TIN 330 Bioindustrial Technology 32 3 TechnoEconomy Aspects

TIN 330 Bioindustrial Technology 3(2 -3) Techno-Economy Aspects in Bioindustry Agroindustrial Technology Department

TECHNO-ECONOMY ASPECT need for every stage in designing a project or industry / bioindustry Industrial Design Stages : 1. Observation/formulation of process /idea (sales prediction, competition, demand etc. ) 2. Pre-evaluation of economy and market aspects (cost, profit, capital return, price etc) 3. Development of data for economy analysis design (market anylisis & costs) 4. Economy analysis 5. Detail analysis of engineering (info of equipments, factory construction etc. ) 6. Purchasing of Equipments 7. Factory Construction 8. Trial (production, process control, training etc. ) 9. Production

FEASIBILIY STUDY Based on pre-evaluation the project has possibility to success Aspects of Feasibility Study : 1. Market & Marketing 2. Technique and Technologies 3. Project Operation Management 4. Economy & Finance

FERMENTATION PROCESS • If a fermentation process is to yield a product at a competitive price, the chosen microorganism should give desired end product in predictable, and economically adequate, quantities. • To develop a successful fermentation process (Stanbury and Whitaker, 1984) : Ø The highest-yielding strain of microorganism should be used ØThe capital investment in the bioreactor/fermentor and ancillary equipment should be confined to a minimum equipment reliable and may use in a range of fermentation process Ø Raw materials should be cheap as possible and utilized efficiently. A search for possible alternative materials might be made even when a process is operational

Skema Umum Bioproses Pengembangan Inokulum Kultur Stok Labu Kocok Biomassa Cairan Fermentasi Bioreaktor Inokulum Supernatan Bebas Sel Sterilisasi Media Ekstraksi Produk Formulasi Media Bahan Baku Media Pemisahan Sel Bioreaktor Pemurnian Produk Pengemasan produk Penanganan Limbah Cair

Fermentation Process (cont. ) Ø There should be a saving in labour whenever possible and automation should be used where it is possible Ø When a batch process is operated, the growth cycle should be as short as possible to obtain the highest yield of product and allow for maximum utilization of equipment. To achieve this objective it may be possible to use fed-batch culture Ø Recovery and purification procedures should be as simple and rapid as possible Ø The effluent discharge should be kept to a minimum Ø Heat and power should be used efficiently Ø Space requirements should be kept to a minimum, but there should be some allowance for potential expansion.

The consideration of so many criteria means that there may have to be a compromise for the particular set of circumstances relating to an individual process. In any process it is important to know the cost breakdown, so we can know where the biggest potential saving may be Achieved components contributing to the process cost are : - Raw materials - Fixed-cost - Utilities - Labour

FERMENTATION ECONOMICS Cost of fermentation product (P) = Cprod Cpd, Cpr, Cms, Cop. . . (1) where : Cprod = total economic costs of products Cpd Cpr Cms Cop = cost of product and process development including the costs of obtaining regulatory approval = cost of production = cost of marketing and sales = opportunity costs associated with lost product and sales

Cpr = Cpr CF, CV . . . (2) where : Cpr = cost of production depends on the product CF = fixed costs of production i. e. pretreatment of substrate, fermentation product recovery, effluent disposal CV = variable costs of production i. e. raw material cost product yield : - volumetric productivity - product concentration - scale of plant

Cop = Cop Clost sales, Clost product where : Cop = opportunity costs associated with lost product and sales Clost sales = opportunity cost of lost sales due to delays in production schedule because of : - regulatory problems - product quality - marketing problems - fermentation and product separation process development delays Clost product = opportunity cost of lost product due to process or equipment failures because of : - contamination - mutation - insufficient product yield - mechanical failure

BIOTECHNOLOGICAL PROCESSES Raw material cost + Substrate preparation Fermentation process Product recovery including waste disposal Product Total cost of production = raw material supply and preparation cost + fermentation costs + product recovery cost

FERMENTATION ECONOMICS www. ucd. ie/indmicro/damien/Lecture%201. ppt r OBJECTIVE - yield a product at a competitive price BASIC OBJECTIVES. Capital investment minimum Inexpensive raw materials High yielding strain of microorganism Labour saving and automation Batch Production cycles as short as possible Recovery and purification - simple & rapid Minimise waste streams Heat and power used efficiently Space requirement minimised

MAJOR AREAS OF COST MINIMISATION 1. 2. 3. 4. 5. 6. 7. 8. 9. Isolation and handling of microorganism Plant and equipment Media Air sterilisation Heating and cooling Aeration and agitation Recovery cost Process time and duration Prevention of contamination (Stanbury and Whitaker, 1984. Principles of Fermentation Technology)

1. Isolation of Microorganism - Isolation programmes are time consuming, expensive and may be something a gamble, particularly when searching for new antibiotics. - If the type of microbial process is already known then it may be possible to design a screening procedure with prescribed selection pressures specifying desirable, and eliminating undesirable, characters. This type of screening may be extremely cost effective and productive.

Example : In the searching of suitable microorganisms for SCP production, many of the objectives used have an economic basis ! Selection strain of Thermoactinomyces : - Grow optimally at 550 C reduce cooling problems - Contain high methionine useful as a protein supplement - Filamentous growth form harvested by simple filtration Selection strain of Methylophilus methylotrophus : - High efficiency of methanol dissimilation - Fast growth rate - Genetically stable in continuous culture - Contain high protein and absence of toxin and pathogenic properties

Strain selection of enzyme production : - High enzyme production - Genetic stability - Could produce the enzyme constitutively - Could utilize media components efficiently STRAIN IMPROVEMENT - Mutation/selection program can be very cost effective Time and money that is worth spending on a mutation/ selection program depend on size of the manufacturing process e. g. mutation and combined with medium development increase the penicillin yields significantly

2. Plant and Equipment - Empirical relationship between cost and size of equipment, facility size increases, its cost increase cost 1/cost 2 = (size 1/size 2)n n : scale factor (e. g. brewing = 0. 6; SCP = 0. 7 -0. 8) - Factors should be considered before deciding on the scale of operation e. g : Ø cooling and aeration requirements Ø method of fermentation vessel construction Ø decrease in surface area to volume ratio which decrease the effectiveness of a cooling jacket - Smaller bioreactor allow for fluctuating demand of different products (e. g beer)

3. Media Fermentation ØThe cost of production medium : 38 – 73 % of the total production cost Ø The organic carbon source is usually the most expensive component contributing to the cost of the process Ø The availability and costs medium component may be fluctuated use an alternative medium if any unusual situation happens. A variety of waste materials potentially as a cheap carbon sources, but has many restriction such as variability of the materials, impurities which make downstream processing more difficult, high water content of making transport costly, geographical location, quantities produced and limited seasonal availability. Ø The source of basic materials can cause considerable variation in product yield (e. g. Ca. CO 3 in penicillin G production)

4. Utility (Air Sterilization, Heating & Cooling, and Aeration & Agitation Usually included in the category of utilities are the cost for : steam, electricity, water and water treatment for bioprocess utilities costs can range from less than 5 % to more than 20 % of the production cost. Utility consumption can only be obtained from a detailed process flow sheet and plant layout. • Air Sterilization : - Air sterilization by heating too costly for full-scale operation single-stage compressors with filters and turbocompressors were most economical

Utility (cont. ) • Heating and Cooling : - Heating for sterilization of the medium, fermenter (before and after fermentation) - Cooling to remove heat generated during fermentation - To reduce cooling requirements, the specific energy input may be minimized through the use of air-lift fermenter or use thermophiles and thermotolerant microorganism. • Aeration and Agitation : - Only aerobic fermentation categorized as a major economic consideration - Fermentations having a high O 2 demand must be agitated with sufficient power to maintain a uniform environment and to disperse the stream of air introduced by aeration

5. Recovery Cost - Factors contributing to these costs : Ø Yield losses Ø High energy and maintenance cost (e. g filtration & centrifugation) Ø High cost of solvents and other raw materials used in recovery and refining of products

6. Process time and Duration Ø Productivity (g product/L. h) is based on a combination of the time for the actual fermentation and the time to prepare the fermenter ready for the next run Ø Effect of running time (fermentation time) on productivity and product cost Ø A larger initial inoculum would increase Xo and shorten the process time Ø Use faster-growing microorganism and/or higher yielding strains Ø Growth phase or production phase can be extended by the use of batch or continuous feed

PRODUCTIVITY In a batch process productivity must be calculated for the complete cycle. The total time (t) for a fermentation may be calculated; t = 1/ m (ln [Xf/Xo] ) + t. T + t. L + t. D where m = maximum specific growth rate Xo = initial cell conc. Xf = final cell conc. t. T = turn-around time (washing, filling, sterilisation, etc) t. D = delay time until inoculation t. L= lag time after inoculation

The overall productivity P P = Xf/ t It will be possible from this equation to determine the effect of process changes on the overall productivity. For example : - Larger initial inoculum would increase Xo and shorten the process time. - Actively growing inoculum would reduce the lag time (t. L)

Effect of running time on productivity and cost - optimum time of harvesting

7. Prevention of Contamination Ø Contamination always add costs to any fermentation process. Most fermentations cannot survive serious contaminations so the medium must be discarded. Moderate fermentations does not require the medium to be discarded but it might affect the yields. Ø Certain fermentations are more prone to contamination than others. This involves cases in which foaming is a problem. Ø Some are more sensitive to phage infections like bacterial fermentations So there has to be an alternate method for the contaminant growth. Such methods include low p. H of the medium, heat treatment of the medium and inclusion of certain chemicals so as to retard contaminant growth.

Waste Disposal : Costs attributed to waste disposal vary from minimal to maximal factor in fermentation process. A critical consideration is the acceptance of waste by Municipal's STW (Sewage Treatment Works); as they might want pre treatment of wastes before the acceptance. In the latter case the fermentation company must have its own waste treatment plant. Disposal of wastes is no longer simple in contrast to historical disposal in the rivers, streams or other water bodies. Certain fermentations require the waste to be sterilized before disposal.

Fermentation Economics : http: //microbiologyprocesses. blogspot. com/2012/03/fermentation-economics-objective-of-any. html (Reference: Casida, L. E. Industrial Microbiology) The objective of any successful fermentation process is the ability to produce a fermentation product. Thus the product must be sold to recover all the costs along with desired profit. Manufacturing should be done in accordance with the market demand. So there could be 2 possibilities : First possibilty is : That the market for so called product already exist because the same or similar product has previously been sold by others. Second possibilty is : a newly manufactured or discovered product e. g. a new antibiotic will require a market to be established.

It is necessary to estimate the size of the present and potential market and the increase in demand for a compound. The life expectancy of a compounds are also have to be predicted even when covered by a patent Example : industrial enzyme for detergent

Microbial processes may be economically viable for compound that have a complicated structure, are chemically or thermally unstable, and for which a multistage chemical synthesis would be expensive e. g : - antibiotics - corticosteroids - L-amino acids - Vitamins “high-cost-low- volume products” “Low-cost-high-volume products’ : - Ethanol only be competitive with synthetic ethanol from crude oil if the fermentation plant was in area where cheap supplies of carbohydrate as raw material were available

How can We Improve Process Economics? (Gerard Fleming : www. nuigalway. ie/. . . /a. _introduction_to_fermentation_. ppt 1. Better Product Yields • The amount of product we get for a given amount (or in practice, cost) of substrate (raw material). • Important when substrates are a major proportion of product costs e. g SCP 2. Higher Product Titres • The concentration of product when we harvest the bioprocess • Important when purification costs are a major proportion of product costs

3. Volumetric Productivity • The amount of product produced per unit volume of production bioprocess or per unit time. (or, in crude terms “how fast does the process go”) • NOTE : “Time” includes down time, turn-round time etc. • High Volumetric Productivity minimises the contribution of fixed costs to the cost of the product.

Large Scale Processes Volume 10, 000 L to 100, 000 L+ Product value Low (Low value added) Product types Biomass, Bulk chemicals, Antibiotics, Most enzymes R&D development Fermentation Technology/process engineering, strain and medium manipulation etc. to improve process economics R & D Cost Low

Small Scale Processes Volume 100 L to 1, 000 L Product value High (High value added) Product types Therapeutics, Diagnostics, Products from recombinant micro-organisms & cell cultures. R & D Thrust Initial product development, validation and approval. Genetic Engineering R & D Cost High

Major Groups of Large Scale Processes 1. Biomass 2. Enzymes 3. Metabolites – Primary Products of Catabolism e. g. Citric acid – Intermediates e. g. glycine in Nitrogen metabolism – Secondary products e. g. penicillin 4. Biotransformations

Biomass • Bakers Yeast (Saccharomyces cerevisiae) • Bacterial Insecticides (Bacillus thuringensis) • Nitrogen Fixing Inoculants (bacteria: e. g. Rhizobium)

Biomass • Single cell protein: – For Animal feed • Upgrading low value agricultural products: – Cellulose – Starch • Use yeasts or fungi • Profit margins very small – competitive market – For Human consumption • Fungi (eg Fusarium venenatum )

Enzymes • Often depolymerases /hydrolases (eg. Amylases, Proteases) • Large range of uses (and purities): – Food – Pharmaceuticals – Detergents – Industrial Microbiology (Medium Preparation) – Leather Preparation

Enzymes • Organisms used for production: – Bacteria (especially Bacillus) – Yeasts (eg Saccharomyces) – Fungi (eg Mucor) • Problems caused the cell’s control systems (induction, repression) may need to be overcome: – Mutate/engineer organism – Medium formulation – Process manipulation (substrate supply)

Ethanol: – C 3 H 6 O 3 Converts to C 2 H 5 OH+ CO 2 – Beverages • Organism: Yeast (Saccharomyces cervisiae or uvarum) • Some substrates immediately available: – Grape juice (Wine, Brandy) – Sugar Cane (Rum) • Some substrates need pre-treatment to depolymerise starch and protein: – Malt (Beer, Whisky) – Cereals, potatoes etc. plus malt , enzymes etc (vodka, other spirits, some beers etc. ) – Post-fermentation treatment may include distillation (spirits) and/or maturation.

• Ethanol Fuel/Industrial Alcohol – Organisms: • Yeasts • Bacteria (Zymomonas): fast but sensitive to product. – Substrates: Cheap Agricultural products: • Sucrose (Sugar Cane) • Starch type products (Hydrolyze with enzymes etc. or obtain organism with amylase activity) – Very low value added/Competitive market (but Government support? ). – Conventional distillation step can make the process uneconomical: • Use vacuum (low temperature) distillation during fermentation.

Primary Metabolites –Metabolic Intermediates • Intermediates in metabolic pathways (TCA cycle, pathways leading to protein and nucleic acid production etc. ). • Levels of intermediate pools generally low in healthy “wild type” organisms – Need to develop industrial strains: • Overcome feedback inhibition/repression.

Primary Metabolites –Metabolic Intermediates • Examples: – Citric Acid (Soft Drinks, Foods etc. ) – Lysine (Essential AA, Calcium absorption, Building blocks for protein) – Glutamic acid (Monosodium Glutamate precursor) – Phenylalanine (Aspartame precursor) • Organisms Yeasts. Fungi, Bacteria: – Corynebacterium for amino acid production

Secondary Metabolites • Not part of the “central” metabolic pathways • Producers: – Actinomycetes (eg Streptomyces) – Fungi (eg Penicillium) – Sporeforming bacteria (Bacillus) • Produced as growth slows/stops in batch cultures (stationary phase) • Antibiotics are of major industrial importance

Secondary Metabolite production in Batch Culture • 1. Trophophase – Culture is nutrient sufficient – Exponential Growth – No Product Formation

Secondary Metabolite production in Batch Culture • 2 Idiophase – Carbon limitation – Growth slowing or stopped – Product formation – HARVEST AT THE END OF THIS PHASE

Secondary Metabolite production in Batch Culture • 3 Senescence – Product formation ceases. – Degeneration/lysis of mycelium (Fungi, Actinomycetes) – Product degraded/used by culture.

Biotransformation • Use cells or enzyme as “catalysts” to perform one or two step transformation of substrate. • Use cells several times: – Fungal/Actinomycete mycelium – Immobilised bacteria or yeast cells packed into a column • Examples: – Transformations of sterols by Mycobacterium fortuitum”. – Ethanol to Acetic acid (immobilised Acetobacter)