Larissa M Benavente, Adam S. Goldberg, H. Myburg, Joseph M. Chiera, Michael Zapata, L. V. Zyl
‘omics and systems biology have led to paradigm shifts in biology and medicine. This success has drawn the attention of the bioprocessing industry where their application is increasingly more prevalent. systems biology uses system-level high dimensional data generated via ‘omics technologies to provide a holistic view of the production cell lines. We discuss how systems biology drives rational process improvement and cell engineering strategies, highlighting seminal studies in prokaryotes and mammalian cell lines that combined multi-‘omics and modeling to provide insights into the behavior of production cell lines. Despite its recognized potential, there are challenges and limitations to overcome to fully implement and realize benefits heralded by systems biology for biomanufacturing: increasing titer, yield, quality, process efficiency and stability.
{"title":"The application of systems biology to biomanufacturing","authors":"Larissa M Benavente, Adam S. Goldberg, H. Myburg, Joseph M. Chiera, Michael Zapata, L. V. Zyl","doi":"10.4155/PBP.15.12","DOIUrl":"https://doi.org/10.4155/PBP.15.12","url":null,"abstract":"‘omics and systems biology have led to paradigm shifts in biology and medicine. This success has drawn the attention of the bioprocessing industry where their application is increasingly more prevalent. systems biology uses system-level high dimensional data generated via ‘omics technologies to provide a holistic view of the production cell lines. We discuss how systems biology drives rational process improvement and cell engineering strategies, highlighting seminal studies in prokaryotes and mammalian cell lines that combined multi-‘omics and modeling to provide insights into the behavior of production cell lines. Despite its recognized potential, there are challenges and limitations to overcome to fully implement and realize benefits heralded by systems biology for biomanufacturing: increasing titer, yield, quality, process efficiency and stability.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"341-355"},"PeriodicalIF":0.0,"publicationDate":"2015-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.12","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Speed is often positioned as a key element in the development of any novel therapeutic. After all, reducing development timelines can have a beneficial impact in managing investment cycles (crucial for small biotech), facilitate the introduction of translational medicine (bench to bedside and back to bench) and extend market exclusivity awarded by intellectual property rights. Yet speed is precisely a largely absent attribute in the development of virtually any new drug, and we could argue that biopharmaceuticals, because of the intrinsic complexities associated with their production, are perhaps the worst positioned amongst most drug classes. As an optimistic estimate, the road for a lead biopharmaceutical candidate to reach first-in-human clinical trials could take between 1.5 and 2 years of, sometimes perilous, travel involving a considerable out-ofpocket investment at a very high risk. High risk because an immense majority of products in development will fail (sometimes catastrophically) at some point during their development. Below I discuss how past development and manufacturing challenges during the onset of biopharmaceuticals have conditioned the evolution of manufacturing praxis and the perception of risk in the industry. I would also like to discuss how a two-tier manufacturing paradigm, addressing separately early prototype versus commercial requirements, could change dramatically how biopharmaceutical development is approached today, perhaps opening the door to new treatments for medical conditions that today are still largely out-of-reach for protein-based therapeutics, such as infectious diseases.
{"title":"Toward a two-tier process-development paradigm: prototype versus commercial biomanufacturing","authors":"J. Zurdo","doi":"10.4155/PBP.15.5","DOIUrl":"https://doi.org/10.4155/PBP.15.5","url":null,"abstract":"Speed is often positioned as a key element in the development of any novel therapeutic. After all, reducing development timelines can have a beneficial impact in managing investment cycles (crucial for small biotech), facilitate the introduction of translational medicine (bench to bedside and back to bench) and extend market exclusivity awarded by intellectual property rights. Yet speed is precisely a largely absent attribute in the development of virtually any new drug, and we could argue that biopharmaceuticals, because of the intrinsic complexities associated with their production, are perhaps the worst positioned amongst most drug classes. As an optimistic estimate, the road for a lead biopharmaceutical candidate to reach first-in-human clinical trials could take between 1.5 and 2 years of, sometimes perilous, travel involving a considerable out-ofpocket investment at a very high risk. High risk because an immense majority of products in development will fail (sometimes catastrophically) at some point during their development. Below I discuss how past development and manufacturing challenges during the onset of biopharmaceuticals have conditioned the evolution of manufacturing praxis and the perception of risk in the industry. I would also like to discuss how a two-tier manufacturing paradigm, addressing separately early prototype versus commercial requirements, could change dramatically how biopharmaceutical development is approached today, perhaps opening the door to new treatments for medical conditions that today are still largely out-of-reach for protein-based therapeutics, such as infectious diseases.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"179-183"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mammalian cell culture media used for the manufacture of therapeutic protein have advanced systematically from serum-containing into animal-free, protein-free and chemically defined formulations over the past decades. Initially driven by patient safety concerns associated with the use of animal-derived medium components, and later by inconsistent cell culture performance due to variability in plant-derived raw material lots, many biologics manufacturers redirect their focus on the development of proprietary media formulations and implementation of well-controlled chemically defined raw materials in all cell culture media and feeds for production processes. This article will provide an overview of current trends and objectives of industrial medium development efforts for therapeutic protein production.
{"title":"Development of protein-free medium for therapeutic protein production in mammalian cells: recent advances and perspectives","authors":"W. L. Ling","doi":"10.4155/PBP.15.8","DOIUrl":"https://doi.org/10.4155/PBP.15.8","url":null,"abstract":"Mammalian cell culture media used for the manufacture of therapeutic protein have advanced systematically from serum-containing into animal-free, protein-free and chemically defined formulations over the past decades. Initially driven by patient safety concerns associated with the use of animal-derived medium components, and later by inconsistent cell culture performance due to variability in plant-derived raw material lots, many biologics manufacturers redirect their focus on the development of proprietary media formulations and implementation of well-controlled chemically defined raw materials in all cell culture media and feeds for production processes. This article will provide an overview of current trends and objectives of industrial medium development efforts for therapeutic protein production.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"215-226"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70353051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The commercial potential of monoclonal antibodies (mAbs) has been continuously increasing during the last years alongside with the number of approved mAb-based drugs and clinical trials. Despite their effectiveness and safety, the general access to this class of biopharmaceuticals is barred by high selling prices. Downstream processing is now considered the bottleneck in the manufacturing of mAbs. Therefore, the design of novel and economic operations and their implementation in the current technology platforms constitutes a pressing need. This review provides an insight into the current state-of-the-art in mAbs purification, focusing on multimodal chromatography as one of the viable options to upgrade the established purification train.
{"title":"Multimodal chromatography: debottlenecking the downstream processing of monoclonal antibodies","authors":"I. Pinto, M. Aires-Barros, A. Azevedo","doi":"10.4155/PBP.15.7","DOIUrl":"https://doi.org/10.4155/PBP.15.7","url":null,"abstract":"The commercial potential of monoclonal antibodies (mAbs) has been continuously increasing during the last years alongside with the number of approved mAb-based drugs and clinical trials. Despite their effectiveness and safety, the general access to this class of biopharmaceuticals is barred by high selling prices. Downstream processing is now considered the bottleneck in the manufacturing of mAbs. Therefore, the design of novel and economic operations and their implementation in the current technology platforms constitutes a pressing need. This review provides an insight into the current state-of-the-art in mAbs purification, focusing on multimodal chromatography as one of the viable options to upgrade the established purification train.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"220 1","pages":"263-279"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Antibody immunogenicity: does bioprocessing hold all the answers?","authors":"H. Waldmann","doi":"10.4155/PBP.15.4","DOIUrl":"https://doi.org/10.4155/PBP.15.4","url":null,"abstract":"","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"175-177"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The biopharmaceutical market is driven by the steady increase in demand for therapeutic proteins produced in mammalian cells. Glutamine is a main nitrogen source and also a main energy source with glucose in mammalian cell cultures for therapeutic protein production. As a result of glutamine metabolism and the natural decomposition of glutamine, ammonia, which is known to negatively affect cell growth, protein production and sialylation of recombinant glycoprotein, is necessarily accumulated in a culture medium. This review highlights the current strategies and achievements in overcoming the negative effect of ammonia through the glutamine substitution by less ammoniagenic substrates, such as glutamate, pyruvate and α-ketoglutarate.
{"title":"Glutamine substitution: the role it can play to enhance therapeutic protein production","authors":"T. Ha, G. Lee","doi":"10.4155/PBP.15.6","DOIUrl":"https://doi.org/10.4155/PBP.15.6","url":null,"abstract":"The biopharmaceutical market is driven by the steady increase in demand for therapeutic proteins produced in mammalian cells. Glutamine is a main nitrogen source and also a main energy source with glucose in mammalian cell cultures for therapeutic protein production. As a result of glutamine metabolism and the natural decomposition of glutamine, ammonia, which is known to negatively affect cell growth, protein production and sialylation of recombinant glycoprotein, is necessarily accumulated in a culture medium. This review highlights the current strategies and achievements in overcoming the negative effect of ammonia through the glutamine substitution by less ammoniagenic substrates, such as glutamate, pyruvate and α-ketoglutarate.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"249-261"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hidemasa Kato, Keiko Hiraki-Kamon, M. Eitoku, H. Kiyosawa, C. Neeley, Y. Okazaki
Popular belief assumes that human pluripotent cells can now be obtained in any lab or company by induced pluripotent stem (iPS) cell reprogramming. However, the difficulties in robustly producing human iPS-derived cells that are fit for drug discovery are becoming increasingly apparent. This is because we still have not come up with a strict definition of pluripotency. Our attempts at prospectively identifying differentiation-defective human iPS cells using teratoma assays or marker expression have clearly failed to date. Here, we will revisit how conventional pluripotency tests have failed in evaluating iPS cells adequately for drug discovery and emphasize two aspects of developmental transitions (what we call here a cell's chronological value and the segregation of factors as it differentiates) to elucidate inherent problems with our current understanding of human iPS cells. Finally, we challenge the field by presenting our perspective on distinguishing good human iPS cells from bad ones.
{"title":"Exploring standards for industrializing human induced pluripotent stem cells","authors":"Hidemasa Kato, Keiko Hiraki-Kamon, M. Eitoku, H. Kiyosawa, C. Neeley, Y. Okazaki","doi":"10.4155/PBP.15.9","DOIUrl":"https://doi.org/10.4155/PBP.15.9","url":null,"abstract":"Popular belief assumes that human pluripotent cells can now be obtained in any lab or company by induced pluripotent stem (iPS) cell reprogramming. However, the difficulties in robustly producing human iPS-derived cells that are fit for drug discovery are becoming increasingly apparent. This is because we still have not come up with a strict definition of pluripotency. Our attempts at prospectively identifying differentiation-defective human iPS cells using teratoma assays or marker expression have clearly failed to date. Here, we will revisit how conventional pluripotency tests have failed in evaluating iPS cells adequately for drug discovery and emphasize two aspects of developmental transitions (what we call here a cell's chronological value and the segregation of factors as it differentiates) to elucidate inherent problems with our current understanding of human iPS cells. Finally, we challenge the field by presenting our perspective on distinguishing good human iPS cells from bad ones.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"199-213"},"PeriodicalIF":0.0,"publicationDate":"2015-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70353152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael Felo, Y. Kang, James A. Hamzik, P. Balderes, D. Ludwig
Flocculation technologies offer significant benefits to industrial mammalian cell culture processes, including increased clarification efficiency, impurity removal and process simplification. In this paper, the application and performance of flocculation technologies employed in the harvest process of monoclonal antibody Chinese hamster ovary cell culture are reviewed. Attention has been placed on technologies enhancing the removal of cells, cellular debris and reduction in impurities while maintaining the antibody in the product stream. Many flocculants are systematically evaluated with respect to their mechanism of action, impact on downstream processing and product quality, and potential disadvantages. Practical considerations and future directions for application of flocculation in antibody manufacturing are discussed.
{"title":"Industrial application of impurity flocculation to streamline antibody purification processes","authors":"Michael Felo, Y. Kang, James A. Hamzik, P. Balderes, D. Ludwig","doi":"10.4155/PBP.15.2","DOIUrl":"https://doi.org/10.4155/PBP.15.2","url":null,"abstract":"Flocculation technologies offer significant benefits to industrial mammalian cell culture processes, including increased clarification efficiency, impurity removal and process simplification. In this paper, the application and performance of flocculation technologies employed in the harvest process of monoclonal antibody Chinese hamster ovary cell culture are reviewed. Attention has been placed on technologies enhancing the removal of cells, cellular debris and reduction in impurities while maintaining the antibody in the product stream. Many flocculants are systematically evaluated with respect to their mechanism of action, impact on downstream processing and product quality, and potential disadvantages. Practical considerations and future directions for application of flocculation in antibody manufacturing are discussed.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"115-125"},"PeriodicalIF":0.0,"publicationDate":"2015-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.15.2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70352411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Endres, S. J. Fraser, W. Edwards, S. Beutel, T. Scheper
Aim: Bioreactors are an essential component in every biotechnological process. Due to the multitude of different microbial and mammalian organisms used for production of complex products, novel concepts for customized cultivations are necessary. Results: A ceramic capillary-based bioreactor enabling a novel approach for steady-state biofilm cultivation is presented. A model for the determination of the efficiency of this system was developed by comparing its productivity to conventional stirred tank reactors using the production of recombinant xylanase by Aspergillus niger D15 (xyn2) as a model process. Conclusion: The presented bioreactor provides an ideal platform for the cultivation of shear-sensitive, filamentous growing microorganisms producing valuable secreted secondary metabolites or recombinant products.
{"title":"Steady-state biofilm cultivation of Aspergillus niger D15 in a ceramic capillary membrane bioreactor","authors":"C. Endres, S. J. Fraser, W. Edwards, S. Beutel, T. Scheper","doi":"10.4155/PBP.14.61","DOIUrl":"https://doi.org/10.4155/PBP.14.61","url":null,"abstract":"Aim: Bioreactors are an essential component in every biotechnological process. Due to the multitude of different microbial and mammalian organisms used for production of complex products, novel concepts for customized cultivations are necessary. Results: A ceramic capillary-based bioreactor enabling a novel approach for steady-state biofilm cultivation is presented. A model for the determination of the efficiency of this system was developed by comparing its productivity to conventional stirred tank reactors using the production of recombinant xylanase by Aspergillus niger D15 (xyn2) as a model process. Conclusion: The presented bioreactor provides an ideal platform for the cultivation of shear-sensitive, filamentous growing microorganisms producing valuable secreted secondary metabolites or recombinant products.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"101-113"},"PeriodicalIF":0.0,"publicationDate":"2015-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.14.61","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70349052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Viral clearance studies are mandated prior to entering clinical trials and for commercial launch of biopharmaceuticals. These studies are a key component of risk mitigation to reduce the potential for iatrogenic transmission of pathogenic viruses. This paper reviews regulatory guidance and practical strategies for designing viral clearance studies. Essential elements of a developmental phase-appropriate viral clearance package are detailed. These include scale-down model qualification, virus spike experiments and validation (clearance evaluation) of manufacturing process steps. Heuristics and learnings from available data are shared. Developments in this area including generic validation strategies, multiviral spiking strategies and use of newer model viruses for nonconventional substrates are also described. This review provides a framework for a comprehensive viral validation package for regulatory submissions.
{"title":"Viral clearance for biopharmaceutical downstream processes","authors":"A. Shukla, H. Aranha","doi":"10.4155/PBP.14.62","DOIUrl":"https://doi.org/10.4155/PBP.14.62","url":null,"abstract":"Viral clearance studies are mandated prior to entering clinical trials and for commercial launch of biopharmaceuticals. These studies are a key component of risk mitigation to reduce the potential for iatrogenic transmission of pathogenic viruses. This paper reviews regulatory guidance and practical strategies for designing viral clearance studies. Essential elements of a developmental phase-appropriate viral clearance package are detailed. These include scale-down model qualification, virus spike experiments and validation (clearance evaluation) of manufacturing process steps. Heuristics and learnings from available data are shared. Developments in this area including generic validation strategies, multiviral spiking strategies and use of newer model viruses for nonconventional substrates are also described. This review provides a framework for a comprehensive viral validation package for regulatory submissions.","PeriodicalId":90285,"journal":{"name":"Pharmaceutical bioprocessing","volume":"3 1","pages":"127-138"},"PeriodicalIF":0.0,"publicationDate":"2015-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4155/PBP.14.62","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"70349145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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