An alternative uniformity of dosage units test
The European Pharmacopoeia, Japanese Pharmacopoeia, and United States Pharmacopeia (USP) contributed to the ICHharmonized
pharmacopeial specification (e.g., USP <905> and Ph. Eur. 2.9.40) for the content UDU, which is based on either 10 or 30 dosage units. The PhRMA CMC SET proposed an alternative to
the ICH test to address the issue of developing acceptance criteria for increased sample size due to PAT. The tabletsampling
procedure (e.g., one tablet every three minutes) is established before batch manufacture. The resulting sample size is determined
by the sampling procedure, and is larger than 30 dosage units, more likely 100 to 500 units. The PhRMA CMC SET test, called
the "LargeN" test in this paper, is a onetiered counting test for uniformity of dosage units. The nonparametric test is
based on counting the number of dosage units outside the 85–115% range of label claim and rejects the batch if that count
is outside the set limit.
Table I: LargeN test acceptance limit for various n.

The number of units (Y) outside the target interval (85–115% LC) is binomially distributed with parameters n (sample size) and p (true proportion outside). When p = 0.048, the quality level (QL) calculated corresponds to 95.2% coverage, associated with a 50% probability of complying
with the ICH UDU test. The test translates to finding the largest integer t, called c, such that: c = max{t ; Prob(Y ≤ t  p = 0.048) ≤ 0.5}. Table I provides c for various sample sizes. For example, if 500 units are tested and 23 or fewer results are outside 85–115% LC, the batch
passes the test.
Figure 1: LargeN (various percent label claim [LC]) operating characteristic curves for n = 100 with International Conference
on Harmonizations (ICH) uniformity of dosage units (UDU) test (100% LC). StDev is standard deviation. (ALL FIGURES ARE COURTESY
OF THE AUTHORS)

The test is designed to be more conservative than the ICH UDU test for all levels of batch quality where the probability of
accepting a batch is less than 0.5. The acceptance limit, c, depends on the sample size, n.
Figure 2: LargeN (various percent label claim [LC]) operating characteristic curves for n = 500 with International Conference
on Harmonizations (ICH) uniformity of dosage units (UDU) test (100% LC). StDev is standard deviation.

Figures 1 and 2 show operating characteristic (OC) curves for the LargeN test for sample sizes of 100 and 500, respectively,
compared to the OC curve for the ICH UDU test when the batch mean is 100% LC. Here, the probability to accept the batch is
plotted against batch standard deviation with curves varying by batch mean. If the mean is off target, the standard deviation
must decrease to maintain constant coverage; this change results in the shift to the left in the curves. Also, the test is
symmetric; a mean of 98% produces the same OC curve as a mean of 102%. Note that for the sample size of 500, the probability
of accepting the lot under the LargeN test is slightly higher than passing the ICH UDU test for small standard deviations;
this higher probability is expected because increasing the sample size results in a more discriminating test.
