Adaptive Statistical Methods for Category Specific Release Testing of Drug Products

项目摘要/摘要 这项提议的主要目标是生成数据并制定统计抽样/分析战略 协助FDA/COER政策起草基于数据的指导，以支持使用适当的统计数据 工具和标准。为实现这一目标，将在以下具体目标下安排工作： 1)最近分发的药品的选择：制定选择的理由，以确定主要 基于剂型的复杂性和包括剂量在内的关键特征的剂型分类， 释放机制，BCS，治疗指数，以及制造方法。2)抽样组织和数据 生成：组织抽样，以确保为统计范围收集足够的数据 待开发和测试的治疗方法。生成所选关键质量(化学和物理)的数据 属性(例如，片剂重量、硬度、脆碎度、含量测定、含量均匀度和溶出度)，并确定 整个样本的均值和方差。3)当前/建议模型的比较估计精度： 使用当前标准和替代模型的能力来预测与实际情况相对应的均值和方差 从实验中观察到的。4)生成特定剂型类别的标准和替代方案 统计方法：开发和确定适合批次的类别间和类别内可变性的方法 对所研究的剂型类别进行释放。 药品执行方式的多变性是产品召回的一个主要原因，而且可能是负面的 在患者群体中的结果。这种变异性可能体现在物理化学特性上。 所生产的最终剂型、其传递药物物质的方式或其保留所需药物的方式 随时间变化的行为，即自我生活。过程控制和产品测试的目标是评估 该制剂在释放时形成，以检测问题并预测其货架期内可能出现的问题。 因为不同的剂型可能被设计成具有不同的性能，并且在一系列 特征，拟议的项目将提供关于可变性的详尽基准 目前市场上销售的一系列剂型和先进的统计分析工具，这些工具是为身份而量身定做的 确定的每一类剂型中有意义的可变性。这将由自适应的 指导试验和开发所需剂型类别的统计方法 特定的工具。该项目的意义在于：1)它将提供有针对性的统计方法 适用于主要剂型类别的产品发布和故障排除，以及2)这些 办法将便利新药产品和仿制药产品的审评和审批。 总而言之，这意味着更高的质量、更短的上市时间和更低的成本。

Project Summary/Abstract The main goal of this proposal is to generate data and develop a statistical sampling/analysis strategy to aid FDA/COER policy in drafting data-based guidance in support of the use of appropriate statistical tools and standards. The goal will be addressed by organizing the work under the following specific aims: 1) Selection of recently distributed pharmaceutical products: Develop a selection rationale to identify major dosage form categories based on the complexity of the dosage form and key characteristics including dose, release mechanism, BCS, therapeutic index, and manufacturing method. 2) Sampling organization and data generation: Organize the sampling to insure that sufficient data are collected for the range of statistical treatments to be developed and tested. Generate the data for selected critical quality, chemical and physical attributes (e.g., tablet weight, hardness, friability, assay, content uniformity, and dissolution) and determine the mean and variance of the entire sample. 3)Comparative estimation accuracy of current/proposed models: Using current standards and alternate models' ability to predict the means and variance against those actually observed from experimentation. 4) Generate standards and alternates for dosage form category specific statistical methods: Develop and identify approaches for inter and intra-category variability suitable for lot release for the categories of dosage forms studied. Variability in the way drug products perform is a major reason for product recalls and potentially negative outcomes in the patient population. This variability may be manifested in the physical-chemical characteristics of the final dosage form as produced, the way it delivers the drug substance, or the way it retains the desired behavior with time, i.e., the self-life. The goal of process control and product testing is to assess the quality of the dosage forms upon release to detect issues and to anticipate problems that may occur during its shelf-life. Because different dosage forms may be designed to perform differently and be variable over a range of characteristics, the proposed project will provide both an exhaustive benchmarking of the variability over the range of dosage forms currently marketed and advanced statistical analysis tools that are “tailored” to identity meaningful variability within each categories of dosage form identified. This will be driven by an adaptive statistical approach for directing the experimentation as well as developing to desired dosage form category specific tools. The significance of the project is that; 1) it will provide targeted statistical methods to be applied to product release and trouble shooting for the major dosage form categories, and 2) these methods will facilitate the review and approval of new drug products and generic drug products. Together this means higher quality, reduced time to market, and reduced cost.