Application Note

Innovative Chemicals For Process Intensification In Cell Culture Media

Protein Analysis With Size Exclusion Chromatography (SEC)

L-Tyrosine is a key amino acid for both cellular metabolism and protein synthesis and its depletion in fed-batch processes has been correlated with a drop in specific productivity1 and with protein sequence variants.

This critical amino acid presents an extremely low solubility, especially at neutral pH. The use of tyrosine di-sodium salt concentrations above 1 g/L in feeds induces precipitation and increases the risk of media instability, mainly through co-precipitation of other amino acids. This may lead to sub-optimal performance due to insufficient supply of nutrients and finally to low performing processes.

L-cysteine is a sulphur-containing amino acid which is oxidized to the dimer L-cystine in the presence of air, oxygen or metal containing catalysts such as copper. L-cysteine is freely soluble, L-cystine has a reduced solubility in water6 and often precipitates in neutral pH feeds.

To overcome these limitations, common fed-batch processes use highly concentrated alkaline feeds which create the need for complex control strategies to minimize pH spikes during feed additions. In order to remove this alkaline feed, tyrosine and cysteine were chemically modified to phospho-Ltyrosine disodium salt7 and S-sulfocysteine sodium salt respectively. The combination of both chemicals allows the integration of both amino acid sources in highly concentrated, neutral pH feeds (Figure 1B) and thus provide a unique way to simplify fed-batch processes by enabling the development of stable and neutral pH main feeds.

This brief provides a rrocess guidance for the use of the modified amino acids Phospho-Tyrosine Disodium Salt EMPROVE® EXPERT and Sulfo-Cysteine Sodium Salt Sesquihydrate EMPROVE® EXPERT in fed-batch processes.

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