Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms

Introduction to the Example 实例简介

This is an example pharmaceutical development report illustrating how ANDA applicants can move toward implementation of Quality by Design (QbD). The purpose of the example is to illustrate the types of pharmaceutical development studies ANDA applicants may use as they implement QbD in their generic product development and to promote discussion on how OGD would use this information in review.

Although we have tried to make this example as realistic as possible, the development of a real product may differ from this example. The example is for illustrative purposes and, depending on applicants’ experience and knowledge, the degree of experimentation for a particular product may vary. The impact of experience and knowledge should be thoroughly explained in the submission. The risk assessment process is one avenue for this explanation. At many places in this example, alternative pharmaceutical development approaches would also be appropriate.

Notes to the reader are included in italics throughout the text. Questions and comments may be sent to GenericDrugs@fTable of Contents



1.1 Executive Summary 概述
1.2 Analysis of the Reference Listed Drug Product 分析参考列表药品
1.2.1 Clinical 临床
1.2.2 Pharmacokinetics 药动学
1.2.3 Drug Release 药物释放
1.2.4 Physicochemical Characterization 理化性质
1.2.5 Composition 成分
1.3 Quality Target Product Profile for the ANDA Product ANDA药品的目标药品质量概述 1.4 Dissolution Method Development and Pilot Bioequivalence Studies
1.4.1 Dissolution Method Development 溶出方法开发
1.4.2 Pilot Bioequivalence Study 中试生物等效性研究
2.1 Components of Drug Product 制剂成分
2.1.1 Drug Substance 原料药 Physical Properties 物理性质 Chemical Properties 化学性质 Biological Properties 生物学性质
2.1.2 Excipients 辅料 Excipient Compatibility Studies 辅料相容性研究 Excipient Grade Selection 辅料级别选择
2.2 Drug Product 制剂
2.2.1 Formulation Development 处方开发 Initial Risk Assessment of the Formulation Variables 处方变量的初始风险评估 Drug Substance Particle Size Selection for Product Development
制剂开发中的原料药粒径选择 Process Selection 工艺选择 Formulation Development Study #1 处方开发研究#1 Formulation Development Study #2 处方开发研究#2 Formulation Development Conclusions 处方开发结论 Updated Risk Assessment of the Formulation Variables 更新的处方变量风险评估 2.2.2 Overages 过量投料
2.2.3 Physicochemical and Biological Properties 理化和生物学性质
2.3 Manufacturing Process Development 生产工艺开发
2.3.1 Initial Risk Assessment of the Drug Product Manufacturing Process da.hhs.gov制剂生产工艺的初始风险评估
2.3.2 Pre-Roller Compaction Blending and Lubrication Process Development预碾压混合和润滑工艺开发

2.3.3 Roller Compaction and Integrated Milling Process Development碾压和集成粉碎工艺开发
2.3.4 Final Blending and Lubrication Process Development 最终混合和润滑工艺开发

2.3.5Tablet Compression Process Development压片工艺开发
2.3.6Scale-Up from Lab to Pilot Scale and Commercial Scale从实验室规模放大至中试规模和工业规模 Scale-Up of the Pre-Roller Compaction Blending and Lubrication Process预碾压混合和润滑工艺的放大 Scale-Up of the Roler Compaction and Integrated Milling Process碾压和集成粉碎工艺的放大 Scale-Up of the Final Blending and Lubrication Process最终混合和润滑工艺的放大 of the Tablet Compression Process 压片工艺的放大
2.3.7Exhibit Batch申报批
2.3.8Updated Risk Assessment of the Drug Product Manufacturing Process更新的制剂生产工艺风险评估
2.4Container Closure System 容器密封系统
2.5Microbiological Attributes 微生物属性
2.7 Control Strategy控制策略
2.7.1Control Strategy for Raw Material Attributes原材料属性的控制策略
2.7.2Control Strategy for Pre-Roller Compaction Blending and Lubrication预碾压混合和润滑的控制策略
2.7.3Control Strategy for Roller Compaction and Integrated Milling碾压和集成粉碎的控制策略
2.7.4Control Strategy for Final Blending and Lubrication 最终混合和润滑的控制策略
2.7.5Control Strategy for Tablet Compression压片的控制策略
2.7.6Product Lifecycle Management and Continual Improvement产品生命周期管理和持续改进

List of Abbreviations缩略语表

List of Abbreviations 缩略语表
ANDA: Abbreviated New Drug Application 简明新药申请
ANOVA: Analysis of Variance 方差分析
AUC: Area Under the Curve 曲线下面积
AV: Acceptance Value 合格判断值
BE: Bioequivalence 生物等效性
BU: Blend Uniformity 混合均匀度
CCF: Central Composite Face-centered 中心复合表面
CFR: Code of Federal Regulations 美国联邦法规
CMA: Critical Material Attribute 关键物质属性
Cmax: Concentration Maximum 最大浓度
CPP: Critical Process Parameter 关键工艺参数
CQA: Critical Quality Attribute 关键质量属性
CU: Content Uniformity 含量均匀度
df: degrees of freedom 自由度
DOE: Design of Experiments
DS: Drug Substance 实验设计
ER: Extended Release 延迟释放
f2: Similarity factor 相似因子

HPC: Hydroxypropyl Cellulose 羟丙基纤维素
HPMC: Hydroxypropyl Methylcellulose 羟丙甲纤维素
ICH: International Conference on Harmonization 国际协调会议
IR: Immediate Release 速释
IVIVC: In Vitro-In Vivo Correlation 体内外相关性
IVIVR: In Vitro-In Vivo Relationship 体内外相关性
LOD: Loss on Drying 干燥失重
MCC: Microcrystalline Cellulose 微晶纤维素
MFT: Minimum Film-forming Temperature 最低成膜温度
MR: Modified Release 缓释
NIR: Near-infrared 近红外
No.: Number 数字
Nrev: Number of revolutions 转速
PEG: Polyethylene Glycol 聚乙二醇
PG: Propylene Glycol 丙二醇
PSD: Particle Size Distribution 粒度分布
PVAc: Polyvinyl Acetate 聚乙酸乙烯酯
PVP: Polyvinylpyrrolidone, Povidone 聚乙烯吡咯烷酮,聚维酮
QTPP: Quality Target Product Profile 目标药品的质量概况
R2: Coefficient of Determination 决定系数
RLD: Reference Listed Drug 参考目录药品
RSD: Relative Standard Deviation 相对标准偏差
RT: Room Temperature 室温
SLS: Sodium Lauryl Sulfate 十二烷基硫酸钠
SSG: Sodium Starch Glycolate 羧甲基淀粉钠
TEC: Triethyl Citrate 柠檬酸三乙酯
Tmax: Time for achieving Maximum Plasma Concentration 血药浓度达峰时间
TPI: Terahertz Pulse Imaging 太赫兹脉冲反射成像技术
XRPD: X-Ray Powder Diffraction X 射线粉末衍射


有机化合物的波谱解析(第七版)药明康德 译