QbD enabled Process Variable Study to Develop Sustained Release Chitosan-Alginate Embedded Delivery System for Improved Patient Compliance

Abstract The current investigation entail systematic Quality by Design (QbD)-enabled approach for the development of Sustained released embedded drug delivery systems of L-Arginine employing ionic gelation technique to attain improved patient compliance. Hence, in this QbD enabled systematic approach; quality target product profile (QTTP) was defined and critical quality attributes (CQAs) were identified. Further the risk assessment studies were undertaken through Ishikawa fish bone diagram to locate the critical material attributes (CMAs) and/or critical process parameters (CPPs) for the formulation of beads that may affect CQAs of drug product. A face centered central composite design (CCD) for two factors at three levels each with α =1 was employed for the optimization process to checkout the impact of concentration of sodium alginate and concentration of chitosan as CMAs which wereprior identified from risk assessment study and further evaluated for CQAs viz. bead size, swelling index and percent drug entrapment. The optimum formulation was embarked upon by using mathematical model being developed yielding desired CQAs. Thereby chitosan coated calcium-alginate delivery system was successfully developed by strategically employing QbD approach.In a nutshell, the presentinvestigation reports the successful development of optimized chitosan coated alginate beads employing QbD approach which can serve as a platform for other drugs too.

Vendor qualification: Utilization of solid state characterization “Toolbox” to assess material variability for active pharmaceutical ingredient

One of the credos for a successful product development, early clinical trial supplies, achieving full-scalemanufacturability and speed to the market is the vendor qualification. The focus of this paper is to employ a systematicapproach to qualify different active pharmaceutical ingredient (API) suppliers. In this context, API sourced from twodifferent vendors used in product development, where prototype formulations manufactured with identical componentsand specifications demonstrated significant variations in drug product performance attributable to vendor-to-vendorvariability. Prototype prepared using API (Vendor 1) showed disintegration of tablets in 4.5 minutes which compliedwith in-house specifications, whereas it was >15 minutes for the prototype prepared from API (Vendor 2). In orderto understand these differences, a vast array of solid state techniques were employed to compare the critical materialattributes of API (GDCS1902) from two different Vendors. Furthermore, these tools were orthogonally applied tounderstand whether API from two Vendors demonstrated any process-induced transformations, such as processinduced polymorphism, process-induced crystal disorder, and process-induced fragmentation. The results of thesemeasurements indicated the presence of fine particles of varied morphology with API (Vendor 1), while API (Vendor2) showed more medium-sized uniform particles. Formulation process modification to induce API fragmentation insitu was carried out for the API from Vendor 2. This modification produced desired granule properties which were thensubjected to drug performance tests and was found to match the specification. This study demonstrates the importanceof understanding the critical material attributes to match the final product performance when multiple vendors wereselected.

Application of quality by design in granulation process for ginkgo leaf tablet (Ⅳ)： influence and control of raw materials' quality variation / 中国中药杂志

Raw materials' quality variation could affect the quality consistency of product and the clinical efficacy. In this paper, the high shear wet granulation (HSWG) process of the ginkgo leaf tablet was taken as the research object. Ginkgo biloba extracts and excipients microcrystalline cellulose collected from various sources and batches were used to simulate raw materials' quality variation. Real-time torque was recorded to analyze the viscosity of the wetting mass, and then by combining with physical fingerprint, the impact of physical quality variation of powders on granule properties could be investigated. Based on regime map thesis, whether the granules' nucleation mode was in mechanical dispersion regime was determined by calculating dimensionless parameters, which would lead to the unstable output in considerations of granule yield ratio and particle size distribution (PSD) curve. The orthogonal partial least square (OPLS) model was adopted to build the relationship between the micromeritic properties and the mediangranule size (D50) of Ginkgo biloba granules and then the critical material attributes (CMAs) were screened by variable importance in the projection (VIP) indexes. The results demonstrated that the properties of powders including hygroscopicity, angle of repose, Hausner ratio, Carr index, D10 and loss on drying affected the granule size. Besides, Ginkgo biloba granules were compressed into tablets. In view of tensile strength analysis, the raw materials' quality variation did not result in decrease of tensile strength of the ginkgo leaf tablets. The design space of critical quality attributes (CQAs) and the process design space which could cope with raw materials' quality variation were proved to be robust..