Parametric Two-Tier Sequential Quality Assurance Test of Delivery Dose Uniformity of Multiple-Dose Inhaler and Dry Powder Inhaler Drug Products

Abstract

The delivery dose uniformity is one of the most critical requirements of dry powder inhaler and metered dose inhaler products. In 1998, the U.S. Food and Drug Administration recommended a two-tier acceptance sampling plan in the Draft Guidance of Metered Dose Inhaler and Dry Powder Inhaler Drug Products Chemistry, Manufacturing and Controls. The two-tier procedure is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity. It employed a zero tolerance criterion. In addition, it has a near-zero probability acceptance at the second tier. In this article, a two-tier sequential tolerance interval approach is proposed that is equivalent to a two-tier two one-sided testing procedure. It controls the probability of the product delivering below a prespecified effective dose and the probability of the product delivering over a prespecified safety dose.

Key Words:

• Delivered dose uniformity
• Double one-sided test
• FDA draft guidance method
• Tolerance interval
• Two-tier group sequential

ACKNOWLEDGMENTS

The authors acknowledge the contributions of Drs. Robert T. O'Neill and Moheb Nars of U.S. Food and Drug Administration for the many discussions on the parametric confidence interval approaches that led to the draft of this article.

This article represents the author' opinion only and not the official position of U.S. FDA.