Because ammonia affects cell growth and metabolism, it is conceivable that it also affects the product expression. Either directly or indirectly, ammonia can affect the product concentration obtained in the culture and thus the process efficiency.
The indirect effect of ammonia on production results from the reduced cell growth rate and subsequent cell density achieved in the culture. Even though the specific productivity may not have been altered, the cell density and longevity of the culture can be restricted by high ammonia levels. Thus, cultures with high ammonia levels result in lower product concentrations. Several studies have reported a decrease in monoclonal antibody production at high ammonia concentrations, mainly because of lower cell densities obtained (6,70,71). Figure 4b presents the effect of ammonia on antibody titer and specific productivity for a murine hybridoma line in batch culture. Although the titer was reduced, the specific antibody production rate remained constant under these conditions.
The direct effect of ammonia on specific productivity varies and the mechanism(s) are poorly understood. Dyken and Sambanis (95) observed a slight increase in protein secretion from AtT-20 cells. Ammonia was reported to alter the secretion rate of interferon (INF) y (96) and synthesis of INF-/; (97); however, the specific production rates were not provided in these studies. Hansen and Emborg (86) reported a decrease in tissue-type plasminogen activator (t-PA) production from CHO cells at high ammonia concentrations. Specific antibody productivity was evaluated for a number of hybridoma cell lines in the literature. Glacken (87) reported a decrease in antibody productivity at elevated ammonia levels for the C-1606 hybridoma line. Other investigators, however, reported an unaltered specific antibody production rate (6,70,71).
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