- Email: [email protected]
Importance of technical operations: lessons from evolving biotherapeutics production methods
Update 6 Schouten, H.J. and Jacobsen, E. (2008) Cisgenesis and intragenesis, sisters in innovative plant breeding. Trends Plant Sci. 13, 260– 261 7 Black, V. (2008) Hot Potato. GM Potatoes in South Africa – A Critical Analysis, African Centre for Biosafety (available at http://www. biosafety-info.net/file_dir/3133148883b973d0a6.pdf) 8 Swandby, H. (2008) GMOs in South Africa. 2008 Overview, African Centre for Biosafety, (available at http://www.biosafetyafrica.net/ index.html/images/stories/dmdocuments/gmosinsouthafrica.pdf) 9 Convention on Biological Diversity (2009) The Cartagena Protocol on Biosafety, CBD Secretariat (available at http://www.cbd.int/biosafety/) 10 Gray, A.J. and Raybould, A.F. (1998) Reducing transgene escape routes. Nature 392, 653–654
Trends in Biotechnology Vol.27 No.11 11 Gurian-Sherman, D. (2007) Transgene Escape! But No One Has Called out the Guards, The Bioscience Resource Project (available at http:// www.bioscienceresource.org/commentaries/article.php?id=7) 12 Burke, D. (2004) GM food and crops: what went wrong in the UK? Many of the public’s concerns have little to do with science. EMBO Rep. 5, 432–436 13 MacKenzie, D. (2008) How the humble potato could feed the world. New Sci. 2667, 30–33 14 Haslberger, A.G. (2003) Codex Guidelines for GM foods include the analysis of unintended effects. Nat. Biotechnol. 21, 739–741 0167-7799/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2009.08.004 Available online 14 September 2009
FORUM: Science & Society
Importance of technical operations: lessons from evolving biotherapeutics production methods Pratik Jaluria and Derek N. Adams Fermentation and Cell Culture Development, Technical Operations, Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, CT 06410, USA
Research and development connect technology and innovation to product design. However, the term is often used to refer to only a subset of the necessary disciplines to the exclusion of technical operations. Here, we argue that the importance of technical operations is undeniable, offering possible solutions by drawing on lessons from outdated biotherapeutics production methods and highlighting advances in the field.
Argument Considered the lifeline of biopharmaceutical companies, and rightly so, research and development connects technology and innovation to product design, broadly drawing on many different scientific and engineering disciplines. However, the term is often used to refer to only a subset of these disciplines, such as molecular biology, immunology and pharmacology, to the exclusion of the manufacturing process and analytical development, collectively referred to here as technical operations. This narrow view, perpetuating a sense that technical operations make less of a scientific contribution or are less valuable to the overall biopharmaceuticals business than other fields, runs contrary to real-life examples. Here, we argue that the importance of technical operations is undeniable, offering possible solutions by drawing on lessons from outdated biotherapeutics production methods and highlighting advances in the field. Defining roles and functions Many critical and distinct functions can be attributed to technical operations, including cell line development, process development, assay development, analytical characterization and technology transfer. Figure 1 depicts how Corresponding author: Jaluria, P. ([email protected]).
612
various groups involved in biotherapeutics development interface and provides a brief description of their roles. Essentially, technical operations design and test methods and processes, thereby serving as a link between research and manufacturing. Despite such a vital role, technical operations are often excluded from the critical path of drug development, regardless of the extraordinary technical knowledge required. In fact, coordination among groups is paramount in the transfer of knowledge from the laboratory to the manufacturing facility [1,2]. Without scientists, engineers and technicians to perform these and related roles, essential therapeutics could not be produced, leaving brilliant ideas as merely ideas, without fulfulling the potential to help patients and save lives. Illustrations Vaccines, therapeutic proteins and other biopharmaceuticals together constitute the fastest growing segment of the pharmaceutical market [1]. Advances in biotherapeutics production methods, largely arising from innovation stemming from technical operations, include improved productivity, shorter manufacturing times and the incorporation of relatively safe and traceable raw materials [3]. Collectively, these and other advances highlight the impact and substantial influence that development-associated groups can have on the production of biotherapeutics. Below, we describe two opposing examples. The first example, related to outdated influenza vaccine production methods, illustrates how undervaluing the role of technical operations can lead to a failure to meet public health needs. The second example relates to improvements in monoclonal antibody production highlighting how prioritization and encouragement can drive innovation. The recent emergence of pandemic influenza strains (H5N1 and H1N1) has reaffirmed the view of public health organizations that current vaccine production methods
Update
Trends in Biotechnology
Vol.27 No.11
Figure 1. Functional groups for the development and production of biotherapeutics. Various groups within technical operations and their interactions with external groups, including research, clinical development and manufacturing, are depicted. Additional details regarding the functionality of each group are also provided.
cannot meet global demand [4]. Technical operations are critical for rapid vaccine development and manufacturing. Currently, commercially available influenza vaccines are produced using a protracted process, requiring months of development and a substantial supply of embryonated chicken eggs. It has long been lamented that vaccine production in eggs has significant limitations compared to modern biotherapeutics production methods, yet industry has been slow to apply such modern production methods [4,5]. A highly conservative regulatory culture is partially to blame and has hindered the development of alternate production methods by discouraging investment in new ideas [2,5]. However, because of recent events, resource allocation and investment are now being shifted to drive the development of rapid, efficient and economical production methods [6]. As alternatives to egg-based systems, companies are beginning to produce, test and license vaccines using virus-like particles and other cellculture-based technologies [4]. For instance, a variety of mammalian cells such as Madin-Darby canine kidney (MDCK) cells, insect cells (Spodoptera frugiperda) and bacterial cells (Escherichia coli) are being used to develop new vaccine candidates. To commercialize these types of vaccine candidates, expertise in technical operations is necessary and is only now being fully used [7]. In contrast, the production of monoclonal antibodies illustrates the breadth of possibilities when technical oper-
ations are valued and prioritized. Representing a growing segment of the biotherapeutics market, monoclonal antibodies are required in relatively large doses at substantial cost. Initially, these molecules were produced in batchmode cell cultures in serum-containing culture media at scales of 10–100 L with a productivity of 0.01–0.1 g/L [3]. Over the past two decades, technology has improved such that these molecules are now produced in fed-batch or continuous cell cultures in protein-free media at scales of up to 25 000 L at productivity in excess of 5 g/L. Such substantial progress is the result of innovation in different facets of technical operations, including the development of highly productive and robust cell lines and of chemically defined culture media, bioreactor process engineering and high-yield platform technologies for the production and purification of more than 100 kg per batch. Other examples of technical operations advances are shown in Table 1. As a corollary, the development and characterization of generic biotherapeutics (i.e. biosimilars) will require the expertise of technical operations owing to the complexity and challenges associated with their production [8,9]. Combating perceptions Recognizing the problem described above, the FDA and other regulatory agencies have introduced initiatives, detailed discussion of which can be found elsewhere, designed to stimulate innovation in production methods
Table 1. Examples of Advances in Technical Operations & General Biotechnology Processing General Function Cell line development
Process development
Analytical testing Technology transfer
Specific Developments Identification and assessment of novel host cells and expression systems that improve product quality and productivity Ability to screen many candidates for distinct properties including expression and stability Protein-free, chemically-defined culture media Dramatic increase in productivity and process yield Improved robustness and performance Incorporation of high-throughput technologies to rapidly develop assays Utilization of –omics tools to screen and characterize molecules Conception and deployment of platform technologies to expedite technology transfers within 12-18 months Integration of multiple departments into advisory groups charged with oversight and project execution 613
Update [10]. One initiative is process analytical technology (PAT), which aims to guide industry towards adopting more progressive approaches to develop and monitor production methods. The underlying principle behind this initiative is that rigorous scientific rationale in conjunction with multivariate analysis and design of experiments can be applied to identify key characteristics of a product and to develop methods to track or predict these characteristics [10]. For instance, replacing manual sampling with realtime, on-line analytical tools could more rapidly identify and address problems as they occur, without sacrificing an entire batch. In shifting the paradigm away from ‘‘process equals product’’, PAT relies on knowledge (i.e. how a process performs and the critical factors that impact the process) to ensure robustness and consistency. The broader framework for this approach, termed quality by design (QbD), recognizes that technical operations are essential in establishing and maintaining product quality, an undeniable acknowledgment of their importance in the life cycle of biopharmaceuticals [1,10]. Although the specifics of these initiatives are beyond the scope of this article, it should be mentioned that QbD fundamentally provides a system to assign and manage risk without relying solely on procedures. Another way by which perceptions regarding technical operations are changing is through enhanced communication between many different groups. As inter-departmental projects are initiated, scientists, managers and others are collaborating in ways that foster mutual understanding. In the current market, timelines are decreasing and demands are escalating, requiring more coordinated effort among varying groups [4,7]. Without resorting to tactics of self-promotion, technical operations groups can improve their visibility by continuing to deliver quality processes and methods within shorter timelines.
614
Trends in Biotechnology Vol.27 No.11
Concluding remarks Technical operations affect metrics from the cost of goods to consistency in product quality while working with constraints (i.e. cost, speed, resources, equipment, regulatory environment, etc.). Performance within such constrained environments requires procedural expertise, ingenuity and technical knowledge. As companies acknowledge the impact and value of technical operations through regulatory initiatives and pathways for biosimilars, technological advances will facilitate greater efficiencies and further innovation. The demands placed on these groups are not without cause because their work is directly responsible for the delivery of valuable products to patients; all the more reason to appreciate their contributions. References 1 Wurm, F.M. (2007) Manufacturing of biopharmaceuticals and implications for biosimilars. Kidney Blood Pressure Res. 30 (Suppl.), 6–8 2 Pisano, G.P. (1997) The Development Factory: Unlocking the Potential of Process Innovation, Harvard Business Press 3 Wurm, F.M. (2004) Production of recombinant protein therapeutics in cultivated mammalian cells. Nat. Biotechnol. 22, 1393–1398 4 Ulmer, J.B. et al. (2006) Vaccine manufacturing: challenges and solutions. Nat. Biotechnol. 24, 1377–1383 5 Davies, M.N. and Flower, D.R. (2007) Harnessing bioinformatics to discover new vaccines. Drug Discov. Today 12, 389–395 6 Gupta, P. and Lee, K.H. (2007) Genomics and proteomics in process development: opportunities and challenges. Trends Biotechnol. 25, 324– 330 7 Sterling, J. (2008) Strengthening the biotechnician workforce. Genet. Eng. Biotechnol. News 28 (14), 78–79 8 Covic, A. and Kuhlmann, M.K. (2007) Biosimilars: recent developments. Int. Urol. Nephrol. 39, 261–266 9 Miller, H.I. (2009) Biogenerics: the hope and the hype. Trends Biotechnol. 27, 443–444 10 Rathore, A.S. and Winkle, H. (2009) Quality by design for biopharmaceuticals. Nat. Biotechnol. 27, 26–34 0167-7799/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2009.08.003 Available online 16 September 2009
Trends in Biotechnology Vol.27 No.11 11 Gurian-Sherman, D. (2007) Transgene Escape! But No One Has Called out the Guards, The Bioscience Resource Project (available at http:// www.bioscienceresource.org/commentaries/article.php?id=7) 12 Burke, D. (2004) GM food and crops: what went wrong in the UK? Many of the public’s concerns have little to do with science. EMBO Rep. 5, 432–436 13 MacKenzie, D. (2008) How the humble potato could feed the world. New Sci. 2667, 30–33 14 Haslberger, A.G. (2003) Codex Guidelines for GM foods include the analysis of unintended effects. Nat. Biotechnol. 21, 739–741 0167-7799/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2009.08.004 Available online 14 September 2009
FORUM: Science & Society
Importance of technical operations: lessons from evolving biotherapeutics production methods Pratik Jaluria and Derek N. Adams Fermentation and Cell Culture Development, Technical Operations, Alexion Pharmaceuticals, Inc., 352 Knotter Drive, Cheshire, CT 06410, USA
Research and development connect technology and innovation to product design. However, the term is often used to refer to only a subset of the necessary disciplines to the exclusion of technical operations. Here, we argue that the importance of technical operations is undeniable, offering possible solutions by drawing on lessons from outdated biotherapeutics production methods and highlighting advances in the field.
Argument Considered the lifeline of biopharmaceutical companies, and rightly so, research and development connects technology and innovation to product design, broadly drawing on many different scientific and engineering disciplines. However, the term is often used to refer to only a subset of these disciplines, such as molecular biology, immunology and pharmacology, to the exclusion of the manufacturing process and analytical development, collectively referred to here as technical operations. This narrow view, perpetuating a sense that technical operations make less of a scientific contribution or are less valuable to the overall biopharmaceuticals business than other fields, runs contrary to real-life examples. Here, we argue that the importance of technical operations is undeniable, offering possible solutions by drawing on lessons from outdated biotherapeutics production methods and highlighting advances in the field. Defining roles and functions Many critical and distinct functions can be attributed to technical operations, including cell line development, process development, assay development, analytical characterization and technology transfer. Figure 1 depicts how Corresponding author: Jaluria, P. ([email protected]).
612
various groups involved in biotherapeutics development interface and provides a brief description of their roles. Essentially, technical operations design and test methods and processes, thereby serving as a link between research and manufacturing. Despite such a vital role, technical operations are often excluded from the critical path of drug development, regardless of the extraordinary technical knowledge required. In fact, coordination among groups is paramount in the transfer of knowledge from the laboratory to the manufacturing facility [1,2]. Without scientists, engineers and technicians to perform these and related roles, essential therapeutics could not be produced, leaving brilliant ideas as merely ideas, without fulfulling the potential to help patients and save lives. Illustrations Vaccines, therapeutic proteins and other biopharmaceuticals together constitute the fastest growing segment of the pharmaceutical market [1]. Advances in biotherapeutics production methods, largely arising from innovation stemming from technical operations, include improved productivity, shorter manufacturing times and the incorporation of relatively safe and traceable raw materials [3]. Collectively, these and other advances highlight the impact and substantial influence that development-associated groups can have on the production of biotherapeutics. Below, we describe two opposing examples. The first example, related to outdated influenza vaccine production methods, illustrates how undervaluing the role of technical operations can lead to a failure to meet public health needs. The second example relates to improvements in monoclonal antibody production highlighting how prioritization and encouragement can drive innovation. The recent emergence of pandemic influenza strains (H5N1 and H1N1) has reaffirmed the view of public health organizations that current vaccine production methods
Update
Trends in Biotechnology
Vol.27 No.11
Figure 1. Functional groups for the development and production of biotherapeutics. Various groups within technical operations and their interactions with external groups, including research, clinical development and manufacturing, are depicted. Additional details regarding the functionality of each group are also provided.
cannot meet global demand [4]. Technical operations are critical for rapid vaccine development and manufacturing. Currently, commercially available influenza vaccines are produced using a protracted process, requiring months of development and a substantial supply of embryonated chicken eggs. It has long been lamented that vaccine production in eggs has significant limitations compared to modern biotherapeutics production methods, yet industry has been slow to apply such modern production methods [4,5]. A highly conservative regulatory culture is partially to blame and has hindered the development of alternate production methods by discouraging investment in new ideas [2,5]. However, because of recent events, resource allocation and investment are now being shifted to drive the development of rapid, efficient and economical production methods [6]. As alternatives to egg-based systems, companies are beginning to produce, test and license vaccines using virus-like particles and other cellculture-based technologies [4]. For instance, a variety of mammalian cells such as Madin-Darby canine kidney (MDCK) cells, insect cells (Spodoptera frugiperda) and bacterial cells (Escherichia coli) are being used to develop new vaccine candidates. To commercialize these types of vaccine candidates, expertise in technical operations is necessary and is only now being fully used [7]. In contrast, the production of monoclonal antibodies illustrates the breadth of possibilities when technical oper-
ations are valued and prioritized. Representing a growing segment of the biotherapeutics market, monoclonal antibodies are required in relatively large doses at substantial cost. Initially, these molecules were produced in batchmode cell cultures in serum-containing culture media at scales of 10–100 L with a productivity of 0.01–0.1 g/L [3]. Over the past two decades, technology has improved such that these molecules are now produced in fed-batch or continuous cell cultures in protein-free media at scales of up to 25 000 L at productivity in excess of 5 g/L. Such substantial progress is the result of innovation in different facets of technical operations, including the development of highly productive and robust cell lines and of chemically defined culture media, bioreactor process engineering and high-yield platform technologies for the production and purification of more than 100 kg per batch. Other examples of technical operations advances are shown in Table 1. As a corollary, the development and characterization of generic biotherapeutics (i.e. biosimilars) will require the expertise of technical operations owing to the complexity and challenges associated with their production [8,9]. Combating perceptions Recognizing the problem described above, the FDA and other regulatory agencies have introduced initiatives, detailed discussion of which can be found elsewhere, designed to stimulate innovation in production methods
Table 1. Examples of Advances in Technical Operations & General Biotechnology Processing General Function Cell line development
Process development
Analytical testing Technology transfer
Specific Developments Identification and assessment of novel host cells and expression systems that improve product quality and productivity Ability to screen many candidates for distinct properties including expression and stability Protein-free, chemically-defined culture media Dramatic increase in productivity and process yield Improved robustness and performance Incorporation of high-throughput technologies to rapidly develop assays Utilization of –omics tools to screen and characterize molecules Conception and deployment of platform technologies to expedite technology transfers within 12-18 months Integration of multiple departments into advisory groups charged with oversight and project execution 613
Update [10]. One initiative is process analytical technology (PAT), which aims to guide industry towards adopting more progressive approaches to develop and monitor production methods. The underlying principle behind this initiative is that rigorous scientific rationale in conjunction with multivariate analysis and design of experiments can be applied to identify key characteristics of a product and to develop methods to track or predict these characteristics [10]. For instance, replacing manual sampling with realtime, on-line analytical tools could more rapidly identify and address problems as they occur, without sacrificing an entire batch. In shifting the paradigm away from ‘‘process equals product’’, PAT relies on knowledge (i.e. how a process performs and the critical factors that impact the process) to ensure robustness and consistency. The broader framework for this approach, termed quality by design (QbD), recognizes that technical operations are essential in establishing and maintaining product quality, an undeniable acknowledgment of their importance in the life cycle of biopharmaceuticals [1,10]. Although the specifics of these initiatives are beyond the scope of this article, it should be mentioned that QbD fundamentally provides a system to assign and manage risk without relying solely on procedures. Another way by which perceptions regarding technical operations are changing is through enhanced communication between many different groups. As inter-departmental projects are initiated, scientists, managers and others are collaborating in ways that foster mutual understanding. In the current market, timelines are decreasing and demands are escalating, requiring more coordinated effort among varying groups [4,7]. Without resorting to tactics of self-promotion, technical operations groups can improve their visibility by continuing to deliver quality processes and methods within shorter timelines.
614
Trends in Biotechnology Vol.27 No.11
Concluding remarks Technical operations affect metrics from the cost of goods to consistency in product quality while working with constraints (i.e. cost, speed, resources, equipment, regulatory environment, etc.). Performance within such constrained environments requires procedural expertise, ingenuity and technical knowledge. As companies acknowledge the impact and value of technical operations through regulatory initiatives and pathways for biosimilars, technological advances will facilitate greater efficiencies and further innovation. The demands placed on these groups are not without cause because their work is directly responsible for the delivery of valuable products to patients; all the more reason to appreciate their contributions. References 1 Wurm, F.M. (2007) Manufacturing of biopharmaceuticals and implications for biosimilars. Kidney Blood Pressure Res. 30 (Suppl.), 6–8 2 Pisano, G.P. (1997) The Development Factory: Unlocking the Potential of Process Innovation, Harvard Business Press 3 Wurm, F.M. (2004) Production of recombinant protein therapeutics in cultivated mammalian cells. Nat. Biotechnol. 22, 1393–1398 4 Ulmer, J.B. et al. (2006) Vaccine manufacturing: challenges and solutions. Nat. Biotechnol. 24, 1377–1383 5 Davies, M.N. and Flower, D.R. (2007) Harnessing bioinformatics to discover new vaccines. Drug Discov. Today 12, 389–395 6 Gupta, P. and Lee, K.H. (2007) Genomics and proteomics in process development: opportunities and challenges. Trends Biotechnol. 25, 324– 330 7 Sterling, J. (2008) Strengthening the biotechnician workforce. Genet. Eng. Biotechnol. News 28 (14), 78–79 8 Covic, A. and Kuhlmann, M.K. (2007) Biosimilars: recent developments. Int. Urol. Nephrol. 39, 261–266 9 Miller, H.I. (2009) Biogenerics: the hope and the hype. Trends Biotechnol. 27, 443–444 10 Rathore, A.S. and Winkle, H. (2009) Quality by design for biopharmaceuticals. Nat. Biotechnol. 27, 26–34 0167-7799/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2009.08.003 Available online 16 September 2009