Scientific Publications by FDA Staff

Ther Innov Regul Sci 2014 Sep;48(5):613-22

Statistical Properties of Large Sample Tests for Dose Content Uniformity.

Shen MY, Tsong Y, Dong XY

The European Union (EU) test for uniformity of dosage units using large sample sizes was published in European Pharmacopoeia 7.7 in 2012. There are 2 alternative tests. Option 1 is a parametric two-sided tolerance interval-based method modified with an indifference zone and counting units outside of (0.75 M, 1.25 M) (here, M is defined by sample mean, (X) over bar, as M = 98.5% if (X) over bar < 98.5%, M = 101.5% if <(X)over bar> > 101.5%, and M = (X) over bar otherwise). Option 2 is a nonparametric counting method with an additional indifference-zone concept. The authors extended the parametric two one-sided tolerance interval-based method that was proposed for dose content uniformity testing based on 30 tablets to large sample sizes with the restriction that all operating characteristic curves of the two one-sided tolerance intervals for any given sample size intersect with the operating characteristic curve of the US Pharmacopoeia harmonized method for a sample size of 30 at the acceptance probability of 90% when the individual tablets with on-target mean are assumed to be normally distributed. This paper studies the acceptance probabilities in relation to the batch mean and batch standard deviation among the 2 EU options and the authors' proposed method. The acceptance probabilities of EU options 1 and 2 and the proposed method were compared using simulation; results revealed that both EU options 1 and 2 produce larger acceptance probabilities when the batch mean is off-target. Furthermore, for a given standard deviation, the acceptance probability of EU option 2 at a mean 102% of the label claim is larger than that at a mean of 100% of the label claim under the normality assumption.