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.
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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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