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.
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.
Anurag S. Rathore, PhD, is a consultant, Biotech CMC Issues, and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.
Articles by Anurag S. Rathore, PhD