title: Quality-by-design (QbD): an integrated approach for evaluation of powder blending process kinetics and determination of powder blending end-point.
abstract: The objective of this study was to develop an integrated process monitoring approach for evaluating powder blending process kinetics and determining blending process end-point. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients (HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near-infrared spectroscopy scan of the powder mixture for obtaining the time course of the blending process. The evaluation of the blending process kinetics and process end-point was studied through three quantitative approaches: (1) Spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. It was found that the powder blending experienced an initial rapid process to reach a quasi- end point within the first few minutes. Afterwards, a demixing occurred. Then, a real blending end-point was reached as characterized by an inflection point. ANOVA shows that the compositions of ibuprofen and MCC are the most statistically significant variables that impact the time required to reach the blending end-point. This highlighted the critical importance of developing quantitative chemometric approaches to extract critical process information and generate essential process knowledge to enable real-time release of the blending process.
authors.affiliation: Division of Product Quality Research (DPQR, HFD-940), OTR/OPS/CDER/FDA, FDA White Oak Campus Life Science Building 64, 10903 New Hampshire Ave, Silver Spring, Maryland 20993, USA.
authors.forename: Huiquan
authors.initials: H
authors.lastname: Wu
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods* / Q000592:standards*; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards; D023381:Endpoint Determination / Q000379:methods* / Q000592:standards*; D011208:Powders / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011786:Quality Control; D019265:Spectroscopy, Near-Infrared / Q000379:methods / Q000592:standards
chemical_list: D011208:Powders