Achieve Success with Biosimulation

Feb. 16, 2005
Biosimulation, if done right, aids in allocating equipment, managing utility requirements and optimizing processes. Here's how to apply simulation to improve purification.
Biosimulation allows engineeringteams to size and allocateequipment more efficiently.Photo courtesy of Fluor Corp.By Brian Schmidt, Process Engineer, Fluor Corp.Process simulation is widely used in petrochemicals manufacturing and outside the process industries. The technique, which mathematically models a process to determine the impacts of change, is now becoming more popular for bioprocess development.
Editor's Note: All figures for this article are contained in a single PDF document which may be accessed by clicking the "Download Now" button at the end of the article.
The reasons for simulation’s higher profile are clear: Biosimulation allows engineering teams to size and allocate equipment more efficiently, and to determine utility requirements early in the development process. In addition, it also permits process optimization.But biosimulation for its own sake, without clearly defined goals, wastes time and money. Using simulation effectively requires that key variables be identified early on in the project, including throughput, “uptime” or equipment utilization, potential bottlenecks, schedules and resource allocation. It also requires that goals be stated clearly, early on, so that the right type, quantity and quality of information is fed to the model.In general, simulation can help users:
  • Size utility generation, and even distribution and storage requirements and equipment, in order to more accurately and efficiently use peak and average utility consumption data

  • Determine Clean-in-Place (CIP) requirements, including those for skids, water and cleaning chemicals

  • Perform economic analyses to determine project feasibility, profitability and payback

  • Optimize the process, by testing the effect of various scenarios on throughput and other variables.
Using a biopurification train model as an example, this article will discuss tips on how to make any bioprocess simulation more efficient and to achieve significant increases in throughput. Model development: goal settingThe first step in developing a process model is to identify what the goals of the effort will be. The design team must identify what it hopes to accomplish and what questions the model will address. The model may be used to:
  • Debottleneck a process
  • Size equipment
  • Size utility systems
  • Track raw materials used in the process
In each case, different types of information will be required. Goal setting establishes what information must be gathered and dictates how the model will be structured. In general, the more questions the model must answer, the more information it will require.Information gatheringOnce goals have been identified, the team must gather the data needed to develop the process model. Each modeling objective will require a different type of information, depending on the final model’s focus. Most models will require the following:
  • Process flow information and process operating parameters;

  • Process flow diagrams (PFDs), piping and instrumentation diagrams;

  • (P&IDs) and process descriptions will be required to ensure the flow and connectivity of unit operations. Information on how each of the unit operations works, including identification of each major step of each unit operation.
Duration can be expressed in time or as a set of process conditions that can be used by the software to calculate the duration of each step. For example, transfer rate and batch size can be used to calculate how long a transfer from tank to tank will take. Process descriptions may provide detail on how each of the unit operations operates depending on the level of detail. It may be necessary to obtain data by reviewing Standard Operating Procedures (SOPs) or interviewing design team members and operations staff, who can help identify such hard-to-determine factors as manual operations within the process.Additional data such as raw material properties, utility design flow rates, and data on utility consumption, manpower and costs—and this is only a partial list. When data are not available, as is usually the case during a new facility conceptual design project, assumptions can be made using generic data that can be replaced once real data are available.Building a model for a purification trainOnce the appropriate data have been gathered, the model can be built. We’ll apply this concept to a biopurification train. First, model the product’s path through the process. Generally, it helps to break this portion of the project down into smaller steps, and to work with one unit operation at a time.Then, for each operation, enter its process information, its scheduling links and its equipment data. After data for the first unit operation has been entered, make sure that the model accepts and works with these data. This extra step will save time later on by eliminating the need to debug multiple units individually.Some suggestions:
  • Model directly whenever possible; don’t model operations that reference operating parameters from other areas of the process.

  • In the case of purification, start with the chromatography, viral filtration and ultrafiltration systems, rather than from the buffer preparation and buffer hold systems, which reference data from other areas of the process. For example, buffer hold tanks that feed chromatography systems get their pull-out durations and volumes of buffer fed to the chromatography columns from the chromatography system itself.

  • Operating parameters such as the column volume, linear velocity and equipment details determine the amount of buffer supplied to the chromatography system and the pull-out durations. In contrast, modeling the buffer hold tank first would require inputs to be re-entered or scheduling links to be re-established once the chromatography system had been built into the model.

  • Establish templates that can be used for similar unit operations. Once a unit operation has been set up, data can easily be copied and pasted into the modeling flowsheet to model another similar or identical unit. All of the activities of the first unit operation will copy to the second, but remember that activities with external references will need to be set up again.

  • Once the product path has been modeled, move on to other areas in the process. Now is the time to model buffer preparation and hold areas. But there are ways to reduce the time entailed. Again, templates can be established for equipment that is used several times during each product batch.

  • Consider a tank used in buffer preparation. This tank may be shown on the model flowsheet multiple times to signify that multiple buffer batches are made in that tank. Assigning the same equipment tag number to a tank that is used multiple times in the process accounts for the fact that it is a single tank.
Clean in placeThis modular approach will also help when modeling CIP systems. For each piece of equipment, consider CIP as an activity to be modeled, then assign individual skids so that each one is tracked based on the amount of time that it is occupied while cleaning a piece of equipment.Within the CIP activity of the piece of equipment, the following data can be entered:
  • cleaning cycle/recipe
  • water consumption, based on equipment size or a user-defined value
  • cleaning chemicals and air consumption, both of which can also be tracked.
CIP cycles and recipe data should be entered into the model as it is developed because the cycles are factored into the utilization of a piece of equipment. Entering the CIP cycles and recipes as the model is developed also makes it easy to copy and paste relevant data.Plant utilitiesIf the model will be used to analyze utility systems, data should be entered as it would with CIP, as the model is developed.However, it is important to consider how the utilities are being used. Utilities can either be categorized as ingredients in the process, a method typically used for Water for Injection (WFI), or as entities that don’t come into direct contact with the product stream—for example, clean steam and chilled water.The overall usage of WFI can be tracked by plotting WFI as an ingredient to all the mixtures over time, while clean steam and chilled water can be entered into the model as auxiliary utilities. The overall usage of each utility can be tracked over time.Conflict resolutionThe final phase of building a model is resolving any scheduling conflicts so that no piece of equipment must operate more than once at a time. Such conflicts are common within buffer preparation systems and CIP skids.Always start with process equipment such as the buffer prep tanks when resolving conflicts. Generally, it’s good practice to shift the operation of the equipment earlier or later in the schedule to eliminate overlap with other operations.Remember to consider the ramifications of any changes you make. For example, a buffer prep tank that provides just-in-time buffer to a chromatography system may delay a chromatography operation if the batching operation is moved later in the schedule. In such cases, it’s usually best to move the operation forward. Once the process equipment conflicts have been resolved, then consider any CIP skid.CIP skid conflicts can be resolved in several ways. One option is to postpone equipment cleaning by the CIP skid until the skid becomes available. A second method is to reassign the cleaning of the equipment to a different CIP skid that is available. Yet another approach is to shift the entire operation so that there isn’t a CIP conflict. Remember to consider each conflict individually. Not every CIP skid conflict can be resolved by applying only one of the three methods. Evaluate the process schedule, the CIP schedule and the capabilities of the CIP system to make the best decision. Data analysisAfter re-entering the necessary data into the model and resolving schedule conflicts, the model can be used to answer the questions posed in the goal-setting phase. Data such as equipment utilization and utility consumption charts and the process schedule can be used to challenge assumptions for equipment allocation and sizing, utility consumption and overall process throughput.
Editor's Note: All figures for this article are contained in a single PDF document which may be accessed by clicking the "Download Now" button at the end of the article.
Equipment utilizations are helpful in determining whether enough equipment has been allocated or whether the size of the equipment is appropriate. Highly utilized equipment can prevent overall throughput goals from being achieved, as shown in Figure 1, in which a single buffer prep tank has schedule overlap between two different batches. Figure 2 shows the impact of adding a second buffer prep tank.Generally, the cycle time of the operation can be reduced by increasing the capacity of a piece of equipment. Higher capacity will allow the batch to be processed at a higher rate, thus reducing the cycle time and utilization, as shown in Figure 3, in which a column was replaced with one having a larger diameter. Utility consumption charts are used to illustrate the instantaneous demand of a particular utility system. The charts can be customized to show instantaneous levels in storage equipment based on generation capabilities and storage capacity. These charts are used to confirm equipment sizing and to confirm assumptions made on the overall usage of each utility. The model does not give an exact picture of the utility consumption because support equipment, such as autoclaves and parts washers, is not included in the model while the major process users of utilities are. Figure 4 shows a WFI consumption chart, identifying when the process requires the most WFI. Raw material consumption charts and labor demand charts are also useful. Process simulation is a powerful tool for a process design team. Careful planning and use of a modular approach can ensure success. About the Author Brian Schmidt has over seven years of experience, primarily in the pharmaceutical/biotechnology industry. He has led Fluor Corp.’s process simulation efforts for numerous client projects. Schmidt joined Fluor in 2001. Previously, he was a process engineer at Hartel Corp. He has a B.S. in chemical engineering from the University of Wisconsin, Madison.