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Scaling up of renewable chemicals
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ScienceDirect Scaling up of renewable chemicals Karl Sanford1, Gopal Chotani1, Nathan Danielson1 and James A Zahn2 The transition of promising technologies for production of renewable chemicals from a laboratory scale to commercial scale is often difficult and expensive. As a result the timeframe estimated for commercialization is typically underestimated resulting in much slower penetration of these promising new methods and products into the chemical industries. The theme of ‘sugar is the next oil’ connects biological, chemical, and thermochemical conversions of renewable feedstocks to products that are drop-in replacements for petroleum derived chemicals or are new to market chemicals/materials. The latter typically offer a functionality advantage and can command higher prices that result in less severe scale-up challenges. However, for drop-in replacements, price is of paramount importance and competitive capital and operating expenditures are a prerequisite for success. Hence, scale-up of relevant technologies must be interfaced with effective and efficient management of both cell and steel factories. Details involved in all aspects of manufacturing, such as utilities, sterility, product recovery and purification, regulatory requirements, and emissions must be managed successfully. Addresses 1 DuPont Industrial Biosciences, 925 Page Mill Road, Palo Alto, CA 94304, USA 2 DuPont Industrial Biosciences, 198 Blair Bend Drive, Loudon, TN 37774, USA Corresponding author: Sanford, Karl ([email protected])
Current Opinion in Biotechnology 2016, 38:112–122 This review comes from a themed issue on Energy biotechnology Edited by Andrew S Ball and Jamie HD Cate
http://dx.doi.org/10.1016/j.copbio.2016.01.008 0958-1669/# 2016 Elsevier Ltd. All rights reserved.
pressing need to successfully scale these processes at the first attempt. Creating the necessary process flow sheets, assessing cost sensitivities, and identifying bottlenecks upfront by the use of modeling, simulation, and technoeconomic analysis, will aid in a successful scale-up [3–6]. In this article, we review various categories germane to a fermentation based process scale up (Figure 1), for the production of bio-industrial products. The volumes of bio-based products (derived from renewables, not necessarily fermentation based, and excluding biofuels) globally are estimated to be 50 billion kilos per year and these volumes are anticipated to grow significantly in the near future [7]. The growth of biobased products is occurring at a rate 3–4% per year globally. In 2013, the United States alone generated $126 billion direct sales of biobased products. The steady progress made in the manufacturing of these products over the recent years with a line-up of products and stages of scaleup is shown in Table 1. The difficulties associated with scale-up are reflected in the delays and/or severely reduced volumes commercialized compared to the announced capacities. Getting from the laboratory scale to market is an enormous challenge, particularly for start-up type companies that may excel in certain aspects but lack all that is needed to scale up. A thorough analysis of the current world-wide production capacity and projected capacities to year 2020 of the most important biobased building blocks that are precursors of polymers has been performed by Dammer et al. [8]. A comprehensive assessment of the commercialization status of both biofuels and biochemicals is reported by Barovsky et al. [9]. Comprehensive reviews by Choi et al. [10] and Chen et al. [11] on the production of top building block chemicals provide the commercial status of over 30 initiatives, many of which are in the ‘preparing’ for commercialization stage.
Commercial scale — successes and failures Introduction Low petroleum prices have made the successful introduction of new bio-based processes more difficult and risky. But global climate change scenarios demand more sustainable manufacturing processes for the chemical and materials industries. Although the arbiter of what is sustainably advantaged is a life cycle assessment, as a general rule, bio-renewable processes use less toxic chemicals and operate at ambient temperature/pressure, thus are considered advantageous [1,2]. Hence, there is a Current Opinion in Biotechnology 2016, 38:112–122
Industrial enzymes, ethanol based biofuels, lactic acid, and 1,3-propanediol exemplify some of the early successes of commercial scale-up. The process for commercial production of 1,3-propanediol for Sorona1 polymer is based on a unique collaboration between technology leaders DuPont and Tate & Lyle [12]. The process has become a hallmark of an emerging commercially viable biomaterial era, competing with and complementing petrochemically derived materials [13]. The production of lactic acid based biomaterial (polylactide polymers) from corn sugar led by NatureWorks1 LLC is another www.sciencedirect.com
Scaling up of renewable chemicals Sanford et al. 113
Figure 1
Agriculture
Renewables
Feedstocks
Milling
Bioprocesses
Cell Factories
Production plants
Biochemicals
Markets
Applications
RENEWABLES
FEEDSTOCKS
BIOPROCESSES
BIOCHEMICALS
MARKETS Current Opinion in Biotechnology
High yielding agricultural crops combined with efficient steel and cell factories will enable product & process innovations for sustained success. Better products, competitive economics, and positive environmental impact are absolutely essential for successful launch of new chemicals from renewable feedstocks.
example of successful commercialization. The current market size for its production is approaching 200 000 tons/year [10]. The production route employs a fermentation process to produce two chiral isomers of lactic acid from glucose, which are then combined to form lactide isomers and polymerized to polylactic acid (PLA). Scale up for PLA is complex since it involves combining biological processes with polymerization chemistry and materials science. Additional successes include companies such as Myriant Corporation, BioAmber Inc. and Succinity GmbH that recently have entered commercial phase for bio-based production of succinic acid with announced capacities of 10–30 ktons/year culminating significant R&D and scale-up efforts [14]. In contrast, KiOR Inc.’s technology [15] focused on the thermal conversion of biomass to drop-in transportation fuels had significant scale-up issues. SEC filings state that KiOR’s commercial facility ran significantly below nameplate capacity of 500 ton-per-day. The facility was unable to reach steady state due to structural design bottlenecks and reliability that limited the amount of wood that it could input to its Biomass Fluid Catalytic Cracking system. This setback occurred despite running a pilot plant at 10 ton-per-year and a demonstration plant at www.sciencedirect.com
10 ton-per-day capacities. KiOR’s impediment demonstrated that combination of two known but disparate technologies can pose significant challenges (KiOR Q2 2014 10Q report, http://www.sec.gov/Archives/edgar/ data/1418862/000143774914014972/kior20140630_10q. htm). As a result, KiOR has faced liquidity issues. Another recent failure to scale up is the production of polyhydroxyalkanoate-based plastics by Telles, LLC, the joint venture between ADM and Metabolix. The uncertainty around projected capital and production costs, combined with the rate of market adoption, led to projected financial results that were too uncertain (ADM Press Release, January 12, 2012, http://www.sec. gov/Archives/edgar/data/7084/000119312512011819/ d282748dex992.htm). As a result, ADM took a $339 million dollar charge on their Clinton, Iowa production facility (ADM Q2 2012 Financial Report, http://www.adm.com/ en-US/investors/Documents/ADM%20FYQ212%20 Earnings%20Presentation.pdf). The resulting termination of alliance validates that long-term commitment to process improvement and market development is essential even in very late stages of scale up. Microbial fermentation processes utilizing living cell factories add an additional level of complexity related to life functions [16] unlike the scale-up Current Opinion in Biotechnology 2016, 38:112–122
114 Energy biotechnology
Table 1 Scale-up projects for manufacture of biobased chemicals Company
Product
Location
Processes using corn starch, syrup, sucrose, or cassava NatureWorks, LLC Polylactic acid Blair, NE, USA
Process
Capacity, tons/year
Start-up
Chemical conversion of lactic acid produced through the anaerobic fermentation of corn syrup. Aerobic recombinant E. coli fermentation of corn syrup.
140 000
Q2, 2002
66 000
Q4, 2006
200 000
Q3, 2010
54 600 (18 MM gal./year) 2000
Q2, 2012
27 200
Q4, 2012
10 000
Q4, 2012
8000
Q1, 2013
13 600
Q2, 2013
20 000
Q2, 2014
100 000
Q2, 2014
30 000
Q3, 2015
4500
Q4, 2015
Chemical conversion of biodieselderived glycerin. Solvay Epicerol technology using glycerin from Palm oil. Anaerobic Klebsiella pneumoniae fermentation of glycerin.
660 000
Q4, 2011
100 000
Q1, 2012
20 000
Q1, 2013
Anaerobic Klebsiella pneumoniae fermentation of glycerin.
2500
Q1, 2013
Anaerobic Klebsiella pneumoniae fermentation of glycerin.
12 000
Q4, 2015
BioForming1 platform technology using catalysts to convert plant sugars into hydrocarbon molecules. Assimilation of CO2 into ethanol using recombinant Cyanobacterium sp.
28.35 (10 000 gal./year) 300 (100 000 gal./year) 40 000
Q1, 2010
DuPont Tate & Lyle Bio Products, LLC Braskem
1,3-Propanediol
Loudon, TN, USA
Ethylene
Gevo
Isobutanol
Rio Grande do Sul, Brazil Luverne, MN, USA
Chemical conversion of ethanol derived from sucrose fermentation to ethylene. Recombinant yeast fermentation of corn starch/carbohydrates.
Solazyme
Algal oil (3G)
Peoria, IL, USA
Genomatica/DuPont Tate & Lyle Bio Products Reverdia
1,4-Butanediol
Loudon, TN, USA
Recombinant Chlorella protothecoides fermentation of corn syrup. Microaerobic recombinant E. coli fermentation of corn syrup.
Succinic acid
Amyris
Farnesene
Cassano Spinola, Italy Sao Paulo, Brazil
Myriant
Succinic acid
Solazyme Solazyme
Algal oil (3G), Algal flour Algal oil (3G)
Bioamber
Succinic acid
Rivertop Renewables Processes using glycerin Archer Daniels Midland PTT Zhangjiagang Glory Biomaterial Co. Ltd. Heilongjiang Chenneng Bioengineering Co. Ltd. (HCB) Zouping Mingxing Chemical Co. Ltd.
Glucaric acid as a substrate Propylene glycol Epichlorohydrin 1,3-Propanediol
1,3-Propanediol
Lake Providence, LA, USA Clinton, IA, USA Orindiu´va, Brazil Sarnia, Canada Danville, VA (DTI) Decatur, IL Map Ta Phut, Thailand Zhangjiagang City, China Hangzhou, China
Zouping County, Shandong Province, China Processes using lignocellulosic material as a substrate Virent Bio-gasoline Madison, WI, USA 1,3-Propanediol
Algenol
Ethanol (4G)
Fort Meyers, FL, USA
BetaRenewables
Ethanol (2G)
Crescentino, Italy
GranBio and BetaRenewables
Ethanol (2G)
Sa˜o Miguel dos Campos, Alagoas, Brazil
Poet-DSM Advanced Biofuels
Ethanol (2G)
Emmetsburg, IA, USA
Current Opinion in Biotechnology 2016, 38:112–122
Low-pH recombinant yeast fermentation of starch. Recombinant yeast fermentation of sucrose. Recombinant E. coli fermentation of corn syrup. Recombinant Chlorella protothecoides fermentation of corn syrup. Recombinant Chlorella protothecoides fermentation of sucrose. Cargill recombinant yeast technology using corn syrup. Nitric acid oxidation of glucose.
Arundo donax (giant cane) pretreatment via the ProesaTM process followed by fermentation with recombinant yeast. Sugarcane straw/bagasse pretreatment via the ProesaTM process followed by fermentation with Celere2L1 recombinant yeast. Corn stover pretreatment followed by fermentation with recombinant Saccharomyces.
Q2, 2012
Q4, 2013
Q1, 2014
64 510 (21.6 MM gal./year)
Q3, 2014
59 734 (20 MM gal./year)
Q3, 2014
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Table 1 (Continued ) Company
Product
Location
Virent
p-Xylene
Madison, WI, USA
Abengoa
Ethanol (2G)
Hugoton, KS, USA
DuPont Industrial BioSciences
Ethanol (2G)
Nevada, IA, USA
Thermochemical and hybrid thermochemical processes Coskata Ethanol (2G) Madison, PA, USA
LanzaTech
Ineos Bio
Fulcrum BioEnergy; Sierra Biofuels Plant
Ethanol (2G) and 2,3-butanediol Ethanol (2G)
Shanghai, China
FT syncrude
McCarran, NV, USA
Vero Beach, FL, USA
Process Catalysts to convert plant sugars into p-xylene. Corn stover pretreatment followed by fermentation with recombinant Saccharomyces. Corn stover pretreatment followed by fermentation with recombinant Zymomonas mobilis. Clostridium sp. fermentation of biomass-derived producer (CO + H2) gas. Clostridium autoethanogenum fermentation of steel mill gas. Clostridium ljundalhlii fermentation of biomass-derived producer (CO + H2) gas. Thermochemical conversion of municipal solid waste using gasification and Fischer–Tropsch processes.
Capacity, tons/year
Start-up
9.98
Q3, 2014
74 667 (25 MM gal./year) 89 600 (30 MM gal./year)
Q4, 2014
2091 (0.7 MM gal./year) 300 (0.1 MM gal./year) 23 893 (8 MM gal./year) 29 867 (10 MM gal./year)
Q4, 2009
Q4 2015
Q4, 2011
Q4, 2014
Q3, 2017
1 U.S. gallon of ethanol is equal to 2.98669E 3 metric tons (25 8C). 1 U.S. gallon of isobutanol is equal to 3.0358E 3 metric tons (25 8C).
of chemical processes where the chemical reaction kinetics and stoichiometry are often well understood with a data based history of minimizing scale up difficulties [17]. In spite of this, chemical or thermochemical processes that use biomass encounter complexities of feedstock variability, impurities, and supply chain issues.
New routes and processes to renewable chemicals Perhaps, the bio-based industry might develop faster through development of processes and products targeted for unmet needs, rather than compete with chemical processes of proven record. It is harder to displace highly efficient, environmentally favorable and sustainable chemical processes of established products with widespread use. Hybrid processes, combining biochemical and chemical processes will enhance competitiveness of biobased products [18]. For example, bio-based polymers and bioplastics will grow their market share by synergizing and collaborating with the chemical process industry [19]. A deeper knowledge of systems biology and an integrated approach to process engineering will expand uses of biocatalysis (by enzymes or whole cells) as part of a manufacturing process [20]. Development of cell factories will rely on advances in the use of synthetic biology and metabolic pathway engineering. The conversion of cellulosic biomass into fermentable sugars could accelerate building biochemical plants (MIT Technology Review, http://www.technologyreview.com/ news/427145/cellulosic-ethanol-gets-a-100-millionboost/). The use of biomass derived fermentable carbon for the production of biosurfactants, biomaterials, and www.sciencedirect.com
biofuels is being employed by several companies [21]. Abengoa S.A., Beta-Renewables SpA., DuPont, and PoetDSM Advanced Biofuels, LLC, have successfully demonstrated conversion of cellulosic sugar to ethanol on a large scale with commercial deployment underway. DuPont has shown a fully integrated pilot process at a scale of 250 000 gallons ethanol per year at its Vonore, Tennessee plant. This pilot scale facility has demonstrated conversion of a variety of biomass feedstocks first to sugars and at the end to ethanol and thus generated the necessary data to build and operate a full scale plant that will produce 30 million gallons of ethanol per year at Nevada, Iowa, using corn stover (corn residues, including cobs, stalks, leaves) collected within a 30-mile radius. The company has begun to license this technology to third parties to produce biochemicals and biofuels. Decades of industrial experience, combined with scientific advances in metabolic engineering and synthetic biology, have now enabled the establishment of biorefineries. However, the success of a biorefinery platform will depend on the integration of processes at all stages from reliable feedstock to building the cell factory, to development of the fermentation process, downstream processing and product application. Simplification of processes is the key to improving the chances for a successful scale-up. One such approach is simultaneous enzyme(s) production and fermentation in which the fermenting organism can produce enzymes to release fermentable sugars from complex carbohydrate feedstock, and convert the released sugars to products. Such integration, called Consolidated Bioprocessing (CBP), has been put to use for production of ethanol Current Opinion in Biotechnology 2016, 38:112–122
116 Energy biotechnology
from starch by yeast [22], and there are proposals for developing CBP for biomass conversion using the cellulolytic fungus, Trichoderma reesei [23]. CBP without any enzyme(s) addition at start of fermentation, will not involve a separate enzyme production process, but to date there are no commercial examples of this approach. Pursuit of extreme productivity
Volumetric productivities of commercial fermentation processes typically fall within the range of 3–5 g/L/hour which is as much as 10-fold less than of many chemical processes. Notwithstanding differences in productivities (inverse of reactor residence time) due to temperature and pressure effects on chemical and biocatalysts, fermentation processes would benefit from use of higher cell densities (lower water content). In other words, current fermenter productivities are typically limited by gas solubility, mixing and heat transfer rates. One approach that uncouples cell density from these limitations is use of cell free production systems [24]. As outlined by Swartz [25] ‘The ability to exploit a cell’s contents and capabilities unimpeded by cell walls opens new opportunities for the field of biochemical engineering. Cell-free biology could become the basis for making products from hydrogen to cancer vaccines and more’. Progress in developing cell-free metabolic engineering includes demonstrations of pathways extending beyond 8 enzyme steps, near theoretical mass yields, volumetric productivities of several g/L/hour and scale-up into the hundreds of liters. Cell-free catalysis has been used not only in academia [26,27] but also for the commercial production of protein therapeutics [28]. Can the cell-free platform be considered for the fermentation-based production of free acid-form of certain chemical compounds? Among the building block chemicals outlined by the US Department of Energy that can be produced from sugars via a bioprocess, eight out of the top 12 are acids, with a fermentation process run at low pH being identified as key for commercialization [29,30]. In other words, pursuit of a cell factory chassis that is compatible with low pH production would offer benefits of reduced contamination and remove the need for sterilization. The fermentation production of the free acid-form of these chemicals could be beneficial due to its favorable impact on product recovery as well as by-product formation.
these objectives, a discovery to delivery approach that integrates a synthetic bio-operating system, chemical engineering practices, process safety, sustainability, and socio-economics considerations must be implemented [31]. Scale-up challenges are usually dependent on whether the product is a specialty or commodity chemical, where the difference in volumes of production can be of several orders of magnitude. Nevertheless, key success factors across the spectrum of volumes are listed in Table 2 and derive from personal and industry leaders’ experiences [32]. Factors relevant to scale up that need to be considered are discussed below. Feedstock availability and cost
Sugarcane, beet, grain, or biomass, are used as a source of fermentable carbon to produce an ever-growing list of biochemicals and co-product streams of significant value [33]. One of the major factors driving economics for production of renewable chemicals is feedstock availability and cost, and scale-up strategies must take this variable into account. Scale-up success depends largely on the correct matching of feedstock to process design. Today, most large scale processes utilize traditional carbohydrate feedstocks. For corn based ethanol, feedstock commonly represents greater than 50% of total production costs (https://www.extension.iastate.edu/agdm/ energy/xls/d1-10ethanolprofitability.xlsx). The cost of sugar feedstock has decreased dramatically from recent highs and is now very close to historical averages when adjusted for inflation. On the other hand, petroleum oil price is significantly lower than its inflation adjusted average, as a result of increased production in the US and a demand that has remained flat globally (Economist December 8, 2014, http://www.economist.com/blogs/ economist-explains/2014/12/economist-explains-4). This will clearly represent a headwind for biobased chemicals and fuels that compete directly with petroleum based materials (Figure 2). A good deal of effort has been directed at analyzing feedstock availability and costs of alternative sources including cellulosic biomass and macro and microalgae
Table 2
Factors relevant to scale-up
Key success factors for scale-up
A number of prevailing factors need to be considered and optimized when attempting to take a technological process into full commercial production. A major ramp-up in design, development, demonstration and deployment is needed to engineer predictable, controllable, and cost effective processing systems. Engineering principles have been and will continue to be critical for fulfillment of ever-increasing needs for environmentally efficient production of food, feed, chemicals, and energy. To meet
Integration of multiple disciplines Consistency from start to finish Working from same master plan Clear understanding of risk factors Strong mathematical and economic modeling Pilot where you operate Upfront approach to safety and regulatory Focus on waste stream minimization Product specifications determined early
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Scaling up of renewable chemicals Sanford et al. 117
Figure 2
$35.00
$120.00
$30.00
$100.00
$25.00 $80.00 $20.00 $60.00 $15.00 $40.00 $10.00
$20.00
$5.00
$1990
$1995
2000
2005
#11 Sugar ($/100lb)
2010
Corn $/bu
2015
2020
Oil WTI $/bbl Current Opinion in Biotechnology
Historic sugar, corn and petroleum feedstock price correlations. Inflation adjusted price for crude, #11 sucrose, and yellow #2 dent corn. Solid horizontal lines on chart indicate average adjusted price for each commodity. Note that prices for sugar and corn are trending towards historic averages, whereas that for petroleum appears to have moved significantly below its historic average. Data from EIA and USDA
[34,35]. The U.S. Department of Energy’s 2011 Billion Ton Study Update indicates that 600–1000 million tons of terrestrial biomass is available in the continental United States alone at a farmgate or forest roadside price of $60/ ton or less (http://www1.eere.energy.gov/bioenergy/pdfs/ billion_ton_update.pdf). Despite this, the current estimated cost for sugars from cellulosic biomass is more than that from sugarcane or corn. A range of tactics are being considered to bring the costs of lignocellulosic sugars down. These include improved enzyme activity [36], improved production organisms [37], valorization of the lignin component of the biomass [38] and CBP, which reduces the overall capital and operational expenses [39]. These and other efforts are anticipated to drive lignocellulosic feedstocks to more favorable economics. In addition, the value of byproducts generated from lignocellulosic feedstocks, including lignin, must be realized analogous to the cost offset provided by the value-added products derived from sugarcane or corn based processes. Despite technical success of a bio-process, feedstock availability at competitive cost can pose huge logistics issues; where the feedstocks www.sciencedirect.com
are available does not often align with where the end products are needed. Biocatalyst design considerations
Every bioprocess starts with the best possible biocatalyst, the cell factory, built by integrated science and engineering (Figure 3). The two main biocatalysts used in current bioprocesses are: Firstly, enzymes with wide range of activities and properties, especially for production of fermentable sugars; and, finally, engineered micro-organisms to produce chemicals. Today, most enzymes used in bioprocesses are of microbial origin, but their structures are not necessarily native to the host, that is, they are engineered. Protein engineering has allowed optimizing enzyme properties for specific use, and a number of different approaches have significantly improved enzyme performance [40]. Moreover, the engineered proteins need to be expressed at high levels in production strains that are approved by the regulatory agencies for no adverse effect in humans, animals, or the environment. Although a cell factory platform could accelerate process Current Opinion in Biotechnology 2016, 38:112–122
118 Energy biotechnology
Figure 3
performing biocatalyst is prudent as it would mean less capital, lower variable cost, and a simpler process. Strain Pilot phase
Physiology Fermentation
Solid Product Drying
Recovery Formulation Concentration Liquid Product Current Opinion in Biotechnology
Integrated science and engineering competencies applied to design and operate efficient cell factories.
development, a biocatalyst is usually created on a case-bycase basis. The availability of efficient and robust enzymes to process a large variety of feedstocks will remain critical for a successful biorefinery concept. The biocatalyst has a strong influence on the capital needed and determines the fixed portion of the production cost for the entire process. For example, oxygen requirement and method of its supply to the fermenters, is an important cost determinant (lower the oxygen demand, lower are the costs for agitation, pressure and aeration, allowing a bigger bioreactor scale) [41]. However, the heat generated by a process is proportional to the oxygen use, and therefore cooling costs can increase with the scale. Moreover, either addition of air/oxygen or generation of carbon dioxide, results in the formation of foam, which often is stabilized by proteins in the fermentation medium [42]. To control foam and better utilize the bioreactor capacity upon scale-up, process compatible antifoams have to be added, thereby optimizing the bioreactor–antifoam interactions for robust process. Thus, generating a better
Past experience from process scale up has shown that a rapid transfer of technological process from laboratory to commercial scale often fails. Especially, new commercial processes with new technology risks justify a pilot plant project. However, the commercial plant must be thoroughly and rigorously developed and documented to provide basis for the pilot plant. The understanding of the commercial plant package, with its risks and impact of alternatives/uncertainties needs to flow into the scope and breadth of the actual pilot plant operation. The essential elements for necessity of a pilot plant are listed in Table 3. It is axiomatic that Pilot Plants do not make money. Therefore, the justification for a pilot plant is strictly linked to the target commercial process. Integration of processes
The primary objective of fermentation scale-up is the integration of feedstock conversion and cell factory operation to produce the needed biochemicals. During bioprocess development cycle, the changes made in upstream unit operations can affect the downstream elements. The performance of cell factory during fermentation impacts the recovery and formulation units of the process. Therefore, an optimized integrated bioprocess development flow (Figure 4), can provide considerable time and money savings. Knowledge based on prior scale up experience, as well as that tapped from other industries is important in enabling a predictable scale up. Defining predictive metrics for effective scale up with appropriate project management skills is essential in scale up activities. Companies developing innovative technologies have an advantage in achieving competitive performance in shorter timeframes [43]. Process integration by combining unit operations can simplify and even enable the economics required for commercialization [2,44]. A distinct set of considerations like mixing, temperature, pH, pressure control requirements, biocatalyst robustness,
Table 3 Why a pilot plant Need to test process technology and fill gaps in understanding that are critical to the Commercial Scale. Need to gather essential data that is instrumental to successful scale-up of the Commercial plant for minimal cost, excellent quality and operate effectively against production performance goals. Gain Understanding of the operation of integrated process and develop longer term understandings of expected (and unexpected) process concerns. Produce product material for end use customers and tests. Build confidence in customers of ability to deliver quality products. Demonstrate ability to safely and effectively design, build and operate a facility with mitigations and strategies for any process hazard (flammability, toxicity, etc.). Reduce risk of non-performance at Commercial Scale.
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Figure 4
Fermentation Enzymology
Recovery
Protein engineering
Formulation
Design & Operate Cell Factories Scale up Expression
Metabolic pathway engineering
Cost-efficient, largescale manufacturing Current Opinion in Biotechnology
Typical steps of integrated bioprocessing.
feedstock compositions appear to govern scale up of industrial bioprocesses. Bioreactor scale-up, characterized by transport phenomena, relies on optimally supplying carbon, oxygen, nitrogen, etc. to the microorganisms during production process. Standardized high capability fermenters are designed by understanding complex mixing, mass and heat transfer phenomena at various scales. However, the influence on cell physiology as scale changes requires additional measuring techniques. There is a clear need for a deeper understanding that distinguishes cell phenomena that occur at bench versus production scales [45]. Investment in this area might be analogous to Process analytical technology, defined by the US FDA for pharmaceutical manufacturing processes, that is, better design, analysis and control of processes through the measurement of critical parameters for both understanding and achieving consistency of scale-up. Current knowledge on cell physiology of microbes used in industrial fermentations has been derived from laboratory conditions of rapid growth and high metabolic activity. However, in industrial processes, microbial growth rates can be extremely slow approaching zero, and cell productivity often drops after reaching a peak. In commercial processes, carbon efficient production requires uncoupling microbial growth from product formation to maintain high productivity. Study of continuous culture cell recycle [46] could be a useful tool to investigate microbial physiology at low to no growth. Minimizing cell mass, www.sciencedirect.com
especially when costs for inactivation of genetically modified cell mass are high would be economically advantageous. Improving scale-up methods is essential to achieve the goals of high productivity uncoupled from growth, and high product yield sustained over prolonged period of fermentation. Regulatory requirements
The development of non-pathogenic and non-toxigenic recombinant microbial production strains when well characterized by generally accepted safety evaluation procedures [47] have found wide acceptance by regulatory agencies such as the US FDA [48] and US EPA (http:// www.epa.gov/opptintr/biotech/pubs/rulesupc.htm). Under the Toxic Substances Control Act (TSCA), EPA regulates the use of intergeneric microorganisms in commerce or commercial research (http://www.epa.gov/oppt/ biotech/pubs/biorule.htm). Regulations also differ country by country but irrespective of legislation, it is prudent for the product manufacturer to ensure that the production process, the potential product, and its intended use are safe before introduction. For example, the general acceptance of the safety of bioprocess based products tested against international standards by the Joint FAO/ WHO Expert Committee on Food Additives (JECFA, http://www.fao.org/food/food-safety-quality/scientificadvice/jecfa/en/), has allowed increased enzyme manufacture and use worldwide over the last few decades. It is imperative to keep in mind that safety issues relating to Current Opinion in Biotechnology 2016, 38:112–122
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Table 4 Factors affecting capital Readiness of the manufacturing facility Source commercial raw materials and supplies Produce a working cell bank and validate the cell bank for use in manufacturing Establish process equivalence of pilot/lab system to unit operations in manufacturing the manufacturing process using a ‘satellite’ approach Rank order process sensitivities to assess process robustness Scaling factor reliability for economies Distributed manufacturing options
environmental release are minimized when the genetically modified organisms are well characterized, designed to barely survive in the general environment, and grown under contained good large-scale industry practices.
Capital investment
Capital justification for commercialization, especially with new technology risks, often undergoes a stage-wise process (Table 4). Capital costs in some cases have been reduced by creatively ‘recycling’ production plants. For example, Butamax Advanced Biofuels LLC, Gevo, Inc. and Green Biologics Ltd. have focused on retrofitting existing ethanol plants for butanol production rather than building new ones (The New York Times, http://nyti.ms/1CbWh1X), offering benefits of infrastructure already in place. Yet another approach to managing capital investment has appeared in the form of distributed manufacturing, for example, Green Ethanol Micro-Distillery using modular equipment for small-scale biofuel production. Green Social Bioethanol is propagating its rural scale robust, low maintenance enzymatic hydrolysis and fermentation process. Their versatile and efficient model aims to utilize a wide variety of starch and sugar feedstocks to supply fuel, feed, and fertilizer sustainably across the world including remote areas (https://www.ashoka.org/fellow/eduardo-mallman). Distributed manufacturing is projected to gain traction as synthetic biology evolves [49], namely, the assembly of standardized bio-components by applying system design principles to build customized bioprocesses targeted to meet specific human needs.
Concluding remarks/perspectives Scale-up is not a separate activity posted onto a research and development phase; it must be integrated with the project from the very beginning. Since scale-up usually marks the beginning of significant capital expenditure, a strong economic justification for the biomanufacturing process is a prerequisite for success. The observation that many early stage biotechnology companies in particular have suffered severe market capitalization losses due to scale-up challenges and subsequent delays underscores its importance. Pricing of feedstocks, competition, market conditions, policy and regulatory changes, etc., represent the headwinds that must be faced when considering commercialization. Current Opinion in Biotechnology 2016, 38:112–122
The formative integration of synthetic biology with process engineering and application to improve scale-up methodology is essential for success. Such a technological combination will drive to a future state where the high throughput cell ‘design, build, and test cycle’ is accomplished at bench scale in high throughput mini-reactors that accurately mimic reactor conditions at large scale. The decision on how to scale up a process is dictated by managing risk/reward. The opportunity for next generation scale-up is to improve the probability of success, that is, increasing speed to market, limiting capital/time at pilot stage and maximizing value creation. One way to accelerate this process would be through the framework of a National Network for Manufacturing Center directed at bio-manufacturing (http://manufacturing.gov/nnmi. html). Such an infrastructure would be focused on bridging the gap between R&D and commercialization grounded by the roadmap for the industrialization of biotechnology (http://www.nap.edu/catalog/19001/ industrialization-of-biology-a-roadmap-to-acceleratethe-advanced-manufacturing).
Acknowledgements The authors thank F Glenn Gallagher, Vincent Sewalt and Eli Ben-Shoshan for helpful comments and Roopa Ghirnikar for expert overall manuscript design and preparation.
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12. Kurian JV: A new polymer platform for the future — SoronaW from corn derived 1,3-propanediol. J Polym Environ 2005, 13:159-167. Delves into the importance of product specifications for polygrade monomers such as 1,3-propanediol and highlights the downstream work required to make polyester.
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Current Opinion in Biotechnology 2016, 38:112–122
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ScienceDirect Scaling up of renewable chemicals Karl Sanford1, Gopal Chotani1, Nathan Danielson1 and James A Zahn2 The transition of promising technologies for production of renewable chemicals from a laboratory scale to commercial scale is often difficult and expensive. As a result the timeframe estimated for commercialization is typically underestimated resulting in much slower penetration of these promising new methods and products into the chemical industries. The theme of ‘sugar is the next oil’ connects biological, chemical, and thermochemical conversions of renewable feedstocks to products that are drop-in replacements for petroleum derived chemicals or are new to market chemicals/materials. The latter typically offer a functionality advantage and can command higher prices that result in less severe scale-up challenges. However, for drop-in replacements, price is of paramount importance and competitive capital and operating expenditures are a prerequisite for success. Hence, scale-up of relevant technologies must be interfaced with effective and efficient management of both cell and steel factories. Details involved in all aspects of manufacturing, such as utilities, sterility, product recovery and purification, regulatory requirements, and emissions must be managed successfully. Addresses 1 DuPont Industrial Biosciences, 925 Page Mill Road, Palo Alto, CA 94304, USA 2 DuPont Industrial Biosciences, 198 Blair Bend Drive, Loudon, TN 37774, USA Corresponding author: Sanford, Karl ([email protected])
Current Opinion in Biotechnology 2016, 38:112–122 This review comes from a themed issue on Energy biotechnology Edited by Andrew S Ball and Jamie HD Cate
http://dx.doi.org/10.1016/j.copbio.2016.01.008 0958-1669/# 2016 Elsevier Ltd. All rights reserved.
pressing need to successfully scale these processes at the first attempt. Creating the necessary process flow sheets, assessing cost sensitivities, and identifying bottlenecks upfront by the use of modeling, simulation, and technoeconomic analysis, will aid in a successful scale-up [3–6]. In this article, we review various categories germane to a fermentation based process scale up (Figure 1), for the production of bio-industrial products. The volumes of bio-based products (derived from renewables, not necessarily fermentation based, and excluding biofuels) globally are estimated to be 50 billion kilos per year and these volumes are anticipated to grow significantly in the near future [7]. The growth of biobased products is occurring at a rate 3–4% per year globally. In 2013, the United States alone generated $126 billion direct sales of biobased products. The steady progress made in the manufacturing of these products over the recent years with a line-up of products and stages of scaleup is shown in Table 1. The difficulties associated with scale-up are reflected in the delays and/or severely reduced volumes commercialized compared to the announced capacities. Getting from the laboratory scale to market is an enormous challenge, particularly for start-up type companies that may excel in certain aspects but lack all that is needed to scale up. A thorough analysis of the current world-wide production capacity and projected capacities to year 2020 of the most important biobased building blocks that are precursors of polymers has been performed by Dammer et al. [8]. A comprehensive assessment of the commercialization status of both biofuels and biochemicals is reported by Barovsky et al. [9]. Comprehensive reviews by Choi et al. [10] and Chen et al. [11] on the production of top building block chemicals provide the commercial status of over 30 initiatives, many of which are in the ‘preparing’ for commercialization stage.
Commercial scale — successes and failures Introduction Low petroleum prices have made the successful introduction of new bio-based processes more difficult and risky. But global climate change scenarios demand more sustainable manufacturing processes for the chemical and materials industries. Although the arbiter of what is sustainably advantaged is a life cycle assessment, as a general rule, bio-renewable processes use less toxic chemicals and operate at ambient temperature/pressure, thus are considered advantageous [1,2]. Hence, there is a Current Opinion in Biotechnology 2016, 38:112–122
Industrial enzymes, ethanol based biofuels, lactic acid, and 1,3-propanediol exemplify some of the early successes of commercial scale-up. The process for commercial production of 1,3-propanediol for Sorona1 polymer is based on a unique collaboration between technology leaders DuPont and Tate & Lyle [12]. The process has become a hallmark of an emerging commercially viable biomaterial era, competing with and complementing petrochemically derived materials [13]. The production of lactic acid based biomaterial (polylactide polymers) from corn sugar led by NatureWorks1 LLC is another www.sciencedirect.com
Scaling up of renewable chemicals Sanford et al. 113
Figure 1
Agriculture
Renewables
Feedstocks
Milling
Bioprocesses
Cell Factories
Production plants
Biochemicals
Markets
Applications
RENEWABLES
FEEDSTOCKS
BIOPROCESSES
BIOCHEMICALS
MARKETS Current Opinion in Biotechnology
High yielding agricultural crops combined with efficient steel and cell factories will enable product & process innovations for sustained success. Better products, competitive economics, and positive environmental impact are absolutely essential for successful launch of new chemicals from renewable feedstocks.
example of successful commercialization. The current market size for its production is approaching 200 000 tons/year [10]. The production route employs a fermentation process to produce two chiral isomers of lactic acid from glucose, which are then combined to form lactide isomers and polymerized to polylactic acid (PLA). Scale up for PLA is complex since it involves combining biological processes with polymerization chemistry and materials science. Additional successes include companies such as Myriant Corporation, BioAmber Inc. and Succinity GmbH that recently have entered commercial phase for bio-based production of succinic acid with announced capacities of 10–30 ktons/year culminating significant R&D and scale-up efforts [14]. In contrast, KiOR Inc.’s technology [15] focused on the thermal conversion of biomass to drop-in transportation fuels had significant scale-up issues. SEC filings state that KiOR’s commercial facility ran significantly below nameplate capacity of 500 ton-per-day. The facility was unable to reach steady state due to structural design bottlenecks and reliability that limited the amount of wood that it could input to its Biomass Fluid Catalytic Cracking system. This setback occurred despite running a pilot plant at 10 ton-per-year and a demonstration plant at www.sciencedirect.com
10 ton-per-day capacities. KiOR’s impediment demonstrated that combination of two known but disparate technologies can pose significant challenges (KiOR Q2 2014 10Q report, http://www.sec.gov/Archives/edgar/ data/1418862/000143774914014972/kior20140630_10q. htm). As a result, KiOR has faced liquidity issues. Another recent failure to scale up is the production of polyhydroxyalkanoate-based plastics by Telles, LLC, the joint venture between ADM and Metabolix. The uncertainty around projected capital and production costs, combined with the rate of market adoption, led to projected financial results that were too uncertain (ADM Press Release, January 12, 2012, http://www.sec. gov/Archives/edgar/data/7084/000119312512011819/ d282748dex992.htm). As a result, ADM took a $339 million dollar charge on their Clinton, Iowa production facility (ADM Q2 2012 Financial Report, http://www.adm.com/ en-US/investors/Documents/ADM%20FYQ212%20 Earnings%20Presentation.pdf). The resulting termination of alliance validates that long-term commitment to process improvement and market development is essential even in very late stages of scale up. Microbial fermentation processes utilizing living cell factories add an additional level of complexity related to life functions [16] unlike the scale-up Current Opinion in Biotechnology 2016, 38:112–122
114 Energy biotechnology
Table 1 Scale-up projects for manufacture of biobased chemicals Company
Product
Location
Processes using corn starch, syrup, sucrose, or cassava NatureWorks, LLC Polylactic acid Blair, NE, USA
Process
Capacity, tons/year
Start-up
Chemical conversion of lactic acid produced through the anaerobic fermentation of corn syrup. Aerobic recombinant E. coli fermentation of corn syrup.
140 000
Q2, 2002
66 000
Q4, 2006
200 000
Q3, 2010
54 600 (18 MM gal./year) 2000
Q2, 2012
27 200
Q4, 2012
10 000
Q4, 2012
8000
Q1, 2013
13 600
Q2, 2013
20 000
Q2, 2014
100 000
Q2, 2014
30 000
Q3, 2015
4500
Q4, 2015
Chemical conversion of biodieselderived glycerin. Solvay Epicerol technology using glycerin from Palm oil. Anaerobic Klebsiella pneumoniae fermentation of glycerin.
660 000
Q4, 2011
100 000
Q1, 2012
20 000
Q1, 2013
Anaerobic Klebsiella pneumoniae fermentation of glycerin.
2500
Q1, 2013
Anaerobic Klebsiella pneumoniae fermentation of glycerin.
12 000
Q4, 2015
BioForming1 platform technology using catalysts to convert plant sugars into hydrocarbon molecules. Assimilation of CO2 into ethanol using recombinant Cyanobacterium sp.
28.35 (10 000 gal./year) 300 (100 000 gal./year) 40 000
Q1, 2010
DuPont Tate & Lyle Bio Products, LLC Braskem
1,3-Propanediol
Loudon, TN, USA
Ethylene
Gevo
Isobutanol
Rio Grande do Sul, Brazil Luverne, MN, USA
Chemical conversion of ethanol derived from sucrose fermentation to ethylene. Recombinant yeast fermentation of corn starch/carbohydrates.
Solazyme
Algal oil (3G)
Peoria, IL, USA
Genomatica/DuPont Tate & Lyle Bio Products Reverdia
1,4-Butanediol
Loudon, TN, USA
Recombinant Chlorella protothecoides fermentation of corn syrup. Microaerobic recombinant E. coli fermentation of corn syrup.
Succinic acid
Amyris
Farnesene
Cassano Spinola, Italy Sao Paulo, Brazil
Myriant
Succinic acid
Solazyme Solazyme
Algal oil (3G), Algal flour Algal oil (3G)
Bioamber
Succinic acid
Rivertop Renewables Processes using glycerin Archer Daniels Midland PTT Zhangjiagang Glory Biomaterial Co. Ltd. Heilongjiang Chenneng Bioengineering Co. Ltd. (HCB) Zouping Mingxing Chemical Co. Ltd.
Glucaric acid as a substrate Propylene glycol Epichlorohydrin 1,3-Propanediol
1,3-Propanediol
Lake Providence, LA, USA Clinton, IA, USA Orindiu´va, Brazil Sarnia, Canada Danville, VA (DTI) Decatur, IL Map Ta Phut, Thailand Zhangjiagang City, China Hangzhou, China
Zouping County, Shandong Province, China Processes using lignocellulosic material as a substrate Virent Bio-gasoline Madison, WI, USA 1,3-Propanediol
Algenol
Ethanol (4G)
Fort Meyers, FL, USA
BetaRenewables
Ethanol (2G)
Crescentino, Italy
GranBio and BetaRenewables
Ethanol (2G)
Sa˜o Miguel dos Campos, Alagoas, Brazil
Poet-DSM Advanced Biofuels
Ethanol (2G)
Emmetsburg, IA, USA
Current Opinion in Biotechnology 2016, 38:112–122
Low-pH recombinant yeast fermentation of starch. Recombinant yeast fermentation of sucrose. Recombinant E. coli fermentation of corn syrup. Recombinant Chlorella protothecoides fermentation of corn syrup. Recombinant Chlorella protothecoides fermentation of sucrose. Cargill recombinant yeast technology using corn syrup. Nitric acid oxidation of glucose.
Arundo donax (giant cane) pretreatment via the ProesaTM process followed by fermentation with recombinant yeast. Sugarcane straw/bagasse pretreatment via the ProesaTM process followed by fermentation with Celere2L1 recombinant yeast. Corn stover pretreatment followed by fermentation with recombinant Saccharomyces.
Q2, 2012
Q4, 2013
Q1, 2014
64 510 (21.6 MM gal./year)
Q3, 2014
59 734 (20 MM gal./year)
Q3, 2014
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Scaling up of renewable chemicals Sanford et al. 115
Table 1 (Continued ) Company
Product
Location
Virent
p-Xylene
Madison, WI, USA
Abengoa
Ethanol (2G)
Hugoton, KS, USA
DuPont Industrial BioSciences
Ethanol (2G)
Nevada, IA, USA
Thermochemical and hybrid thermochemical processes Coskata Ethanol (2G) Madison, PA, USA
LanzaTech
Ineos Bio
Fulcrum BioEnergy; Sierra Biofuels Plant
Ethanol (2G) and 2,3-butanediol Ethanol (2G)
Shanghai, China
FT syncrude
McCarran, NV, USA
Vero Beach, FL, USA
Process Catalysts to convert plant sugars into p-xylene. Corn stover pretreatment followed by fermentation with recombinant Saccharomyces. Corn stover pretreatment followed by fermentation with recombinant Zymomonas mobilis. Clostridium sp. fermentation of biomass-derived producer (CO + H2) gas. Clostridium autoethanogenum fermentation of steel mill gas. Clostridium ljundalhlii fermentation of biomass-derived producer (CO + H2) gas. Thermochemical conversion of municipal solid waste using gasification and Fischer–Tropsch processes.
Capacity, tons/year
Start-up
9.98
Q3, 2014
74 667 (25 MM gal./year) 89 600 (30 MM gal./year)
Q4, 2014
2091 (0.7 MM gal./year) 300 (0.1 MM gal./year) 23 893 (8 MM gal./year) 29 867 (10 MM gal./year)
Q4, 2009
Q4 2015
Q4, 2011
Q4, 2014
Q3, 2017
1 U.S. gallon of ethanol is equal to 2.98669E 3 metric tons (25 8C). 1 U.S. gallon of isobutanol is equal to 3.0358E 3 metric tons (25 8C).
of chemical processes where the chemical reaction kinetics and stoichiometry are often well understood with a data based history of minimizing scale up difficulties [17]. In spite of this, chemical or thermochemical processes that use biomass encounter complexities of feedstock variability, impurities, and supply chain issues.
New routes and processes to renewable chemicals Perhaps, the bio-based industry might develop faster through development of processes and products targeted for unmet needs, rather than compete with chemical processes of proven record. It is harder to displace highly efficient, environmentally favorable and sustainable chemical processes of established products with widespread use. Hybrid processes, combining biochemical and chemical processes will enhance competitiveness of biobased products [18]. For example, bio-based polymers and bioplastics will grow their market share by synergizing and collaborating with the chemical process industry [19]. A deeper knowledge of systems biology and an integrated approach to process engineering will expand uses of biocatalysis (by enzymes or whole cells) as part of a manufacturing process [20]. Development of cell factories will rely on advances in the use of synthetic biology and metabolic pathway engineering. The conversion of cellulosic biomass into fermentable sugars could accelerate building biochemical plants (MIT Technology Review, http://www.technologyreview.com/ news/427145/cellulosic-ethanol-gets-a-100-millionboost/). The use of biomass derived fermentable carbon for the production of biosurfactants, biomaterials, and www.sciencedirect.com
biofuels is being employed by several companies [21]. Abengoa S.A., Beta-Renewables SpA., DuPont, and PoetDSM Advanced Biofuels, LLC, have successfully demonstrated conversion of cellulosic sugar to ethanol on a large scale with commercial deployment underway. DuPont has shown a fully integrated pilot process at a scale of 250 000 gallons ethanol per year at its Vonore, Tennessee plant. This pilot scale facility has demonstrated conversion of a variety of biomass feedstocks first to sugars and at the end to ethanol and thus generated the necessary data to build and operate a full scale plant that will produce 30 million gallons of ethanol per year at Nevada, Iowa, using corn stover (corn residues, including cobs, stalks, leaves) collected within a 30-mile radius. The company has begun to license this technology to third parties to produce biochemicals and biofuels. Decades of industrial experience, combined with scientific advances in metabolic engineering and synthetic biology, have now enabled the establishment of biorefineries. However, the success of a biorefinery platform will depend on the integration of processes at all stages from reliable feedstock to building the cell factory, to development of the fermentation process, downstream processing and product application. Simplification of processes is the key to improving the chances for a successful scale-up. One such approach is simultaneous enzyme(s) production and fermentation in which the fermenting organism can produce enzymes to release fermentable sugars from complex carbohydrate feedstock, and convert the released sugars to products. Such integration, called Consolidated Bioprocessing (CBP), has been put to use for production of ethanol Current Opinion in Biotechnology 2016, 38:112–122
116 Energy biotechnology
from starch by yeast [22], and there are proposals for developing CBP for biomass conversion using the cellulolytic fungus, Trichoderma reesei [23]. CBP without any enzyme(s) addition at start of fermentation, will not involve a separate enzyme production process, but to date there are no commercial examples of this approach. Pursuit of extreme productivity
Volumetric productivities of commercial fermentation processes typically fall within the range of 3–5 g/L/hour which is as much as 10-fold less than of many chemical processes. Notwithstanding differences in productivities (inverse of reactor residence time) due to temperature and pressure effects on chemical and biocatalysts, fermentation processes would benefit from use of higher cell densities (lower water content). In other words, current fermenter productivities are typically limited by gas solubility, mixing and heat transfer rates. One approach that uncouples cell density from these limitations is use of cell free production systems [24]. As outlined by Swartz [25] ‘The ability to exploit a cell’s contents and capabilities unimpeded by cell walls opens new opportunities for the field of biochemical engineering. Cell-free biology could become the basis for making products from hydrogen to cancer vaccines and more’. Progress in developing cell-free metabolic engineering includes demonstrations of pathways extending beyond 8 enzyme steps, near theoretical mass yields, volumetric productivities of several g/L/hour and scale-up into the hundreds of liters. Cell-free catalysis has been used not only in academia [26,27] but also for the commercial production of protein therapeutics [28]. Can the cell-free platform be considered for the fermentation-based production of free acid-form of certain chemical compounds? Among the building block chemicals outlined by the US Department of Energy that can be produced from sugars via a bioprocess, eight out of the top 12 are acids, with a fermentation process run at low pH being identified as key for commercialization [29,30]. In other words, pursuit of a cell factory chassis that is compatible with low pH production would offer benefits of reduced contamination and remove the need for sterilization. The fermentation production of the free acid-form of these chemicals could be beneficial due to its favorable impact on product recovery as well as by-product formation.
these objectives, a discovery to delivery approach that integrates a synthetic bio-operating system, chemical engineering practices, process safety, sustainability, and socio-economics considerations must be implemented [31]. Scale-up challenges are usually dependent on whether the product is a specialty or commodity chemical, where the difference in volumes of production can be of several orders of magnitude. Nevertheless, key success factors across the spectrum of volumes are listed in Table 2 and derive from personal and industry leaders’ experiences [32]. Factors relevant to scale up that need to be considered are discussed below. Feedstock availability and cost
Sugarcane, beet, grain, or biomass, are used as a source of fermentable carbon to produce an ever-growing list of biochemicals and co-product streams of significant value [33]. One of the major factors driving economics for production of renewable chemicals is feedstock availability and cost, and scale-up strategies must take this variable into account. Scale-up success depends largely on the correct matching of feedstock to process design. Today, most large scale processes utilize traditional carbohydrate feedstocks. For corn based ethanol, feedstock commonly represents greater than 50% of total production costs (https://www.extension.iastate.edu/agdm/ energy/xls/d1-10ethanolprofitability.xlsx). The cost of sugar feedstock has decreased dramatically from recent highs and is now very close to historical averages when adjusted for inflation. On the other hand, petroleum oil price is significantly lower than its inflation adjusted average, as a result of increased production in the US and a demand that has remained flat globally (Economist December 8, 2014, http://www.economist.com/blogs/ economist-explains/2014/12/economist-explains-4). This will clearly represent a headwind for biobased chemicals and fuels that compete directly with petroleum based materials (Figure 2). A good deal of effort has been directed at analyzing feedstock availability and costs of alternative sources including cellulosic biomass and macro and microalgae
Table 2
Factors relevant to scale-up
Key success factors for scale-up
A number of prevailing factors need to be considered and optimized when attempting to take a technological process into full commercial production. A major ramp-up in design, development, demonstration and deployment is needed to engineer predictable, controllable, and cost effective processing systems. Engineering principles have been and will continue to be critical for fulfillment of ever-increasing needs for environmentally efficient production of food, feed, chemicals, and energy. To meet
Integration of multiple disciplines Consistency from start to finish Working from same master plan Clear understanding of risk factors Strong mathematical and economic modeling Pilot where you operate Upfront approach to safety and regulatory Focus on waste stream minimization Product specifications determined early
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Figure 2
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Historic sugar, corn and petroleum feedstock price correlations. Inflation adjusted price for crude, #11 sucrose, and yellow #2 dent corn. Solid horizontal lines on chart indicate average adjusted price for each commodity. Note that prices for sugar and corn are trending towards historic averages, whereas that for petroleum appears to have moved significantly below its historic average. Data from EIA and USDA
[34,35]. The U.S. Department of Energy’s 2011 Billion Ton Study Update indicates that 600–1000 million tons of terrestrial biomass is available in the continental United States alone at a farmgate or forest roadside price of $60/ ton or less (http://www1.eere.energy.gov/bioenergy/pdfs/ billion_ton_update.pdf). Despite this, the current estimated cost for sugars from cellulosic biomass is more than that from sugarcane or corn. A range of tactics are being considered to bring the costs of lignocellulosic sugars down. These include improved enzyme activity [36], improved production organisms [37], valorization of the lignin component of the biomass [38] and CBP, which reduces the overall capital and operational expenses [39]. These and other efforts are anticipated to drive lignocellulosic feedstocks to more favorable economics. In addition, the value of byproducts generated from lignocellulosic feedstocks, including lignin, must be realized analogous to the cost offset provided by the value-added products derived from sugarcane or corn based processes. Despite technical success of a bio-process, feedstock availability at competitive cost can pose huge logistics issues; where the feedstocks www.sciencedirect.com
are available does not often align with where the end products are needed. Biocatalyst design considerations
Every bioprocess starts with the best possible biocatalyst, the cell factory, built by integrated science and engineering (Figure 3). The two main biocatalysts used in current bioprocesses are: Firstly, enzymes with wide range of activities and properties, especially for production of fermentable sugars; and, finally, engineered micro-organisms to produce chemicals. Today, most enzymes used in bioprocesses are of microbial origin, but their structures are not necessarily native to the host, that is, they are engineered. Protein engineering has allowed optimizing enzyme properties for specific use, and a number of different approaches have significantly improved enzyme performance [40]. Moreover, the engineered proteins need to be expressed at high levels in production strains that are approved by the regulatory agencies for no adverse effect in humans, animals, or the environment. Although a cell factory platform could accelerate process Current Opinion in Biotechnology 2016, 38:112–122
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Figure 3
performing biocatalyst is prudent as it would mean less capital, lower variable cost, and a simpler process. Strain Pilot phase
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Integrated science and engineering competencies applied to design and operate efficient cell factories.
development, a biocatalyst is usually created on a case-bycase basis. The availability of efficient and robust enzymes to process a large variety of feedstocks will remain critical for a successful biorefinery concept. The biocatalyst has a strong influence on the capital needed and determines the fixed portion of the production cost for the entire process. For example, oxygen requirement and method of its supply to the fermenters, is an important cost determinant (lower the oxygen demand, lower are the costs for agitation, pressure and aeration, allowing a bigger bioreactor scale) [41]. However, the heat generated by a process is proportional to the oxygen use, and therefore cooling costs can increase with the scale. Moreover, either addition of air/oxygen or generation of carbon dioxide, results in the formation of foam, which often is stabilized by proteins in the fermentation medium [42]. To control foam and better utilize the bioreactor capacity upon scale-up, process compatible antifoams have to be added, thereby optimizing the bioreactor–antifoam interactions for robust process. Thus, generating a better
Past experience from process scale up has shown that a rapid transfer of technological process from laboratory to commercial scale often fails. Especially, new commercial processes with new technology risks justify a pilot plant project. However, the commercial plant must be thoroughly and rigorously developed and documented to provide basis for the pilot plant. The understanding of the commercial plant package, with its risks and impact of alternatives/uncertainties needs to flow into the scope and breadth of the actual pilot plant operation. The essential elements for necessity of a pilot plant are listed in Table 3. It is axiomatic that Pilot Plants do not make money. Therefore, the justification for a pilot plant is strictly linked to the target commercial process. Integration of processes
The primary objective of fermentation scale-up is the integration of feedstock conversion and cell factory operation to produce the needed biochemicals. During bioprocess development cycle, the changes made in upstream unit operations can affect the downstream elements. The performance of cell factory during fermentation impacts the recovery and formulation units of the process. Therefore, an optimized integrated bioprocess development flow (Figure 4), can provide considerable time and money savings. Knowledge based on prior scale up experience, as well as that tapped from other industries is important in enabling a predictable scale up. Defining predictive metrics for effective scale up with appropriate project management skills is essential in scale up activities. Companies developing innovative technologies have an advantage in achieving competitive performance in shorter timeframes [43]. Process integration by combining unit operations can simplify and even enable the economics required for commercialization [2,44]. A distinct set of considerations like mixing, temperature, pH, pressure control requirements, biocatalyst robustness,
Table 3 Why a pilot plant Need to test process technology and fill gaps in understanding that are critical to the Commercial Scale. Need to gather essential data that is instrumental to successful scale-up of the Commercial plant for minimal cost, excellent quality and operate effectively against production performance goals. Gain Understanding of the operation of integrated process and develop longer term understandings of expected (and unexpected) process concerns. Produce product material for end use customers and tests. Build confidence in customers of ability to deliver quality products. Demonstrate ability to safely and effectively design, build and operate a facility with mitigations and strategies for any process hazard (flammability, toxicity, etc.). Reduce risk of non-performance at Commercial Scale.
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Figure 4
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Typical steps of integrated bioprocessing.
feedstock compositions appear to govern scale up of industrial bioprocesses. Bioreactor scale-up, characterized by transport phenomena, relies on optimally supplying carbon, oxygen, nitrogen, etc. to the microorganisms during production process. Standardized high capability fermenters are designed by understanding complex mixing, mass and heat transfer phenomena at various scales. However, the influence on cell physiology as scale changes requires additional measuring techniques. There is a clear need for a deeper understanding that distinguishes cell phenomena that occur at bench versus production scales [45]. Investment in this area might be analogous to Process analytical technology, defined by the US FDA for pharmaceutical manufacturing processes, that is, better design, analysis and control of processes through the measurement of critical parameters for both understanding and achieving consistency of scale-up. Current knowledge on cell physiology of microbes used in industrial fermentations has been derived from laboratory conditions of rapid growth and high metabolic activity. However, in industrial processes, microbial growth rates can be extremely slow approaching zero, and cell productivity often drops after reaching a peak. In commercial processes, carbon efficient production requires uncoupling microbial growth from product formation to maintain high productivity. Study of continuous culture cell recycle [46] could be a useful tool to investigate microbial physiology at low to no growth. Minimizing cell mass, www.sciencedirect.com
especially when costs for inactivation of genetically modified cell mass are high would be economically advantageous. Improving scale-up methods is essential to achieve the goals of high productivity uncoupled from growth, and high product yield sustained over prolonged period of fermentation. Regulatory requirements
The development of non-pathogenic and non-toxigenic recombinant microbial production strains when well characterized by generally accepted safety evaluation procedures [47] have found wide acceptance by regulatory agencies such as the US FDA [48] and US EPA (http:// www.epa.gov/opptintr/biotech/pubs/rulesupc.htm). Under the Toxic Substances Control Act (TSCA), EPA regulates the use of intergeneric microorganisms in commerce or commercial research (http://www.epa.gov/oppt/ biotech/pubs/biorule.htm). Regulations also differ country by country but irrespective of legislation, it is prudent for the product manufacturer to ensure that the production process, the potential product, and its intended use are safe before introduction. For example, the general acceptance of the safety of bioprocess based products tested against international standards by the Joint FAO/ WHO Expert Committee on Food Additives (JECFA, http://www.fao.org/food/food-safety-quality/scientificadvice/jecfa/en/), has allowed increased enzyme manufacture and use worldwide over the last few decades. It is imperative to keep in mind that safety issues relating to Current Opinion in Biotechnology 2016, 38:112–122
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Table 4 Factors affecting capital Readiness of the manufacturing facility Source commercial raw materials and supplies Produce a working cell bank and validate the cell bank for use in manufacturing Establish process equivalence of pilot/lab system to unit operations in manufacturing the manufacturing process using a ‘satellite’ approach Rank order process sensitivities to assess process robustness Scaling factor reliability for economies Distributed manufacturing options
environmental release are minimized when the genetically modified organisms are well characterized, designed to barely survive in the general environment, and grown under contained good large-scale industry practices.
Capital investment
Capital justification for commercialization, especially with new technology risks, often undergoes a stage-wise process (Table 4). Capital costs in some cases have been reduced by creatively ‘recycling’ production plants. For example, Butamax Advanced Biofuels LLC, Gevo, Inc. and Green Biologics Ltd. have focused on retrofitting existing ethanol plants for butanol production rather than building new ones (The New York Times, http://nyti.ms/1CbWh1X), offering benefits of infrastructure already in place. Yet another approach to managing capital investment has appeared in the form of distributed manufacturing, for example, Green Ethanol Micro-Distillery using modular equipment for small-scale biofuel production. Green Social Bioethanol is propagating its rural scale robust, low maintenance enzymatic hydrolysis and fermentation process. Their versatile and efficient model aims to utilize a wide variety of starch and sugar feedstocks to supply fuel, feed, and fertilizer sustainably across the world including remote areas (https://www.ashoka.org/fellow/eduardo-mallman). Distributed manufacturing is projected to gain traction as synthetic biology evolves [49], namely, the assembly of standardized bio-components by applying system design principles to build customized bioprocesses targeted to meet specific human needs.
Concluding remarks/perspectives Scale-up is not a separate activity posted onto a research and development phase; it must be integrated with the project from the very beginning. Since scale-up usually marks the beginning of significant capital expenditure, a strong economic justification for the biomanufacturing process is a prerequisite for success. The observation that many early stage biotechnology companies in particular have suffered severe market capitalization losses due to scale-up challenges and subsequent delays underscores its importance. Pricing of feedstocks, competition, market conditions, policy and regulatory changes, etc., represent the headwinds that must be faced when considering commercialization. Current Opinion in Biotechnology 2016, 38:112–122
The formative integration of synthetic biology with process engineering and application to improve scale-up methodology is essential for success. Such a technological combination will drive to a future state where the high throughput cell ‘design, build, and test cycle’ is accomplished at bench scale in high throughput mini-reactors that accurately mimic reactor conditions at large scale. The decision on how to scale up a process is dictated by managing risk/reward. The opportunity for next generation scale-up is to improve the probability of success, that is, increasing speed to market, limiting capital/time at pilot stage and maximizing value creation. One way to accelerate this process would be through the framework of a National Network for Manufacturing Center directed at bio-manufacturing (http://manufacturing.gov/nnmi. html). Such an infrastructure would be focused on bridging the gap between R&D and commercialization grounded by the roadmap for the industrialization of biotechnology (http://www.nap.edu/catalog/19001/ industrialization-of-biology-a-roadmap-to-acceleratethe-advanced-manufacturing).
Acknowledgements The authors thank F Glenn Gallagher, Vincent Sewalt and Eli Ben-Shoshan for helpful comments and Roopa Ghirnikar for expert overall manuscript design and preparation.
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