A Statistical Approach to Evaluating the Manufacture of Furosemide Tablets The authors evaluated the manufacturing data of 40-mg tablets

of furosemide, a potent diuretic. Mar 2, 2011 By: Tlia de Souza Botelho, Vanessa Franco Tavares, Ctia Panizzon Dal Curtivo, Silvie Rosa Balzan Sarolli, Marcio Adriano Fernandes, Carmen Maria Dunaduzzi, Raimar Lbenberg, Ndia Araci Bou-Chacra Pharmaceutical Technology Volume 35, Issue 3, pp. 112-121

Table II: Values of the AndersonDarling statistics (AD) and p-values performed for powder mixture conformity, uniformity of dosage units, and % released. Materials Furosemide was supplied by Alcon Biosciences. Crospovidone was provided by ISP. Lactose monohydrate was purchased from Doremus. Talc was supplied by Indukern, and magnesium stearate by Inbra. The authors bought pregelatinized starch from Colorcon and maize starch from Cargill. Purified water was supplied by Prati-Donaduzzi. All the materials were of Brazilian Pharmacopoeia grade, as stated by the suppliers. Methods Manufacturing process of 40-mg furosemide tablets. Three consecutive 380-kg batches of 40-mg furosemide tablets were manufactured by wet granulation. The powders were mixed in a bin blender (VZD-400, Vanguard) for 20 min. at 18 rpm (see Table III: Estimated variance Figure 1). Next, powders were sieved through a 0.5-mm sieve and loaded into the high-shear mixer (MIC-P, Comasa, Buenos component for furosemide content in the powder blend. Aires). The granulation liquid was then sprayed tangentially into the moving powder mixture using a pneumatic atomizer at 1.0 bar atomizing air pressure and a speed of 80 rpm. The powder was mixed for 5 min. before the granulation was started. The spray rate was 40 g/min. The granules passed through a 2.5-mm sieve, dried at 50 3 C in an oven for 24 h, passed through a 1.25-mm screen, and finally lubricated with magnesium stearate. The compression was performed employing a 50-station double rotary tableting machine (2000/50, Lawes, So Paulo). The speed was kept constant at 75,000 tablets/h. The Lawes tableting machine was dedicated equipment to produce furosemide tablets only.

Furosemide assay by ultraviolet-visible spectrophotometer. The assays were performed in duplicate according to the Brazilian Pharmacopoeia (11). The ultraviolet-visible (UV-vis) spectrophotometer (800XI, Femto, So Paulo), UV = 271 nm, was used, and the standard and sample concentrations of furosemide were diluted to 0.6 mg/mL using 0.1 N HCl.

Figure 3: Capability analysis of the content (mg) of furosemide in the powder mixture. CL is control level, CP is process capability, Cpk is processcapability index, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, and USL is upper specification limit. Dissolution of furosemide tablets. The dissolution test of furosemide tablets from the different batches (i.e., at the beginning, in the middle, and at the end of the process) was carried out in triplicate using USP Apparatus 2 (paddle method). The dissolution test was performed using 900 mL of pH 5.8 phosphate buffer at 37.0 0.5 C at 50 rpm. Aliquots (5 mL each) were withdrawn at a predetermined time interval of 60 Figure 4: Control charts of min. The samples were filtered through a 0.45-m membrane individual and moving range filter. The furosemide assay was performed by (MR) of the individual tablet spectrophotometer UV-vis (Femto) UV = 271 nm. The USP 32 weights (mg) for the left and specification for dissolution of furosemide tablets is not less than right sides of the tableting 80% (Q) of furosemide dissolved in 60 min in 900 mL of pH 5.8 machine. LCL is lower control phosphate buffer (12). limit, LSL is lower specification limit, UCL is upper control limit, USL is upper specification limit, and X is individual value. Sampling plan and statistical analysis. The sampling plan included the collection of 10 g of the powder mixture in 10 specific locations (see Figure 1). For the tablets, a minimum of 200 units on the right and left side of the double rotary tableting machine were collected. The uniformity of dosage units of furosemide was calculated using 30 tablets per batch (i.e., 10 tablets in the beginning, 10 in the middle, and 10 at the end of the tableting process). For the Table IV: Tablet weights (mg) for dissolution test, a total of six tablets for each batchat the beginning, in the middle, and at the end of the processwere analyzed. The statistical analysis of left and right the three consecutive batches was evaluated by using Minitab software, version sides of the tableting 15 (Minitab, State College, PA). machine for the three batches.

The process stability was evaluated using individual and moving-range charts as well as standard-deviation charts (I-MRR/S), considering a subgroup size of 10. The normal distribution was evaluated by the AndersonDarling test. For non-normal distributions according to the AndersonDarling test, the Box Cox family of power transformations was used to obtain an Figure 5: Capability analysis of approximate Gaussian distribution (13). the tablet weights for three batches. Cp is process capability, Cpk is processcapability index, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, USL is upper specification limit, and X is individual value. The process capability indices were calculated when the analyzed parameter was normally distributed or when its distribution was close to the normal distribution (6, 14). The fully nested analysis of variance (ANOVA) was performed to estimate variance components for each response variable (i.e., mixture content, tablet weight, dosage-unit uniformity, and dissolution). All factors were assumed to be random. The mean comparison between the tablet weights from the two sides of the tableting machine was performed using one-way ANOVA. Results and discussion Content of furosemide in the powder mixture. The relative standard deviation of the method was 0.43%. Random 10-g samples of the mixed powder were taken from 10 places within the bin blender (see Figure 1). Table I shows the data of the three consecutive batches. The powder blends met the acceptance criteria and the specifications (90.0110.0%). The control charts did not show a special cause of variation (see Figure 2). Considering the analysis of locations, the one-way ANOVA was used to test for differences among the locations (see Figure 1). The analysis revealed no statistical difference between the locations (p value = 0.959).

Table V: Tablet weight of furosemide (mg) versus left and right side of the tableting machine.

Table VI: Values of the uniformity of dosage units.

The p value for the AndersonDarling normality test was 0.069 (> 0.05), indicating a normal distribution (see Table II). This test was developed to be especially sensitive to deviations from normality in the distribution tails. For capability analysis, the tails are the most critical part of the distribution (15). To understand process variation, the authors performed a fully nested ANOVA (see Table III). The result showed that 72.90% of the observed variation in the furosemide content resulted from a batch factor. Thus, to minimize the process variability, the causes of the variation among batches required further investigation.

Figure 6: Control chart for individual, move range (MR) and standard deviation (StDev). The subgroup size was 10 (I-MR-R/S) for the uniformity of dosage units. LCL is lower control limit, S is standard deviation, and UCL is upper control limit. The indices of 2.19 and 2.23 for Cpk and Cp, respectively, revealed that this process is statistically centered and robust (see Figure 3). The estimated nonconformity for the powder mixing process was less than 1 ppm. Cp and Cpk indices equal or above 1.0 correspond to a satisfactory low proportion of nonconformity (16). However, for a good process under statistical control, Cpk Figure 7: Capability analysis of should be greater than 1.5 (17). the uniformity of dosage units of furosemide tablets. Cp is process capability, Cpk is process-capability index, CL is control level, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, and USL is upper specification limit. Evaluation of the tablet weight. Figure 4 shows the individual tablet weights for each batch taken from the left and right sides of the tablet machine. The tablet weight was chosen as a surrogate for the process stability of the compression step. As shown in Figure 4, the two values above and the five values below the control limits, among 1200 samples analyzed, cannot support the assumption that this process was unstable. The mean tablet weight was 164.22 4.25 mg. In addition, all values were within the specification limits. The lower specification limit Table VII: Estimated variance (LSL) was 152 mg, and the upper specification limit (USL) was component for uniformity of 177 mg (see Table IV). However, a few outliers can have a large dosage units of furosemide. influence on the process-capability indices, as evidenced in Figure 5. The process capability indices were 1.00 and 0.98 for Cp and Cpk, respectively, revealing a high proportion of nonconformity (2751.21 ppm). Although interbatch variability could have contributed to the results, further investigation to address the high nonconformity was

needed. Issues that may cause weight variation are powder flow problems, improper die fill, and powder size distribution. In addition, a comparison of the tablet weights at the two sides of the tableting machine was performed (see Table V). The p value (one-way ANOVA) was 0.522, showing that the tablet weights for both sides did not differ significantly. The residuals plot indicated a normal distribution and the absence of special causes of variation. Similar results were reported in a study where a double-station Kilian tableting machine (IMA Kilian, Kln, Germany) was used to manufacture metamizol tablets (18). Table VIII: Values of the % drug released using tablet dissolution of furosemide tablet at the beginning. Evaluation of the uniformity of dosage units. Table VI shows the dosage-unit uniformity for each batch for three different time periods: the beginning, middle, and end of the process. No special causes of variability were observed in the control charts Figure 8: Control chart for (see Figure 6). The p value for the AndersonDarling test was individual, move range (MR), equal to 0.010, which revealed a non-normal distribution (> 0.05, and standard deviation see Table II). The BoxCox method was used to transform the (StDev). The subgroup size values into a normal distribution ( = 4.5) (13). In a similar way, was 18 (I-MR-R/S) for the % non-normal process capability indices were determined using a released using tablet generalized distribution described by Pal (19). The authors dissolution. LCL is lower used spreadsheets to illustrate how easily the necessary control limit, S is standard calculation can be performed. The transformed values were used deviation, UCL is upper to calculate the process-capability indices. Cp and Cpk were 1.43 control limit, and X is and 1.27, respectively. The difference in values indicated that the individual value. process was not statistically centered. However, the predicted nonconformity rate was low (70.32 units), as shown in Figure 7.

The estimated source of variance showed that 54.19% of the observed variability was within a sampling group, 27.83% resulted from the sampling time point, and 17.98% resulted from the batch (see Table VII). To optimize this manufacturing process, the causes of the variations among the batches and the statistically noncentered profile of this process should be Figure 9: Capability analysis of investigated. % released using tablet dissolution. Cp is process capability, Cpk is processcapability index, CPL is process capability relative to lower specification limit, CPU is process capability relative to upper specification limit, LSL is lower specification limit, PPM is parts per million, StDev is standard deviation, and USL is upper specification limit. Evaluation of the dissolution of furosemide tablets. The dissolution of furosemide tablets was evaluated for each batch at the beginning, the middle, and the end of the process (see Table VIII). Figure 8 indicates that the process stability was achieved because no special cause of variation was observed. The p value for the AndersonDarling test was equal to 0.006, which Table IX: Estimated variance confirmed a non-normal distribution (see Table II). The component for the % drug transformed data (BoxCox method, = 5) were used to released using tablet calculate Cp and Cpk, which were 3.46 and 2.29, respectively. dissolution of furosemide. The estimated nonconforming proportion was low (0.00 ppm), and the process was slightly not statistically centered (see Figure 9). The estimated cause of variance showed that 40.34% resulted from a batch factor, and 17.23% from the sampling group (see Table IX). Conclusion The statistical approach used in the process evaluation of the blending, tableting, dosage-unit uniformity, weight variation, and dissolution behavior led to better process understanding of the manufacturing process. The results showed that fully nested ANOVA is a powerful tool to identify sources of variability. The process capability indices helped the authors to understand process performance and the potential for process optimization. Although a limited number of batches were investigated, the statistical methods identified possible approaches for process improvement in the manufacturing of furosemide tablets. Tlia de Souza Botelho is a student, Vanessa Franco Tavares is a student, Ctia Panizzon Dal Curtivo is a student, and Ndia Araci Bou-Chacra* is an assistant professor of

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