title: Quality assurance test of delivered dose uniformity of multiple-dose inhaler and dry powder inhaler drug products.
abstract: The delivered dose uniformity is one of the most critical requirements for dry powder inhaler (DPI) and metered dose inhaler products. In 1999, the Food and Drug Administration (FDA) issued a Draft Guidance entitled Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products-Chemistry, Manufacturing and Controls Documentation and recommended a two-tier acceptance sampling plan that is a modification of the United States Pharmacopeia (USP) sampling plan of dose content uniformity (USP34<601>). This sampling acceptance plan is also applied to metered dose inhaler (MDI) and DPI drug products in general. The FDA Draft Guidance method is shown to have a near-zero probability of acceptance at the second tier. In 2000, under the request of The International Pharmaceutical Aerosol Consortium, the FDA developed a two-tier sampling acceptance plan based on two one-sided tolerance intervals (TOSTIs) for a small sample. The procedure was presented in the 2005 Advisory Committee Meeting of Pharmaceutical Science and later published in the Journal of Biopharmaceutical Statistics (Tsong et al., 2008). This proposed procedure controls the probability of the product delivering below a pre-specified effective dose and the probability of the product delivering over a pre-specified safety dose. In this article, we further propose an extension of the TOSTI procedure to single-tier procedure with any number of canisters.
authors.affiliation: a Office of Biostatistics/Office of Translational Sciences , Center for Drug Evaluation and Research, U.S. Food and Drug Administration , Silver Spring , Maryland , USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Dong
authors.forename: Meiyu
authors.initials: M
authors.lastname: Shen
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lostritto
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D001702:Biopharmaceutics / Q000592:standards / Q000706:statistics & numerical data*; D002626:Chemistry, Pharmaceutical; D016001:Confidence Intervals; D003627:Data Interpretation, Statistical; D058995:Dry Powder Inhalers / Q000592:standards*; D004867:Equipment Design; D017408:Guidelines as Topic; D006801:Humans; D015233:Models, Statistical; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000592:standards*; D011208:Powders; D011336:Probability; D011785:Quality Assurance, Health Care / Q000592:standards*; D011786:Quality Control; D018401:Sample Size; D013678:Technology, Pharmaceutical / Q000379:methods / Q000592:standards / Q000706:statistics & numerical data*
chemical_list: D000336:Aerosols; D004364:Pharmaceutical Preparations; D011208:Powders
keywords: Delivered dose uniformity; FDA Draft Guidance method; Tolerance interval; Two one-sided tests; Two-tier group sequential