The goal of cell culture process intensification is to increase volumetric productivity, generally by increasing viable cell density (VCD), cell specific productivity or production bioreactor utilization in manufacturing. In our previous study, process intensification in fed-batch production with higher titer or shorter duration was demonstrated by increasing the inoculation seeding density (SD) from ~ 0.6 (Process A) to 3-6 × 10 6 cells/mL (Process B) in combination with media enrichment. In this study, we further increased SD to 10-20 × 10 6 cells/mL (Process C) using perfusion N-1 seed cultures, which increased titers already at industrially relevant levels by 100% in 10-14 day bioreactor durations for four different mAb-expressing CHO cell lines. Redesigned basal and feed media were critical for maintaining higher VCD and cell specific productivity during the entire production duration, while medium enrichment, feeding strategies and temperature shift optimization to accommodate high VCDs were also important. The intensified Process C was successfully scaled up in 500-L bioreactors for 3 of the 4 mAbs, and quality attributes were similar to the corresponding Process A or Process B at 1000-L scale. The fed-batch process intensification strategies developed in this study could be applied for manufacturing of other mAbs using CHO and other host cells.
At the request of the UK Department of Health, samples of 25 commercial UK cigarette brands were provided to LGC Ltd a for smoke analysis. The brands reflected a high market share (58% in July 2001) and included a wide range of blend and product styles manufactured and imported into the UK.= 0.76), suggesting a minor role of other design features on constituents yield variability. This was confirmed by the application of multiple regression analysis to the data. A subset of five brands, retested at another laboratory, gave between-laboratory differences in mean constituent yields of as much as 2.5-fold. Consideration of these results, other likely sources of analytical variation in this study and a review of other studies, clearly indicates that any tolerance values to be associated with individual smoke constituent measurements will be greater than those for NFDPM, and in some cases, much greater. Consistent with the reported results from other large studies it is concluded that, under ISO smoking conditions, smoke constituent yields are largely predictable, if NFDPM and CO yields are known, for a standard cigarette. Given these observations and the likely limitations of analytical determination, the need for routine measurement of smoke constituent yields, other than NFDPM, nicotine or CO, on standard cigarettes, is questionable.
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