No abstract

The occurrence of glass delamination is a serious concern for parenteral drug products. Over the past several years, there has been a series of product recalls involving glass delamination in parenteral drugs stored in vials which has led to heightened industry and regulatory scrutiny. In this study, a two-pronged approach was employed to assess the inner surface durability of vials and pre-filled syringes. Non-siliconized syringes were used in order to directly compare glass to glass performance between vials and syringes. The vial and syringe performance was screened with pharmaceutically relevant formulation conditions. The influence of pH, buffer type, ionic strength, and glass type and source was evaluated. In addition, an aggressive but discriminating formulation condition (glutaric acid, pH 11) was used to ascertain the impact of syringe processing. Advanced analytical tools including inductively coupled plasma/mass spectrometry, scanning electron microscopy, atomic force microscopy, and dynamic secondary ion mass spectroscopy showed significant differences in glass performance between vials and syringes. Pre-filled syringes outperform vials for most tests and conditions. The manufacturing conditions for vials lead to glass defects, not found in pre-filled syringes, which result in a less chemically resistant surface. The screening methodology presented in this work can be applied to assess suitability of primary containers for specific drug applications.

No abstract

The self-associative properties of apolipoprotein A-I(Milano) (apoA-I(M)) were investigated in relationship to its anion exchange behavior on Q-Sepharose-HP with and without the addition of urea as a denaturant. Self-association was dependent on protein and urea concentration and both influenced interactions of the protein with the chromatographic surface. In the absence of urea, apoA-I(M) was highly associated and existed primarily as a mixture of homodimer, tetramer and hexamer forms. Under these conditions, since the binding strength was greater for the oligomer forms, broad, asymmetrical peaks were obtained in both isocratic and gradient elution. Adding urea depressed self-association and caused unfolding. This resulted in sharper peaks but also decreased the binding strength. Thus, under these conditions chromatographic elution occurred at lower salt concentrations. The adsorption isotherms obtained at high protein loadings were also influenced by self-association and by the varying binding strength of the differently associated and unfolded forms. The isotherms were thus dependent on protein, urea, and salt concentration. Maximum binding capacity was obtained in the absence of urea, where adsorption of oligomers was shown to be dominant. Adding urea reduced the apparent binding capacity and weakened the apparent binding strength. A steric mass action model accounting for competitive binding of the multiple associated forms was used to successfully describe the equilibrium binding behavior using parameters determined from isocratic elution and isotherm experiments.