Retrospective statistical analysis of lyophilized protein formulations of progenipoietin using PLS: Determination of the critical parameters for long-term storage stability
Although certain criteria have become recognized as being essential for a stable lyophilized formulation, the relative importance of different stability criteria has not been demonstrated quantitatively. This study uses multivariate statistical methods to determine the relative importance of certain...
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Published in | Journal of pharmaceutical sciences Vol. 93; no. 10; pp. 2609 - 2623 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Hoboken
Elsevier Inc
01.10.2004
Wiley Subscription Services, Inc., A Wiley Company Wiley American Pharmaceutical Association |
Subjects | |
Online Access | Get full text |
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Summary: | Although certain criteria have become recognized as being essential for a stable lyophilized formulation, the relative importance of different stability criteria has not been demonstrated quantitatively. This study uses multivariate statistical methods to determine the relative importance of certain formulation variables that affect long-term storage stability of a therapeutic protein. Using the projection to latent structures (PLS) method, a retrospective analysis was conducted of 18 formulations of progenipoietin (ProGP), a potential protein therapeutic agent. The relative importance of composition, pH, maintenance of protein structure (as determined by infrared (IR) spectroscopy), and thermochemical properties of the glassy state (as measured by differential scanning calorimetry (DSC)) were evaluated. Various stability endpoints were assessed and validated models constructed for each using the PLS method. Retention of parent protein and the appearance of degradation products could be adequately modeled using PLS. The models demonstrate the importance of retention of native structure in the solid state and controlling the pH. The relative importance of Tg in affecting storage stability was low, as all of the samples had Tg values above the highest storage temperature (40°C). However, other indicators of molecular mobility in the solid state, such as change in ΔCp upon annealing, appear to be important, even for storage below Tg. For the first time, the relative importance of certain properties in controlling long-term storage stability could be assessed quantitatively. In general, the most important parameters appear to be pH and retention of native structure in the solid state. However, for some stability endpoints, the composition (concentration of protein or various excipients), as well as some DSC parameters, were found to be significant in predicting long-term stability. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2609−2623, 2004 |
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Bibliography: | ark:/67375/WNG-FDW7LTJN-8 ArticleID:JPS20170 istex:6A761D10874C0008DA72914F7AEF8E455FA65DE5 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3549 1520-6017 |
DOI: | 10.1002/jps.20170 |