Impact Evaluation of Changes in the Manufacturing Line of Cyproterone Acetate through Analysis of Comparative Dissolution Profile

Abstract

In recent years, FDA has placed more emphasis on a dissolution profile comparison in the area of post-approval changes and biowaivers. A dissolution profile comparison between pre-change and post-change products, or regarding different strengths, helps assure similarity in product performance and signals bioinequivalence. This work aims to evaluate the impact caused by the change of the tablet compression machine in the manufacturing of 50 mg cyproterone acetate tablets, by examining the comparative dissolution profile between different batches of the drug. For this purpose, the following method was used: the dissolution medium was composed of sodium dodecyl sulfate 0.07 % in 0.01 M hydrochloric acid, apparatus II (paddle), paddle rotation at 100 revolutions per minute, 900 mL volume of medium in each vessel, 37.5 ± 0.5 0C of medium temperature. Aliquots of 5.0 mL of sample were collected at 5, 10, 15, 20, 30 and 45 minutes. Then, the solutions of the sample and the standard (50.5 μg /mL) were evaluated using a spectrophotometer with wavelength adjusted to 285 nm. From this the comparative dissolution profile was plotted considering the drug percentage dissolved for each batch in study as a function of the dissolution time. The two drug lots tested were manufactured in the same industry using different compression machines in the production line. Statistical analysis of data was performed and the similarity ATINER CONFERENCE PAPER SERIES No: PHA2014-0916 6 factor (f2) was calculated. For this study, 12 different tablet batches were used, in a total of 12 cyproterone acetate determinations per batch for each collected time reported. The results, calculated in the percentage of cyproterone dissolved in the medium, indicated that both lots of drugs tested showed values greater than 85% (Q> 70 %) in the first 15 minutes of analysis. The mean final results (45 minutes) were equivalent to 107.73 % (RSD = 2.98 %) and 108.58 % (RSD = 1.44 %), respectively, independently of the changes on the compression machine used in the manufacturing line. The statistical analysis was used to evaluate result variability and to determine the similarity factor among the different batches of drugs tested (f2 = 57.64), what allowed to conclude that the drugs tested showed similar dissolution profile. The results of dissolution efficiency calculation are: 83.14 % (RSD = 1.89) to dissolution profiles obtained to the cyproterone tablets manufactured with compression machine 1 and 79.83 % (RSD = 1.93) to the cyproterone tablets manufactured with compression machine 2. Statistical analysis showed that the differences observed between the results The results based on the statistical calculations of f2 showed equivalence in the dissolution profile, and different performances based on calculation of the dissolution efficiency (D.E.). However, the dissolution method could be reevaluated to analyze properly the product in study, fast dissolving formulation, using discriminative conditions.