Roche – hanns-christian.mahler@roche.com

Key Interactions of Polysorbates in Protein Formulations

Surfactants, such as polysorbates, are frequently used for formulating protein therapeutics. They protect proteins against interface-induced stresses. This includes protection against aggregation and precipitation caused by air/liquid interfaces (e.g. shaking), by ice/liquid interfaces (e.g. freezing and thawing) and against adsorption of protein often observed with various surfaces (e.g. manufacturing equipment). This talk will include examples of all these aspects. Polysorbates are mixtures of fatty acid esters and are for the use in pharmaceutical products typically synthesized chemically. A number of synthesis side products occur and are still found in the final excipient raw material, making polysorbates a critical excipient, with high degree of variability. Polysorbates also provide a number of other challenges. For example, their adsorption behaviour may make them adsorb to certain manufacturing equipment (e.g. filters), they can induce pseudoallergenic reactions in dogs (making preclinical testing of protein formulations challenging) and finally, they can degrade as bulk and even in the protein formulations over storage time, due to hydrolysis and oxidation. Degradation products may alter protein stability and/or cause findings in drug products that require further attention. This talk will include studies done on polysorbate degradation and discuss impact, as well. Interestingly, various hypotheses exist for how polysorbates stabilize proteins. This makes the assessment of variability and degradation challenging. Direct interaction with protein structures has been discussed. Likely, effects of polysorbates are due to their surface-active nature and consequent interactions at interfaces, competing with proteins and thus leading to indirect stabilization by minimizing protein/interface-interactions.

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