Three-Stage Sequential Statistical Dissolution Testing Rules

Abstract

The U.S. Pharmacopoeia (USP) general monograph provides a standard for dissolution compliance with the requirements as stated in the individual USP monograph for a tablet or capsule dosage form. The USP monograph sets performance limit on dissolution in terms of a specific percentage Q that the drug product is required to be dissolved at a specified time. Japan Pharmacopoeia provides acceptance rules different from USP. However the objective of the acceptance rules was not defined in terms of the inference of the whole lot by either USP, European Pharmacopoeia (EP) or Japan Pharmacopoeia (JP). The operating characteristics’ curves of these rules are all shown to be sensitive to the true mean dissolution and do not reject a lot which has a large percentage of tablets that dissolve with less than the specified limit Q. This is especially true when the mean dissolution is close to the specification value. We proposed that the goal of the dissolution test sampling plan is to accept a lot at least 90% of the tablets dissolved more than a pre-specified amount Q at the specific time. The group sequential procedure derived accordingly is shown to outperform both USP and JP in controlling the type I error rate under normality assumption.

Key Words:

• Dissolution test
• Sampling inspection
• Hypothesis of coverage probability
• Operating characteristics
• 3-Stage test
• Group sequential test
• Tolerance interval

Acknowledgment

The authors want to thank the two referees’ careful reading and comments that lead to the much improved version of the manuscript.

Notes

^#The views expressed in this paper are the authors' professional opinions. They do not represent the official positions of the U.S. Food and Drug Administration.