(336g) Critical Issues in the Development of Commercial Natural Gas to Industrial Chemicals Bioprocesses

The low cost and abundant supply of natural gas make it America’s greatest untapped energy resource, leading to the development of technologies for natural gas conversion to compounds of greater value. Intrexon has developed the first natural gas-to-liquids bioconversion platform powered by methantrophic fermentation, which applies synthetic biology to program bacteria and produce higher value materials. Our innovative genetic toolbox allows us to engineer the biology of the methanotroph to more efficiently convert natural gas into a wide range of valuable chemicals and fuels. These applications include isobutanol, farnesene, 1,4-butanediol, 2,3-butanediol, isoprene and isobutyraldehyde – the building blocks for industrial and consumer products like fuels, synthetic rubber, acrylics, resins and spandex.

Using a methanotrophic bioprocess to produce fuels and chemicals has several advantages. Natural gas bioconversion offers scaling opportunities beyond traditional gas-to-liquid (GTL) facilities, as well as biomass feedstock facilities. The theoretical yields of methanotroph/methane exceed that of yeast/sugar approaches by a wide margin. Biocatalytic processes that achieve high yields under milder processing conditions allow for reduced capital and operation expenditures, offering greater economic viability. To successfully bring this technology to commercial scale, consideration must be given not only to optimizing the bacterial metabolic pathway, but to key issues in the fermentor design, downstream processing, scale-up and overall plant economics.

At any scale, aerobic natural gas fermentation must overcome the challenge of gas-to-liquid transfer of low solubility gases to increase bioavailability of gas substrates to the bacteria. A low gas-to-liquid mass transfer rate reduces the bacterial productivity and process yield, which in turn increases fermentor size, capital cost, operating costs and may add additional equipment necessary to recycle gases. During commercial scale-up of gas fermentation processes, these factors can become cost prohibitive. Standard stirred tank reactors become unfeasible for use at larger scales, as the agitator power input and size become excessive. There are many fermentor designs currently available to increase the overall mass transfer coefficient of these gases. However, capital and operating expenditures of the reactor are critical metrics for evaluating commercialization feasibility. Unique fermentor configurations can greatly increase capital cost by raising the cost of fabrication and decreasing the ability to receive competitive bids. These unique fermentors also may not create a homogenous, well-mixed broth – which increases the cost of controls and instrumentation. The economic feasibility of gas transfer designs must be balanced with the biologic effects of reactor forces on the bacteria. Methods of increasing mass transfer often include increasing turbulence in the reactor, which can create detrimental effects on the bacteria through high shear forces, high pressure and vacuum areas, and dissolved gas substrate inhibition. Careful equipment selection and pilot trials are necessary to determine the various effects of gas transfer methods on mass transfer rates and cell viability.

Downstream process selection for commercialization is a balance of biologic limitations, technical feasibility, capital cost, operating cost and the risk of cutting-edge over well-established techniques. The developing bioprocess must be iterated upon the limitations of strain engineering and practicality of downstream processing techniques. Fermentation broth concentrations may be low to product inhibition on the cell, but this increases the size and energy requirement of downstream equipment. Cutting-edge technologies can increase the efficiency of low titer separation and reduce energy inputs, which can be capital intensive and unproven at commercial scales. Genetic engineering tools can increase the tolerance of the bacteria to products. However, the directed or natural evolution process requires time.

A minimum broth titer must be determined through techno-economic modeling of processes at each stage of process development and refinement. Bioprocesses also create metabolic byproducts which can add unit operations, and therefore cost, to the downstream purification process. Some byproducts may originate from the genetic pathway or from commercial feedstocks, as they are often lower in purity and have higher variability than those at the research scale. Additional downstream steps must be evaluated to determine if they are technically and economically feasible to meet final product specifications for sale, or if the byproduct genetic pathways can be manipulated to terminate production and not add cost to the overall process.

Furthermore, certain tools that aid in genetic engineering and strain development at the research and development scale must be eliminated or retooled to create commercially viable strains. During development, production pathways are often introduced to the bacteria through plasmids which carry antibiotic resistance. To avoid the material cost and downstream separation of the antibiotic at commercial scale, the genetic material must be integrated into the chromosome. This genomic integration may affect the strain’s capability to produce product at previously observed yields, titers and rates. Another common development tool is that production pathways may be turned on or off using an externally applied chemical inducer. At scale, these chemical inducers can add material cost as well as affect downstream processes and product purity. Induction systems may be completely removed for commercial scale or based off an easily controllable environmental switch.

Favorable plant economics are necessary to move forward with commercialization of a technology. Scale is carefully selected based on a comparison of the production rate, fermentation productivity and yield targets to revenue, capital and operating costs. The plant location is an important selection factor, as costs are affected by utility rates in the area and/or co-location of the plant with shared infrastructure.

Traditional engineering workflows, specifically front-end loading strategy, were used to shape the commercial scale process design of Intrexon’s natural gas to chemical plants. The biologic, technical and economic commercial feasibilities of the end-to-end natural gas to isobutanol process were critical to Intrexon’s plant design. Laboratory scale learnings were applied to select technology that was commercially feasible at demonstration scale. This demonstration scale design was scaled down to pilot scale, where the operation will yield learnings into refinement of at-scale design, equipment selection, empirical data on heating and cooling, and controls strategies and feedback to further iterations on genetics.