The Application of Systems Biology to Biomanufacturing
Total Page：16
File Type：pdf, Size：1020Kb
Pharmaceutical Review Benavente, Goldberg, Myburg, Chiera, Zapata & Thevan Zylapplication of systems biology to bioman- ufacturing 3 Review 2015/05/26 The application of systems biology to biomanufacturing Pharm. Bioprocess. Abstract ‘omics and systems biology have led to paradigm shifts in biology and Larissa Benavente‡,1, Adam medicine. This success has drawn the attention of the bioprocessing industry where Goldberg‡,1, Henrietta their application is increasingly more prevalent. systems biology uses system-level Myburg1, Joseph Chiera1,2, 1,3 high dimensional data generated via ‘omics technologies to provide a holistic view Michael Zapata III & Len van Zyl*,1,4 of the production cell lines. We discuss how systems biology drives rational process 1ArrayXpress, Inc., 617 Hutton Street, improvement and cell engineering strategies, highlighting seminal studies in Suite 107, Raleigh, NC 27606, USA prokaryotes and mammalian cell lines that combined multi-‘omics and modeling to 2Phytotron, North Carolina State provide insights into the behavior of production cell lines. Despite its recognized University, Campus Box 7618, Raleigh, potential, there are challenges and limitations to overcome to fully implement and NC 27695-7618, USA 3 realize benefits heralded by systems biology for biomanufacturing: increasing titer, Management, Innovation & Entrepreneurship, North Carolina State yield, quality, process efficiency and stability. University, Campus Box 7229, Raleigh, NC 27695-7229, USA The biopharmaceutical industry is a power- Upstream methods for cell line development 4Biotechnology Group, North Carolina State University, Campus Box 7247, house within the biotechnology sector, with and process optimization are time consuming, Raleigh, NC 27695-7247 tremendous technological and economic expensive and labor intensive. These limita- *Author for correspondence: growth since its inception. Experts forecast tions represent, perhaps, the most significant [email protected] continuous strong market growth, with biolog- bottlenecks in bioprocessing. In addition, ‡Authors contributed equally ics accounting for more than 50% of the top these upstream methods lack the mechanistic 10.4155/PBP.15.12 100 prescription sales by 2018 [1] . Over the past understanding of how and why process con- several decades, improvements in manufactur- ditions, or any implemented changes, bring ing processes and product quality were mainly about the desired outcome – be it increased driven by increased sales and tighter regulatory titers, higher product quality or process stabil- requirements due to initiatives such as Quality ity. This laborious effort must be repeated for by Design (QbD) and Process Analytical every new production cell line and associated 4 Technology (PAT). As a result, titers have protein product. At best, it results in highly jumped more than 100-fold, from subsingle variable and unpredictable bioprocesses, both digit yields (in gram per liter) to today’s dou- in terms of productivity as well as product ble-digit production levels [2,3]. From a regula- quality. These process inconsistencies are com- 2015 tory perspective, this impressive achievement monplace and cannot support the expected must be accompanied by a quality-driven bio- growth in market demand nor the economic manufacturing framework, founded on inte- and regulatory challenges faced by manufac- grative systems and data-driven methods that turers. The biopharmaceutical industry can contribute to process understanding and where greatly benefit from technological innovations critical process parameters are identified, mon- that drive rapid and adaptive change, ulti- itored and controlled [4]. To keep up with ever- mately providing a competitive advantage, and increasing market and regulatory demands allowing it to focus on improving efficiency, and the competition from biosimilars, the flexibility, convenience and quality [2,5–9]. biopharmaceutical industry is continuously Biologics are complex molecules with challenged to increase its efficiency and make unique quality attributes that require complex better products cheaper. production systems. Mammalian cell lines are part of 10.4155/PBP.15.12 © 2015 Future Science Ltd Pharm. Bioprocess. (2015) 3(4), 341–355 ISSN 2048-9145 341 Review Benavente, Goldberg, Myburg, Chiera, Zapata III & van Zyl Key terms make it functional. With no relationships, there sim- ply is no system [15] . Hence, systems theory studies how Quality by Design: A scientific, risk-based, holistic and the constituent parts of the whole system interact with proactive approach based on a deliberate design effort from product formation through product marketing. one another and the subsequent attempt to generate a si mplified model of how the system functions. Process analytical technology: Part of the QbD With this in mind, one definition for systems biology concept that provides tools to design, analyze and control pharmaceutical manufacturing processes through the is the study and subsequent mathematical modeling of measurement of critical process parameters (CPP) that the components that constitute a biological system, their affect critical quality attributes (CQA). interactions and the system’s resulting emergent proper- Biosimilar: A subsequent version of a biologic medical ties. Emergent properties are outcomes from the interac- product whose active drug constituent was made by a tions among the model’s constituent parts which are not living organism, or from a living organism by means of DNA obvious from looking at any of its individual components recombinant or controlled gene expression methods. on their own. This contrasts with the traditional reduc- ideally suited for this purpose due to their ability to gen- tionist approach, of taking apart the system and study- erate complex human-like glycan profiles and other post- ing its parts in isolation in an attempt to simplify and translational modifications that are critical for product understand it. While very successful for many years, and efficacy and safety. At the same time, this inherent com- providing answers to focused biological questions involv- plexity of biological systems is also a primary contributor ing a limited number of biological entities, reductionism to process variability and inconsistency. This conflicts has its limitations [16] . Conversely, instead of focusing on with the quality framework enforced by QbD and PAT, a single system component, or subset thereof, in systems which is based on a better understanding of the bio- biology a system-wide approach is taken. For example, manufacturing process. It is not possible to fully under- by studying the entire transcriptome and proteome of stand the process(es) without considering the biology a cell or organism, and more importantly, the interac- of the different cell line(s) used and their relationship tions between and across them, one can learn how sys- to the products they synthesize. In order to overcome tems behave under different, changing conditions and this variability and inconsistency, bioprocess scientists environments, both intra- and extra-cellular. It also seeks and engineers need to have a better understanding of to understand the mechanisms employed by the cell to the cells and their intracellular processes relevant to maintain its homeostasis and to prevent, or reduce, mal- biomanufacturing, including protein translation, post- function and failure. Ultimately, by mathematical mod- translational modifications, folding, aggregation, traf- eling and simulation, systems biology aims to identify ficking and secretion. Without this knowledge, any the basic functional biological circuits that give rise to the optimizations that lead to production gains observed for diver sity and complexity of biological phenomena [11,16]. one cell line are not likely transferrable to another and There are currently different views on the principles, cannot be fully implemented across the entire produc- methodologies and implementation of systems biology, tion portfolio. Developing an in-depth understanding varying from a more pragmatic approach to a more of the biology of these production cell lines is key for theoretical one ([17,18] and references therein), but this sustained biomanufacturing. systems biology is poised falls outside of the scope of this review. Nevertheless, to tackle many of these challenges, particularly the areas we believe that each view has its own merit, not neces- of pr ocess optimization and cell line development. sarily being mutually exclusive, and add value to biol- ogy as the study of life. Since this review focuses on the What is systems biology? applications of systems biology for biomanufacturing, Perhaps the simplest answer to this question is that sys- we follow the more pragmatic line of thought in the tems biology is the application of systems theory to a discussion below as we feel it more immediately, and biological system. As a unique field of study, systems perhaps more appropriately, addresses the ch allenges biology grew in popularity in the latter part of the and needs of this particular industry. 1990s with the work of Hood and Kitano [10,11] . The application has been suggested as far back as the 1950s Systems biology & biomanufacturing: with the work of Mesarovic and Bertalanffy on general how can it help? systems theory [12–14]. This answer, however, immedi- Biomanufacturing performance is determined by the ately leads to the next question, what is a system? A sys- interaction of