Acceptance Limits for the New ICH USP 29 Content-Uniformity Test

Revisions to the United States Pharmacopeia's (USP) uniformity test require manufacturers to establish new acceptance limits. The authors present their method for calculating acceptance limits consistent with USP's revised content-uniformity test requirements.
Oct 02, 2007

As part of the International Conference on Harmonization (ICH) effort, the US Pharmacopeia (USP) has revised General Chapter ‹905›, "Uniformity of Dosage Units." The revision became official on January 1, 2007 through the Sixth Interim Revision Announcement to USP 29–NF 24 in Pharmacopeial Forum (1). The final revised version is the result of many discussions, as well as several evaluations and recommendations by Pharmaceutical Research and Manufacturers of America's (PhRMA) Chemistry, Manufacturing, and Controls Statistics Expert Team (2–4). Bergum published a method for constructing acceptance limits that relates the acceptance criteria directly to multiple-stage tests such as the USP content-uniformity and dissolution tests (5). Bergum and Utter (6, 7) discussed several statistical techniques for evaluating content uniformity. Bergum wrote an SAS program that implements his method (8). The program performs calculations and generates acceptance-limit tables. Since the USP test for content uniformity has been revised, new mathematical calculations and a new SAS program have been developed to generate acceptance-limit tables.

The acceptance limits are defined to provide, with a stated confidence level of (1 – α) 100%, that there is at least a stated probability (P) that a sample taken from a batch would pass the content-uniformity test. For example, one can have 95% confidence that future samples from the batch have at least a 95% probability that they will pass the USP content-uniformity test. For the revised USP test, these tables change with the confidence level (1 – α), the probability bound (P), the sample size (n), and the target content per dosage unit. Confidence levels as well as values for P are typically 50%, 90%, or 95%. A Parenteral Drug Association technical report recommends a 90% confidence level to provide 95% coverage (9). A 50% confidence level can be considered a "best estimate" of the coverage.

Revised content-uniformity test

The revised content-uniformity test is a two-stage test. The uniformity of dosage units for the revised test can be demonstrated by either content uniformity or weight variation. The derivations that follow are based on the individual dosage values obtained by either of the two methods. Let S i be the criteria of passing stage i, i = 1, 2. To perform the content-uniformity test, test 10 dosage units. The requirements are met if S 1 is satisfied. Otherwise, test the next 20 units. The requirements are met if S 2 is satisfied. Let L 1 = 15. The criteria of S 1 and S 2 are as follows:

S 1 = the acceptance value (defined below) of the first 10 dosage units is ≤ L 1

S 2 = a) the acceptance value of the 30 dosage units is ≤ L 1

b) no dosage unit deviates from the calculated value of M (defined below) by more than 25% of M

T is the target content per dosage unit at the time of manufacture, expressed as a percentage of the label claim. Unless otherwise specified in the individual monograph, T is the average of the limits specified in the potency definition in the individual monograph. We now define M as follows: