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Anurag Rathore |
Creation and qualification of scale-down models are essential for performing several critical activities that support process validation and commercial manufacturing. As shown in Figure 1, these activities include process characterization and production support studies that are performed to evaluate column and membrane lifetimes, demonstrate clearance of host-cell impurities and viruses, and troubleshoot manufacturing issues. While the underlying fundamentals are relatively the same as those when scaling up, some unique considerations should be taken when scaling unit operations down.1-4 The goal when scaling down is to create a small-scale or lab-scale system that mimics the performance of its large-scale (pilot or manufacturing) counterpart, when both the process parameters are varied within their operating ranges and also when a process parameter deviates outside its operating range. Before it can be used for lab studies, the scale-down model needs to be qualified and its equivalence to large-scale examined. Data from an inaccurate scale-down model could result in conclusions that may not be applicable to large-scale, resulting in an unsuccessful process-validation campaign or continued lot failures in a manufacturing campaign.
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This article is divided into two segments. The first part focuses on an upstream unit operation — fermentation. The next segment will cover two downstream unit operations — chromatography and filtration. The combined article is the fifth in the “Elements of Biopharmaceutical Production” series.
Figure 1. Scale-down Models are Best Utilized for Process Characterization and Production Support |
HARDWARE SCALE-DOWN GUIDELINES
Fermentation processes often involve several scales of operation, encompassing inoculum development, seed expansion, and production fermentation. The differences in volumes between the steps in a single fermentation process can be 10X to 100X for the pilot scale, and 1,000 to 100,000X for the production scale. This may cause the fermentation processes to be challenging to scale down and the specific process parameters, vessel geometries, and operational control strategies must be evaluated for each step. Some general guidelines to consider in developing a representative scale-down model follow.
Practitioners use the terms “similar reactor” or “similar vessel geometries” to describe optimal conditions for a scale-down strategy. However, similarity in vessel geometry does not necessarily imply identical systems, although this would be the most attractive option. Instead, geometric similarity means that the overall aspect ratios of each vessel (small vs. large) are close enough to not impact performance. More importantly, the impeller and sparger designs and placements within the vessel are nearly identical.
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