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Long-Term CB.Hep-1 Monoclonal Antibody Production in a Single-Use Bioreactor on a Rocker Platform with Serum- and Protein-Free Media

by Alberto Galván, Rodolfo Valdés, Marcos González, Hasel Aragón, Daily Hernández, Sigifredo Padilla, Leonardo Gómez, David Gailán, Yanet Villegas, Andrés Tamayo, Adelma Pérez, Bárbara Pérez, Maylín Lao, Yodelis Calvo, Aneet Fernández, Lianys Lee, Jania Suarez, Judey García, and Eduardo Ojito
Volume 14, Issue 4 (Winter 2015/2016)

Rocker bag bioreactors have been used successfully in cultivating cells because they provide good nutrient distribution and cell suspension while eliminating the need to validate cleaning and sterilization. Therefore, this study examined the long-term performance of a 50 L single-use bag bioreactor on a rocking platform in CB.Hep-1 monoclonal antibody (mAb) production. For such a purpose, the bioreactor was operated in a continuous mode with a mixture of serum-free media (SFM) for 62 days, and with protein-free medium (PFM) for another 62 days. Stationary phase culture results with SFM were: cell concentration of 1.57 ± 0.2 × 106 cells mL-1, specific growth rate of (μ)=0.0202, cell viability of 91.1 ± 6.4%, mAb concentration of 44.6 ± 11.1 μg mL-1, cell-specific secretion of 28.8 ± 8.1 pg cell-1 , and mAb yield of 42.4 ± 4.0 mg L-1. After SFM was replaced by PFM, there were statistically different results (p<0.05) in a cell concentration of 2.56 ± 0.2 × 106 cells mL-1, cell viability of 97.0 ± 1.1%, mAb concentration of 90.1 ± 28.2 μg mL-1, and mAb yield of 76.6 ± 10.6 mg L-1. However, the cell-specific secretion of 38.0 ± 6.0 pg cell-1 was statistically similar, but only with the first batch run with SFM. Average purification recovery from the SFM and PFM supernatants was 74.6 ± 7.9% and 70.9 ± 11.2%, respectively. The recovery and biochemical properties of the CB.Hep-1 mAb cultured with either media composition were similar to those found with CB.Hep-1 mAb produced by ascites. Regardless of whether SFM or PFM is used, it can be concluded that the 50 L single-use bag bioreactor on a rocker platform was suitable for long-term CB.Hep-1 production and can result in a 36 g yield in 125 days...

Citation:
Galván A, Valdés R, González M, Aragón H, Hernández D, Padilla S et al. Long-term CB.Hep-1 monoclonal antibody production in a single-use bioreactor on a rocker platform with serum- and protein-free media. BioProcess J, 2016; 14(4): 4–13. http://dx.doi.org/10.12665/J144.Valdes.

Posted online January 12, 2016.

 
Achieving Excellence in Biopharmaceutical Development and Manufacturing by Using Appropriate Manufacturing Practices (AMPs)

by Mark F. Witcher, PhD
Volume 14, Issue 4 (Winter 2015/2016)

Biopharmaceutical manufacturing will continue to be increasingly challenging as medical knowledge and understanding rapidly advance. Many new therapies and products will utilize cellular, viral, genetic, and epigenetic approaches along with a repertoire of increasingly complex proteins targeting a rapidly increasing inventory of newly discovered biomarkers. Manufacturing these products efficiently, consistently, and reliably will require sophisticated manufacturing approaches, methods, and controls. In addition, growing patient, societal, and even regulatory pressures demand that new therapeutics be developed and manufactured quickly, reliably, and efficiently. Historically, manufacturing has been viewed and managed in terms of minimizing patient safety risks. The focus has been on not harming the patient through inadequate manufacturing practices and controls. This approach is the basis for regulatory defined current good manufacturing practice (cGMP) guidelines that establish minimum standards and practices for regulatory oversight to assure product quality...

Citation:
Witcher MF. Achieving excellence in biopharmaceutical development and manufacturing by using appropriate manufacturing practices (AMPs). BioProcess J, 2016; 14(4): 30–6. http://dx.doi.org/10.12665/J144.Witcher.

Posted online January 12, 2016.

 
A Qualitative Risk-Benefit Structure for Developing and Manufacturing Biopharmaceuticals

by Mark F. Witcher, PhD
Volume 14, Issue 3 (Fall 2015)

Developing and manufacturing biopharmaceuticals is a complex endeavor that will become even more challenging as the field of medicine expands into a broader range of therapies that includes cellular, genetic, epigenetic, and proteins with more specific biomarkers and functions. New manufacturing process technologies utilizing single-use systems, high-performance perfusion bioreactors, and continuous/semi-continuous processing will add further complexity. To better serve the patient population, a biopharmaceutical development and manufacturing enterprise should address all of the patient’s needs. The enterprise must minimize the therapy’s safety risks while providing the benefits of timely, efficient, and reliable access to effective biopharmaceutical products. Achieving the benefits while controlling patient risks can be aided by understanding a qualitative risk-benefit structure that defines the quality of the product in terms of its overall value to the patient. This paper seeks to begin the process of developing a comprehensive risk-benefit structure that can be used by a biopharmaceutical development-manufacturing enterprise to successfully develop and optimize a therapy’s value...

Citation:
Witcher MF. A qualitative risk-benefit structure for developing and manufacturing biopharmaceuticals. BioProcess J, 2015; 14(3): 4–12. http://dx.doi.org/10.12665/J143.Witcher.

Posted online October 9, 2015.

 
Selection of Clarification Methods for Improved Downstream Performance and Economics

by Sarah Le Merdy
Volume 14, Issue 3 (Fall 2015)

The production of biopharmaceutical drugs typically involves a biological expression within a bacterial, yeast, or mammalian cell expansion system. Getting to the final product requires multiple purification steps, from primary clarification to the final formulation and sterile filtration. The aim of the initial purification steps is not to purify the stream perfectly but rather, to prepare the stream for finer and more specific purification steps further downstream. Apart from efficiently removing contaminants, the clarification stages also need to maintain high product recovery whilst being consistent and robust. The finer downstream purification stages represent the largest portion of production costs; and for monoclonal antibodies (MAb), they can represent up to 80% of the overall cost. This cost is, however, heavily impacted by the quality of the feed stream that has been produced. Early clarification and purification steps, although seemingly crude, are critical in removing contaminants and maintaining a cost-effective process further downstream. Selecting them scientifically, based on chosen performance markers, could thus improve the performances of downstream operations. After reviewing the typical feed stream compositions, this article reviews the existing literature and shows the advantages of thoroughly investigating and then selecting a clarification method that provides the best downstream performance and economics...

Citation:
Le Merdy S. Selection of clarification methods for improved downstream performance and economics. BioProcess J, 2015; 14(3): 50–5. http://dx.doi.org/10.12665/J143.LeMerdy.

Posted online October 9, 2015.

 
Next Generation Vaccines: Development of a Novel Streptococcus pneumoniae Multivalent Protein Vaccine

by Paola Cecchini, Claire Entwisle, Michael Joachim, Yin Pang, Kate A. Dalton, Sue Hill, Ann McIlgorm, Win-Yan Chan, Jeremy S. Brown, Camilo A. Colaco, Chris R. Bailey, and Sue W. Clarke
Volume 14, Issue 3 (Fall 2015)

Polysaccharide-based vaccines are widely used to protect against Streptococcus pneumoniae (S. pneumoniae) infections in infants and the elderly. However, their use is limited by strain specificity, which restricts both their geographical and economical utility. There is an urgent need for protein-based vaccines that are likely to provide broader, more economical protection against the global burden of pneumococcal disease. In this paper, we describe the pre-clinical development of a multi-subunit protein vaccine that can be manufactured efficiently and economically to meet this need. Genetically engineered Streptococcus pneumoniae TIGR4 B7.1 PlyD6 cell substrate was constructed to deliver non-toxic Ply. PnuBioVax™ S. pneumoniae vaccines were produced at ImmBio in a 1 L-scale fermenter as development batches. The process has been successfully “tech transferred” to a CMO for scale-up and production of toxicology and clinical supplies. Pre-clinical immunogenicity tests showed promising results for PnuBioVax. Rabbit sera generated by PnuBioVax were able to produce surface binding antibody and complement-mediated killing of S. pneumoniae for both TIGR4 and the heterologous strain 15B (not covered by pneumococcal conjugate vaccine [PCV]-13). No overall benefit to the immunogenicity by the addition of Alhydrogel was seen in the total IgG response. In passive protection studies in mice, serum raised against PnuBioVax in rabbits protected against challenge by S. pneumoniae TIGR4...

Citation:
Cecchini P, Entwisle C, Joachim M, Pang Y, Dalton KA, Hill S, McIlgorm A, Chan W-Y, Brown JS, Colaco CA, Bailey CR, Clarke SW. Next generation vaccines: development of a novel Streptococcus pneumoniae multivalent protein vaccine. BioProcess J, 2015; 14(3): 18–33. http://dx.doi.org/10.12665/J143.Colaco.

Posted online October 9, 2015.

 
Coming ‘Round to Spheroid Culture

by Bhaskar S. Mandavilli, Cindy Neeley, MaryKay Bates, and Magnus Persmark
Volume 14, Issue 3 (Fall 2015)

Cells cultured in 2D can differ in terms of both physiology and cellular responses compared with cells in vivo. This has led to a surge in the popularity of using 3D culture techniques as mounting evidence suggests that culturing cells in 3D is more representative of the in vivo environment, even to the extent that the gene expression profiles of cells from 3D cultures more accurately reflect clinical expression profiles than those observed in 2D cultures. 3D culture offers the potential for more accurate models of drug delivery and efficacy, as well as numerous clinical and research applications, and is becoming increasingly capable of integrating into high-throughput activities. Spheroids, or sphere cultures, have become an especially exciting area of 3D in vitro culture due to their great potential for use in studies that investigate growth and function of both malignant and normal tissues. These sphere cultures have contributed considerably to our knowledge of cellular responses thanks to the accuracy with which they reflect the in vivo system. This is primarily a result of the fact that cells do not normally grow or interact in isolation, but instead form complex interactions with other cells and the surrounding microenvironment. Thus, the creation of a 3D environment that incorporates spheroids closely mimics in vivo, allowing researchers to incorporate cell-cell interactions, nutrient gradients, and diffusion kinetics in their in vitro models. Researchers have been making use of these culture methods across multiple fields for a number of years and have made considerable contributions to our knowledge of cellular interactions and behaviors. Spheroids offer particular benefits in cancer biology where they contribute immense value in examining the growth and behavior of tumors since they share several key histomorphological and functional traits that include the formation of cell-cell contacts, decreased proliferation, increased survival rates, and a hypoxic core...

Citation:
Mandavilli BS, Neeley C, Bates M, Persmark M. Coming ‘round to spheroid culture. BioProcess J, 2015; 14(3): 44–9. http://dx.doi.org/10.12665/J143.Persmark.

Posted online October 9, 2015.

 
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