![]() ![]() 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 > 101.5%, and M = (X) over bar otherwise). The European Union (EU) test for uniformity of dosage units using large sample sizes was published in European Pharmacopoeia 7.7 in 2012. In other words, once a batch with the variability at the intersecting point is accepted based on modified method, this batch will be accepted no less than 90% of the time tested with the USP harmonized method. 4 In particular, the proposed method is modified to have its operating characteristic (OC) curve for any given sample size intersect the OC curve of the USP harmonized method with a sample size of 30 at the acceptance probability of 90% when the individual tablets with 100% LC mean content are assumed to be normally distributed. In this article, we propose an acceptance sampling method for large sample sizes based on parametric two one-sided tolerance intervals, which is an extension of the method proposed by Tsong and Shen 3 and Tsong et al. ![]() 3 Shen and Tsong 2 pointed out that USP harmonized test modified with indifference zone would have higher probability of acceptance at any given product variability than the parametric two-sided tolerance interval test when the batch mean deviated from 100% of the label claim (LC). Such indifference-zone concept was originally recommended in US Pharmacopoeia (USP) harmonized dose content uniformity test (USP ) and was shown to introduce bias by Shen and Tsong 2 and Tsong and Shen. The operating curves of the proposed procedure are compared with those of the USP test to illustrate the difference in acceptance probability against the mean and variance of the lot. On the other hand, testing against an upper specification is to assure that the drug product is not over-dosed for the sake of safety. Testing against a lower specification is to assure that the drug product is not under-dosed for the sake of efficacy. We propose a parametric tolerance interval procedure to test a two-sided specification that is equivalent to the test of two one-sided hypotheses. But the "no-difference zone" criteria modification for off-target products make the approaches biased in favor of off-target products. The new European Pharmacopeia (EP) and USP harmonized test adopted a tolerance interval approach. In comparison to the Japan Phamacopeia (JP) procedure, USP procedure is less discriminative between lots with on-target mean and small variance and lots with off-target mean and large variance. It is, however, often used mistakenly for lot quality assurance. The United States Pharmacopeia (USP) content uniformity sampling acceptance plan consisting of a two-stage sampling plan with criteria on sample mean and number of out-of-range tablets is the standard for compendium. ![]()
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