Fuel ethanol and high protein feed from corn and corn-whey mixtures in a farm-scale plant

Distiller's wet grain (DWG) and 95% ethanol were produced from corn in a farm-scale process involving batch cooking-fermentation and continuous distillation-centrifugation. The energy balance was 2.26 and the cost was $1.86/gal (1981 cost). To improve the energy balance and reduce costs, various modifications were made in the plant. The first change, back-end (after liquefaction) serial recycling of stillage supernatant at 20 and 40% strengths, produced beers with 0.2 and 0.4% (v/v) more ethanol, respectively, than without recycling. This increased the energy balance by 0.22-0.43 units and reduced costs by $0.07-$0.10/gal. The DWGs from back-end recycling had increased fat. The second change, increasing the starch content from 17-19% to 27.5%, increased the ethanol in the beer from 10.5-14.9% at a cost saving of $0.41/gal. The energy balance increased by 1.08 units. No significant change was seen in DWG composition. The third change, using continuous cascade rather than batch fermentation, permitted batch-levels of ethanol (10%) in the beer but only at low dilution rates. Both the cost and energy balance were decreased slightly. The DWG composition remained constant. The last change, replacing part of the corn and all of the tap water in the mash with whole whey and using Kluyveromyces fragilis instead of Saccharomyces cerevisiae during fermentation, resulted in an energy balance increase of 0.16 units and a $0.27/gal cost reduction. Here, 10% ethanolic beers were produced and the DWGs showed increased protein and fat. Recommendations for farm-scale plants are provided.     

Very large scale monoclonal antibody purification: the case for conventional unit operations

Technology development initiatives targeted for monoclonal antibody purification may be motivated by manufacturing limitations and are often aimed at solving current and future process bottlenecks. A subject under debate in many biotechnology companies is whether conventional unit operations such as chromatography will eventually become limiting for the production of recombinant protein therapeutics. An evaluation of the potential limitations of process chromatography and filtration using today's commercially available resins and membranes was conducted for a conceptual process scaled to produce 10 tons of monoclonal antibody per year from a single manufacturing plant, a scale representing one of the world's largest single-plant capacities for cGMP protein production. The process employs a simple, efficient purification train using only two chromatographic and two ultrafiltration steps, modeled after a platform antibody purification train that has generated 10 kg batches in clinical production. Based on analyses of cost of goods and the production capacity of this very large scale purification process, it is unlikely that non-conventional downstream unit operations would be needed to replace conventional chromatographic and filtration separation steps, at least for recombinant antibodies.     

Improved ethanol yield and reduced minimum ethanol selling price (MESP) by modifying low severity dilute acid pretreatment with deacetylation and mechanical refining: 2) Techno-economic analysis

ABSTRACT: BACKGROUND: Our companion paper discussed the yield benefits achieved by integrating deacetylation, mechanical refining, and washing with low acid and low temperature pretreatment. To evaluate the impact of the modified process on the economic feasibility, a techno-economic analysis (TEA) was performed based on the experimental data presented in the companion paper. RESULTS: The cost benefits of dilute acid pretreatment technology combined with the process alternatives of deacetylation, mechanical refining, and pretreated solids washing were evaluated using cost benefit analysis within a conceptual modeling framework. Control cases were pretreated at much lower acid loadings and temperatures than used those in the NREL 2011 design case, resulting in much lower annual ethanol production. Therefore, the minimum ethanol selling prices (MESP) of the control cases were $0.41-$0.77 higher than the $2.15/gallon MESP of the design case. This increment is highly dependent on the carbohydrate content in the corn stover. However, if pretreatment was employed with either deacetylation or mechanical refining, the MESPs were reduced by $0.23-$0.30/gallon. Combing both steps could lower the MESP further by $0.44 ~ $0.54. Washing of the pretreated solids could also greatly improve the final ethanol yields. However, the large capital cost of the solid--liquid separation unit negatively influences the process economics. Finally, sensitivity analysis was performed to study the effect of the cost of the pretreatment reactor and the energy input for mechanical refining. A 50% cost reduction in the pretreatment reactor cost reduced the MESP of the entire conversion process by $0.11-$0.14/gallon, while a 10-fold increase in energy input for mechanical refining will increase the MESP by $0.07/gallon. CONCLUSION: Deacetylation and mechanical refining process options combined with low acid, low severity pretreatments show improvements in ethanol yields and calculated MESP for cellulosic ethanol production.     

A simplified techno-economic model for the molecular pharming of antibodies

By the end of 2017, the Food and Drug Administration had approved a total of 77 therapeutic monoclonal antibodies (mAbs), most of which are still manufactured today. Furthermore, global sales of mAbs topped $90 billion in 2017 and are projected to reach $125 billion by 2020. The mAbs approved for human therapy are mostly produced using Chinese hamster ovary (CHO) cells, which require expensive infrastructure for production and purification. Molecular pharming in plants is an alternative approach with the benefits of lower costs, greater scalability, and intrinsic safety. For some platforms, the production cycle is also much quicker. But do these advantages really stack up in economic terms? Earlier techno-economic evaluations have focused on specific platforms or processes and have used different methods, making direct comparisons challenging and the overall benefits of molecular pharming difficult to gauge. Here, we present a simplified techno-economic model for the manufacturing of mAbs, which can be applied to any production platform by focusing on the most important factors that determine the efficiency and cost of bulk drug manufacturing. This model develops economic concepts to identify variables that can be used to achieve cost savings by simultaneously modeling the dynamic costs of upstream production at different scales and the corresponding downstream processing costs for different manufacturing modes (sequential, serial, and continuous). The use of simplified models will help to achieve meaningful comparisons between diverse manufacturing technologies.     

Technology and economics of ethanol production from fodder beets via solid-phase fermentation

Summary Operating conditions for our semi-continuous, solid-phase fermentation system were optimized for conversion of fodder beets to fuel ethanol and distiller's wet feed (DWF). This information was then used to estimate operating parameters achievable in a commercial plant, and likely baseline production costs of such a plant. Initial acidification of pulp to pH 2.9–3.2 was effective in controlling bacterial contamination. The maximum operating capacity of the fermentor was approximately 92%, with 75% used for commercial application. A fermentation time of 24 h was sufficient to completely ferment the beet pulp to 8–9% (v/v) ethanol. Based on these parameters, a fodder beet cost of $19.25/metric ton ($17.50/ton), other operating and capital costs, and a PF credit of $0.14/L ($0.53/gal), ethanol production costs were estimated to be $0.49/L ($1.87/gal).     

A continuous, farm-scale, solid-phase fermentation process for fuel ethanol and protein feed production from fodder beets

Fuel ethanol (95%) was produced from fodder beets in two farm-scale processes. In the first process, involving conventional submerged fermentation of the fodder beets in a mash, ethanol and a feed (PF) rich in protein, fat, and fiber were produced. Ethanol yields of 70 L/metric ton (7 gal/ton) were obtained; however, resulting beers had low ethanol concentrations [3-5% (v/v)]. The high viscosity of medium and low sugar, beet mashes caused mixing problems which prevented any further increase of beet sugar in the mash. The severely limited the maximum attainable ethanol concentration during fermentation, thereby making the beer costly to distill into fuel ethanol and the process energy inefficient. In order to achieve distillably worthwhile ethanol concentrations of 8-10% (v/v), we developed and tested a solid-phase fermentation process (continuous). In preliminary trials, this system produced fermented pulp with over 8% (v/v) ethanol corresponding to an ethanol yield of 87 L/metric ton (21 gal/ton). Production costs with this novel process are $0.47/L ($1.77/gal) and the energy balance is 2.11. These preliminary cost estimates indicate that fodder beets are potentially competitive with corn as an ethanol feedstock. Additional research, however, is warranted to more precisely refine individual costs, energy balances and the actual value of the PF.     

Process design and economic studies of alternative fermentation methods for the production of ethanol

Cell recycle and vacuum fermentation processes are described for the continuous production of ethanol. Preliminary process design studies are employed to make an economic comparison of these alternative fermentation schemes with continuous and batch fermentation technologies. Designs are based on a production capacity of 78,000 gal 95% ethanol (EtOH)/day employing molasses as the fermentation substrate. The studies indicate that a 57% reduction in fixed capital investment is realized by continuous rather than batch operation. Further decreases in required capital investment of 68 and 71% over batch fermentation were obtained for cell recycle and vacuum operation, respectively. However, ethanol production costs were dominated by the cost of molasses, representing over 75% of the total manufacturing cost. But, when a reasonable yeast by-product credit was assumed, the net production cost for 95% ethanol was estimated at 82.3 and 80.6 cent/gal, for the cell recycle and vacuum processes, respectively.     

Chemical and morphological characterization of sugarcane bagasse submitted to a delignification process for enhanced enzymatic digestibility

Background

While advantages of biofuel have been widely reported, studies also highlight the challenges in large scale production of biofuel. Cost of ethanol and process energy use in cellulosic ethanol plants are dependent on technologies used for conversion of feedstock. Process modeling can aid in identifying techno-economic bottlenecks in a production process. A comprehensive techno-economic analysis was performed for conversion of cellulosic feedstock to ethanol using some of the common pretreatment technologies: dilute acid, dilute alkali, hot water and steam explosion. Detailed process models incorporating feedstock handling, pretreatment, simultaneous saccharification and co-fermentation, ethanol recovery and downstream processing were developed using SuperPro Designer. Tall Fescue (Festuca arundinacea Schreb) was used as a model feedstock.

Results

Projected ethanol yields were 252.62, 255.80, 255.27 and 230.23 L/dry metric ton biomass for conversion process using dilute acid, dilute alkali, hot water and steam explosion pretreatment technologies respectively. Price of feedstock and cellulose enzymes were assumed as $50/metric ton and 0.517/kg broth (10% protein in broth, 600 FPU/g protein) respectively. Capital cost of ethanol plants processing 250,000 metric tons of feedstock/year was $1.92, $1.73, $1.72 and $1.70/L ethanol for process using dilute acid, dilute alkali, hot water and steam explosion pretreatment respectively. Ethanol production cost of $0.83, $0.88, $0.81 and $0.85/L ethanol was estimated for production process using dilute acid, dilute alkali, hot water and steam explosion pretreatment respectively. Water use in the production process using dilute acid, dilute alkali, hot water and steam explosion pretreatment was estimated 5.96, 6.07, 5.84 and 4.36 kg/L ethanol respectively.

Conclusions

Ethanol price and energy use were highly dependent on process conditions used in the ethanol production plant. Potential for significant ethanol cost reductions exist in increasing pentose fermentation efficiency and reducing biomass and enzyme costs. The results demonstrated the importance of addressing the tradeoffs in capital costs, pretreatment and downstream processing technologies.     

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     

Manufacturing Cost Modeling for Product Design

The process of product design is driven toward achieving design specifications while meeting cost targets. Designers typically have models and tools to aid in functional and performance analysis of the design but few tools and little quantitative information to aid in cost analysis. Estimates of the cost of manufacture often are made through a cost multiplier based on material cost. Manufacturing supplies guidelines to aid in design, but these guidelines often lack the detail needed to make sound design decisions. A need was identified for a quantitative way for modeling manufacturing costs at Motorola. After benchmarking cost modeling efforts around the company, an activity-based costing method was developed to model manufacturing cycle time and cost. Models for 12 key manufacturing steps were developed. The factory operating costs are broken down by time, and cost is allocated to each product according to the processing it requires. The process models were combined into a system-level model, capturing subtle yet realistic operational detail. The framework was implemented in a software program to aid designers in calculating manufacturing costs from limited design information. Since the information tool provides an estimate of manufacturing costs at the design prototype stage, the development engineer can identify and eliminate expensive components and reduce the need for costly manufacturing processing. Using this methodology to make quantitative trade-offs between material and manufacturing costs, significant savings in overall product costs are achieved.     

Cost-Effectiveness of a Home Based Intervention for Secondary Prevention of Readmission with Chronic Heart Disease

The aim of this study is to consider the cost-effectiveness of a nurse-led, home-based intervention (HBI) in cardiac patients with private health insurance compared to usual post-discharge care. A within trial analysis of the Young @ Heart multicentre, randomized controlled trial along with a micro-simulation decision analytical model was conducted to estimate the incremental costs and quality adjusted life years associated with the home based intervention compared to usual care. For the micro-simulation model, future costs, from the perspective of the funder, and effects are estimated over a twenty-year time horizon. An Incremental Cost-Effectiveness Ratio, along with Incremental Net Monetary Benefit, is evaluated using a willingness to pay threshold of $50,000 per quality adjusted life year. Sub-group analyses are conducted for men and women across three age groups separately. Costs and benefits that arise in the future are discounted at five percent per annum. Overall, home based intervention for secondary prevention in patients with chronic heart disease identified in the Australian private health care sector is not cost-effective. The estimated within trial incremental net monetary benefit is -$3,116 [95%CI: -11,145, $4,914]; indicating that the costs outweigh the benefits. However, for males and in particular males aged 75 years and above, home based intervention indicated a potential to reduce health care costs when compared to usual care (within trial: -$10,416 [95%CI: -$26,745, $5,913]; modelled analysis: -$1,980 [95%CI: -$22,843, $14,863]). This work provides a crucial impetus for future research to understand for whom disease management programs are likely to benefit most.     

Techno-economic evaluation of producing ethanol from softwood: comparison of SSF and SHF and identification of bottlenecks

The aim of the study was to evaluate, from a technical and economic standpoint, the enzymatic processes involved in the production of fuel ethanol from softwood. Two base case configurations, one based on simultaneous saccharification and fermentation (SSF) and one based on separate hydrolysis and fermentation (SHF), were evaluated and compared. The process conditions selected were based mainly on laboratory data, and the processes were simulated by use of Aspen plus. The capital costs were estimated using the Icarus Process Evaluator. The ethanol production costs for the SSF and SHF base cases were 4.81 and 5.32 SEK/L or 0.57 and 0.63 USD/L (1 USD = 8.5SEK), respectively. The main reason for SSF being lower was that the capital cost was lower and the overall ethanol yield was higher. A major drawback of the SSF process is the problem with recirculation of yeast following the SSF step. Major economic improvements in both SSF and SHF could be achieved by increasing the income from the solid fuel coproduct. This is done by lowering the energy consumption in the process through running the enzymatic hydrolysis or the SSF step at a higher substrate concentration and by recycling the process streams. Running SSF with use of 8% rather than 5% nonsoluble solid material would result in a 19% decrease in production cost. If after distillation 60% of the stillage stream was recycled back to the SSF step, the production cost would be reduced by 14%. The cumulative effect of these various improvements was found to result in a production cost of 3.58 SEK/L (0.42 USD/L) for the SSF process.     

Economic assessment of batch biodiesel production processes using homogeneous and heterogeneous alkali catalysts

An economic feasibility study on four batch processes for the production of biodiesel ranging from 1452 tonnes/year (5000 l/day) to 14,520 tonnes/year (50,000 l/day) is conducted. The four processes assessed are the (1) KOH-W process, characterized by a homogeneous KOH catalyst and hot water purification process; (2) KOH-D process, characterized by a homogeneous KOH catalyst and vacuum FAME distillation process; (3) CaO-W process, characterized by a heterogeneous CaO catalyst and hot water purification process; and (4) CaO-D process, characterized by a heterogeneous CaO catalyst and vacuum FAME distillation process. The costs of the waste cooking oil, fixed costs, and manufacturing costs for producing 7260 tonnes/year (25,000 l/day) of biodiesel by means of the four processes are estimated to be $248–256, $194–232, and $584–641 per tonne of biodiesel, respectively. Among the four processes, the manufacturing costs involved in the CaO-W process are the lowest, in the range from 1452 tonnes/year to 14,520 tonnes/year.     

Decision-support software for the industrial-scale chromatographic purification of antibodies

The high therapeutic and financial value offered by polyclonal antibodies and their fragments has prompted extensive commercialization for the treatment of a wide range of acute clinical indications. Large-scale manufacture typically includes antibody-specific chromatography steps that employ custom-made affinity matrices to separate product-specific IgG from the remainder of the contaminating antibody repertoire. The high cost of such matrices necessitates efficient process design in order to maximize their economic potential. Techniques that identify the most suitable operating conditions for achieving desired levels of manufacturing performance are therefore of significant utility. This paper describes the development of a computer model that incorporates the effects of capacity changes over consecutive chromatographic operational cycles in order to identify combinations of protein load and loading flowrate that satisfy preset constraints of product yield and throughput. The method is illustrated by application to the manufacture of DigiFab, an FDA-approved polyclonal antibody fragment purified from ovine serum, which is used to treat digoxin toxicity (Protherics U.K. Limited). The model was populated with data obtained from scale-down experimental studies of the commercial-scale affinity purification step, which correlated measured changes in matrix capacity with the total protein load and number of resin re-uses. To enable a tradeoff between yield and throughput, output values were integrated together into a single metric by multi-attribute decision-making techniques to identify the most suitable flowrate and feed concentration required for achieving target levels of DigiFab yield and throughput. Results indicated that reducing the flowrate by 70% (from the current level) and using a protein load at the midpoint of the range currently employed at production scale (approximately 200-500 g/L) would provide the most satisfactory tradeoff between yield and throughput.     

Economics of microsurgical cases and routine cases in a medical center

This report describes the economic impact of microsurgical cases and routine plastic surgery cases in our medical center. The study is based on a financial analysis of the practices of two surgeons. Financial data of patient encounters (admission to the hospital or a surgical unit) identified with each surgeon were categorized into microsurgical and related cases and routine cases (including cosmetic procedures and general hand cases). Revenues, costs, and profits were tabulated. Data were analyzed for 2 fiscal years (1994-95 and 1995-96). Analysis of the first fiscal year showed that microsurgery encounters (n = 188) generated $4.4 million in revenue with a profit margin after direct costs of $2.5 million (57 percent) and a net profit, after indirect costs, of $1 million (23 percent). Routine encounters (n = 262) generated $1.7 million with a net loss of -$145,000 after direct and indirect costs. In the second fiscal year, microsurgery encounters (n = 230) had income of $4.7 million, a profit over direct costs of $2.5 million (53 percent), and a net profit after indirect costs of $0.9 million (19 percent). Routine cases (n = 202) in the same period earned $1.3 million with a net loss of -$107,000. This analysis formulates a comprehensive definition of microsurgical practice and shows that cases within this definition generated dramatically higher hospital incomes and profits compared with routine plastic surgical practice. In the circumstances of our medical center, development of this subspecialty is fiscally justifiable.     

Maximizing binding capacity for protein A chromatography

Advances in cell culture expression levels in the last two decades have resulted in monoclonal antibody titers of ≥10 g/L to be purified downstream. A high capacity capture step is crucial to prevent purification from being the bottleneck in the manufacturing process. Despite its high cost and other disadvantages, Protein A chromatography still remains the optimal choice for antibody capture due to the excellent selectivity provided by this step. A dual flow loading strategy was used in conjunction with a new generation high capacity Protein A resin to maximize binding capacity without significantly increasing processing time. Optimum conditions were established using a simple empirical Design of Experiment (DOE) based model and verified with a wide panel of antibodies. Dynamic binding capacities of >65 g/L could be achieved under these new conditions, significantly higher by more than one and half times the values that have been typically achieved with Protein A in the past. Furthermore, comparable process performance and product quality was demonstrated for the Protein A step at the increased loading. © 2014 American Institute of Chemical Engineers Biotechnol. Prog., 30:1335–1340, 2014     

A numerical evaluation of a hollow fiber extractive fermentor process for the production of ethanol

The economics of a process for the production of ethanol employing a hollow fiber extractive fermentor have been investigated. A computer simulation of the process incorporating a mathematical model of the fermentor was used to calculate the mass and energy balances. The results of the process simulation were read into a computer spreadsheet programmed with the economic calculations from which a final ethanol product cost was obtained. The process was found to be as competitive as conventional fermentation processes even at the currently high cost--$4/sq ft--of hollow fibers. It was determined that the 1986 price of 46.2 cents/L of ethanol produced by the process would be reduced by 1.8 cents/L for every $1/sq foot drop in the price of hollow fibers. A comparison of this process with conventional fermentation processes indicates that its potential savings lie in its ability to use a concentrated sugar feed, and the fermentor's increased productivity and ability to produce a concentrated ethanol stream which is removed by the extracting solvent.     

Affinity chromatography as a tool for antibody purification

The global antibody market has grown exponentially due to increasing applications in research, diagnostics and therapy. Antibodies are present in complex matrices (e.g. serum, milk, egg yolk, fermentation broth or plant-derived extracts). This has led to the need for development of novel platforms for purification of large quantities of antibody with defined clinical and performance requirements. However, the choice of method is strictly limited by the manufacturing cost and the quality of the end product required. Affinity chromatography is one of the most extensively used methods for antibody purification, due to its high selectivity and rapidity. Its effectiveness is largely based on the binding characteristics of the required antibody and the ligand used for antibody capture. The approaches used for antibody purification are critically examined with the aim of providing the reader with the principles and practical insights required to understand the intricacies of the procedures. Affinity support matrices and ligands for affinity chromatography are discussed, including their relevant underlying principles of use, their potential value and their performance in purifying different types of antibodies, along with a list of commercially available alternatives. Furthermore, the principal factors influencing purification procedures at various stages are highlighted. Practical considerations for development and/or optimizations of efficient antibody-purification protocols are suggested.     

Schistosomiais and Soil-Transmitted Helminth Control in Niger: Cost Effectiveness of School Based and Community Distributed Mass Drug Administration

Background

In 2004 Niger established a large scale schistosomiasis and soil-transmitted helminths control programme targeting children aged 5–14 years and adults. In two years 4.3 million treatments were delivered in 40 districts using school based and community distribution.

Method and Findings

Four districts were surveyed in 2006 to estimate the economic cost per district, per treatment and per schistosomiasis infection averted. The study compares the costs of treatment at start up and in a subsequent year, identifies the allocation of costs by activity, input and organisation, and assesses the cost of treatment. The cost of delivery provided by teachers is compared to cost of delivery by community distributers (CDD).The total economic cost of the programme including programmatic, national and local government costs and international support in four study districts, over two years, was US$ 456,718; an economic cost/treatment of $0.58. The full economic delivery cost of school based treatment in 2005/06 was $0.76, and for community distribution was $0.46. Including only the programme costs the figures are $0.47 and $0.41 respectively. Differences at sub-district are more marked. This is partly explained by the fact that a CDD treats 5.8 people for every one treated in school.The range in cost effectiveness for both direct and direct and indirect treatments is quantified and the need to develop and refine such estimates is emphasised.

Conclusions

The relative cost effectiveness of school and community delivery differs by country according to the composition of the population treated, the numbers targeted and treated at school and in the community, the cost and frequency of training teachers and CDDs. Options analysis of technical and implementation alternatives including a financial analysis should form part of the programme design process.