Protein pharmaceuticals aggregation

In peptide/protein pharmaceuticals, the GAS process is predominantly applied for the preparation of microparticulate protein powders as an alternative to common drying processes. However, Winters et al. [69] reported an increase of P-sheet aggregates during the precipitation of lysozyme, trypsin, and insulin as a consequence of stress parameters such as organic solvent, pressure, and shear forces. One reason... 

Organic solvents are often used in the manufacture, purification, precipitation and crystallization of protein pharmaceuticals (Sukumar et al., 2005). Water miscible solvents such as ethanol, acetonitrile and propanol have been utilized to promote the stabilization of reversible denaturation and aggregation, with recovery of the native conformation. For example, insulin has been precipitated and/or crystallized in a wide variety of solvents (Brange and Lanlqaer, 1993). 

Large aggregates of proteins which exhibit an opalescent or hazy appearance may be easily measured by light scattering phenomena. Protein pharmaceutical products are commonly evaluated visually for clarity and degree of opalescence a relatively simple turbidi-... 

While it is convenient to use the term aggregates as a catch-all for the undesirable large-species-content of a protein pharmaceutical product, it is important to recognize that the aggregating protein solution comprises a kinetically... 

H. R. Costantino, R. Langer, and A. M. Klibanov, Solid-phase aggregation of proteins under pharmaceutically relevant conditions, J. Pharm. Sci., 83, 1662 (1994). 

Chi, E.Y., Krishnan, S., Randolph, T.W., and Carpenter, J.F. 2003. Physical stability of proteins in aqueous solution mechanism and driving forces in nonnative protein aggregation. Pharmaceutical Research 20(9), 1325-1336. 

According to current PDA guidelines, an acceptable pharmaceutical product should exhibit less than 10% deterioration after 2 years.5 Protein biopharmaceuticals usually have to be stored under refrigerated conditions or freeze dried to achieve an acceptable shelf life. EL IS As for aggregates and product variants as discussed previously would be applicable for determining shelf life. 

After spray drying, rice starch containing <0.5% protein is present as clusters of 10-2011 m. At 1.5% and again at 6.0% protein, increased formation of spheres of 30-70 qm is observed. The presence of these spheres is responsible for improved dispersibility and gel smoothness.26 It has also been suggested that the unique absorption properties of the sphere aggregates may have application in holding and dispersement of flavor material or pharmaceuticals.27... 

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