SBE Supplement: Commercializing Industrial Biotechnology - Use Cost Models to Guide R&D | AIChE

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SBE Supplement: Commercializing Industrial Biotechnology - Use Cost Models to Guide R&D

Applying cost models throughout the development of microbial strains and production processes can reduce the time and cost of commercializing new fermentation products.

Imagine a future in which most consumer and industrial products are created from sugar, sunlight, and garbage — transformed by microbial catalysts into a cornucopia of useful chemicals and materials. As the worldwide population expands and nonrenewable resources are increasingly depleted, it is critical to develop renewable sources of chemicals and materials from plentiful feedstocks, and to develop chemicals and materials with novel beneficial properties.

Engineered microorganisms are a key to solving this challenge, as they can be used to manufacture a diverse array of renewable specialty chemicals, commodity chemicals, pharmaceuticals, and fuels. Many such products are already on the market, and an even larger number are under development. In addition to their sustainability benefits, these bio-based approaches to chemical production can also address technical challenges such as stereospecificity and novel material properties, as well as economic challenges such as supply and price fluctuations and natural product scarcity.

Recent developments in synthetic biology have enabled a dazzling array of proof-of-concept demonstrations in academia, but the path to commercialization of new fermentation products remains long and costly. Research and development (R&D) must reduce the costs and time required to move products to market. From improving microbial strains to optimizing scalable processes for fermentation and product recovery, this effort typically takes 10–20 years and $70–150 million (1).

This highly interdisciplinary R&D requires computational and data scientists, molecular biologists and biochemists, assay developers, high-throughput screening (HTS) specialists, analytical chemists, and chemical engineers focused on fermentation, recovery, and applications development. Management of the R&D program requires a common framework for decision-making that extends across all of these disciplinary specialties. Appropriate techno-economic analyses (i.e., cost models) can provide this framework to facilitate communication, accelerate development, maximize efficient use of resources, and avoid costly missteps. Cost models for the production process should be developed early and used as a guide throughout the entire R&D program.

This article summarizes general recommendations and specific approaches used at Amyris for applying cost models to decision-making throughout R&D. It addresses creation of an R&D pipeline with predictable scale-down and scale-up fidelity, simplification of the cost model to emphasize major cost drivers that can be improved by strain and process changes, and application of the simplified cost model to guide strategic and tactical decisions.

Amyris is an industrial bioscience company that has successfully commercialized production of isoprenoids from sugar via fermentation with engineered microbes. For example, in the Biofene farnesene-production program at Amyris, the yeast Saccharomyces cerevisiae has been extensively engineered and evolved for high product yield and productivity of an anabolic isoprenoid product in an oxygen-limited, sugar-fed fermentation.

High-fidelity scale-down and scale-up

Generating the technology for industrial-scale production of chemicals with lower cost, more abundant supply, and/or improved performance involves four stages:

  1. Identify the target molecule, biosynthetic pathways, and fermentation feedstock(s).
  2. Create and test initial microbial strains in initial processes to demonstrate proof-of-concept.
  3. Improve the strains and processes iteratively. Work on downstream chemistry and application development often begins at this stage.
  4. Scale up production from the laboratory scale to the commercial scale.

Sometimes, the initial commercial-scale production marks the end of R&D for a product. In other cases, processes are scaled up before the final strain and process are ready, and R&D continues in parallel for subsequent rounds of manufacturing. This rapid prototyping produces larger volumes of product earlier (for downstream development, certification, etc.), generates valuable feedback for the plant design team, enables more-accurate cost estimations, and helps in refining scale-down models of different unit operations.

Initial proof-of-concept. Once the target molecule, biosynthetic pathway, and fermentation feedstock are chosen, strains that produce the target molecule are constructed and screened. Metabolic engineering is the field of study and practice in which chemical reactions inside cells are redirected to maximize the formation of a target product and minimize the formation of byproducts (1). Sometimes metabolic engineers seek a microbial host that naturally makes the target molecule and then enhance production in that host. In other instances, metabolic engineers choose a microbial host that does not naturally make the target molecule but has other advantages (e.g., genetic malleability, extensive background information and tools, favorable regulatory status, fermentation robustness), and then introduce the chosen metabolic pathway.

Introduction of a non-native biosynthesis pathway and optimization of any biosynthesis pathway are facilitated by the powerful genetic engineering tools developed by practitioners of synthetic biology. Synthetic biology pairs mathematical modeling for design and interpretation of new biological systems with an increasingly powerful suite of tools for large-scale manipulation of genomes and cellular behaviors (2).

While building and testing initial strains that make the product of interest, it is critical to consider factors that impact process development and subsequent strain improvement. For example: Is the product toxic to the host cells? Will the product be transported across the cell membrane or need to be extracted from the cells? Can a product yield (i.e., mass of product made divided by mass of feed consumed) sufficient for commercial viability be achieved?

The last question depends on the maximum potential product yield calculated from stoichiometries of all metabolic reactions available in the organism (3). If that is too low, the feasibility of introducing new metabolic reactions (with more favorable stoichiometry) into the organism can be considered. For example, the native metabolism in S. cerevisiae requires too much sugar and oxygen per mole of isoprenoid to be cost-competitive with petroleum fuels. However, implementation of a modified central carbon metabolism using enzymes from other organisms increases the maximum theoretical product yield from sugar by 1.25-fold and increases the oxygen efficiency by 3.3-fold (4), thereby greatly reducing the cost of manufacturing. Although this approach is quite challenging, Amyris has employed it successfully.

The initial proof-of-concept (POC) for a new fermentation product includes, at a minimum, demonstration of a baseline strain, fermentation process, and recovery process. A primary goal of the POC process development is to establish a general process and identify the key unit operations, as well as the initial operating conditions, to inform a preliminary cost model.

Improvements in strain performance and process development. The path from the POC to the strain and process suitable for manufacturing is long and expensive. The overall goal is to devise the lowest-cost combination of microbial strain, feedstock source and preparation process, fermentation process, and downstream recovery process that delivers a product that meets specifications. Preparation of the manufacturing technology transfer package requires careful consideration and management of the interactions among microbial strain, process, measurement technology, and economics...

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