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Promote downstream processing
Downstream processing design can increase the facility output through improving the overall process yield or higher batch quality in mass and volume. This happen because the supply of the raw materials is optimized.

1. Promote low cost in raw materials
Downstream can be corporate with upstream processing after the harvest of raw materials, because most of the downstream processing uses waste or the same raw materials as upstream processing. This can then promote the supply of cheaper raw materials, and the product from upstream processing will be added value when the downstream processing takes place. We can see that when the farmers have done the weeding process with machinery, they can use grass to obtain ethanol. The waste is then used as raw materials for downstream processing.

2. Increase supply of raw material
If there are some available raw materials in the area, the supply of the raw materials can be increased by signing some contracts with local farmers or local mines in the area. For example, India, which has cooper and iron mining, can exploit the waste from the mining. Besides, Indonesia has many minerals like volcanic ash used to make fertilizers such as phosphorus, which is needed to be done in downstream processing to increase value of the finished product. Moreover, the downstream cycle of processing can also increase the supply of raw material, which can be seen when it includes microbial harvesting like fermentation. This is because downstream processing can promote cultivation, such as cloning bacteria or microorganisms, and can be stored through freeze drying under  -55 °C. This can keep the enzyme or microbial solution in powder and can provide more raw materials, so it can reduce the cost of raw materials per production in downstream processing.

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1. Aniq Naqiuddin Bin Jemali (S28373)
2. Abidin Undun (S28351)
3. Richie Dathoo Anak Nikan (S28371)
4. Leong Wan Teng (S26740)

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Advantages
1. Provide competitive advantages for domestic processor
The downstream processing can provide some competitive advantages for domestic processor because downstream processing can promote the supply of raw materials and other products that have been reached 100 % or purified during peak demand periods. During the periods of high demand for raw materials in downstream processing, local downstream processing can also benefit from it. Since the downstream facilitates a larger operation process in a single production, two or three operators can be used to set up fermentation with a small biotechnology company in a short period.

2. Country as major critical raw materials
For countries with serious shortages of raw materials, downstream processing can promote the increase of raw material, and the supply of dry raw materials can be shipped to those countries where raw materials are not enough raw materials to obtain the production of some single products.

3. Increase cost for counterpart foreign manufacture
Downstream processing can also help improve the ability to recover the past processing costs, such as the fouling cell membrane in HPLC or other equipment that requires high maintenance costs. This happens because downstream processing promotes a process that minimizes the use of the raw materials and save costs. In this process, product waste can be used to produce another product. For the countries with large amount of the raw material, the government can levy taxes on foreign manufacturers to use raw materials by supply raw materials and can make taxes on that country. This is because the foreign country that does not have the sensitive raw material, need to open the plant in the country that have the raw material such as Shell, where the need to open some of the plant to process the oil and gas in Malaysia because Malaysia has crude oil as raw material. By conducting this kind of trade in this downstream processing, the income can be increased and the demand for labor to produce products can also be increased, while the supply of raw material comes from Malaysia.

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Downstream processing is the major cost of producing macromolecules including proteins and enzymes. Therefore, the development of efficient and economical downstream processing strategies is important in microbiology, biochemistry, and biotechnology. For example, the fermentation processes used by biopharmaceutical manufacturers have led to an increase in quantities of therapeutic proteins, causing capacity bottlenecks in the subsequent downstream processing and is associated with high costs. Downstream processing comprises up to 80% of the entire production costs. Thus, the producers have recognized the present demand for improvement and have shifted their focus from improving the upstream process to improving the downstream process.

Costs and Benefits

The economic evaluation of a biological product production project usually includes capital investment estimation, operating cost estimation, and profitability analysis. For example, the average cost of new drug development is between US$20 to US$500 million, which is high because it includes research and development (R&D) expenditures for all unsuccessful products. In other words, the actual average development cost of each successful drug may be $20 to $50 million, but due to more than 90% of new projects have never been commercialized, the average overall R&D cost soars to the above figures. This reinforces the need for effective process design tools and methods that can help engineers and scientists to effectively evaluate and eliminate non-promising project ideas in the early stages of product and process development.

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The productivity of the fermentation process has an impact on the capacity utilization of a bioreactor, ranging from 50 kg per bioreactor to 200 kg per bioreactor depending on whether the titer is 250 mg or 2000 mg L−1. It is, therefore, obvious that there is enormous potential to improve the manufacturing processes by innovation. However, the time-frame for significant improvements is about 5 years, the outcome unpredictable. Yet, capital investment in more of the same technology will range from € 300 to € 500 million over a time-frame of 5 years and requires well-trained employees, pre-requisite to reliable production startup. Therefore, innovation and capital investment must go hand in hand to maintain leadership, maximize flexibility and minimize capital expenditure. For this challenge biopharmaceutical manufacture demands very strong commitment to process: science; including all aspects of genetic engineering; fermentation; downstream process technology; fill, finish; quality control; quality assurance, if major long term improvements are to be made. Commitment to major investments is also required, while skilled staff have to be hired and trained. However, with such commitment, the biopharmaceutical industry enjoys above-market growth in sales, while contributing to the improvement of the health of mankind.

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Capital investment for a new plant includes three main items, which are direct fixed capital (DFC), working capital, and start-up and validation cost. 1. DFC for small biotechnology facilities is usually in the range of $30 to $60 million, whereas for large facilities is in the range of $100 to $250 million. The DFC costs need to pay for the raw materials (for 1-2 months), labor (for 2-3 months), utilities (for a month), waste treatment/disposal (for a month), and other miscellaneous expenses.

2. Working capital accounts for these investments in temporary expenses and consumable materials. The working capital required for a process is usually 10% to 20% of the DFC.

3. Start-up and validation costs can also represent a significant capital investment for a biopharmaceutical plant, in which the value is usually 5% to 10%.

Operating cost to run a biochemical plant is the sum of all expenses associated with raw materials, labor, utilities, waste disposal, and overhead. 1. Raw materials account for the cost of all fermentation media, recovery chemicals, and cleaning materials. For high value products, the buffers used for product recovery and equipment cleaning may be a major part of the materials cost.

2. Labor is estimated based on the total number of operators, and the total number of operators is derived from the sum of the operator requirements for various operations based on time. In a single product facility, the number of operators per shift must be based on maximum demand during the shift. In a multi-product facility, each product line can employ a certain number of dedicated operators and use floating operators during peak demand periods. In general, a company that handles high-value products assigns at least one operator to each processing step (such as centrifugation, membrane filtration, and chromatography) during its operations. The setting of the steps may require multiple operators to perform in a short period of time.

3. Utilities accounts for the cost of electricity, heating, and cooling utilities, where the amounts are calculated as part of the material and energy balance. For instance, clean stream is mainly used for sterilizing equipment, or for sterilizing fermentation media. The purified water used for buffer preparation and equipment cleaning is considered as a utility and not as a raw material, thus increasing the cost contribution of utilities.

4. Waste treatment/disposal accounts for the treatment of wastewater and the disposal of solid and hazardous materials. The quantity and composition of the various waste streams are derived from the material balance. The cost of treatment and disposal can be obtained by multiplying the amount by the unit cost. For example, the cost of treating low biological oxygen demand (BOD) wastewater by municipal wastewater treatment facilities is usually $0.2 -$0.5/m³. The disposal of contaminated solvents from chromatographic steps and other regulated compounds becomes a major expense because their unit disposal costs are between $2 and $20 per kilograms.

5. Equipment-dependent cost accounts for the depreciation of fixed capital investment, equipment maintenance, insurance, property taxes, and other overhead expenses. The government allows companies to depreciate equipment within 5 to 7 years and buildings within 25 to 30 years. The annual equipment maintenance cost can be estimated as a percentage of the equipment purchase cost, which is usually 10%. Insurance premium rate depends to a large extent on the maintenance of a safe factory in good state of repair. The insurance premium for most biological treatment facilities is in the range of 0.5% to 1% of the DFC. Handling of flammable, explosive, or hazardous toxic materials often results in higher insurance rates. The property taxes are usually 2% to 5% of DFC. The factory expenses show overhead costs incurred by the operation of non-process-oriented facilities and organizations, such as accounting, payroll, fire protection, security, and cafeterias, and their costs are in the range of 5% to 10%.

6. Miscellaneous accounts for ongoing research and development, process validation, and other overhead expenses including royalties, advertising, and sales. If any part of the process or any equipment used in the process is covered by a patent not assigned to the company doing the new project, a license to use the teachings of that patent must be negotiated, and some form of royalties is usually required. Advertising and sales pay for expenses related to sales department activities.

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Werner, R. G. (2004). Economic aspects of commercial manufacture of biopharmaceuticals. Journal of Biotechnology, 113(1-3), 171-182.

Petrides, D. (2000). Bioprocess design and economics. Bioseparations science and engineering, 1-83.

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Employing uniform Particle Size
Uniform the particle size chromatography resins in order to increase the productivity at the lower cost. This resin has demonstrated higher dynamic binding capacity and reduces buffer consumption thus lowering the impact on existing facilities.

Example devices that been used for this method is Praesto® Jetted A50 where it produces resins beads with very narrow size distribution. The combination of uniform agarose particles with a novel Protein A ligand resulting a resin with very high capacity at a wide range of flow velocities.

(Diagram 1: Praesto® Jetted A50)

This technology is capable of producing uniform particle size chromatographic resins from ~15 to 250 micron. This technology results in beads that have more uniform size when compared with the standard technology which generates a wide variety of beads size.

(Diagram 2: Process for Jetting)

Advantages:

·       Improved resolution

·       Lowering the cost

·       Improved resolution

·       Longer resin lifetime

·       More consistent packing characteristic.

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The profitability and attractiveness of a project can be evaluated from the perspective of investment by estimating the capital investment, operating costs, and revenues of the project. There are various measures to assess profitability, and the simplest method includes gross profit margin, return on investment (ROI) and payback period. The calculation formula is shown as the image below.
The gross profit is equal to annual revenues minus the annual operating cost and net profit is equal to gross profit minus income taxes plus depreciation. All variables are averaged over the lifetime of a project. The net-present-value (NPV) and internal-rate-of-return (IRR) take into account the cash flows of a project during its evaluation life and change in monetary value over time.