Qualification and Validation
in
Active Pharmaceutical Ingredients Production
Section 1
答怎么读
Introduction 原料药生产中的确认与验证
第1部分
导论
Introduction
Becau its products are intended for human consumption, the pharmaceutical industry is amongst the most highly regulated business in the world. All nations have some form of drug regulation and corresponding bodies to enforce that regulation.
-Here, it is the State Food and Drug Administration that ensures compliance with the Drug Administrati
on Law of the People’s Republic of China.
-In the United States, it is the U.S. Food and Drug Administration
-In Canada, it is the Therapeutic Products Directorate of the federal Ministry of Health 导论
因为药品是供人使用，制药工业是世界上规范最严的业务。所有国家都有药品规范的一些形式和相应的机构来实施这种规范。
-在中国是国际食品药品监管局（SFDA），保证符合中华人民共和国的药品管理法
-在美国是食品药品监管署（FDA）
-在加拿大，是联邦卫生部所属的药品监管司（TPD）
Introduction
Key elements that a company must have to comply with
pharmaceutical regulation:
• a quality management group
•qualified and trained employees
•standard operating procedures
•documentation and engineering change control
•analytical testing of raw materials, intermediates, and finished products and inventory control and disposition of the materials •detailed, traceable records of all manufacturing and testing activities
•adequately designed and maintained buildings and facilities facility qualification, equipment qualification and utilities qualification •adequately designed and operated process equipment and utilities
process validation and cleaning validation 导论
一个公司的关键部分是符合制药规范：
•一个质量管理团队
•合格与训练有素的员工
•标准操作程序
•文件与工程变更控制
•原材料、中间体和成品的分析检测以及这些物料的仓
储管理与布局
•详细的、可追溯的所有关于制造与检测作业的记录
•恰当地设计与维护建筑与设施
设施确认、设备确认与工具确认
•恰当地设计与操作设备与工具
工艺验证与清洗验证
Why are Qualification and Validation necessary?
The simple answer is that regulatory authorities require the
activities to be undertaken by pharmaceutical companies.
United States Food and Drug Administration:
“…validation is establishing documented evidence which provides a high degree of assurance that a specific process…will consistently produce a product meeting its predetermined specifications and
quality characteristics.”*
*Guidelines on General Principles of Process Validation,FDA, May, 1987确认与验证为什么是必要的？
a、简单的回答是药监管理机构要求制药厂承担这
些义务
美国食品药品监管署（FDA）：
“…验证是为确保一个专门过程…可以持续地生产满足预设规格与质量特征的一个产品而反复建立的书面依据。”*
*工艺验证总则指南，FDA，1987年5月
b. Regulatory Requirements of Qualification and Validation
Currently, the US FDA and the European Medicines Agency (EMEA) adhere to the International Committee on Harmonization (ICH)
Guidance Q7A
Qualification, ICH definition:
“Action of proving and documenting that equipment or ancillary
systems are properly installed, work correctly, and actually lead to the expected results. Qualification is part of validation, but the
individual qualification steps alone do not constitute process
validation.”b. 确认与验证的法规要求
目前，美国FDA与欧洲药品署（EMEA）遵循国际协调委员会（ICH）指南Q7A
ICH关于确认的定义：
“证明并记载设备或辅助系统适当安装、使用正确、并实际上产生期望的结果。确认是验证的一部分，但是个别确认步骤并不构成工艺验证。”
Conquences of Inadequate Qualification and Validation:
Warning Letters from the US FDA
六年级必读书目API facility in China in 1999 issued a warning letter for, amongst other deficiencies:
“Unsuitable water systems were ud for processing and equipment
cleaning. Specifically: …Water systems were not validated…Lack of any piping in instrument drawings of the deionized water …system…Lack of a monitoring program for water systems supplying water for API processing and equipment cleaning.”
API facility in China in 2000 issued a warning letter for:
“…Equipment cleaning records are incomplete and equipment
cleaning procedures have not been validated…”
The same facility was issued a warning letter from a follow-up inspection:“…Process validation for one API was inadequate in that it was not
performed following a written protocol, critical processing parameters were not identified, and the scale-up …step was not included in the validation study…”不恰当的确认和验证的后果：来自美国FDA的警告信1999年为下列原因发给中国原料药厂家警告信，在其它缺陷中：“采用不适合的水系统来进行工艺和设备清洗。特别是：…水系统没有验证…在去离子水…系统的装置系统图中没有任何管道，缺乏对用于原料药工艺和设备清洗的水供应系统的监控程序。”
200年为下列原因发给中国原料药厂家的警告信:
“…设备清洗记录是不完整的，并且清洗设备程序没有经过验证…”
在后续跟进过程中对同一家厂家发出的警告信：张根硕歌曲
“…针对一个API的工艺验证不恰当，因为没有按照书面方案来执行。
关键工艺参数没有得到说明，且放大…步骤并没有包括在验证研究中…”
Conquences of Inadequate Qualification and Validation:
Warning Letters from the US FDA
API and drug product facility in USA received a warning letter in 2006 that included:
“…The written program designed to assure proper performance of
automatic, mechanical, or electronic equipment is For
example {SOP XYZ}, Inspection and Testing of Manufacturing Equipment, which applies to all activities for testing and inspection of equipment at …, and the Installation Qualification Manufacturing Equipment form do not fully describe the requirement for equipment qualification, including
environmental conditions for equipment operation, any necessary ancilliary equipment needed for operation, and routine maintenance required. There is not requirement for a Performance Qualification protocol…”不恰当的确认和验证的后果：来自美国FDA的警告信2006年美国一家原料药和药品厂家收到的一封警
告信中包括：
后悔的一件事作文
“…为确保自动化的、机械的或电子化的设备完好运行的书面程序不恰当…例如{SOP XYZ}, 生产设备的检查与测试，是应用于在…..的设备的测试与检查所有作业的，安装确认（IQ）生产设备表没有完整描述设备确认的要求，包括设备操作的环境条件、为操作所需的任何辅助设备、要求的日常维护。没有运行确认方法的要求…”
b. Regulatory Requirements of Qualification and Validation
12.3 Qualification
Before initiating process validation activities appropriate qualification of critical equipment and ancillary systems should be completed.
Qualification is usually carried out by conducting the following
activities, individually or combined:
y Design Qualification
休息近义词y Installation Qualification
y Operational Qualification
阿根廷蚁
y Performance Qualification b.确认与验证的法规要求（续）
12.3 确认
爱你是最好的时光在启动工艺验证作业前，关键设备与辅助系统的适当确认需要完成。确认一般执行以下作业，单独作业或合并：
y设计确认（DQ）
y安装确认（IQ）
y操作确认（OQ）
y运行确认（PQ）
b. Regulatory Requirements of Qualification and Validation
12.3 Qualification cont’d
Design Qualification (DQ):
“documented verification that the propod design of the facilities, equipment, or systems is suitable for the intended purpo”b.确认与验证的法规要求（续）
12.3 确认（续）
设计确认(DQ):
“书面核实提议的设施、设备或系统的设计是适合目标用途的”
b. Regulatory Requirements of Qualification and Validation
12.3 Qualification cont’d
Installation Qualification (IQ):
“documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufacturer’s recommendations and/or ur requirements”b.确认与验证的法规要求（续）
12.3 确认（续）
安装确认(IQ):
“书面核实安装或修改的设备或系统符合原先批准的设计、制造商的推荐和/或用户的要求”番茄的营养价值
