title: Detection of lot-to-lot variations in the amorphous microstructure of lyophilized protein formulations.
abstract: Reconstitution of lyophilized protein formulations sometimes results in a cloudy solution, depending on the compositions and manufacturing conditions, which causes quality concerns. In this study, the lyophilized protein formulation of recombinant human Interleukin-11 (rhIL-11) was investigated using different lots with varying dissolution behaviors upon reconstitution due to differing processing conditions. In an attempt to distinguish the solid structures in the different lots, relatively new techniques such as inverse gas chromatography (IGC) and thermally stimulated depolarized current (TSDC) as well as powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) were adopted for analysis. PXRD, DSC, and IGC all failed to distinguish between the solid structures, but TSDC was able to discern the differences. Interestingly, TSDC suggested that the variations in dissolution behavior were attributable to the differences in molecular mobility and the micro heterogeneity of amorphous components in the solid structures. Since even the cloudiest reconstituted solutions became transparent in several minutes, it was likely that the differences in the solid structures of the different lots of lyophilized cakes were slight. This study demonstrates the usefulness of TSDC in the analysis of lot-to-lot variations in amorphous pharmaceuticals.
authors.affiliation: Pharmaceutical Analysis, Pharmaceutical Research and Technology Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan. yutaka.hirakura@jp.astellas.com
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hirakura
authors.forename: Hideto
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Mizuno
authors.forename: Hideo
authors.initials: H
authors.lastname: Miyanishi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kitamura
mesh_terms: D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D002849:Chromatography, Gas; D003460:Crystallization; D018360:Crystallography, X-Ray; D005612:Freeze Drying; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry*; D009391:Nephelometry and Turbidimetry; D019999:Pharmaceutical Solutions / Q000737:chemistry / Q000592:standards; D033362:Powder Diffraction; D011487:Protein Conformation; D011786:Quality Control; D011994:Recombinant Proteins / Q000737:chemistry; D012995:Solubility; D013678:Technology, Pharmaceutical / Q000379:methods*; D013997:Time Factors; D014867:Water / Q000737:chemistry
chemical_list: C508611:IL11 protein, human; D017370:Interleukin-11; D019999:Pharmaceutical Solutions; D011994:Recombinant Proteins; D014867:Water