Introduction

Fermentation as Production Technology

Fermentation is to be conceived as a production technology competing with natural extraction, organic chemistry, and biocatalysis. All three technologies to access chemical products have their own advantages and disadvantages.

Raw material extraction, which may be regarded as the first production technology, uses natural crops as reactors with controlled cultivation to make chemical products. The production technology is facing limited arable land that could alternatively be used for food production, and an expansion is critical. The cultivation period might be long and define a critical hurdle in case a period of several years is required. Raw material extraction often bears a high extraction cost since the product is mixed with various other crop ingredients. The low content of the target molecule in the biomass might be increased to improve production economics. Subject of raw material extraction might be a natural variety (wild type), a non-natural variety derived by breeding, or a genetically modified variety obtained by plant biotechnology (Chawla 2003; Kempken and Kempken 2004). Most of the agronomic varieties applied for industrial food production were obtained by breeding and possess a higher product content and thereby provide a higher yield per ha than the original natural varieties. Given the inherent disadvantages, natural extraction has in many instances been supplemented or been replaced by organic chemistry, like for natural dyes (Wittke 1984), flavors, and fragrances.

Organic chemistry offers a broad range of potential reaction conditions with respect to temperature, pressure, pH, and organic solvents. It often facilitates high yield (turnover × selectivity), high productivity (space-time-yield), and reasonable investment efforts. Accordingly, the technology has seen a tremendous development and is broadly applied in the petrochemical and chemical industry (Arpe 2007). Organic chemistry has allowed a significant reduction of production costs and enabled the synthesis of many molecules and polymers or plastics, respectively, not found in nature. It has often replaced, supplemented, or at least partially pushed back natural extraction into niche markets, like e.g. in the case of terpenes (Breitmaier 2005) and vanillin (Banerjee and Chattopadhhyay 2018; Kaur and Chakraborty 2013).

Biocatalysis uses enzymes as catalysts and is favored in case an enantioselective synthesis is needed to derive, e.g. chiral alcohols or amines (Hilterhaus et al. 2016). The technology is in some instances applied in high-volume applications, such as the isomerization of glucose into fructose for the soft drink industry (Schmid 2016), but it is often a niche technology for complicated molecular functionality not accessible via organic chemistry within a reasonable number of steps (Faber 2011). Biocatalysis is favored in case the needed raw material conversion is merely an isomerization or a hydrolysis since no cofactors are required. Thus, most of the industrial enzymes applied in the food, feed, or detergent industry are hydrolases, which exclusively rely on water as a cofactor (Sahm et al. 2013). On the other hand, if the needed raw material conversion is a redox reaction in which electrons are transferred, the biocatalyst depends on cofactors like NADH or FAD, which are very costly. For the synthesis of low-volume fine chemicals with sufficient value perspective, suitable cofactor regeneration systems are available (Wu et al. 2021; Grunwald 2018), but synthesis routes for low-value commodity products are often not commercially feasible.

Fermentation has historically covered the microbial conversion of carbohydrates in the absence of oxygen. The term was originally introduced by Louis Pasteur: "La fermentation c'est la vie sans l'air" (Schegel 1992). Fermentation initially happened accidentally if non-sterilized carbohydrate containing food or biomass was stored in the absence of oxygen and was then culturally developed as an on purpose conservation technology. The cultural history of e.g. alcoholic beverages mirrors the long-term development of fermentation technology. The conceptual restriction of fermentation as an exclusively anaerobic process was later given up, and the meaning of the term now comprises the anaerobic and the aerobic conversion of chemical feedstocks by prokaryotic or eukaryotic hosts (Schegel 1992). The application field of fermentation may be differentiated into "White Biotech," the production of fuels and chemical intermediates, "Red Biotech," the production of recombinant proteins and human antibodies for pharma application (Lee and Kildegaard 2020); and "Industrial Enzymes," the production of enzymes for application in industrial processes. The focus of this book in on "White Biotech."

Rising Interest in Fermentation as Production Technology

Production costs and price, respectively, have been up until now, for chemical high-volume products the most important and, in some cases, the single decisive purchase criterion. The products are regarded as "commodities," opposed to "specialties", with low-volume demand, higher molecular functionality, and potentially customization to meet the defined requirements of single customers. The marketing of high-volume chemicals appeals to molecular functionality and specification. The low-cost level of the still dominant petrochemistry is mainly enabled by the circumstance that oil refining to make gasoline for automotive combustion engines generates byproducts like naphtha, which is handed over to chemical companies to feed a cracker (Baerns et al. 2013; Jess and Wasserscheid 2013). The cracker reassembles the C-C bonds of naphtha to derive the main four petrochemical aliphatic intermediates, i.e. ethylene, propylene, isobutene, butadiene, and the three aromatic intermediates, i.e. benzene, toluene, and xylene.

Fermentation is the technology of choice for producing pharma proteins, antibodies ("Red Biotech") and enzymes ("Industrial Enzymes"). Though there is an increasing interest in fermentation technology for high-volume chemicals with much less advanced molecular functionality ("White Biotech"), which receives promotion in national industry development plans. The US bioeconomy strategy pursues the direction of "moving beyond fuels toward biobased and bio-enabled production of chemicals and other products" (A Bioeconomy Strategy 2022). The growing importance of fermentation as production technology and the increasing share of "white biotechnology" to replace petrochemistry are due to several reasons (Rosales-Calderon and Arantes 2019; Tsuge et al. 2016; Jang et al. 2012).

Biobased raw materials and product carbon footprint considerations are gaining importance, although production costs are still the most important sourcing criterion for chemical products. Chemicals might additionally be marketed with reference to their biobased origin if the raw material is derived from natural sources and the integrated carbon has originally been derived from carbon dioxide captured out of the atmosphere via photosynthesis. The interest in biobased products represents a rising trend for about 20-30 years. Biobased origin was traditionally an advantage for chemicals applied in the food or cosmetic industry with high proximity to the final consumer, which achieved a price premium in the market (Ravenscroft 2019; Ravenscroft 2013). The price premium is required since the production starting with natural extraction and some chemical conversion steps is often more costly than a petrochemical synthesis. It can be observed that in parallel to food ingredients and cosmetics also markets for biobased chemical intermediates are developing, and petrochemistry is facing competition from alternative feedstocks. The reason of this trend reflects the growing customer demand for natural products and the concern that the high carbon dioxide emissions associated with petrochemistry need to be overcome for climate protection. The trend is enforced by national and international regulation and shifting customer attention as well.

The claim of a biobased origin might be achieved via the direct use of a natural feedstock or mediated via a mass balance approach in which the biobased carbon origin of natural feedstocks is allocated to a petrochemically generated product. Fermentation technology profits from the trend toward biobased feedstocks since glucose and sucrose are biobased and derived from, e.g. corn, wheat, sugar beet, sugarcane, or cassava. Fermentation might be the technology providing the lowest production cost, such as in the case of ethanol, lactic acid, citric acid, glutamic acid, and lysine, and has become the leading technology irrespective of its conversion of biobased feedstocks. On the other hand, in case fermentation incurs higher cost than petrochemistry, a price upside in the market is required. Biotech companies and startups were often inclined to overestimate the biobased price premium. Fermentation technology was often able to provide a sound production process, though the marketing success was limited given a cost level above petrochemistry. It turned out that the market success of fermentative products often requires cost equivalence or functional...