Abstract
Objective: Ritonavir is an antiretroviral drug used for HIV-AIDS treatment. The purpose of this research work was to implement the quality by design (QbD) approach in formulation of ritonavir sustained-release pellets by industrially applied extrusion spheronization technique.
 Methods: Pellets were prepared by extrusion spheronization method and evaluated for their physicochemical properties. Initially, on the basis of prior knowledge Quality Target Product Profile (QTTP) element was identified and further Critical Quality Attributes (CQA) elements were defined. Risk assessment (RA) was done by two tools as failure mode and effect analysis (FMEA) and fishbone diagram (Ishikawa plot). Placket Burman design was implemented as a screening design using seven high-risk factors (spheronization speed, spheronization time, extrusion speed, drying method, PVP K 30, cross povidone, and solvent). Optimization study was done by 23 full factorial design with three critical factors as (spheronization speed, extrusion speed and PVP K 30). The in vitro drug release was studied in both gastric and intestinal fluids for 12 h using USP Ι apparatus. Control space was established for the sustained release pellets.
 Results: Among all batches obtained in 23 full factorial design, batch R7 was found to be effective with carr’s index value of 5.281, percentage yield of 69.6%, time required to release 50% drug was 8 h and percent drug release after 12 h was found 83.132 %, R7 batch was selected as optimized batch. Statistical analysis showed model terms were significant.
 Conclusion: We can conclude that; sustained-release pellets of ritonavir were successfully designed using QbD approach.
Highlights
Quality by design (QbD) is the combination of three International Conferences of Harmonization Guidelines i.e. (Q8) pharmaceutical development, (Q9) quality risk management and (Q10) pharmaceutical quality system [1]
The aim of QbD is to build the product quality process than the simple test process which is based on four important elements: (i) Identification of Quality Target Product Profile (QTPP), (ii) Determination of Critical Quality Attributes (CQAs) by Critical Process Parameters (CPP), Critical Material Attributes (CMA). (iii) Assessment of risk by Failure Mode Effect Analysis (FMEA) and Ishikawa Plot (Fishbone Diagram). (iv)Establishment of Design Space (DS) and Control Space (CS) [3, 4]
A fishbone diagram was preformed according to ICH Q8 R2, to identify critical process parameters and critical material attributes of CQAs that affects the quality of pellets shown in fig
Summary
Quality by design (QbD) is the combination of three International Conferences of Harmonization Guidelines i.e. (Q8) pharmaceutical development, (Q9) quality risk management and (Q10) pharmaceutical quality system [1]. Quality by design (QbD) is the combination of three International Conferences of Harmonization Guidelines i.e. QbD is defined as “A systematic approach to development that begins with predefined objectives and important product and process understanding and process control, based on robust supporting science and quality risk management” [2]. Design Space (DS) is defined as ‘The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality” [5, 6]. Pellets are defined as spherical, free-flowing granules with a narrow size distribution typically varying between 500 to 1500 μm for pharmaceutical applications. Sustained release drug delivery system in form of pellets formulation comes up with plenty of advantages like less gastric irritation, maximized drug absorption, improve drug bioavailability, improve flow properties, reduce drug plasma fluctuation and reduce potential side effects, Wang et al [7]. The critical factor that impact extrusion spheronization are spheronization speed, spheronization time, extrusion speed, drying method, PVP k30, crosspovidone, solvent, mixing time, spheronization load and extruder time all these factors were evaluated as per QbD principles, Sirisha et al, Kandukuri et al [8, 9]
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