Quality By Design Based Development Of Metformin Hydrochloride Extended-release Tablets

Objective： Quality by Design (QbD) was used in developing of metforminhydrochloride extended-release tablets.The generic product is expected to be similar withthe RLD in drug release profiles,and to have a good stability. The purpose is to illustratehow pharmaceutical development studies can move toward implementation of QbD andprepare technology for further development of metformin product.Method:(1) The quality target product profile (QTPP) was defined initially. Then,identification of critical quality attributes (CQAs) was based on the seve-rity of harm to apatient (safety and efficacy) resulting from failure to meet that quality attribute of the drugproduct. This study focused on those CQAs including assay and dissolution.(2) A riskassessment of the formulation variables was performed to evaluate the impact that eachattribute could have on the drug product CQAs. The high risk attributes were identified andevaluated by a full-factorial Design of Experiments (DOE) with three center point. Finally,critical material attributes (CMAs) were determined, and a control strategy was proposed.Based on the results of the formulation development studies, the risk assessment of theformulation variables was updated.(3) A risk assessment of the overall drug productmanufacturing process was performed to identify the high risk steps that could affect thefinal drug product CQAs. Subsequently,a24-1fractional factorial Design of Experiments(DOE) with three center points was used to study the impact of these parameters. And,Critical Process Param-eters (CPPs) were defined and a design space was established.Then, a control strategy for CPPs was proposed to reduce the risks.(4) A dissolutionmethod was developed to evaluate the generic product and the RLD. The similaritiesbetween the two in-vitro dissolution profiles were assessed by similarity factor (f2)(5)Stability tests were studied under stress conditions, accelerated stability conditions andlong-term stability conditions.(6) The release mechanism of optimiz-ed formulation wasinvestigated. Results:(1)Formulation development test shown the percentage of Chitosan in theChitosan/HPMC combination had a significant impact on similarity factor(f2). To get amaximum similarity factor,5%Chitosan in the Chitosan/HP-MC combination wasselected for the finalized formulation.(2) Drug product ma-nufacturing process studyshown that the significant factors affecting dissolution were impeller speed, granulationtime and tablet hardness. Based on the results of the study, a design space for the drugproduct manufacturing process was defined. A control space was established based ondesign space and prese-nted as impeller speed (from260to440rpm), granulation time(from120to360seconds) and tablet hardness (from90to118N)(3) The genericmetformin extend-tablet was similar with the RLD in dissolutio-n profiles when theformulation and proccess were finalized.(4) The generic metformin extended-tablet had agood stability. The6months of accelerated stabil-ity and6months of long-term stabilitydata shown there were no significant changes in dissolution profiles.(5) The genericmetformin extended-tablet release followed the Fickian diffusion.Conclusion: The generic metformin extended-tablet was similar with theRLD in drug release profiles, which matched the QTPP. The model (regressionequation about formulation or process parameters) established in the study could predictthe similar factor satisfactorily. The control strategy was developed to assure the productquality. The outcome of the study shown QbD methodology is useful to get expectedresults in drug development efficiently. A robust contr-ol strategy can ensure flexiblemanufacturing process and consistent production of quality drugs.