TK 4009 Bioproses Industrial

3 Maret 2015

Chapter 9 Industrial Biotechnology in the Chemical and Pharmaceutical Industries

• Global initiatives such as, for example, the United Nations Environment Program, the World Summit on Sustainable Development in Johannesburg, and the Global Product Strategy and Responsible Care program of the International Council of Chemical Associations (ICCA ) are aimed at minimizing significant adverse effects of the use and production of chemicals on the environment and human health.

• The minimization of waste in relation to product is the goal of both green chemistry and white/industrial biotechnology where nature’s catalysts are leading the way in industrial process designs.

• Since biocatalysts are easily degradable and non - toxic, procedures using biocatalytic tools have not only found their way into industrial large - scale production in the chemical and pharmaceutical industries, but are also finding increased application in the research and development phase. An overview of some of these processes will begiven in this chapter.

Beta - Lactam Antibiotics Building Blocks

Beta - Lactam Antibiotics The Side - Chains

• A wide variety of side - chains for β - lactam antibiotics have been developed over the years.

• This was originally done by diastereomer crystallization, which means that a chiral acid (e.g., camphorsulfonic acid) is added to the racemate, forming diastereomeric salts, of which only one crystallizes. This is still the dominating process for D – PG production, although enzymatic processes have been described.

• D - HPG, on the other hand, is only made by an enzymatic process via a hydantoin

Beta - Lactam Antibiotics Enzymatic Semi - Synthesis

• New β - lactam antibiotics were originally made by adding new side - chains to the fungal fermentation broth, but that had limited success because of the selective uptake of these compounds by the fungi. For the chemical coupling of side – chain and nucleus, two processes have been developed, both of which suffer from disadvantages such as deep cooling (Dane salt method) and reactive chemicals (Dane salt and Dane anhydride method). Recent research, initially at NOVO, Denmark, and completed by DSM and the universities of Delft, Groningen, Nijmegen, and Wageningen in the Netherlands has led to the development of an enzymatic coupling process, using the same or similar penicillin acylase as was used for the removal of the side - chain in the fungal β - lactam antibiotic (see Scheme 9.2 ). For thermodynamic reasons, the D - (H)PG amide is used instead of the free acid.

Beta - Lactam Antibiotics Enzymatic Semi - Synthesis

• A production plant for cephalexin based on this reaction was opened by DSM Chemferm in Barcelona (Spain) in the late 1990s. The new process has clear environmental benefits as well as improved product quality and product stability [4] . Overall, compared with the traditional chemical routes, the combination of direct fermentation of the 7 - ADCA structure together with the biocatalytic side -chain replacement has led to improvements of 50% or more on important parameters such as solid waste formation, emissions to air, energy need, toxicity, and risk potential and consumption of reagents and solvents

Chiral Building Blocks

• The benefi ts of biocatalytic production routes lie not only in the way a product is manufactured but also in the knowledge acquired about the routes not chosen. Thus a network of bridges between stoichiometric, catalytic, and biocatalytic reactions is created upon which new productions can be based

Building Blocks for Polymers

• Acrylamide is a building block for polyacrylamide, which is widely used in the laboratory for separation in chromatography and electrophoresis or as a water - soluble thickener in wastewater treatment and paper making. The monomer is made by the addition of one molecule of water to acrylonitrile, which in turn is made from naphtha - derived propene and ammonia. The conversion of acrylonitrile to acrylamide has been done for many decades using a copper - based catalyst at 80 – 140 ° C. Although the process is efficient, it produces toxic wastewater containing copper and HCN. The high temperature used leads to undesired polymerization of acrylamide which makes it necessary to purify the product.

• In the 1970s, in the laboratory of Professor Hideaki Yamada in Kyoto (Japan) some microorganisms were found which were able to grow on acrylonitrile. They hydrolyzed the substrate to acrylamide and subsequently to acrylic acid, which was then further metabolized.

Building Blocks for Polymers

• Initially Pseudomonas chloraphis was used, but later optimized Rhodococcus rhodochrous became the standard. The process runs at much lower temperature than the chemical process (0 – 15 ° C), avoiding spontaneous polymerization and subsequent purification. The latter factor appeared to be the key success factor in economic terms. Both the substrate and the product are reactive compounds but the cell - free extract tolerates up to 500 g/l of substrate when immobilized in polyacrylamide.

Building Blocks for Polymers

• Polylactic acid ( PLA ) has properties comparable to those of polyethylene and polypropylene. It is less heat resistant but much more biodegradable. The joint venture NatureWorks (now owned by Cargill) has a PLA plant in Blair (Nebraska) since 2002, with a production capacity of 140 000 tonnes per year

• Another building block for plastics is 1,3 - propanediol, made by DuPont from glucose in a fermentative process. The microorganism was heavily optimized by pathway engineering. 1,3 - Propanediol produced via fermentation has a lower cost of manufacture than that produced via the competing chemical processes, and uses a renewable feedstock

Fine Chemicals: Statins

• Increased cholesterol levels are a growing concern to the health of the human population and it is no wonder that a cholesterol - lowering medicine like atorvastatin (Lipitor ™) is the best - selling drug at the moment worldwide [6] . Statins are inhibitors of HMG - CoA reductase, an essential enzyme in the biosynthesis of cholesterol.

Amino Acids

• Tidak dibahas, sudah menjadi topik Rancangan Pabrik.

Biocatalytic Processes: Business and Commercial Perspective

• Today the chemical industry produces 27 million tonnes of organic chemicals such as polymers, pharmaceuticals, fine and specialty chemicals, and more for all segments of our daily life worth 2000 billion euros worldwide (Figure 9.6 ). Most products are produced by chemical synthesis starting from simple chemical building blocks produced from fossil oil.

• Industrial biotechnology has been well established in the chemical industry for decades. However, it contributes only 50 billion euros or 2% to the chemical industry’ s sales volume of 2000 billion euros, mainly in the three segments pharmaceuticals, fine and specialty chemistry as well as detergent and hygiene products.

Biocatalytic Processes: Business and Commercial Perspective

• This changing economic environment is already favouring innovative new products and new processes. Cargill ’ s polylactic acid is an example of a new polymer based on biorenewable feedstocks. Lactic acid is produced by fermentation based on sugar and further on polymerization by chemical processes. Combining biotechnological and chemical process steps may represent a prototype for the future chemical industry. Cargill have already invested in a 140 000 tonnes per year plant.

• Since 2004 Evonik have produced the antiknocking agent ethyl tert - butyl ether with a capacity of 250 000 tonnes per year using bioethanol as feedstock. DuPont Engineering Polymers produces Bio - PDO (propanediol) as a starting material for Sorona and other hybrid polymers

Conclusions • When we devise new routes for bulk chemicals, we must look carefully at

the starting material to be used. More specifically, many important bulk chemicals (caprolactam, acrylamide, pyridine, etc.) contain one or more nitrogen atoms. The conversion of molecular nitrogen to ammonia, which is the feedstock for all nitrogen - containing compounds in the (petro)chemical industry, is very energy -intensive. Conversely, biomass contains a lot of nitrogen which has been fixed by nature in the form of amino acids, proteins, and nucleic acids. Proteins in particular comprise a large proportion of the biomass and can be conveniently isolated and it would be very important to consider their constituents (aminoacids) as a feedstock for the bio - based production of nitrogen - containing bulk chemicals.

• In conclusion, the perspectives for industrial biotechnology in the chemical and pharmaceutical industry and for the partnership of the involved sciences of biology, chemistry, and engineering are excellent today and continue a successful traditionof interactions in the past century which has led to enormous contributions to the quality of human life.

Industrial Biotechnology in the Food and Feed Sector

• Since the very beginning of human history, living systems and their extracts have been used on a fully empirical basis to solve one of humanity ’ s most basic needs: how to produce and store food. Cheese and beer production are two examples of our earliest progress in this area. In the case of cheese, a biodegradable product, milk, is transformed into a stable, storable, and tasty derivative.

• In this respect it must be underlined that even if the food and feed sectors are traditionally among the main application areas of biotechnology, the development of new ingredients and processes is becoming increasingly difficult because of tight regulatory constraints.

Food Applications Starch Transformation

• Starch is used to produce food extenders and sugars syrups such as maltodextrins, glucose, dextrose (purifi ed glucose), fructose, maltose, and hydrogenated derivatives (e.g., sorbitol, mannitol). The main sources of starch are corn, potato, wheat, barley, rice, cassava, and sorghum.

• Sudah cukup banyak pembahasan ini. Rancangan Pabrik.

Food Applications Dairy Industry

• Milk transformation into cheese and various processed food products is an intrinsically biological process involving enzymes and microbes,

• Today, industrial milk transformation processes are finely tuned to provide products with constant organoleptic characteristics from a variable raw material.

Food Applications Milk - Clotting Enzymes

Food Applications Milk - Clotting Enzymes

• Cheese Ripening and Flavor

• Lipase

• Proteases

• Lysozyme

• Transglutaminase

• β - Galactosidase

Food Applications Baking Industry

• Amylases

– Fungal α - amylase from Aspergillus oryzae is the most widely used enzyme in baking.

– Overall, the consequences of amylase action are increased bread volume and more homogeneous crumb structure.

– Another target for α - amylase use is the increase of shelf - life of baked products through its anti - staling effect.

Food Applications Baking Industry

• Xylanases

• Insoluble arabinoxylans present in fl our are involved in the disruption of the stability of the gas cells in the dough, while soluble arabinoxylans have positive functional properties, particularly the maintenance of moistness in baked products, which is necessary for good shelf - life performance

Beer - Making Industry

• Malting – One of the key features of brewing is the malting

process. – The addition of exogenous enzymes in order to

optimize wort extraction and achieve full β - glucan hydrolysis.

• Prevention of Chill Haze in Beer – The interaction of proteins with polyphenols during

beer production results in the formation of a haze, particularly during cold storage

– An alternative remedy is to use proteases. Similarly, papain has been used to prevent chill haze by hydrolyzing proteins into peptides

Homework

• Modern Biotechnology:

• 7.4

• 8.3