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CHAPTER 3
COST ANALYSIS
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In spite of remarkable advances in plant cell culture technology, the production cost of metabolites is still high, as estimated by Zenk (5) and by Goldstein (1). The former calculated that the cost would be U.S. $500 per kg of isolated product when it was accumulated in 1 g/L within a period of 15 days in 100 m batch culture. It is true that the cost has decreased since his estimation in 1974, and the producing ability of 1 g/L for 15 days is achievable in the case of some compounds such as rosmarinic acid, but it is still too expensive to produce food stuffs, food additives or pharmaceuticals which can be more easily produced by alternative ways such as chemical synthesis, extraction from plants or by microbial fermentation.
Zenk stated that industrial plant cell culture techniques would be introduced only if the plant product under consideration is produced at a price equal to or preferably lower than the field-produced product. The only factor determining the industrial realization of plant cell culture is the price by which a given product can be produced.
A very detailed assessment of the costs entailed in theoretical processes has been made by Goldstein et al. (24). Four cases were considered:
| A | (Base state of technology) Final biomass concentration = 200 g fresh wt./L One day doubling time, biomass = 0.693/day One day doubling time, product = 0.693/day Product concentration = 0.05% fresh weight Recycled biomass = 50% |
| B | As for A, but: One day doubling time, product = 6.93/day (10 times increase) Recycled biomass = 90% |
| C | As for B, but: Final biomass concentration = 500 g fresh wt./L (2.5 times increase) |
| D | As for C, but: Product concentration = 0.5% fresh weight (10 times increase). |
The final case (D) would translate into a production of 17.5 g product/L/day, which is well in excess of levels achieved with current technology. The rate of product formation is the major obstacle, but this could be compensated for by increased concentration of product. The calculated manufacturing costs and profit margin for each case assuming production of 104, 105 or 106 kg/yr are shown in Tables 3 and 4. Note that these figures reflect 1980 prices and will have increased since then.
Table 3 Manufacturing Costs for Cases A - D
Production Level (kg/yr) |
104 | 105 | 106 |
| Cost ($/kg) | |||
| Case: A. B. C. D. |
551 323 165 92 |
241 142 72 40 |
106 61 32 18 |
Table 4 Profitability of Cases A - D
The selling price ($) and profit (%) are given for each of the three annual
production levels.
Production Level (kg/yr) |
104 $ % |
105 |
106 $ % |
| Case:
A. B. C. D. |
1,608 5.7 992 17.5 528 18.7 233 10.6 |
683 14.7 421 16.3 223 17.6 100 9.8 |
290 13.8 177 15.3 94 16.6 43 9.1 |
* The selling price was calculated to take into account a 5-year payment on capital and a tax rate of 50%. The formula used was: Selling price/kg = 2 x manufacturing cost/kg + 0.4 (total invested capital/kg) = depreciation/kg.
In the case of scenario (D) with production of 10 kg/yr the selling price could be as low as $43/kg and the manufacturing cost would only be $18/kg. This assessment makes the future of commercial plant cell culture fermentation appear quite viable, but the crucial problems to be overcome are enhancing product levels, recycling the biomass (e.g. through immobilization) and raising the biomass concentration. Some encouraging advances in recent years suggest that these problems may be solved eventually, e.g. shikonin can be produced at a level of 23% of the dry weight (roughly 2.3% or more of fresh weight) and 4 g/L; rosmarinic acid can be produced at a rate of 1 g/L/day in Coleus blumei with a final concentration of 27% of the dry weight (23). A biomass concentration of 40 g dry wt./L was achieved.
Batch fermentation processes are capital intensive, requiring a high initial investment and sophisticated technology. In comparison with microbial cultures, doubling times are long and product yields are low. Furthermore, since production is often not growth-linked, there are many cases where two stage production is necessary, thus increasing costs markedly. Table 5 shows estimated costs for a hypothetical phytochemical produced by plant cell culture fermentation.
Table 5 Batch Fermentation Costs for a Hypothetical Plant Product
as a Function of Product Concentration
| Product Concentration (%) | 0.1 | 1.0 | 10.0 |
| Fixed Capital Investment ($M) | 340 | 84 | 21 |
| Total Production Cost (%/kg) | 5,900 | 1,045 | 228 |
| Assumptions: | Annual production = 20,000 kg Cell doubling time = 60 hr Batch cycle time = 15 d Cell intensity = 20 g/L |
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| The total production cost is the sum of direct and indirect costs, including raw material, labour, utilities, capital eq;uipment depreciation over a 10 year period, maintenance, tax and insurance. Indirect costs were taken as 15% of capital investment | |||
It has been calculated that if rose oil were produced in cell cultures, a fermentation process with a 20% share of the market would yield a net profit of $0.5 M/yr. This assumes a rose oil concentration of 10% dry weight and a cell density of 20 g dry weight/L (24). Fowler (25) suggests that plant products valued at $250-1,500/kg are acceptable production targets for an economically viable process. An initial market penetration of the world or U.S. market has been recommended at between 10 and 20%. This will depend on the size of the market and whether a plant cell fermentation process opens up new market.
Scragg (26) has calculated the effect of run time on productivity. Assuming a product yield of 1% dry weight, biomass yield of 20 g dry weight/L and a bioreactor volume of 1,000 L. A 300 day year was estimated, since time would be required for maintenance, contaminated runs, etc. Fig. 1 shows that as productivity decreases the requisite run time increases. Similarly, as the yield of product increases the reactor volume required decreases expotentially (Fig. 2). Under the conditions described above, a 100,000 L fermentor would be necessary to produce 300 kg/yr.
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 Figure 1: The Effect of Run Time on Bioreactor volume and the production from a 1,000 L Bioreactor |
 Figure 2: The Effect of Yield on Bioreactor Volume and the production from a 1,000 L. Bioreactor |
| Source: Scragg, A.H. In "Security Metabolsim in Plant Cell Cultures", Eds. Morris, P. et al., p. 202-207. Cambridge University Press. | Source: Scragg, A.H. (see Figure 1I |
The most detailed assessment available in the literature for the production of a specific product in plant cell cultures is concerned with the production of ajmalicine from Catharanthus roseus cell cultures (27). In this case, a 20% market penetration was assumed, ie. 800 kg/yr and production was based on the use of a two-stage batch culture process. Stage two parameters include specific productivity of 0.26 mg/g/day (based on final dry weight), final product concentration of 0.06% dry weight and a maximum fresh weight concentration of 160 g/L. It was estimated that the cost of production would be $3,215/kg ajmalicine ($7.30/lb dry biomass) and this compares with $619/kg ($0.70/lb dry biomass) from the intact plant. Clearly, this 5-fold increase in costs is unacceptable from a commercial point of view. This example serves to illustrate the need to chose products that are particularly expensive to produce in the field. Shikonin is a good example, in that the long growing period (3-5 years) and strict climatic requirements mean that the cost of the plant raw material is high $6.80/lb. It has been suggested that a quick way to assess the attractiveness of a cell culture method vs. conventional agriculture, is to calculate a specific biosynthesis rate "based on the final dry weight and the total time of fermentation or land occupation" (27). With shikonin there is a 830-fold increase in plant cell culture, whilst with ajmalicine from C. roseus there was only a 24-fold improvement.
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