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loading the API on the core tablets was carried out, and the CPPs that could affect the CQAs were identified and their associated risk was evaluated. As it was not feasible to conduct a Design of Experiment (DoE) to evaluate all the variables, they were ranked as low-, medium-, and high-risk during the assessment (Table 2). The parame- ters ranked as low and medium risks were set as fixed val- ues. The high-risk variables were evaluated by conduct- ing DoE studies to gain process understanding. Equipment and formulation. An R&D coating system [4] equipped with a 2-liter perforated pan was used to conduct basic and DoE trials. It was equipped with Fischer baffles and a spray nozzle fitted with an anti-bearding nozzle and a 0.8-millimeter insert. In the preliminary tri- als, weighed amounts of paracetamol, HPMC 5, and PEG 6000 were dissolved in a mixture of ethanol and purified water (solvent ratio = 30-to-70) that was sprayed on the tablet cores as the parameters were monitored. DoE. A full factorial DoE was conducted, with pan speed, spray rate, atomizing-air pressure, and nozzle-to- bed distance used as independent variables. Assay and RSD of content uniformity were chosen as dependent responses. Table 3 lists the factors and responses. The purpose of the design was to evaluate the effects of process variables on the responses and provide guid- ance on optimal process conditions to achieve the desired API content uniformity. The experimental design and analysis of the effect estimates and response surface were conducted using Design Expert 9.0.1 software (Stat-Ease, Minneapolis, MN). All other process parameters, such as exhaust temperature, airflow, and differential air pressure, were kept constant in the feasibility study. Based on the number of variables, their levels of study, and the type of study, a 24 factorial design with four factors and two lev- els (i.e., 16 runs) was selected for optimization of the process parameters of the paracetamol-loaded tablet to meet the required QTPP. Results and discussion A risk assessment was conducted as shown in Table 2, and high-risk parameters—based on their strong correla- tion to the CQAs and the QTPP—were considered for the DoE to ensure product quality was pre-defined. Input variables (pan speed, spray rate, atomization-air pressure, and nozzle-to-bed distance) contribute interac- tively to the equilibrium between assay and content uni- formity. These potentially high-risk process variables, as identified during the initial risk assessment, were investi- gated next. Effect of process variables on assay. All batches demonstrated acceptable assay, which was well within the specification limits (95.0 to 105.0 percent w/w). As the half-normal plot in Figure 1 shows, spray rate, atomizing- air pressure, and nozzle-to-bed distance have a significant effect on assay value, whereas the effect of pan speed was minimal. The assay was found to increase with an increase in the spray rate, and it was highest at the short- est nozzle-to-bed distance. This was mainly because the short distance minimized spray drying. An inverse effect on assay was seen when coating at a low spray rate and long nozzle-to-bed distance, as the 3-D surface-response and contour plots show (figures 2 and 3). Effect of process variables on RSD of content unifor- mity. As the half-normal plot in Figure 4 shows, spray rate, atomizing-air pressure, and nozzle-to-bed distance significantly affected the RSD of content uniformity. It increased as the spray rate increased at the minimum noz- zle-to-bed distance. This is mainly because, at a higher spray rate, the process finished faster and because the shorter distance decreased the spray's bed coverage. The 20 April 2015 Tablets & Capsules Table 3 Design of the full factorial DoE to study the effect of process variables on assay of tablets Formulation variables Levels -1 0 +1 Pan speed (rpm) 12 14 16 Spray rate (g/min) 3 6 9 Atomizing air (bar) 1.2 1.4 1.6 Nozzle-to-bed distance (cm) 10 13 16 Responses Target Acceptable ranges Assay 100% w/w 95.0% - 105.0% RSD of content uniformity 4% 6% Figure 1 Effect of coating process variables on tablet assay (half-normal plot) Spray rate Atomizing-air pressure Nozzle-to-bed distance 0.00 0.90 1.80 2.70 3.60 4.50 5.40 6.30 99 95 90 80 70 50 30 20 10 0 Positive effects Negative effects Standardized effect Probability (%) Table 2 Risk assessment of process parameters CQA Pan speed Spray rate Atomization Nozzle-to-bed air pressure distance Assay Low Medium High Medium Content High Medium Medium High uniformity