Assessment of Large-Sample Unit-Dose Uniformity Tests

The authors describe the concept of the limiting discriminatory threshold (LDT) as an objective means of evaluating the inherent quality requirement of a large-sample content-uniformity test.
Oct 02, 2011

On-line measurement methods are often used to implement the process analytical technology (PAT) approach to process understanding and control and offer many advantages over traditional pharmaceutical analytical methods. PAT tends to be fast and nondestructive, and the tools can be integrated into the manufacturing process stream relatively easily. PAT helps improve process understanding and enhance control of product quality. A well-developed PAT method can be applied to perform real-time release testing on a large number of samples per batch. It is not surprising that the application of PAT to the testing of the uniformity of dosage units (UDU) has been the subject of extensive discussion between industry groups and regulatory agencies.

Figure 1: The harmonized uniformity of dosage units (UDU) (hUSP) test flowchart. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
The harmonized UDU test (hUSP) currently described in US Pharmacopeia <905> is the result of the International Conference on Harmonization's (ICH) effort to harmonize the US, EU, and Japanese pharmacopoeia tests and to ensure the consistency of the dosage units within a narrow range around the label claim (1). The hUSP flow chart is summarized in Figure 1.

Using operating characteristic curves to evaluate the performance of the hUSP test

The characteristics of the hUSP test can be summarized by a set of operating characteristic (OC) curves. A UDU test's OC curve is conventionally presented as the probability of lot acceptance (P) versus one key distribution parameter (Q). Assuming the test is characterized by its sample size (n), with possibly other distributional parameters, this relationship can be mathematically defined by the following equation:

Often Q = standard deviation. However, it is common to replace the standard deviation by coverage, which is defined as the percentage of dosage units within an acceptable potency range. It is assumed that the acceptable range is between 85% and 115% of the label claim (LC).

Figure 2: Operating-characteristic curves of the harmonized dose-uniformity test for a range of batch means.
Representative OC curves obtained assuming a normal distribution and a target assay of 100% LC are shown in Figure 2. Under these assumptions, the performance of the hUSP test is symmetrical around 100% LC batch mean. Thus, only the range of 90% to 100% LC of the batch mean needs to be evaluated. It is evident from Figure 2 that the probability of passing the test is quite similar for batches with mean assay between 94% and 100% LC because of the design characteristics of the hUSP test.