood-derived products and products produced in mammalian cell culture, are addressed in specific guidances from the Food and Drug Administration (FDA) and the Committee for Proprietary Medicinal Products (CPMP). These guidance documents suggest that safety is best assured through screening donor material or production cell lines, by controlling animal-derived raw materials used during manufacture, incorporating viral removal and inactivation steps in the production process, and protecting the product from the environment during manufacture. Even though Medicago develops products that are produced in plants, a host that does not support the replication of viruses that infect mammals, various regulatory agencies have advised that the production process should contain one or more operations that remove or inactivate adventitious agents. Medicago has investigated multiple methodologies to accomplish this goal, and has found ultraviolet C (UVC) irradiation treatment to be effective for adventitious agent inactivation in the production process used to manufacture their quadrivalent influenza vaccine without detrimental impact to the product...

Talarico TL, Williams K, Yeh T, Pancorbo B, Bérubé M, Murphy M, Dargis M. Inactivation of adventitious agents by UVC irradiation in a plant-based influenza vaccine production process. BioProcess J, 2017; 16(1): 15–24.

Posted online May 8, 2017.

Identification of Worst-Case Model Viruses for Low and High pH Inactivation

by Raymond Nims, S. Steve Zhou, and Mark Plavsic
Volume 16, Issue 1 (Spring 2017)

In this paper, we review the efficacy data for low and high pH inactivation of viruses in solutions (i.e., liquid inactivation) and discuss the mechanisms of action and the impact of temperature and treatment time, as these are the primary determinants of inactivation efficacy, besides pH, for different viruses. Only enveloped viruses were considered for low pH inactivation, as the literature concerning low pH inactivation of non-enveloped virus is not extensive and low pH is not considered to be an effective inactivation approach for most non-enveloped viruses. We conclude that for low pH treatment of enveloped viruses, and high pH treatment of both enveloped and non-enveloped viruses, an enteric flavivirus such as bovine viral diarrhea virus represents a worst-case model virus...

Nims R, Zhou SS, Plavsic M. Identification of worst-case model viruses for low and high pH inactivation. BioProcess J, 2017; 16(1): 7–14.

Posted online May 8, 2017.

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