Similarity evaluation of dissolution curve of products with large difference in batch dissolution

Abstract: at present, the average dissolution rate is used to evaluate the dissolution curve similarity of test and reference preparations in the research guide of bioequivalence of generic drugs issued by MHLW This study elucidates how to influence the similarity evaluation results of products with large difference in dissolution rate in batches when using the method B of model independent multi variable confidence interval (method B) mentioned in EMA and FDA guidelines The dissolution curves of 61 kinds of oral solid preparations with different dissolution rates were evaluated by mhlwf2 method and two different model independent multivariable confidence interval methods The two different model independent multivariable confidence interval methods were bootstrap statistical verification method (BS method) and Mahalanobis distance multivariable analysis method (MV) Method) Mhlwf2 method and BS method were used to evaluate the dissolution curve similarity of generic drugs and reference drugs, but different results were obtained when Markov distance multivariate analysis was used The analysis of actual dissolution data for products with large intra batch differences can provide valuable information to enhance the understanding of these methods and the possibility of their incorporation into MHLW guidelines Key words: dissolution test; generic drugs; dissolution curve similarity; F2 method; bootstrap analysis; multivariable analysis of variance (ANOVA) post marketing change application of oral solid preparations and generic drug marketing application all require appropriate methods for comparative study of dissolution curve similarity to ensure that generic drugs and original drugs have similar dissolution behavior before and after the change In the EMA, FDA and MHLW bioequivalence guidelines, model independent similarity factor method (method a), difference factor method (F1) and similarity factor method (F2) are recommended for similarity evaluation of dissolution curves In EMA and FDA guidelines, non model dependent multi variable confidence interval (method B) method is allowed to be used to compare the dissolution curve similarity of products with large difference in batch dissolution rate, but the detailed use procedure is not described The use of method B has not been mentioned in the MHLW guidelines Several methods have been reported to evaluate the similarity of products with different dissolution rates Bootstrap method (BS method) simulates the distribution of expected value by calculating the statistical distribution of F2 value and calculates 90% confidence interval for similarity evaluation This method compares the lower limit of the expected F2 value (F2 *) range with the F2 standard to evaluate dissolution similarity The similarity of dissolution curve of products with large difference in dissolution rate batch can also be compared by another multi variable analysis method (MV method), which is realized by Mahalanobis distance (DM) analysis method F2 method is based on Euclidean distance, which is based on the difference of average dissolution rate It is limited to study the differences of the results of different methods to evaluate the similarity of dissolution curve, and it is not clear whether the dissolution curve or simulation data used can represent the dissolution curve data of the products on the market Therefore, in this study, different methods were used to evaluate the dissolution curve similarity of products with different dissolution rates in batches by analyzing the dissolution curves of generic drugs and original drugs on the market in Japan Among 360 groups of data, 61 generic products with large difference in dissolution rate in batches (Fig 1) were selected for similarity evaluation of dissolution curve by F2 method and two methods B method respectively, i.e BS method and MV method The analysis of the actual dissolution data for products with large intra batch differences will provide valuable information to enhance the understanding of these methods and the possibility of their incorporation into the MHLW guidelines The dissolution curve data of materials and methods (6 pieces in each group) were provided by the preparation evaluation working group of the general drug quality expert committee of Japan, which was composed of 11 public health scientific research institutions Among 360 groups (90 generic drugs, 4 dissolution curves and 10 active ingredients) of dissolution curve data reported by the 13th Committee, 61 groups of data showed relatively large intra batch dissolution differences (the coefficient of variation was greater than 20% in 5min or 10min, and greater than 10% after 15min) These data were used for comparison of dissolution curve similarity evaluation methods (Figure 1) Fig 1 Schematic diagram of data selection with large difference in dissolution rate in batches comparison of dissolution curve similarity of mhlwf2 method according to mhlwf2 method of MHLW guide specified test time is as follows: pH 1.2 medium for 2h, other medium for 6h, or the time point when the average dissolution of reference preparation reaches 85% According to the average dissolution of the reference preparation, choose the dissolution rate at 3 or 4 time points The dissolution curve similarity standard is set according to the average dissolution of the reference preparation, that is, F2 ≥ 42 (the average dissolution of the reference preparation reaches 85% in the test time), F2 ≥ 46 (the average dissolution of the reference preparation is between 50-85% in the test time), F2 ≥ 53 (the average dissolution of the reference preparation is less than 50% in the test time) Method B: BS method and MV method BS method are mainly to evaluate the similarity of dissolution curve by calculating F2 value with pheq? Bootstrap 1.2 software According to FDA recommendation, all data points should be used for similarity evaluation before the average dissolution of test preparation and reference preparation reaches 85% The data set of dissolution curves is created by random sampling of dissolution rates within batches at each point in time of the original data The number of dissolution curves created manually is set to 5000 to ensure enough stable results, and the confidence interval is set to 90% When the lower limit of the confidence interval of the expected F2 value (F2 *) calculated by the software is not lower than the acceptable standard of similarity, the dissolution curve is considered to be similar The acceptance standard of similarity is the same as mhlwf2 method According to the MHLW guidelines, the global similarity limit is set as ± 15, ± 12 and ± 9% of the average dissolution of the reference preparation (corresponding to 85%, 50-85% and less than 50% of the dissolution of the reference preparation respectively) The similarity limit is calculated by the global similarity limit, and then it is compared with the real DM Compared with the upper limit (DUM) of 90% confidence interval, when the dum value is less than or equal to the similarity limit, the dissolution curve is considered to be similar In the FDA guidelines, the time point used for method B analysis is not clearly stated, but according to the MHLW guidelines, the time point before 85% dissolution of the reference preparation is used to evaluate the similarity with the dissolution curve Results and discussion in 219 dissolution curve data sets, 61 groups (28%) have large coefficient of variation, according to FDA and EMA related guidelines, 61 groups of data can not be used method a for dissolution curve similarity evaluation The proportion of products with large difference in dissolution quantity in batches is high, so appropriate methods are needed for similarity evaluation (e.g method B) Figure 2 shows the dissolution curve similarity results when mhlwf2 method and two different method B methods are used for evaluation Among 61 groups of dissolution curves, 40, 38 and 24 groups were similar when mhlwf2, BS and MV methods were used for evaluation In addition, the conclusion of mhlwf2 method and BS method are basically similar (Figure 2a) The results of mhlwf2 method and BS method are consistent with 0.9, while the results of mhlwf2 method and MV method are consistent with 0.45 The large difference in the dissolution rate within a batch enlarges the confidence interval of the expected F2 value, resulting in a decrease in the F2 * value Although most of the F2 * values obtained by the BS method are lower than those obtained by the mhlwf2 method (Fig 3), compared with the F2 values obtained by the mhlwf2 method, the differences in the time points used in the analysis and evaluation can explain the higher F2 * values obtained by the BS method Therefore, when using the BS method, it is necessary to specify a suitable time point to calculate the F2 value Figure 2 shows that the number of similarity data sets used for different methods to evaluate dissolution curve by mhlwf2 method and MV method is relatively low, about half of the data are similar by mhlwf2 method and BS method, but not similar by MV method (Figure 2B, c), although the standard deviation of some data points is within 15% (Figure 4a, table 1) When the two dissolution curves intersect each other, it is easy to get inconsistent conclusions when using MV method and mhlwf2 In this case, special attention should be paid to using MV method On the contrary, there are six groups of dissolution data that are evaluated by mhlwf2 method are not similar, while those evaluated by MV method are similar Among them, the two groups of data reach 100% dissolution in a very short time, reducing variance covariance matrix, which makes it easier to reach the MV method similarity standard For example, see Figure 4B and table 2 Fig 3 the number of tablets used in the analysis of the relationship between the F2 value obtained by mhlwf2 method and the lower limit of the confidence interval of BS method F2 * is related to the second degree of freedom in the F distribution The relatively small number of tablets (6 tablets) and limited time points (up to 9 tablets) used for the analysis in this study can explain the different conclusions of the dissolution similarity between MV method and mhlwf2 Fig 4 example of dissolving curve data set with different similarity conclusions obtained by different evaluation methods (a) the evaluation results of mhlwf2 method and BS method are similar, and the evaluation results of MV method are not similar; (b) the evaluation results of MV method are similar, and the evaluation results of mhlwf2 method and BS method are not similar Conclusion based on the actual dissolution curve data, mhlwf2 method B (BS and MV) was used to evaluate the similarity of dissolution curve Using real data set and simulated data volume is equally important for better understanding the advantages and disadvantages of several dissolution curve similarity methods However, these results may vary depending on the criteria applied in each method When using the evaluation method in MHLW guideline, it is necessary to carefully consider, formulate detailed evaluation process and clarify the application reason of the method Original statement: This article is the original manuscript of yaozhi.com, welcome to reprint, reprint please indicate the source and author, thank you!