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Quality Risk Management (QRM): Part III – An Approach for Understanding and Either Accepting or Mitigating the Results of a QRM Analysis

by Mark F. Witcher, PhD
Volume 16, Issue 1 (Spring 2017)

Accepting any identified and evaluated risk is “taking a smart risk.” The acceptance decision, before or after mitigation, is a complex and sometimes difficult choice that is based on the information generated during the ICH Q9 quality risk management (QRM) exercise along with many subjective viewpoints impacted by previous experience, knowledge, risk appetite, and bias. This paper provides an approach for understanding and making acceptance decisions centered around the risk-rating methods that define the severity (harm) and uncertainty (likelihood) of the risk’s consequence occurring. It also builds on concepts developed in the first two parts of this QRM series to provide an overall framework for identifying, evaluating, managing, and accepting a wide variety of biopharmaceutical development and manufacturing risks...

Citation:
Witcher MF. Quality risk management (QRM): part III – an approach for understanding and either accepting or mitigating the results of a QRM analysis. BioProcess J, 2017; 16(1): 25–31. https://doi.org/10.12665/J161.Witcher.Q.

Posted online May 8, 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...

Citation:
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. https://doi.org/10.12665/J161.Talarico.

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...

Citation:
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. https://doi.org/10.12665/J161.Nims.

Posted online May 8, 2017.

 
Opinion
The Key to Meeting Future Challenges: Forcing Complexity into Simplicity by Making it Straightforward

by Mark F. Witcher, PhD
Volume 16, Issue 1 (Spring 2017)

Unless the trend of ever-rising product development costs is reversed, as demonstrated by Eroom’s law (look it up), the development of new biopharmaceutical products is doomed. In my opinion, the primary culprit is the industry’s inability to competently deal with complexity...

Citation:
Witcher MF. The key to meeting future challenges: forcing complexity into simplicity by making it straightforward. BioProcess J, 2017; 16(1): 5. https://doi.org/10.12665/J161.Witcher.T.

Posted online May 8, 2017.

 
Assessment of Affinity Chromatography Matrices in Plantibody Purification from Aqueous Two-Phase Extraction Samples

by Williams Ferro, Tatiana Alvarez, Déborah Geada, Yenisley Medina, José Montero, Andrés Tamayo, Ariadna López, Daily Hernández, Mayra Wood, Tatiana González, Regla Somoza, José García, Dobián Cecilia, Yanara González, Osmaro González, David Gavilán, Mailyn LaO, and Rodolfo Valdés
Volume 15, Issue 4 (Winter 2016/2017)

Plantibody purification is not as efficient as antibody purification from serum, ascites, or mammalian cell cultures. It is characterized by the application of inefficient plantibody solid-liquid extraction systems, low plantibody recovery, and short lifetimes of expensive chromatography matrices. To overcome it, several protocols of liquid-liquid aqueous two-phase extraction (ATPE) combined with affinity chromatography were previously studied to purify the CB.Hep-1 monoclonal antibody, which showed an unexpectedly high recovery. However, a study of ATPE combined with several affinity chromatography matrices to purify plantibodies has not been reported so far. Therefore, a combination of the best ATPE protocol with five specific affinity chromatography matrices to purify a plantibody for vaccine manufacturing is described in this study. Positive outcomes from plantibody recovery (%), specific activity (%), yield (mg purified IgG/L of leaf extract), and productivity (mg purified IgG/L of leaf extract/h) were achieved. Plantibody purity did not show statistical differences among all samples (> 97%, p < 0.05), and protein A leakage was thousands of times smaller than toxic protein A for non-human primates. In summary, the combination of ATPE (10% PEG 4000/15% K2PO4, pH 5.5) with two specific affinity resins were well-suited for large-scale plantibody purification from tobacco plant leaves...

Citation:
Ferro W, Alvarez T, Geada D, Medina Y, Montero J, Tamayo A et al. Assessment of affinity chromatography matrices in plantibody purification from aqueous two-phase extraction samples. BioProcess J, 2017; 15(4): 43–51. https://doi.org/10.12665/J154.Valdes.A.

Posted online February 15, 2017.

 
Purification of a Divalent Version of Antibody Fragments Specific for a Novel Epitope of the Human Vascular Endothelial Growth Factor with Low Aggregate Level and High Purity

by Hasel Aragón, Lincidio Pérez, Dayron Ojeda, Daily Hernández, Sigifredo Padilla, Marcos González, Jorge Gavilondo, Marta Ayala, Alexis Mussachio, Mónica Bequet, Humberto Lamdan, Regla Somoza, Mayda Candelario, Andrés Tamayo, Cristina García, Gisela Calas, Yanara González, Adelma Pérez, and Rodolfo Valdés
Volume 15, Issue 4 (Winter 2016/2017)

Cancer is one of the leading causes of death worldwide, and the second leading cause of death in Cuba. To address this serious health problem, some research has involved suppressing tumor growth by inhibiting the angiogenesis process using several molecules including antibodies. A divalent version of antibody fragments, the CIGB-598a, with a molecular weight between 100 and 110 kDa, has been expressed in CHO cells specific for a novel epitope of the human vascular endothelium growth factor (VEGF). This material has been generated at the Center for Genetic Engineering and Biotechnology to support cancer research efforts. As in other studies involving the purification of recombinant molecules, CIGB-598a exhibited a high degree of aggregation in the CHO cell culture supernatant. This required the design of a downstream process capable of removing high levels of aggregates to obtain a highly pure target molecule for use in preclinical studies and human applications further down the road. We have developed a suitable downstream method based on the combination of three chromatography processes: affinity, cation-exchange, and anion-exchange that recover a relatively low level of CIGB-598a, but at a level of high purity (greater than 95 %) with fewer aggregates (below 1%)...

Citation:
Aragón H, Pérez L, Ojeda D, Hernández D, Padilla S, González M et al. Purification of a divalent version of antibody fragments specific for a novel epitope of the human vascular endothelial growth factor with low aggregate level and high purity. BioProcess J, 2017; 15(4): 32–41. https://doi.org/10.12665/J154.Valdes.P.

Posted online February 15, 2017.

 
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