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Investigation of an Adventitious Agent Test False Positive Signal in a Plant-Derived Influenza Vaccine

by Todd L. Talarico, Michael Murphy, Raymond Nims, Dan Hastings, Jeri Ann Boose, and Dave Dumers
Volume 17, Open Access (October 2018)

Medicago manufactures influenza vaccine virus-like particles (VLPs) in an unusual production platform consisting of Nicotiana benthamiana plants. During the in vitro adventitious agent test (AAT) of certain Medicago B strain influenza vaccine VLP test samples, positive hemagglutination of guinea pig red blood cells was observed on day 14, but not on day 28. The positive result in the assay was surprising because the production process uses no animal-derived raw materials and contains a viral inactivation step. Plant-associated viruses would not be expected to infect the mammalian cell-based assay. No cytopathic effects or hemadsorption of red blood cells was observed in these AATs. The positive hemagglutination was observed at 2–8°C, but not at 36–38 °C, and only in a few of the six detector cell lines used in the assay. Because this is quite an unusual pattern of responses for an AAT, Medicago and the contract testing lab, Eurofins Lancaster Laboratories (ELLI) investigated the positive responses thoroughly for the presence of an adventitious agent or an alternative explanation not involving a viral contaminant. Investigation results indicated that the hemagglutinating activity associated with the vaccine test sample itself was responsible for the positive hemagglutination response. The positive hemagglutination on day 14 of these AATs was deemed an assay artifact, and preventive actions were taken to prevent recurrence of this type of false positive response...

Talarico TL, Murphy M, Nims R, Hastings D, Boose JA, Dumers D. Investigation of an adventitious agent test false positive signal in a plant-derived influenza vaccine. BioProcess J, 2018; 17.

Posted online October 31, 2018.

A Suspension Vero Cell Line for Production of Viral Vaccines and Viral Therapeutics

by Steven Pincus, Cari Sadowski, Emigdio Reyes, and John Madsen
Volume 17, Open Access (October 2018)

Fujifilm Diosynth Biotechnologies (FDB) is a global contract development and manufacturing organization (CDMO) with over 25 years of experience in process development and/or manufacturing of greater than 310 molecules at sites in: Billingham, England; Research Triangle Park, North Carolina; and College Station, Texas. At our College Station location, we specialize in the development and manufacture of virus-based vaccines (attenuated or recombinant viruses), oncolytic viral therapies (such as adenovirus, polio) and gene therapy vectors (such as adeno-associated virus [AAV])...

Pincus S, Sadowski C, Reyes E, Madsen J. A suspension vero cell line for production of viral vaccines and viral therapeutics. BioProcess J, 2018; 17.

Posted online October 17, 2018.

ICH Q12 Should Build on the ICH Q8 Design Space

by Mark F. Witcher, PhD
Volume 17, Open Access (September 2018)

The current draft of ICH Q12 appears to have taken several steps backward in the pursuit of the manufacturing excellence initiated by ICH Q8 (R2) pharmaceutical development and expanded by FDA’s 2011 process validation guidelines...

Witcher MF. ICH Q12 should build on the ICH Q8 design space. BioProcess J, 2018; 17.

Posted online September 5, 2018.


Hepatitis B Surface Antigen Particle Purification by Immunoaffinity Chromatography Based on CDI-CB.Hep-1 mAb Monolithic Supports

by Rodolfo Valdés, Urh Černigoj, Eduardo Sánchez, Daily Hernández, Blass Nemec, Miladys Limonta, Miguel Castillo, Bárbara Pérez, Urška Vidic, Jana Vidič, Mirjan Žorž, Andrés Tamayo, Leonardo Gómez, Williams Ferro, Yurisley Aldama, Nika Lendero Krajnc, Daniela Marc, and Aleš Štrancar
Volume 17, Open Access (June 2018)

Bead matrices have been used in affinity chromatography to purify molecules in multiple applications. For instance, the hepatitis B surface antigen (HBsAg) is one of the molecules purified by this technique for human vaccine development programs. However, the use of monolithic supports have emerged as the advantageous choice for affinity chromatography based on convective mass transfer, a high number of channels, and low backpressures at high flow rates. For this reason, several experiments were conducted to determine the suitability of CB.Hep-1 monoclonal antibody (mAb) immunosorbent developed on carboxyimidazole (CDI)-monolithic supports (ligand concentrations: 0.5, 1.0, and 7.0 mg/mL) for HBsAg particle purification. Key results from this study show the highest amounts of HBsAg adsorbed (3059.31 ± 865.71 μg HBsAg/mL immunosorbent, n = 2), and HBsAg eluted (2884.50 ± 541.01 μg HBsAg/mL immunosorbent, n = 2), were estimated in the 1.0 mg/mL-CDI-CB. Hep-1 mAb monolithic support immunosorbents. In addition, the ligand leakage was always < 3 ng mAb/μg HBsAg (approved limit) in the 1.0 mg/ mL-CDI-CB.Hep-1 mAb immunosorbents. Experiments also evidenced the high purity and molecular homogeneity of purified HBsAg particles (< 95 %) across 20 purification cycles. Therefore, the ligand concentration could be reduced up to 1.0 mg/mL, which would enable a notable decrease in the mAb amount required for vaccine manufacturing, as compared to bead matrices (4.0 mg/mL). This study demonstrated that CDI-CB.Hep-1 mAb monolithic support immunosorbents are best suited for assessing the large-scale purification performance of HBsAg particles for human vaccine development programs at low ligand concentration and high flow rates...

Valdes R et al. Hepatitis B surface antigen particle purification by immunoaffinity chromatography based on CDI-CB.Hep-1 mAb monolithic supports. BioProcess J, 2018; 17.

Posted online June 5, 2018.

Performance Challenging Fetal Bovine Serum (FBS) and FBS Alternatives

by William Siegel
Volume 17, Open Access (May 2018)

Growth performance testing in cell culture is an effective approach to making serum suitability and purchase decisions. An independent commercial testing lab conducted two separate and sequential growth promotion studies to underscore the need for pre-purchase lot performance testing with: (1) FBS; and (2) FBS alternatives. Results from both studies are presented here to compare and contrast:
• FBS lots to each other
• FBS alternatives lots to each other
• FBS alternatives lots to FBS
FBS alternatives are included because they are often overlooked as a cost-effective substitute for FBS, providing, in many cases, equivalent performance. It is advisable to avoid preconceived notions concerning the quality or performance of a serum product without considering the culture system, culture conditions, and the subject cells, which can all have a material impact on its performance in cell culture.
Test – then decide...

Siegel W. Performance challenging fetal bovine serum (FBS) and FBS alternatives. BioProcess J, 2018; 17.

Posted online May 21, 2018.

Integrating Development Tools into the Process Validation Lifecycle to Achieve Six Sigma Pharmaceutical Quality

by Mark F. Witcher, PhD
Volume 17, Open Access (April 2018)

Achieving very high levels of pharmaceutical product quality, particularly for the next generation of biologics, will require proactive use of a broad range of quality and process development tools throughout the therapeutic’s development and manufacturing lifecycle. These tools are most effective when integrated using an expanded form of FDA’s 2011 process validation guidelines. This article explains how process validation can be combined with quality by design (QbD), ICH Q8 design space (DS) and control strategies (CS), process analytical technology (PAT), and quality risk management (QRM) tools to provide a path to manufacturing very high-quality products. The approach establishes clear goals and then proactively builds appropriate control systems during process development to assure continuous control and verification of all manufacturing activities. Prospectively using the tools over the complete manufacturing lifecycle, from preclinical through commercial manufacturing, is particularly important to assure comparability from early product research and development all the way to commercialization. The continued evolution of these quality tools, as well as building new tools, will provide a path for the pharmaceutical industry to reach and maintain Six Sigma levels of product quality...

Witcher MF. Integrating development tools into the process validation lifecycle to achieve six sigma pharmaceutical quality. BioProcess J, 2018; 17.

Posted online April 13, 2018.

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