title: Statistical considerations in setting product specifications.
abstract: According to ICH Q6A (1999), a specification is defined as a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or other criteria for the tests described. For drug products, specifications usually consist of test methods and acceptance criteria for assay, impurities, pH, dissolution, moisture, and microbial limits, depending on the dosage forms. They are usually proposed by the manufacturers and subject to the regulatory approval for use. When the acceptance criteria in product specifications cannot be pre-defined based on prior knowledge, the conventional approach is to use data from a limited number of clinical batches during the clinical development phases. Often in time, such acceptance criterion is set as an interval bounded by the sample mean plus and minus two to four standard deviations. This interval may be revised with the accumulated data collected from released batches after drug approval. In this article, we describe and discuss the statistical issues of commonly used approaches in setting or revising specifications (usually tighten the limits), including reference interval, (Min, Max) method, tolerance interval, and confidence limit of percentiles. We also compare their performance in terms of the interval width and the intended coverage. Based on our study results and review experiences, we make some recommendations on how to select the appropriate statistical methods in setting product specifications to better ensure the product quality.
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: Xiaoyu
authors.initials: X
authors.lastname: Dong
authors.forename: Yi
authors.initials: Y
authors.lastname: Tsong
authors.forename: Meiyu
authors.initials: M
authors.lastname: Shen
mesh_terms: D001702:Biopharmaceutics / Q000592:standards / Q000706:statistics & numerical data*; D002626:Chemistry, Pharmaceutical; D003198:Computer Simulation; D016001:Confidence Intervals; D003257:Consumer Product Safety; D003627:Data Interpretation, Statistical; D017408:Guidelines as Topic; D006801:Humans; D015233:Models, Statistical; D009010:Monte Carlo Method; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000592:standards*; D011786:Quality Control; D012016:Reference Values; D018570:Risk Assessment; D018401:Sample Size; D013678:Technology, Pharmaceutical / Q000379:methods / Q000592:standards / Q000706:statistics & numerical data*
chemical_list: D004364:Pharmaceutical Preparations
keywords: Confidence limit; Percentile; Quality control; Specification; Tolerance interval