SBE Supplement: Commercializing Industrial Biotechnology - Technology Challenges and Opportunities | AIChE

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SBE Supplement: Commercializing Industrial Biotechnology - Technology Challenges and Opportunities

SBE Special Section
June
2016

Industrial biotech is the third wave of modern biotechnology, and it promises to be the biggest wave — bigger than biopharma and agricultural biotech.

Biopharmaceuticals (biopharma) and agricultural biotechnology (ag biotech) are commonly referred to as the first and second waves of modern biotechnology (1). The first biopharamaceutical, human insulin, was approved by the U.S. Food and Drug Administration in 1982 (2). Biopharma global revenue is now $163 billion/yr, accounting for 20% of total pharma revenue, and is growing at twice the rate of conventional pharma (3). The first genetically engineered crops were commercialized in the U.S. and Europe in 1994 (4, 5). Today, ag biotech global revenue is $28 billion/yr, accounts for 10% of agricultural crops globally, and is growing at 11% per year (6).

Industrial biotech, the third wave, already has revenues of approximately $140 billion/yr (1). It is dominated by traditional products, such as ethanol, bulk antibiotics, amino acids, organic acids, enzymes, etc., most of which are now enhanced by the application of genetic engineering techniques.

It seems industrial biotech is at a pivotal point, with tremendous and ongoing growth in technology contributing to a rich pipeline of opportunities: new products; new and more sustainable ways to make established products; and improvements to existing products and processes. The trillion-dollar questions are: When will there be a commercial breakout in industrial biotech as there has been in biopharma and ag biotech? What advances in technology are needed to make that happen?

This article is drawn from the Workshop on Technology Challenges and Opportunities in Commercializing Industrial Biotechnology, sponsored by AIChE’s Society for Bio­logical Engineering (SBE) and held Sept. 28–29, 2015, in San Diego. The workshop brought together industrial biotech stakeholders to share — through presentations, case studies, interactive discussions, and exhibits — perspectives on the state of industrial biotech, as well as to address key areas for technology advancement to benefit commercialization. The attendees represented large and small companies, academia, and government laboratories; the oil and chemical industries, agri-business, biotechnology companies, engineering and construction firms, and consulting companies; as well as private investment concerns. Most of the presentations can be accessed at www3.aiche.org/proceedings/Conference.aspx?ConfID=CIB-2015. Based on the participants’ positive feedback, this will become a recurring event. The next workshop is scheduled to take place in September 2017 in San Diego.

The journey has just begun

Industrial biotech is 15 years into the long journey typical of disruptive technologies, and the sector faces numerous significant challenges. The macro environment has changed from what it was 10 years ago, when oil and natural gas prices were high, a carbon tax was on the horizon, and the tech sector was booming. Today, many industrial biotech initiatives are struggling in an environment of low oil and gas prices and lack of clear, stable government policy. They are competing for capital with information technology (IT) start-ups that require only “caffeine and a laptop.” Furthermore, it is harder to create a compelling case for industrial biotech than biopharma (e.g., “cure cancer”) and ag biotech (e.g., “feed the world”). And, it is operating amid the confusing food vs. fuel debate.

On the other hand, industrial biotech will ultimately have a bigger positive impact on the quality of human life than biopharma, both directly (e.g., nutrition, antibiotic replacement products) and indirectly (long-term health of the planet through sustainable development) (7). In addition, industrial biotech feedstocks will benefit, in terms of abundance and reduced cost, from continuing innovation in agriculture (8–10). Waste materials, biogas, and natural gas will also become important industrial biotech feedstocks.

In this challenging environment, industry must focus on what biotechnology can do well and apply that to solve problems that have near-term commercial value. In doing so, it should embrace some key lessons learned.

Rigorous targeting of which bioproducts to develop is essential and demanding, in part because established producers of competing products (often with depreciated assets) will defend their market positions. Consequently, new bioprocesses for existing products must have at least a 30% cash cost advantage compared with the best available commercial technology. Novel bioproducts must provide a threefold to tenfold improvement in properties over the existing commercial alternatives. Industry should not count on any sort of “green premium” for most products.

Fine chemicals and natural products are appealing in the current commercial environment, as they have higher price points and are less subject to feedstock volatility. Products that cannot be readily made by chemical methods are also attractive targets.

Win-win relationships need to be developed across the entire value chain. Engage downstream partners upfront to reduce market risk. Look for markets where there is a strong pull for new products (e.g., flavors and fragrances, nutrition, agriculture).

Industrial biotech needs a proponent in government that is analogous to the U.S. National Institutes of Health (NIH), which has done a remarkable job of translating its $30-billion/yr expenditures into benefits and in educating the U.S. Congress.

Water is the most mispriced commodity, and is in very short supply in many regions of the world. Most fermentation processes are water-intensive, but opportunities exist to increase recycling and to develop processes with much lower water consumption (such as solid-state fermentation).

Scale-up is expensive, and industry is risk-averse. Many opportunities exist to reduce the risks of scale-up through innovations in lower-cost, more-robust, large-scale processing. This is an ideal area for government investment — for example, as a processing-oriented follow-on to the Defense Advanced Research Projects Agency’s (DARPA) Living Foundries program, which aims to leverage the synthetic and functional capabilities of biology to create a revolutionary, biologically based manufacturing platform to provide access to new materials, capabilities, and manufacturing paradigms.

To make use of C1 feedstocks, anaerobic fermentation of carbon dioxide and hydrogen is appealing. Methane fermentation is challenging, but its viability could be enhanced by a CO2 co-substrate (11).

Process design: Think about full-scale from the start

The best path for process design envisions the entire process at full scale (e.g., feedstock, conversion, separation, etc.) even before experimental work begins. This provides early inputs on key areas such as process economics, scale-up considerations, host microorganism selection, and strain engineering. The pre-experimental planning typically identifies multiple microorganism and processing options for consideration and testing. Thermodynamics is fundamental and should serve as the basis to identify the best metabolic stoichiometries, fermentation rates, and operating conditions.

Even with upfront process design insights, it can be tempting to choose a suboptimal microorganism that enables faster initial progress in strain development. But doing so would ultimately yield a suboptimal process with higher production costs. When facing this choice, at least for cost-sensitive fuels and chemicals, it is wise to choose the microorganism and processing equipment that will comprise the lowest-cost process. In particular, look to the micro­organism (which can be thought of as analogous to software) to solve problems rather than adding more unit operations, energy, and materials (which can be thought of as analogous to hardware). Fermentation titer (i.e., concentration), rate, and most importantly yield (which collectively are referred to by the acronym TRY) are typically the most essential process metrics. Processes must operate at 80% or more of theoretical yield to be commercially viable.

It is important to maintain an integrated scientific/engineering approach throughout the experimental program, with clear targets and iterative techno-economic analysis. Avoid project hand-offs from one functional group to another. To accelerate progress and ensure success, bring together the best scientific, engineering, and project management expertise.

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Figure 1. DuPont Tate & Lyle Bio Products Co. makes 1,3-propanediol (bio-PDO) at its plant in Loudon, TN. The plant started operating in 2006 and was expanded in 2011 to its current capacity of 140 million lb/yr. Photo courtesy of DuPont Tate & Lyle Bio Products Co.

DuPont’s development of a new polymer platform based on 1,3-propanediol (PDO) was aided by strong relationships and partnering with Genencor for strain development and Tate & Lyle for feedstock sourcing, process development, piloting, and manufacturing to enable low-cost PDO production. This effective risk-management strategy enabled DuPont Tate & Lyle Bio Products Co. to successfully commercialize bio-PDO in 2006 (Figure 1).

Intrexon’s approach to developing natural gas as a fermentation feedstock is an example of full-scale-first thinking. Natural gas is an appealing feedstock because of its relatively low cost. On an energy basis, the cost of natural gas, at $3/million Btu ($164/ton, 52 GJ/ton), is about 49% of the cost of oil at $40/bbl ($294/ton, 46 GJ/ton) and 18% of the cost of refined carbohydrate feedstocks at $300/dry ton (17 GJ/ton). (Natural gas is also...

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