title: Implementation of a high-throughput ion chromatographic assay to assess glass degradation in drug product formulations.
abstract: The primary container for parenterals is usually composed of glass. Given the recent industry-wide spike in glass-related problems, assays capable of detecting glass degradation before glass-related particles are visible in solution have practical significance. A rapid, high-throughput ion chromatography method coupled with molybdate reaction is described here for detection and quantitation of silicic acid (soluble form of silica) in complex samples. The method involves ion exchange separation of the silicate anion at high pH followed by a post-column derivatization step with sodium molybdate reagent. The resulting molybdo-silicate complex is detected with high sensitivity in the visible wavelength range at 410 nm and correlates to the level of soluble silica in solution. This assay is high-throughput and amenable for implementation during the early phase of product development. The assay provides a direct measurement to assess potential incompatibility between the formulation and its glass container. The Si levels measured by this method showed a direct correlation to the vial surface morphology changes as monitored by differential interference contrast microscopy.
  
  
  
  Recently, the pharmaceutical industry has been faced with glass quality challenges that have resulted in many products being recalled from the market. Monitoring levels of soluble silica in solution is critical because silica is the primary component of glass containers used in the pharmaceutical industry. Given this recent industry-wide increase in glass-related problems, assays capable of detecting glass degradation before glass-related particles are visible in solution have practical significance. A rapid assay to detect the soluble form of silica is presented here. The method presented will enable earlier detection of a formulation and container incompatibility instead of waiting until glass-related particles are visible in solution.
authors.affiliation: Drug Product Development, Process and Product Development, Amgen Inc., Thousand Oaks, CA; and renukat@amgen.com.
authors.forename: Renuka
authors.initials: R
authors.lastname: Thirumangalathu
authors.affiliation: Drug Product Development, Process and Product Development, Amgen Inc., Thousand Oaks, CA; and Current address: University of Southern California, Los Angeles, CA 90089.
authors.forename: Kwun Ngok
authors.initials: KN
authors.lastname: Wong
authors.affiliation: Drug Product Development, Process and Product Development, Amgen Inc., Thousand Oaks, CA; and.
authors.forename: James
authors.initials: J
authors.lastname: Coultas
authors.affiliation: Drug Product Development, Process and Product Development, Amgen Inc., Thousand Oaks, CA; and.
authors.forename: Alison
authors.initials: A
authors.lastname: Hair
authors.affiliation: Drug Product Development, Process and Product Development, Amgen Inc., Thousand Oaks, CA; and.
authors.forename: Deirdre Murphy
authors.initials: DM
authors.lastname: Piedmonte
mesh_terms: D002626:Chemistry, Pharmaceutical; D002852:Chromatography, Ion Exchange / Q000379:methods*; D004345:Drug Industry; D004349:Drug Packaging; D005898:Glass / Q000032:analysis / Q000737:chemistry*; D057166:High-Throughput Screening Assays / Q000379:methods; D006863:Hydrogen-Ion Concentration; D008982:Molybdenum / Q000032:analysis / Q000737:chemistry; D012824:Silicic Acid / Q000032:analysis / Q000737:chemistry*
chemical_list: D012824:Silicic Acid; C044659:molybdate; D008982:Molybdenum
keywords: Formulation container incompatibility; Glass degradation; Glass delamination; Glass dissolution; Glass lamellae; Ion chromatography; Molybdate; Silicic acid; Silico-molybdate complex; Soluble silica