Development of a multidose formulation for a humanized monoclonal antibody using experimental design techniques
Journal Title: The AAPS Journal - Year 2003, Vol 5, Issue 2
Abstract
The purpose of this study was to identify optimal preservatives for a multidose formulation of a humanized monoclonal antibody using experimental design techniques. The effect of antimicrobial parenteral preservatives (benzyl alcohol, chlorobutanol, methyl paraben, propylparaben, phenol, and m-cresol) on protein stability was assessed using size-exclusion chromatography, differential scanning calorimetry, right-angle light scattering, UV spectroscopy, and potency testing using a cell-based fluorescence-activated cell sorting method. A quick, cost-effective preservative screening test was designed. Combinations of preservatives were examined using an I-optimal experimental design. The protein was most stable in the presence of methylparaben and propylparaben, and was compatible with benzyl alcohol and chlorobutanol at low concentrations. Phenol and m-cresol were not compatible with the protein. The I-optimal experimental design indicated that as an individual preservative, benzyl alcohol was promising. The model also indicated several effective combinations of preservatives that satisfied the antimicrobial efficacy and physical stability constraints. The preservative screening test and the experimental design approach were effective in identifying optimal concentrations of antimicrobial preservatives for a multidose protein formulation; (1) benzyl alcohol, and (2) the combination of methylparaben and chlorobutanol were screened as potential candidates to satisfy the regulatory requirements of various preservative efficacy tests.
Authors and Affiliations
Supriya Gupta, Elizabet Kaisheva
Keywords
Related Articles
- EP ID EP681966
- DOI 10.1208/ps050208
- Views 63
- Downloads 0
Scientific and Regulatory Standards for Assessing Product Performance Using the Similarity Factor, f2
The similarity factor, f2, measures the sameness of dissolution profiles. The following commentary is an overview of discussions and presentations from a group of industry and US regulatory experts that have integrated t...
In vitro–In Vivo Correlations: Tricks and Traps
In vitro–in vivo correlation (IVIVC) is a biopharmaceutical tool recommended to be used in development of formulation. When validated, it can speed up development of formulation, be used to fix dissolution limits...
Impact of Anti-Drug Antibodies in Preclinical Pharmacokinetic Assessment
The administration of human biotherapeutics is often associated with a higher incidence of immunogenicity in preclinical species. The presence of anti-drug antibodies (ADAs) in the test samples can affect the accurate me...
Are Cutaneous Microdialysis Cytokine Findings Supported by End Point Biopsy Immunohistochemistry Findings?
Insertion of a cutaneous microdialysis catheter into normal dermis has been shown to induce the production of IL1b, IL6 and IL8 in an innate response to minimal trauma. In the present study, skin biopsy for immunohistoch...
Choice of LC-MS Methods for the Absolute Quantification of Drug-Metabolizing Enzymes and Transporters in Human Tissue: a Comparative Cost Analysis
The online version of this article (doi:10.1208/s12248-014-9712-6) contains supplementary material, which is available to authorized users.