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Throughput Analysis, Debottlenecking, and Economic Evaluation of Integrated Biochemical Processes
Demetri Petrides, Ph.D. President IBC Conference La Jolla, CA November 15, 2000 Good morning Ladies and Gentlemen. I would like to thank the organizers of this event for inviting me and giving me the opportunity to share with you my experience in using CAPD and simulation tools to solve problems related to Throughput Analysis, Debottlenecking, and Economic Evaluation of Integrated Biochemical Processes. INTELLIGEN, INC. Simulation and Design Tools for the Process and Environmental Industries

Outline Introduction Motivation Debottlenecking Theory
Debottlenecking Example Cost Analysis Conclusions INTELLIGEN, INC.

Computer-Aided Process Design and Simulation
INTELLIGEN, INC. Computer-Aided Process Design and Simulation What is computer-aided process design and simulation? In simple words, it is the technology that enables scientists and engineers to model, evaluate, and optimize on the computer integrated processes.

Debottlenecking Questions
How much product can I make in this plant? What limits the current production level? What is the min capital investment for increasing production? What can we do with these tools? Here is a list of questions related to throughput analysis and debottlenecking that can be readily answered with the use of such tools. How much product can we make in an existing facility over a certain period? What equipment or resource limits the current production level? If we wish to increase plant throughput to a higher level, what is the min capital investment that is required? INTELLIGEN, INC.

Cost Analysis Questions
How much would it cost to make a kilo of product? What is the required capital investment for a new plant? Which process is better for making this product? A or B? How can I reduce the operating cost of a process? And here is a list of cost analysis questions that can be readily answered with the use of such tools. How much would it cost to make a certain amount of a product? If we need to build a new facility, what is the required capital investment? If we have alternative processes for making the same product, which process is better from a cost, environmental and other points of view? If our goal is to reduce the operating cost of a process, where should we focus our attention on (what steps)? INTELLIGEN, INC.

The Role of CAPD and Simulation in
Product Development and Commercialization IDEA GENERATION Project Screening, Strategic Planning Development Groups PROCESS DEVELOPMENT Evaluation of Alternatives Common Language of Communication Development Groups Process Engineering Corporate Environmental Manufacturing FACILITY DESIGN Equipment & Utility Sizing and Design Computer-Aided Process Design and Simulation can play an important role throughout the life-cycle of product development and commercialization. At the early stages of idea generation such tools are primarily used for screening and evaluating potential projects. In process development, they are used to evaluate alternatives from a process economics and environmental point of view. They are also used to improve team collaboration by introducing a common language of communication. As we move from development to manufacturing, such tools are used to size equipment and utilities and estimate the overall capital investment. They are also used to fit new products into existing facilities and address issues of process flexibility and operability in multi-product facilities. Finally, in large scale manufacturing they are primarily used for ongoing process optimization, debottlenecking, retrofit design, process scheduling,and production planning. MANUFACTURING On-Going Optimization, Debottlenecking Process Scheduling, Production Planning Manufacturing INTELLIGEN, INC.

Who is Intelligen, Inc.? Established in the early 90’s - MIT spin off
SuperPro Designer Biotechnology Food Processing BioPro Designer Synthetic Pharmaceuticals Specialty Chemicals AgriChemicals Who is Intelligen, Inc.? Our company was founded in the early 90’s to commercialize technology that had been developed at MIT. BioPro Designer was our first product and focused on the needs of the biotech industry. Later the scope of BioPro was expanded to handle the needs of other related industries, such as synthetic pharma, specialty chemicals, etc. and that led to the introduction of BatchPro Designer. In the mid 90’s we initiated an effort to develop a tool for environmental applications, mainly wastewater treatment and air pollution control processes and that effort led to EnviroPro Designer. Lately the capabilities of EnviroPro have been expanded to handle water purification processes (for making ultrapure water for applications in the pharmaceutical and semiconductor industries) and facilitate design of zero water discharge plants. SuperPro is the combination of everything we have and can be used to model and evaluate a wide variety of chemical manufacturing and pollution control processes. BatchPro Designer Water Purification Wastewater Treatment Air Pollution Control EnviroPro Designer INTELLIGEN, INC.

Tool Description - Overview
INTELLIGEN, INC. Tool Description - Overview Intuitive User Interface Wide Variety of Unit Operation Models Databases for Components and Mixtures M&E Balances of Integrated Processes Equipment Sizing and Costing Project Economic Evaluation Process Scheduling Throughput Analysis & Debottlenecking Waste Stream Characterization This slide provides an overview of the key features of SuperPro Designer and in general of all our tools. SuperPro is a MS Windows application with an intuitive user interface that shortens the learning time. It features more than 120 unit procedure models for modeling biochemical, pharmaceutical, specialty chemical, food, product packaging, water purification, wastewater treatment, and air pollution control processes. It is equipped with extensive databases for pure components, mixtures, materials of construction, utilities, etc. It performs M&E balances of integrated processes. It handles equipment sizing and cost estimation. It performs thorough project economic evaluation calculations. For batch processes it facilitates process scheduling, resource tracking, throughput analysis and debottlenecking. It classifies waste streams by predicting flow rates and compositions and facilitates environmental impact assessment. It handles VOC emission calculations from primary (the main process) and secondary (end-of-pipe treatment) sources.

Intuitive User Interface
In terms of the interface, here you see the main window of the application. To model a process, you first create a PFD by selecting unit procedures from the Unit Procedures menu. It is very easy to connect the procedures, register the components and initialize the operations. After that the program is ready to perform the various calculations. SuperPro generates reports in Text and Spreadsheet format and supports OLE for copying and pasting between Windows applications. SOME OF THESE SLIDES CAN BE SUBSTITUTED BY A LIVE DEMO.

Detailed Modeling using Unit Procedures and Operations
INTELLIGEN, INC. Detailed Modeling using Unit Procedures and Operations Double-Click To facilitate detailed modeling of batch processes, with the release of v4.0 (in the beginning of 2000) we introduced the concept of unit procedures. A Unit Procedure is a set of operations that take place in a piece of equipment. In other words, it is the recipe for that step. To specify the recipe of a unit procedure, you simply double click on its icon. That brings up a dialog (shown above) that lists on the left hand side all the operations that are compatible with that type of equipment. Then, the user simply selects and registers the appropriate operations. The registered operations are shown on the right hand side.

Flexible Operation Models (Column Elution)
INTELLIGEN, INC. Flexible Operation Models (Column Elution) The initialization of the various operations is done through dialog windows of this type. For instance, this is the dialog of an Elution operation. The user specifies the volume based on bed volumes, the linear velocity, the elution strategy, etc. I would like to mention that for many of these variables there are good default values that can be used during a first pass. By clicking on the Labor, etc. tab, the user can specify labor requirement for this operation. By clicking on Scheduling, the user can specify the start time of this operation relative to other operations in the same or other unit procedures.

Operations Gantt Chart
INTELLIGEN, INC. Operations Gantt Chart This is the new operations Gantt chart. On the left hand side you can see the various tasks at various levels of detail. At the top you see the entire recipe, then you see the procedures (P-1, P3, etc.) and their operations. For each task you can see its duration, start time and end time. By clicking on the [-] box you can contract (zoom out) the display. On the RHS you see the graphical representation of the various tasks. Different colors are used for the different types of tasks. If you right-click the mouse on a rectangle, you can access the properties of that object. For instance, if you right-click on the rectangle of an operation, you can access and modify the properties of that operation. Then, if you click on “Update Chart” on the menu bar, SuperPro redoes all the simulation calculations and updates the Gantt chart. Both the spreadsheet table and the Gantt chart can be copied and pasted into other applications and printed as a single object (e.g., using Excel).

and Debottlenecking Theory
INTELLIGEN, INC. Throughput Analysis and Debottlenecking Theory

Debottlenecking of Batch Operations
INTELLIGEN, INC. Debottlenecking of Batch Operations Equipment Resources Types of Bottlenecks In a batch manufacturing facility, the annual throughput is equal to the batch throughput times the number of batches that can be processed per year. Consequently, we can increase the annual plant throughput by increasing either the batch throughput or the number of batches per year or both. As we attempt to do that, we run into bottlenecks that are either equipment-related (equipment capacity or scheduling) or resource-related. Resources include utilities, labor demand, and raw material consumption. The bottlenecks that limit the number of batches per year are known are “time or scheduling” bottlenecks. Those that limit the batch throughput are know as batch size or throughput bottlenecks. Let’s see now how to identify and eliminate those bottlenecks in a systematic way. Annual Throughput Batch x Number of Batches per Year =

Equipment Scheduling (Time) Bottlenecks
INTELLIGEN, INC. Equipment Scheduling (Time) Bottlenecks Let’s focus first on Equipment time (scheduling) bottlenecks. The equipment utilization chart enables the user to visualize equipment utilization in time and identify the time (or scheduling) bottleneck, which is the equipment with the longest occupancy time. That equipment determines the min Effective Plant Batch Time and the max number of batches per year. As can be clearly seen, V-101 is the scheduling bottleneck in the above case. If the time bottleneck is utilized by multiple unit procedures, as it is the case above, elimination of sharing (by installation of extra equipment or equipment switching) can eliminate the bottleneck. In that case, C-101 will become the next equipment time bottleneck. Please note that auxiliary equipment, such as CIP and SIP skids, and resources (e.g., utilities, labor, raw material supply) also can become time bottlenecks. Tank (V-101) = Scheduling (Time) Bottleneck Auxiliary Equipment (e.g., CIP and SIP skids) and resources also can become time bottlenecks.

Equipment Capacity Utilization
INTELLIGEN, INC. Equipment Capacity Utilization Equipment Capacity Utilization Liquid Volume Max Liquid Volume = Now lets see how to identify the batch size (throughput) bottlenecks. To identify such bottlenecks, we will need to define three new variables. “Equipment Capacity Utilization” represents the fraction of an equipment’s capacity that is utilized during an operation. This can be easily illustrated with a vessel operation (e.g. reaction). If the red line represents the max allowable liquid level in the vessel during the operation and the blue area represents the actual level, obviously only a fraction of the vessel’s capacity is utilized during that operation, which is equal to the ratio of “Liquid Volume” over “Max Liquid Volume”. For a disk-stack centrifuge, the same can be defined based on throughputs (current throughput divided by max possible throughput for that type of material and that specific equipment item). Equipment Capacity Utilization Operating Throughput Max Throughput =

Equipment Time Utilization
INTELLIGEN, INC. Equipment Time Utilization EPBT Equipment uptime is defined as the total time a piece of equipment is utilized per batch divided by the Effective Plant Batch Time (EPBT). The EPBT represents the time between consecutive batches. In this example, two batches are shown – the first is represented by dark blue bars, and the second is represented by light blue bars. Notice that the second batch begins (at t=22 hours) before the first batch is completed (at t=25.5 hours). The EPBT could be further decreased by shortening the gap between the end of the unit procedures in the first batch and the beginning of those same unit procedures in the next batch (in other words, decreasing the “batch slack” time between the end of utilization of a piece of equipment during one batch and the beginning of utilization of that equipment for the next batch.) Equipment Uptime Total Time Equipment is Utilized per Batch Effective Plant Batch Time (EPBT) =

Equipment Throughput Bottlenecks
INTELLIGEN, INC. Equipment Throughput Bottlenecks To identify throughput equipment bottlenecks in the entire recipe (flowsheet), we simply calculate and plot the Combined equipment utilization for each equipment item. In the above chart, the blue bars represent capacity utilization, the orange represent time utilization, and the green represent combined utilization. The equipment with the highest combined utilization will become the first batch throughput bottleneck as we try to increase batch throughput. How do we eliminate throughput bottlenecks? Elimination of equipment sharing and installation of extra capacity are the common ways. Changes in operating conditions (e.g., level of dilution for protein refolding) may also eliminate certain throughput bottlenecks. Does this methodology work 100%? The answer is NO. Real world limitations in time utilization may lead to situations where a procedure that does not have the max Combined Utilization is the true bottleneck under practical conditions. For instance, if you have a plant with an EPBT of 24 hr and a certain vessel procedure has a cycle time of 16 h, it is very difficult under practical conditions to utilize the remaining 8 h. If this vessel operates at full capacity (size), then, it is the current true bottleneck even if some other procedure has a higher combined utilization. Combined Utilization = Equipment Capacity x Uptime

Potential for Throughput Increase
Equipment Capacity Utilization EPBT Equipment Uptime Current Realistic Theoretical To address the limitation of the “Combined Utilization” methodology for identifying bottlenecks, we have an alternative methodology that is based on the max potential throughput of each procedure. To have a common basis of comparison, the throughput of each procedure is expressed in equivalent final product. The max potential throughput is always estimated at 100% equipment capacity utilization (point to the liquid level in the vessel on the right). Three different values of Max Potential Throughput are calculated based on three different assumptions for Equipment Uptime. The Conservative Max Potential Throughput corresponds to the current uptime. The Theoretical Max Potential Throughput corresponds to 100% equipment uptime, which may not be realistic for procedures whose cycle time is not fully proportional to the amount of material that they process (e.g., vessel procedures – the duration of a batch reaction depends on chemistry and not on amount of material). The Realistic Max Potential Throughput corresponds to a realistic time utilization. For instance if the Effective Plant Batch Time (EPBT) is 24 h and a vessel procedure has a cycle time of 10 h, we will assume an Uptime of 20/24 = 83.3 % that corresponds to two cycles per batch for that procedure. Current Batch Throughput Conservative Max Realistic Max Theoretical Max INTELLIGEN, INC.

Equipment Throughput Bottlenecks
INTELLIGEN, INC. Equipment Throughput Bottlenecks SuperPro calculates and plots the Conservative, Realistic, and Theoretical Max Potential Throughput of the various procedures and identifies the bottleneck of each type. For instance, in this case the column C-103 is the conservative throughput bottleneck whereas the vessel V-101 is the realistic and theoretical bottleneck. Our objective with this methodology is to identify the TRUE bottleneck based on the value of the realistic bottleneck.

Resource Bottlenecks INTELLIGEN, INC.
In a manufacturing facility, if we calculate and plot the instantaneous and cumulative (corresponds to the y-axis on the right) demand of a resource (e.g., WFI) as a function of time, we can identify two types of resource size (capacity) bottlenecks. 1) If the cumulative demand (green line) exceeds the overall cumulative capacity (show the dashed green line at 1,000,000 kg that corresponds to the limit), then we have a throughput bottleneck that can only be eliminated by installing extra capacity or making changes in the process that reduce its demand. 2) If the instantaneous demand (red lines) exceeds the available instantaneous capacity (point to the dashed red line at 21,000 kg/h) at a certain point, then, changes in process scheduling (by delaying certain operations) may eliminate such a bottleneck. Such a delay, however, may cause this resource to become a time bottleneck (this explains how resources become time bottlenecks). The blue line represents averaged demand (over a period of day – adjustable by the user) and enables the user to plan the production (availability) of various resources.

Debottlenecking Strategy
INTELLIGEN, INC. Debottlenecking Strategy Annual Throughput Batch / Effective Batch Time   Increase batch throughput until a size bottleneck is reached. Then, Increase number of cycles of limiting procedure; Rearrange equipment, or; Use new equipment (stagger operation). First always increase batch size till a size bottleneck is reached. Then, make changes in the process to reduce the Effective Plant Batch Time and increase the number of batches. If the size bottleneck unit is underutilized in time, split a batch into multiple cycles around that unit. That offers the opportunity to increase batch size further. If the size bottleneck is also the time bottleneck (which means that that is the true throughput bottleneck), then, consider installing extra equipment of the bottleneck time and stagger its operation. This is common in the case of bioreactors that have long cycle times and are common time bottlenecks. In that case we buy an extra vessel and stagger its operation (relative to the next time bottleneck). For instance, if the cycle of a bioreactor is 10 days, we can buy a second and schedule it to start when the first if half done (after five days). If none of the downstream processing steps has a cycle time greater than 5 days, we manage to double plant capacity this way. If a downstream unit has a cycle time greater than 5 days, then, that unit becomes the new time bottleneck and the staggering of the bioreactors must be based on the cycle time of the time bottleneck step. The MAB throughput analysis example explains the above strategy in greater detail. Our ultimate goal is to have a process where all steps are utilized in size and time close to their full potential. For a dedicated batch facility this can be accomplished rather easily using tools such as SuperPro. For multiproduct facilities, we use SuperPro to estimate the max possible throughput.

Throughput Analysis Example
Production of Therapeutic Monoclonal Antibodies INTELLIGEN, INC.

INTELLIGEN, INC. This flowsheet represents a simplified process for producing therapeutic monoclonal antibodies. The media and inoculum preparation steps were left out for simplicity. Let me quickly walk you through the process. The production bioreactor (V-101) generates approximately 4,000 L of broth per per. The product titer is 1 g/L. The fermentation time is 10 days. The biomass is removed using a membrane diafilter (P-2) and the dilute protein solution is concentrated using another filtration step (P-4). Purification is initiated with a protein-A affinity chromatography (P-6/C-101). The protein-A buffer is exchanged using another membrane filtration step (P-7) and purification proceeds with an Ion Exchange column (P-8/C-102). Ammonium sulfate is added in P-9 to prepare the solution for the Hydrophobic Interaction chromatography step that follows (P-10/C-103). Next we have a virus inactivation and virus removal steps (P-11 and P-12). The purification is completed with another diafiltration and product concentration step (P-13).

Base Case Data INTELLIGEN, INC. Broth Volume = 4,000 L
Bioreactor Volume = 6,500 L Max Working Volume = 6,175 L Product Titer = 1 g/L Recovery Yield = 56% Fermentation Time = 10 days Here are some data for the base case. The broth volume is 4,000L. The bioreactor vessel volume is 6,500 L and the max working volume is 6,175 L. The overall recovery yield is around 56%.

Equipment Utilization Chart (Base Case)
INTELLIGEN, INC. Equipment Utilization Chart (Base Case) Here you see the equipment utilization chart for two consecutive batches of the base case. The effective plant batch time (EPBT – time between consecutive batches) is 11 days. The batch size is 2.3 kg of product. We process 29 per year and generate 67 kg of product. The multiple rectangles for DF-102 represent reuse of that equipment. The same filter handles three different filtration steps. The same holds for V-103, which two different steps. Let’s assume now that the demand for this product is going up. Before we decide to build a new facility, we would like to increase plant throughput to its maximum potential. How can we do with the least capital investment? This is a typical throughput analysis question. V-101 = Scheduling (Time) Bottleneck EPBT = 11 days Batch Throughput = 2.3 kg Batches per Year = 29 Annual Throughput = 67 kg

Capacity, Time, and Combined Utilization Chart (Base Case)
INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Base Case) Let’s have a look at the utilization chart that SuperPro generates for the base case. The blue bars represent capacity utilization, the cyan bars represent time utilization, and the purple bars represent combined utilization. V-101 is identified as the current batch throughput bottleneck because it has the highest combined utilization. Its capacity utilization, however, is only 65%. In other words, the bioreactor is only 65% (of its max working volume of 6,175 L) when it operates in the base case. This creates an opportunity for increasing batch size, which according to the debottlenecking strategy is the first recommended step towards plant throughput increase. Capacity Utilization of Bottleneck Equipment = 65%

Scenario 1 INTELLIGEN, INC. Action
Increase batch size by 54% (broth volume 4,000 L  6,175 L) Warnings Chromatography columns cannot handle new batch in 2 cycles. Action  Increase # of cycles per batch from 2 to 3. New Results Batch throughput Number of Batches per Year Annual Throughput 3.55 kg 29 103 kg If we increase batch size from 4,000 L to 6,175 L (54% increase) and redo the simulation, the chromatography columns generate an error message that they cannot handle the material of a batch in two cycles. I forgot to mention that in the base case each column operates two cycles per batch (it handles the material of a batch in two cycles). To fix the problem, we increase the number of cycles per batch for all the chromatography columns from 2 to 3. We redo the calculations and everything is fine now. The new batch is 3.55 kg of product and we can still process 29 batches per year (no time penalty). The new annual throughput is 103 kg.

Capacity, Time, and Combined Utilization Chart (Scenario 1)
INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Scenario 1) This is the utilization chart for the adjusted batch (scenario 1). Notice that now the capacity utilization of the bioreactor (V-101) is 100% and its time utilization is very close to 100%. How can we increase the plant throughput further? By looking at the chart, you can see that the bioreactor is utilized to its full potential but that is not the case for the recovery equipment. The highest combined utilization of a recovery equipment (DF-102) is only 40%. This creates an opportunity for increasing plant throughput by adding another bioreactor and utilizing the same recovery equipment. This is the objective of scenario #2. Capacity Utilization of Bottleneck Equipment = 100% EPBT = 11 days Batch Throughput = 3.55 kg Batches per Year = 29 Annual Throughput = 103 kg

Scenario 2 Observation Downstream section is underutilized in time.
INTELLIGEN, INC. Scenario 2 Observation Downstream section is underutilized in time. Action Introduce new bioreactor and stagger its operation based on the new time bottleneck equipment. In scenario #2 we consider the impact of an extra bioreactor whose operation is staggered based on the next next time bottleneck.

INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Scenario 2) This slide displays the equipment utilization chart for scenario #2. The blue bars represent the first batch that utilizes the first bioreactor. The cyan bars represent the second batch that utilizes the second bioreactor. The purple bars represent the third batch that utilizes the FIRST bioreactor again. The beginning of the second batch is determined by the new time bottleneck (DF-102). If we did not have that time bottleneck, we would be able to initiate the second batch when the first was 50% done. We see that with an extra bioreactor we manage to increase the number of batches per year from 29 to 39 and the annual throughput to 138 kg. How can we increase the plant throughput further? Since the batch size cannot be increased, we should make changes that reduce the effective plant batch time. It is obvious from the graph that if we add another diafilter, we will manage to reduce the effective plant batch time and increase the number of batches per year. This is the objective of scenario #3. DF-102 = Scheduling (Time) Bottleneck EPBT = 196 h (initial 264 h) Batches per Year = 39 (initial 29) Annual Throughput = 138 kg Number of Bioreactors = 2

Add extra diafilter to eliminate current time bottleneck. New Results Batch throughput Number of Batches per Year Annual Throughput 3.55 kg 44 (29  39  44) 156 kg In scenario #3 we evaluate the impact of an extra diafilter.

INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Scenario 3) This is the equipment utilization chart for scenario #3. With an extra membrane filter, we manage to increase the number of batches from 39 to 44 per year. The annual throughput goes up to 156 kg. Under these conditions the tank V-103 becomes the new time bottleneck. It is obvious that in order to increase the number of batches further we will need an extra tank. That is the object of scenario #4. V-103 = Scheduling (Time) Bottleneck EPBT = h (264 h  196 h  171.5) Batches per Year = 44 (29  39  44) Annual Throughput = 156 kg Number of Bioreactors = 2

Add extra storage tank to eliminate current time bottleneck. New Results Batch throughput Number of Batches per Year Annual Throughput 3.55 kg 58 (29  39  44  58) 206 kg In scenario #4 we consider the impact of an extra storage tank.

INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Scenario 4) With an extra storage tank, we manage to increase the number of batches to 58 and the annual throughput to 206 kg. Under these conditions, the bioreactor (V-101) becomes again the new time bottleneck (the same equipment is also the batch throughput bottleneck). How can we increase the plant throughput further? If we add another bioreactor, we see that DF-102 will become the new time bottleneck and we will not be able to fully utilize the capacity of the extra bioreactor. Let’s see what happens if we add an extra bioreactor along with a new diafilter. V-101 = Scheduling (Time) Bottleneck EPBT = h (264 h  196 h   130.3) Batches per Year = 58 (29  39  44  58) Annual Throughput = 206 kg Number of Bioreactors = 2

Scenario 5 INTELLIGEN, INC. Action Add extra bioreactor and diafilter.
New Results Batch throughput Number of Batches per Year Annual Throughput 3.55 kg 84 (29  39  44  58  84) 298 kg In scenario #5 we consider the impact of an extra bioreactor and an extra diafilter.

INTELLIGEN, INC. Capacity, Time, and Combined Utilization Chart (Scenario 5) This is the equipment utilization chart for scenario #5. We now manage to increase the number of batches to 84 and the annual throughput to 298 kg. In this case there is no equipment sharing. All process steps utilize their own dedicated equipment. Under these conditions one of the storage tanks (V-105) becomes the new time bottleneck. Addition of an extra tank, whose operation is staggered based on the cycle time of the bioreactors, may increase the number of batches per year slightly. Does it make sense to consider the addition of an extra bioreactor? The answer is most likely NO. Presently, the utilization of several downstream equipment items is approaching 100% and if we add another bioreactor, we will not be able to take full advantage of it. In other words, this scenario is pretty close to the optimum under real-world conditions. This simple example illustrates how tools like SuperPro can be used to increase plant throughput in a systematic and economical way. V-105 = Scheduling (Time) Bottleneck EPBT = 89.7 h (264 h  196 h    89.7) Batches per Year = 84 (29  39  44  58  84) Annual Throughput = 298 kg Number of Bioreactors = 3

Comparison INTELLIGEN, INC. 1 3 3 29 2.3 kg 67 kg 1 1 3 3 29 3.5 kg
Scenario Number Bioreactor Vessels Membrane Diafilters Storage Tanks Batches per Year Batch Throughput Annual Throughput 1 3 3 29 2.3 kg 67 kg 1 1 3 3 29 3.5 kg 103 kg 2 2 3 3 39 3.5 kg 138 kg 3 2 4 3 44 3.5 kg 156 kg Here we have a summary of the changes. With relatively limited changes, we managed to increase plant throughput by more than 4 fold. 4 2 4 4 58 3.5 kg 206 kg 5 3 5 4 84 3.5 kg 298 kg

Labor Demand as a Function of Time
INTELLIGEN, INC. Labor Demand as a Function of Time Let’s have a look now at the resource demand for this process. This chart displays the demand for labor as a function of time. We see that for short periods of time we need up to 17 operators. If the corporation is not willing to hire that many people, then, we will have to delay certain operations that contribute to those peaks and SuperPro can help in that by identifying the operations that are responsible for those peaks. Such delays, however, may lead to labor becoming the new time bottleneck. This explains how resources become time bottlenecks.

WFI Demand as a Function of Time
INTELLIGEN, INC. WFI Demand as a Function of Time This chart displays the demand for WFI (water for injection) as a function of time. The red lines represent actual demand. The green line represents cumulative demand and the blue line represents demand averaged over a period of a day.

Cost Analysis INTELLIGEN, INC.
Now let’s have a look at some cost analysis results for the same process.

Cost Analysis Results (Base Case)
Waste Disposal 4% Production Rate 67 kg/yr Lab/QC/QA 1% Equipment Cost $2.3 M Raw Materials 27% Consumables 29% Total Investment $25.4 M Operating Cost $12.9 M/yr Labor-Depended DFC-Dependent 5% Unit Cost $193/g 34% This is a summary of the key cost analysis results for the base case (67 kg/year). For this case, the total equipment cost is $2.3 million, the total capital investment is $25.4 million, and the total annual operating cost is $12.9 million. This leads to a unit cost of $193/g. The pie chart on the right-hand-side shows the distribution of the cost items. The DFC-depended (facility overhead) cost accounts for 34% of the overall manufacturing cost. Depreciation and maintenance of the facility are the main contributors to this cost item. Consumables account for 29% (this includes the chromatography resins and the membranes of the membrane filters that need to be replaced periodically). Raw materials account for 27%. In terms of distribution between upstream and downstream, 43% is associated with the upstream section and 57% with the downstream (recovery and purification). Distribution per Section Upstream Downstream 43 % 57 % INTELLIGEN, INC.

Comparison of Various Options
Base Case Scenario 1 Scenario 2 Scenario 3 Scenario 4 Scenario 5 50 100 150 200 250 300 Unit Cost ($/g) Annual Throughput (kg) This graph shows the plant throughput (dark bars) and the unit manufacturing cost for the various scenarios that we analyzed in our throughput analysis exercise. Going from the base case to the scenario #5, the plant throughput increases from 67 to 298 kg (more than 4 fold). The unit manufacturing cost goes from around $200/g to around $140/g. In other words, the reduction in unit manufacturing cost is not as dramatic. Why? The answer is given in the next slide. INTELLIGEN, INC.

Unit cost of raw materials and consumables remained unchanged
Cost Analysis Results (Scenario 5) Waste Disposal 5% Lab/QC/QA 1% Production Rate 298 kg/yr Raw Materials 36% Consumables 39% Operating Cost $41.1 M/yr Unit Cost $138/g DFC-Dependent Labor-Depended 13% 6% This slide displays the key cost analysis results for scenario #5. In this case, seventy percent of the manufacturing cost is associated with the consumables and the raw materials which scale linearly with the plant throughput. This explains why the reduction in unit manufacturing cost is not as dramatic. However, I must emphasize that in this exercise we assumed that the unit cost (price) of raw materials and consumables remains the same. If you buy four times as much raw materials and consumables and your purchasing people have some descent negotiation skills, they should be able to negotiate better prices and reduce the unit cost of the final product even further. Key Assumption Distribution per Section Upstream Downstream 38 % 62 % Unit cost of raw materials and consumables remained unchanged INTELLIGEN, INC.

INTELLIGEN, INC. SuperPro Designer v5.0 Spring 2001

From Single to Multiple-Recipe Projects
SuperPro v4.5 (current) SuperPro v5.0 Single-Recipe Project Multi-Recipe Project Perform at the Facility Level Scheduling and Planning Resource Tracking Equipment Utilization Debottlenecking SuperPro v5.0 will become available in the spring of The main thrust of v5.0 will be the multi-recipe project capability. The current version of SuperPro does a good job in modeling, analyzing, evaluating, and scheduling a single recipe at a time. Version 5.0 will enable the user to model any number of recipes as part of a single project. The multiple recipes can represent different sections of a long process or different products of a multi-product facility. Version 5.0 will enable users to track at the facility/site level demand for resources and equipment utilization and identify conflicts associated with them. Further, it will facilitate scheduling and planning of multi-product facilities and sites. INTELLIGEN, INC.

Project Architecture Databases SuperPro Project INTELLIGEN, INC. Sites
Recipe 1 Sites Recipe 2 Recipe 3 Facilities Utilities Equipment Multi-Product Manufacturing Facility Labor This is a schematic of the architecture of SuperPro v5.0. Each recipe will be displayed on its own window like the current single-recipe files. In the background, each recipe will be associated with a single facility but several different recipes can share the same facility along with its equipment and resources. Going from v4.5 to v5.0, SuperPro is becoming more database driven. Presently, information about pure components and mixtures, construction materials, and utilities (the green cylinders) is stored in MS Access files. Within the next few months we will be implementing databases for Equipment, Facilities, Sites, and Labor. That will enable users to describe their facilities at their various sites along with the equipment and resources that are available there. Further, Labor will become a more flexible resource and SuperPro will handle any number of labor types (even down to the the level of individual operators). The availability of databases will enhance the Technology Transfer capabilities of SuperPro Designer. Evaluation of options for fitting a new process into a number of alternative facilities will become quite easy. Construction Materials Raw Materials INTELLIGEN, INC.

Display of Multi-Recipe Projects
Each recipe of a multi-recipe project will have its own worksheet, similar to Excel worksheets. For instance, the above screen displays a project with three recipes {Aspirin, Lovastatin, and Viagra}. V5.0 will also provide a facility/site and a product view. The facility/site view will display the facilities and sites involved in a project and the recipes of the various facilities. Double-clicking on a recipe will bring its worksheet to the top. The product view will display the products of a project and the recipes/facilities of each product. For instance, if a product with a long synthesis route is manufactured at three different facilities/sites and involves eight different recipes, this tree-like view will enable users to visualize the interconnectivity among the various recipes. After v5.0 you may expect to see more internet related features in SuperPro and enhanced connectivity with ERP (Enterprise Resource Planning) and MES (Manufacturing Execution System) packages. Worksheets (recipes) INTELLIGEN, INC.

Summary Process Simulation can play a role in:
INTELLIGEN, INC. Summary Process Simulation can play a role in: Facilitating Process Development Improving Team Communication Increasing Plant Throughput Reducing Capital and Operating Cost In summary, we have seen that CAPD and simulation can play a variety of roles during the lifecycle of product development and commercialization. It can facilitate process development by guiding experimental work and introducing a common language of communication so that everybody can make the same assumptions and have a way to document those assumption. It can be used for increasing plant throughput in a systematic way and with the lowest possible capital expenditures. Further, it can be used for identifying the economic hot-spots of a process and minimizing capital and operating cost.

For a fully functional demo of Bioprocess Design & Economics
SuperPro Designer & A book chapter on Bioprocess Design & Economics Go to

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