Applications of process analytical technology (PAT) for in-process and/or end-product release testing are attracting wide interest from both regulators and the pharmaceutical industry. Nondestructive measurement techniques such as near-infrared spectroscopy, together with statistical modeling of the obtained spectrum, facilitate fast and precise measures supporting the vision of improved manufacturing process understanding. Such techniques can generate a significant amount of data in real time and thereby open the possibility of improved process control and capability. In such scenarios, the added value of traditional lot-release testing based on a random sample from the batch is questioned.
One of the potential applications of PAT is real-time evaluation of tablet content uniformity. A related issue is the choice of acceptance criteria in light of the increased sample size because the International Conference on Harmonization's (ICH) uniformity of dosage units (UDU) test is based on either 10 or 30 dosage units (1). To address this issue, the Pharmaceutical Research and Manufacturers of America (PhRMA) Chemistry, Manufacturing, and Controls (CMC) Statistics Expert Team (SET) published an alternative to the ICH test in 2006 that could be used as a batch-release specification when testing a large number of dosage units (2). This proposed test was intended as an alternative, not as a replacement, to the ICH UDU test as the official regulatory method. Through interactions with European and American regulators during the second half of 2009, questions about the PhRMA approach were raised; this feedback highlighted the need to modify the test to achieve quality equivalent to or better than the ICH UDU test across the entire test range.
This paper provides a modified version of the test described in the PhRMA CMC SET paper. This modified test is proposed as an alternative test and not as a replacement; it is intended perform similar to or better than the ICH test with the increased sample size. In both the original and modified tests, the proportion of dosage units within 85–115% of label claim (LC) (the "coverage of 85–115% LC") is proposed as the measure of the uniformity of the batch. The acceptance criteria for these tests are based on counting the number of dosage units in the sample outside 85–115% LC and rejecting the batch if that count is too high. The acceptance criteria for these tests are meant to support effective regulatory application of PAT to processing. The tests are nonparametric; simple to implement, use, and regulate; and are applicable to large sample sizes. The modified version of the PhRMA CMC SET alternate test provides the same or better assurance as the harmonized UDU test with respect to the batch's uniformity.