Application of a decision-support tool to assess pooling strategies in perfusion culture processes under uncertainty

Biopharmaceutical manufacture is subject to numerous risk factors that may affect operational costs and throughput. This paper discusses the need for incorporating such uncertainties in decision-making tools in order to reflect the inherent variability of process parameters during the operation of a biopharmaceutical plant. The functionalities of a risk-based prototype tool to model cost summation, perform mass balance calculations, simulate resource handling, and incorporate uncertainties in order to evaluate the potential risk associated with different manufacturing strategies are demonstrated via a case study. The case study is based upon the assessment of pooling strategies in the perfusion culture of mammalian cells to deliver a therapeutic protein for commercial use. Monte Carlo simulations, which generate random sample behaviors for probabilistic factors so as to imitate the uncertainties inherent in any process, have been applied. This provides an indication of the range of possible output values and hence enables trends or anomalies in the expected performance of a process to be determined.     

A tool for modeling strategic decisions in cell culture manufacturing

The development of a prototype tool for modeling manufacturing in a biopharmaceutical plant is discussed. A hierarchical approach to modeling a manufacturing process has been adopted to confer maximum user flexibility. The use of this framework for assessing the impact of manufacturing decisions on strategic technical and business indicators is demonstrated via a case study. In the case study, which takes the example of a mammalian cell culture process delivering a therapeutic for clinical trials, the dynamic modeling tool indicates how manufacturing options affect the demands on resources and the associated manufacturing costs. The example illustrates how the decision-support software can be used by biopharmaceutical companies to investigate the effects of working toward different strategic goals on the cost-effectiveness of the process, prior to committing to a particular option.     

Integrated continuous bioprocessing: Economic,operational, and environmental feasibility for clinical and commercial antibody manufacture

This paper presents a systems approach to evaluating the potential of integrated continuous bioprocessing for monoclonal antibody (mAb) manufacture across a product's lifecycle from preclinical to commercial manufacture. The economic, operational, and environmental feasibility of alternative continuous manufacturing strategies were evaluated holistically using a prototype UCL decisional tool that integrated process economics, discrete‐event simulation, environmental impact analysis, operational risk analysis, and multiattribute decision‐making. The case study focused on comparing whole bioprocesses that used either batch, continuous or a hybrid combination of batch and continuous technologies for cell culture, capture chromatography, and polishing chromatography steps. The cost of goods per gram (COG/g), E‐factor, and operational risk scores of each strategy were established across a matrix of scenarios with differing combinations of clinical development phase and company portfolio size. The tool outputs predict that the optimal strategy for early phase production and small/medium‐sized companies is the integrated continuous strategy (alternating tangential flow filtration (ATF) perfusion, continuous capture, continuous polishing). However, the top ranking strategy changes for commercial production and companies with large portfolios to the hybrid strategy with fed‐batch culture, continuous capture and batch polishing from a COG/g perspective. The multiattribute decision‐making analysis highlighted that if the operational feasibility was considered more important than the economic benefits, the hybrid strategy would be preferred for all company scales. Further considerations outside the scope of this work include the process development costs required to adopt continuous processing. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 33:854–866, 2017     

Decisional tool to assess current and future process robustness in an antibody purification facility

Increases in cell culture titers in existing facilities have prompted efforts to identify strategies that alleviate purification bottlenecks while controlling costs. This article describes the application of a database‐driven dynamic simulation tool to identify optimal purification sizing strategies and visualize their robustness to future titer increases. The tool harnessed the benefits of MySQL to capture the process, business, and risk features of multiple purification options and better manage the large datasets required for uncertainty analysis and optimization. The database was linked to a discrete‐event simulation engine so as to model the dynamic features of biopharmaceutical manufacture and impact of resource constraints. For a given titer, the tool performed brute force optimization so as to identify optimal purification sizing strategies that minimized the batch material cost while maintaining the schedule. The tool was applied to industrial case studies based on a platform monoclonal antibody purification process in a multisuite clinical scale manufacturing facility. The case studies assessed the robustness of optimal strategies to batch‐to‐batch titer variability and extended this to assess the long‐term fit of the platform process as titers increase from 1 to 10 g/L, given a range of equipment sizes available to enable scale intensification efforts. Novel visualization plots consisting of multiple Pareto frontiers with tie‐lines connecting the position of optimal configurations over a given titer range were constructed. These enabled rapid identification of robust purification configurations given titer fluctuations and the facility limit that the purification suites could handle in terms of the maximum titer and hence harvest load. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 28: 1019–1028, 2012     

Recombinant plant-derived pharmaceutical proteins: current technical and economic bottlenecks

Molecular pharming is a cost-effective platform for the production of recombinant proteins in plants. Although the biopharmaceutical industry still relies on a small number of standardized fermentation-based technologies for the production of recombinant proteins there is now a greater awareness of the advantages of molecular pharming particularly in niche markets. Here we discuss some of the technical, economic and regulatory barriers that constrain the clinical development and commercialization of plant-derived pharmaceutical proteins. We also discuss strategies to increase productivity and product quality/homogeneity. The advantages of whole plants should be welcomed by the industry because this will help to reduce the cost of goods and therefore expand the biopharmaceutical market into untapped sectors.     

Industrialization of mAb production technology: The bioprocessing industry at a crossroads

Manufacturing processes for therapeutic monoclonal antibodies (mAbs) have evolved tremendously since the first licensed mAb product (OKT3) in 1986. The rapid growth in product demand for mAbs triggered parallel efforts to increase production capacity through construction of large bulk manufacturing plants as well as improvements in cell culture processes to raise product titers. This combination has led to an excess of manufacturing capacity, and together with improvements in conventional purification technologies, promises nearly unlimited production capacity in the foreseeable future. The increase in titers has also led to a marked reduction in production costs, which could then become a relatively small fraction of sales price for future products which are sold at prices at or near current levels. The reduction of capacity and cost pressures for current state-of-the-art bulk production processes may shift the focus of process development efforts and have important implications for both plant design and product development strategies for both biopharmaceutical and contract manufacturing companies.     

Fully integrated downstream process to enable next-generation manufacturing

Next-generation manufacturing (NGM) has evolved over the past decade to a point where large biopharmaceutical organizations are making large investments in the technology and considering implementation in clinical and commercial processes. There are many well-considered reasons to implement NGM. For the most part, organizations will not fund NGM unless the implementation benefits the funding organization by providing reduced costs, reduced time, or additional needed capabilities. Productivity improvements gained from continuous purification are shown in this work, which used a new system that fully integrates and automates several downstream unit operations of a biopharmaceutical process to provide flexibility and easy implementation of NGM. The equipment and automation needed to support NGM can be complicated and expensive. Biopharmaceutical Process Development considered two options as follows: (1) design its own NGM system or (2) buy a prebuilt system. PAK BioSolutions offers a turn-key automated and integrated system that can operate up to four continuous purification stages simultaneously, while maintaining a small footprint in the manufacturing plant. The system provides significant cost benefits (~10× lower) compared with the alternative—integration of many different pieces of equipment through a Distributed Control System that would require significant engineering time for design, automation, and integration. Integrated and Continuous Biomanufacturing can lead to significant reductions in facility size, reduced manufacturing costs, and enhanced product quality when compared with the traditional batch mode of operation. The system uses new automation strategies that robustly link unit operations. We present the optimized process fit, sterility and bioburden control strategy, and automation features (such as pH feedback control and in-line detergent addition), which enabled continuous operation of a 14-day end-to-end monoclonal antibody purification process at the clinical manufacturing scale.     

Industrialization of mAb production technology The bioprocessing industry at a crossroads

Manufacturing processes for therapeutic monoclonal antibodies (mAbs) have evolved tremendously since the first licensed mAb product in 1986. The rapid growth in product demand for mAbs triggered parallel efforts to increase production capacity through construction of large bulk manufacturing plants as well as improvements in cell culture processes to raise product titers. This combination has led to an excess of manufacturing capacity, and together with improvements in conventional purification technologies, promises nearly unlimited production capacity in the foreseeable future. The increase in titers has also led to a marked reduction in production costs, which could then become a relatively small fraction of sales price for future products which are sold at prices at or near current levels. The reduction of capacity and cost pressures for current state-of-the-art bulk production processes may shift the focus of process development efforts and have important implications for both plant design and product development strategies for both biopharmaceutical and contract manufacturing companies.Key words: bioprocessing, cell culture, purification, economics, capacity, manufacturing, production, facility, biopharmaceutical     

Fed‐batch and perfusion culture processes: Economic,environmental, and operational feasibility under uncertainty

This article evaluates the current and future potential of batch and continuous cell culture technologies via a case study based on the commercial manufacture of monoclonal antibodies. The case study compares fed‐batch culture to two perfusion technologies: spin‐filter perfusion and an emerging perfusion technology utilizing alternating tangential flow (ATF) perfusion. The operational, economic, and environmental feasibility of whole bioprocesses based on these systems was evaluated using a prototype dynamic decision‐support tool built at UCL encompassing process economics, discrete‐event simulation and uncertainty analysis, and combined with a multi‐attribute decision‐making technique so as to enable a holistic assessment. The strategies were compared across a range of scales and titres so as to visualize how their ranking changes in different industry scenarios. The deterministic analysis indicated that the ATF perfusion strategy has the potential to offer cost of goods savings of 20% when compared to conventional fed‐batch manufacturing processes when a fivefold increase in maximum viable cell densities was assumed. Savings were also seen when the ATF cell density dropped to a threefold increase over the fed‐batch strategy for most combinations of titres and production scales. In contrast, the fed‐batch strategy performed better in terms of environmental sustainability with a lower water and consumable usage profile. The impact of uncertainty and failure rates on the feasibility of the strategies was explored using Monte Carlo simulation. The risk analysis results demonstrated the enhanced robustness of the fed‐batch process but also highlighted that the ATF process was still the most cost‐effective option even under uncertainty. The multi‐attribute decision‐making analysis provided insight into the limited use of spin‐filter perfusion strategies in industry. The resulting sensitivity spider plots enabled identification of the critical ratio of weightings of economic and operational benefits that affect the choice between ATF perfusion and fed‐batch strategies. Biotechnol. Bioeng. 2013; 110: 206–219. © 2012 Wiley Periodicals, Inc.     

Life cycle assessment of fuel cell vehicles a methodology example of input data treatment for future technologies

Life cycle assessment (LCA) will always involve some subjectivity and uncertainty. This reality is especially true when the analysis concerns new technologies. Dealing with uncertainty can generate richer information and minimize some of the result mismatches currently encountered in the literature. As a way of analyzing future fuel cell vehicles and their potential new fuels, the Fuel Upstream Energy and Emission Model (FUEEM) developed at the University of California—Davis, pioneered two different ways to incorporate uncertainty into the analysis. First, the model works with probabilistic curves as inputs and with Monte Carlo simulation techniques to propagate the uncertainties. Second, the project involved the interested parties in the entire process, not only in the critical review phase. The objective of this paper is to present, as a case study, the tools and the methodologies developed to acquire most of the knowledge held by interested parties and to deal with their — eventually conflicted—interests. The analysis calculation methodology, the scenarios, and all assumed probabilistic curves were derived from a consensus of an international expert network discussion, using existing data in the literature along with new information collected from companies. The main part of the expert discussion process uses a variant of the Delphi technique, focusing on the group learning process through the information feedback feature. A qualitative analysis indicates that a higher level of credibility and a higher quality of information can be achieved through a more participatory process. The FUEEM method works well within technical information and also in establishing a reasonable set of simple scenarios. However, for a complex combination of scenarios, it will require some improvement. The time spent in the process was the major drawback of the method and some alternatives to share this time cost are suggested.     

A tool for increasing the lifetime of chromatography resins

There is a steadily increasing demand for speed, cost efficiency, and process understanding within biopharmaceutical process development. To match this, a high-throughput method for screening of cleaning-in-place (CIP) conditions for chromatography resins has been developed. The methodology includes fouling of MabSelect SuRe chromatography resin in 96-well filter plates, cleaning of the fouled resin by incubation in different CIP agents, and finally, analysis of the residual impurities on the resin after cleaning. This article describes the improvements that transformed the method from low throughput and significant manual interference to a totally automated method with high throughput and good reproducibility.     

Economics and success factors of flexible manufacturing systems: The conventional explanation revisited

This article analyzes costs and relative benefits of several hundred flexible manufacturing systems (FMSs) in the world. The analyses are based on the computerized data bases, which make it easy to correlate different cost and benefit indicators with each other and to look for regular patterns and tendencies in the applications. Both investment cost distributions and the system complexity distributions are analyzed. The relative benefits and advantages and their relationships are shown. Finally, technical and economic explanations for successful implementation strategies are given. The results show that there are two classes of economically successful systems. The small-scale and technically compact systems are usually used in small-batch production for the replacement of semimanual production. The main benefits are increased capacity and productivity as well as quality improvements. The large-scale and technically complex systems are used in large-volume production for the replacement of fixed automation and transfer lines. The benefits are mainly due to the increased potential for flexibility and capital savings.     

Medium term planning of biopharmaceutical manufacture using mathematical programming

Regulatory pressures and capacity constraints are forcing the biopharmaceutical industry to consider employing multiproduct manufacturing facilities running on a campaign basis. The need for such flexible and cost-effective manufacture poses a significant challenge for planning and scheduling. This paper reviews the problem of planning and scheduling of biopharmaceutical manufacture and presents a methodology for the planning of multiproduct biopharmaceutical manufacturing facilities. The problem is formulated as a mixed integer linear program (MILP) to represent the relevant decisions required within the planning process and is tested on two typical biopharmaceutical industry planning problems. The proposed formulation is compared with an industrial rule based approach, which it outperforms in terms of profitability. The results indicate that the developed formulation offers an effective representation of the planning problem and would be a useful decision tool for manufacturers in the biopharmaceutical industry particularly at times of limited manufacturing capacity.     

Computer-aided process analysis and economic evaluation for biosynthetic human insulin production-A case study

Human insulin was the first mammalian protein produced in bacteria using recombinant DNA technology. Two technologies were developed; the first based on the separate expression of precursors of chains A and B of insulin, and the second based on the expression of a precursor of proinsulin as a Trp-E fusion protein. Both technologies utilized Escherichia coli as an expression system. Later, a third technology was developed based on a strain of yeast that can secrete a precursor of insulin. The second E. coli process, a variation of which has been commercialized by Eli Lilly and Co., is analyzed in this article from a process design and economic evaluation viewpoint. The objective of this work is to elucidate the technical complexity and high cost associated with the manufacturing of biopharmaceuticals. Human insulin is a good example of a protein-based biopharmaceutical produced in large quantities (a fex tons per year) that requires large scale equipment and presents a multitude of scale-up challenges. Based onthe analysis, a number of conclusions are drawn regarding the cost breakdown and cost dependency on process parameters. Recommendations are made for cost reduction and environmental impact minimization. This analysis was performed using a software tool for computer-aided bioprocess design. (c) 1995 John Wiley & Sons, Inc.     

Decisional tool for cost of goods analysis of bioartificial liver devices for routine clinical use

Background aimsBioartificial liver devices (BALs) are categorized as advanced therapy medicinal products (ATMPs) with the potential to provide temporary liver support for liver failure patients. However, to meet commercial demands, next-generation BAL manufacturing processes need to be designed that are scalable and financially feasible. The authors describe the development and application of a process economics decisional tool to determine the cost of goods (COG) of alternative BAL process flowsheets across a range of industrial scales.MethodsThe decisional tool comprised an information database linked to a process economics engine, with equipment sizing, resource consumption, capital investment and COG calculations for the whole bioprocess, from cell expansion and encapsulation to fluidized bed bioreactor (FBB) culture to cryopreservation and cryorecovery. Four different flowsheet configurations were evaluated across demands, with cell factories or microcarriers in suspension culture for the cell expansion step and single-use or stainless steel technology for the FBB culture step.ResultsThe tool outputs demonstrated that the lowest COG was achieved with microcarriers and stainless steel technology independent of the annual demand (1500–30 000 BALs/year). The analysis identified the key cost drivers were parameters impacting the medium volume and cost.ConclusionsThe tool outputs can be used to identify cost-effective and scalable bioprocesses early in the development process and minimize the risk of failing to meet commercial demands due to technology choices. The tool predictions serve as a useful benchmark for manufacturing ATMPs.     

Mass spectrometric evaluation of upstream and downstream process influences on host cell protein patterns in biopharmaceutical products

For production of different monoclonal antibodies (mAbs), biopharmaceutical companies often use related upstream and downstream manufacturing processes. Such platforms are typically characterized regarding influence of upstream and downstream process (DSP) parameters on critical quality attributes (CQAs). CQAs must be monitored strictly by an adequate control strategy. One such process-related CQA is the content of host cell protein (HCP) which is typically analyzed by immunoassay methods (e.g., HCP-ELISA). The capacity of the immunoassay to detect a broad range of HCPs, relevant for the individual mAb-production process should be proven by orthogonal proteomic methods such as 2D gel electrophoresis or mass spectrometry (MS). In particular MS has become a valuable tool to identify and quantify HCP in complex mixtures. We evaluate up- and DSP parameters of four different biopharmaceutical products, two different process variants, and one mock fermentation on the HCP pattern by shotgun MS analysis and ELISA. We obtained a similar HCP pattern in different cell culture fluid harvests compared to the starting material from the downstream process. During the downstream purification process of the mAbs, the HCP level and the number of HCP species significantly decreased, accompanied by an increase in diversity of the residual HCP pattern. Based on this knowledge, we suggest a control strategy that combines multi product ELISA for in-process control and release analytics, and MS testing for orthogonal HCP characterization, to attain knowledge on the HCP level, clusters and species. This combination supports a control strategy for HCPs addressing safety and efficacy of biopharmaceutical products.     

Economic Assessment of Greenhouse Gas Emissions Reduction by Vehicle Lightweighting Using Aluminum and High‐Strength Steel

The life cycle greenhouse gas (GHG) reduction benefits of vehicle lightweighting (LW) were evaluated in a companion article. This article provides an economic assessment of vehicle LW with aluminum and high‐strength steel. Relevant cost information taken from the literature is synthesized, compiled, and formed into estimates of GHG reduction costs through LW. GHG emissions associated with vehicle LW scenarios between 6% and 23% are analyzed alongside vehicle life cycle costs to achieve these LW levels. We use this information to estimate the cost to remove GHG emissions per metric ton by LW, and we further calculate the difference between added manufacturing cost and fuel cost savings from LW. The results show greater GHG savings derived from greater LW and added manufacturing costs as expected. The associated production costs are, however, disproportionately higher than the fuel cost savings associated with higher LW options. A sensitivity analysis of different vehicle classes confirms that vehicle LW is more cost‐effective for larger vehicles. Also, the cost of GHG emissions reductions through lightweighting is compared with alternative GHG emissions reduction technologies for passenger vehicles, such as diesel, hybrid, and plug‐in hybrid electric powertrains. The results find intensive LW to be a competitive and complementary approach relative to the technological alternatives within the automotive industry but more costly than GHG mitigation strategies available to other industries.     

Examining the sources of variability in cell culture media used for biopharmaceutical production

Raw materials, in particular cell culture media, represent a significant source of variability to biopharmaceutical manufacturing processes that can detrimentally affect cellular growth, viability and specific productivity or alter the quality profile of the expressed therapeutic protein. The continual expansion of the biopharmaceutical industry is creating an increasing demand on the production and supply chain consistency for cell culture media, especially as companies embrace intensive continuous processing. Here, we provide a historical perspective regarding the transition from serum containing to serum-free media, the development of chemically-defined cell culture media for biopharmaceutical production using industrial scale bioprocesses and review production mechanisms for liquid and powder culture media. An overview and critique of analytical approaches used for the characterisation of cell culture media and the identification of root causes of variability are also provided, including in-depth liquid phase separations, mass spectrometry and spectroscopic methods.     

An Integrated Approach of Fuzzy Linguistic Preference Based AHP and Fuzzy COPRAS for Machine Tool Evaluation

Globalization of business and competitiveness in manufacturing has forced companies to improve their manufacturing facilities to respond to market requirements. Machine tool evaluation involves an essential decision using imprecise and vague information, and plays a major role to improve the productivity and flexibility in manufacturing. The aim of this study is to present an integrated approach for decision-making in machine tool selection. This paper is focused on the integration of a consistent fuzzy AHP (Analytic Hierarchy Process) and a fuzzy COmplex PRoportional ASsessment (COPRAS) for multi-attribute decision-making in selecting the most suitable machine tool. In this method, the fuzzy linguistic reference relation is integrated into AHP to handle the imprecise and vague information, and to simplify the data collection for the pair-wise comparison matrix of the AHP which determines the weights of attributes. The output of the fuzzy AHP is imported into the fuzzy COPRAS method for ranking alternatives through the closeness coefficient. Presentation of the proposed model application is provided by a numerical example based on the collection of data by questionnaire and from the literature. The results highlight the integration of the improved fuzzy AHP and the fuzzy COPRAS as a precise tool and provide effective multi-attribute decision-making for evaluating the machine tool in the uncertain environment.