Fed-batch and perfusion-based processes for cell culture are both commonly utilized to produce biopharmaceuticals such as monoclonal antibodies. Each of these processes require the use of concentrated media to help replenish nutrients and reduce any loss in productivity associated with dilution. L-Tyrosine is one amino acid that is especially important for protein synthesis and cellular metabolism. However, the limited solubility of such amino acids can quickly become a limiting factor in the preparation of concentrated media.
Separate pH neutral and extreme pH feeds of L-Tyrosine are not enough
L-Tyrosine has a very low solubility of less than 0.5 g per liter in water at neutral pH. However, its solubility can increase when moving away from the isoelectric point. That is why the use of a separate L-Tyrosine feed with an extreme pH has traditionally been used in addition to the main pH neutral feed to help improve cell performance and batch productivity. However, this approach can face many drawbacks. In particular, the inclusion of this separate feed not only increases process complexity but may create additional risks due to the introduction of higher salt concentrations, potential pH spikes and the precipitation of L-Tyrosine when overdosing.
Replacing L-Tyrosine with Tyrosine dipeptides is the reliable solubility solution
The coupling of L-Tyrosine to glycine via a peptide bond creates a dipeptide that can effectively increase solubility for free L-Tyrosine at a neutral pH. Evonik’s tyrosine dipeptides can serve as a reliable replacement when high concentrations at neutral pH are required. Evonik’s cQrex® GY dipeptide, for example, delivers solubility that is high enough to prepare concentrated feeds without the need to modify pH. Indeed, this Glycyl-L-tyrosine product can increase the solubility at neutral pH by up to 50 times compared to free L-Tyrosine. Because it can be efficiently taken up and metabolized by the cell, full replacement of tyrosine becomes possible. Conversion to cQrex® GY as part of a single feed can significantly reduce process risk due to the resulting reduction in complexity. cQrex™ AY (L-alanyl-L-tyrosine) is also an attractive alternative that can provide more flexibility during media design.