Achieving Process Intensification by Scheduling and Debottlenecking Biotech Processes - An approach to reduce batch time, increase productivity, and decrease costs. - BioPharm International

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Achieving Process Intensification by Scheduling and Debottlenecking Biotech Processes
An approach to reduce batch time, increase productivity, and decrease costs.


BioPharm International
Volume 24, Issue 2, pp. 44-53

CASE STUDY 1: PROCESS SCHEDULING AND DEBOTTLENECKING FOR A SINGLE-PRODUCT BIOTECH FACILITY


Figure 1. Equipment occupancy chart for the upstream process. The X axis denotes process time and the Y axis shows key process equipment.
The objective of this case study was to perform process scheduling and debottlenecking to enable a five-fold process scale-up with minimal capital expenditure on equipment. We also proposed an optimized plan for buffer and media preparation and storage and calculated the number of storage and preparation units required. Data on the existing equipment were provided.


Figure 2. Optimized equipment occupancy chart for the upstream process. The X axis denotes process time and the Y axis shows key process equipment.
The upstream facility produced a 30-L harvest batch every fourth day. The major equipment that existed in the facility included a disposable 40-mL flask, three 500-mL spinner flasks, two 5-L bioreactor, three 30-L bioreactor, a microfiltration unit, and a 30-L harvest storage tank. An EO chart for the upstream process was generated using SuperPro software and is shown in Figure 1. Analysis of the EO chart identified bottlenecking equipment, timescale of equipment usage, reuse of equipment, and excess equipment. In this case, the 30-L bioreactor was the bottleneck and it was evident that the number of spinner flasks was excessive; instead of three, only two are required.


Figure 3. Equipment occupancy chart for debottlenecking for the five-fold scale-up. The X axis denotes process time and the Y axis shows key process equipment.
To increase capacity, a future plan entailed purchasing two 150 L bioreactors and reusing the rest of the equipment from the current facility as much as possible. Figure 2 shows the minimum amount of equipment required and the optimized scheduling for producing a batch in the shortest time period. As we planned to use some of the equipment from the previous facility, the final list of equipment that must be purchased included a disposable 40-mL flask, a 500-mL spinner flasks, a 5-L bioreactor, a 25-L bioreactor, and a 150-L harvest storage tank. It was also decided to reuse the microfiltration unit, which was capable of handling a five-fold increase in throughput. With this scheduling, a batch could be manufactured every six days and 4 h, and the bottlenecking was now the 150-L bioreactor.


Figure 4. Equipment occupancy chart for the downstream process. The X axis denotes process time and the Y axis shows steps for each unit operation.
Figure 3 shows that adding another 150-L bioreactor shifts the bottleneck to the 5-L and 25-L bioreactors and reduces batch production time to five days. Because the downstream process (discussed in the next section) has a batch time of seven days, further debottlenecking of the upstream process was not performed.


Figure 5. Buffer preparation scheme for a single-product biotech facility. Each column denotes a unit operation of the process and the rows denote the time in days.
The downstream process underwent process scheduling and optimization following the procedure outlined above for the upstream process. The resulting EO chart is shown in Figure 4. To enable a five-fold scale-up, it was decided to use the same equipment for chromatography 1( C-1), ultrafiltration (UF), and C-2 unit operations. Scaling of C-3, C-4, and C-5 unit operations was performed in accordance with a scaling factor of 2.5X, and C-6, C-7, and filtration unit operations in accordance with a scaling factor of 5X. The scaling factors were chosen as per the following guideline. The cost of the chromatography columns increases significantly with column size. Also, the column size is smaller for the chromatography steps that are later in the process. Hence, it is economically optimal to split the batch for the first half of the process (i.e., C3 to C5) and then later combine the two process segments in the second half (C6 and thereafter). This strategy minimizes the batch time, capital cost, and labor cost.


Figure 6. Optimized equipment-occupancy chart for buffer preparation and hold-up tanks. The rows denote tanks used in the process, and the columns denote the duration of usage in days.
The buffer preparation plan was scheduled and optimized in view of buffer stability and requirements. Many options were evaluated. The optimal solution with the minimal amount of buffer storage and preparation tanks is shown in Figure 5. An EO chart was made to minimize the amount of equipment by reusing equipment again if permissible. Figure 6 shows one such EO chart. Similar charts were created for all buffer preparation and hold-up equipment to identify the minimum equipment required. For this case study, the requirements are shown in Table 1.


Table 1. Requirements for the first case study
The above case study demonstrates how process scheduling and debottlenecking enable an economically optimal scale-up of the process and optimize the number of buffer and media preparation units. Batch size was increased five fold while buying only two 150-L bioreactors, five chromatography columns (i.e., C-3, C-4, C-5, C-6, C-7), and one 125-L harvest storage tank. In addition, the optimal number of buffer preparation and storage units was also estimated for preparation, and storage of 3,290 L of 30 different buffers per week.


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