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



Figure 2
Because biopharmaceutical processes operate in batch mode, the simulator also must facilitate process scheduling and cycle-time analysis. The results of process scheduling are typically visualized with Gantt charts that display equipment occupancy as a function of time (Figure 2).

Sensitivity and parametric analysis are other common benefits of using such tools. Input parameters can be varied manually or automatically and their impact can be evaluated quickly. If statistical data are available for certain input parameters, their impact on output (decision) variables can be evaluated using Monte Carlo simulation.10

It is important to note, however, that the garbage-in, garbage-out (GIGO) principle applies to all computer models. If critical assumptions and input data are incorrect, the simulation outcome will also be incorrect. Consequently, a certain level of model validation is necessary. In its simplest form, a review of the results by an experienced engineer can play the role of validation.

Process Description

Figure 1 displays the flow diagram of the overall process (the way it is represented in SuperPro Designer). Please note that for simplicity, the buffer preparation and holding activities are omitted from Figure 1. Those activities, however, were taken into account in the detailed models that were built for evaluating the alternatives. The simulation steps are represented by codes that appear in parentheses (e.g., MP-103) throughout the article.

Upstream Processing

The inoculum is initially prepared in 225- mL T-flasks. The material is first moved to roller bottles (2.2 L), then to 20 L, and subsequently to 100-L disposable-bag (Wave rocking) bioreactors. The broth is then moved to a stirred-tank seed bioreactor. The media solution for the seed bioreactor (165 L per batch) is prepared in a tank (MP-101) and then sterilized and fed to the reactor through a 0.2-μm dead-end filter (DE-101).

Serum-free, low-protein media powder is dissolved in water for injection (WFI) in a stainless-steel tank (MP-103). A diluted medium (3%) of 1,628 L is prepared per batch. The solution is sterilized using a 0.2-μm dead-end polishing filter (DE-103). A stirred-tank bioreactor (PBR1) is used to grow the cells that produce the therapeutic MAb. The production bioreactor operates under a fed-batch mode. High media concentrations are inhibitory to the cells so half of the media is added at the start of the process and the rest is fed at a constant rate during fermentation. The concentration of media powder in the initial feed solution is 17 g/L whereas the concentration of the medium added during the fed-batch phase is 156 g/L. The fermentation time is 12 days. The volume of broth generated per bioreactor batch is approximately 2,000 L, containing roughly 4 kg of product. The product titer is approximately 2 g/L.


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