Systematic Evaluation of Single-Use Systems Using Process Simulation Tools - Simulation tools can reveal whether disposables will be economical even after scale-up. - BioPharm International

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Systematic Evaluation of Single-Use Systems Using Process Simulation Tools
Simulation tools can reveal whether disposables will be economical even after scale-up.


BioPharm International Supplements


Results and Discussion

The fermentation time is 12 days; the facility is equipped with four production bioreactors resulting in a cycle time of 3.5 days. Eighty batches can be executed per year (20 per bioreactor). The product titer in the production bioreactors is 2 g/L. With a broth volume of approximately 2,000 L and a downstream yield of 62.5%, the amount of purified MAb produced per batch is 2.5 kg.

Figure 2 displays the equipment occupancy chart for 13 consecutive batches of the 2,000-L stainless-steel process option. The activities (unit procedures) of each batch are displayed with a unique color. The various equipment groups are displayed on the chart. The occupancy of CIP skids is represented by the top six lines. The next two equipment groups correspond to the occupancy of the buffer preparation and holding tanks, respectively. Most of these tanks are reused within a batch. Reuse of a tank (e.g., HV-101) within a batch is represented by multiple rectangles of the same color (one rectangle for each unit procedure using that equipment). Reuse of tanks (for preparing and holding different buffers within a batch) reduces the number of vessels and consequently the capital investment for a new facility. However, it also increases their occupancy and cycle times making them scheduling bottlenecks more likely.

The next equipment group corresponds to three seed (SBR1a, b, and c) and four production bioreactors (PBR1a, b, c, and d). Both the seed and production bioreactors operate in staggered mode (out of phase) to reduce the cycle time of the overall process to 3.5 days. A single downstream line (DSP group) handles all purification batches.


Figure 3
The equipment occupancy chart enables users to visualize equipment utilization and readily identify equipment scheduling bottlenecks that determine the cycle time of the overall process. The production bioreactors (PBR1a, b, c, and d) have the longest cycle time and constitute the scheduling (or cycle time) bottlenecks for the base case. However, if the number of production bioreactors is increased, then the bottleneck will shift to the buffer preparation and holding tanks that have the next highest utilization. Scheduling bottlenecks linked to buffer preparation equipment is not a consideration for the disposables option unless the buffer preparation bag skids are reused.


Table 2. Demand for water for injection (WFI), cleaning materials, and clean steam
Media and buffer preparation cycle times for the disposables option are shorter than in the stainless-steel case because disposable bags generally do not require SIP or CIP steps. The reduced need for cleaning also reduces the required number of CIP skids and the volume of cleaning materials. Figure 3 displays the required number of CIP skids (as a function of time) for the stainless-steel and disposables options, respectively. Six CIP skids are required in the first case, whereas this number is halved for the single-use option, which in turn reduces the capital cost of the single-use option. Table 2 provides information on the demand for cleaning materials for the two cases. The use of disposables reduces the volume of cleaning materials by more than 50%.


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