FDA对原料药厂检查流程

第一篇：FDA对原料药厂检查流程

FDA对原料药厂检查流程

一、概述

“FDA”是美国食品药物管理局(Food and Drug Administration)的英文缩写，它是国际医疗审核权威机构，由美国国会即联邦政府授权，专门从事食品与药品管理的最高执法机关。FDA是一个由医生、律师、微生物学家、药理学家、化学家和统计学家等专业人事组成的致力于保护、促进和提高国民健康的政府卫生管制的监控机构。就原料药而言，FDA检查目的是为了保证从国外进口的原料药的质量充分符合USP的要求，美国政府规定外国的药物生产商向美国出口药物产品，除了要对该产品的样品进行质量检查之外，还要对药物制造企业的相关设施进行检查才能做出批准与否的决定，FDA现场检查由此而生。FDA检查主要分为三类：一是批准前的现场检查(Pre—approval Inspection)，即我们通常说的“FDA检查”，对新药和仿制药品的生产采取的检查行动；二是定期检查（Biennial）,对批准后的药品进行定期的合规性检查，通常两年进行一次；三是基于投诉、召回或不良反应FDA临时决定进行专门的检查或监督。

FDA检查的依据起源于是美国国会1938年颁发的联邦食品、药品和化妆品法案（常缩写为FFDCA，FDCA，或FD&C），该法案赋予美国食品药品监督管理局（FDA）监督监管食品安全、药品、及化妆品的权力。关于药品方面，主要是受“食品、药物及化妆品法案”第501款(a)(2)(b)的管制，即所有药物的制造、加工和包装，均要严格符合cGMP的要求。GMP制度在联邦法规(code 0f Federal Regulations)中的第210和第211条款中有具体规定。不过，自发布以来的GMP主要是为制剂药而制定的。在它的前言中说明：虽然它不是用于原料药，但有许多实例说明对原料药的GMP要求是与第211条款中所制定的要求很近似。因此，FDA就采用第2ll条款作为规范来对原料药厂进行检查。在这点上，FDA对原料药与制剂药的要求都是一样的严格，没有区别。1997年9月，国际协调会议(ICH：InternationalConference 0f Harmonization)公布了专为原料药制定的GMP草案，更切合原料药的生产实际。2001年8月，美国健康人类服务部食品药物管理局药物评价研究中心和生物制品评价研究中心与国际协调会议联合发布了用于活性药物成分(原料药)生产的GMP指南：Guidance for Industry Q7A—Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients)，即Q7A GMP。此后，FDA宣布以这个指南文件为原料药生产的GMP统一标准，并以此对原料药厂进行符合性检查。

二．FDA检查流程

FDA检查通常由一位检查官和一位药物审查化学家或微生物学家到药厂进行4—5日的检查，FDA到药厂后，会和工厂人员先进行一个简短的见面会，在见面会上FDA会首先说明一下检查的背景及检查安排，药厂由负责人向对方介绍所有出席会议人员，出席人员一般包括总经理、质量授权人及各部门的负责人，然后由药厂对工厂进行一个简要的介绍，让检查官对工厂有一个初步的了解。检查主要分为两块：现场视察与文件检查。

2.1 现场检查

原则上，FDA检查官是按照原料药的生产顺序（物流走向），即从原料接受到成品包装再到放行的顺序来先进行现场检查的，但根据环境条件和检查官个人的专业背景、习惯与判断方式的不同，也可能先检查文件再看现场或中间穿插着去检查现场。

检查官的第一站是仓库，包括原料、成品及包材仓库，仓库的关注点物料的管理，FDA不仅要求进厂的起始物料符合预先建立的质量标准，进行良好的储存，还需要能够预防不同物料或不同批次的物料混淆或产生交叉污染的风险。检查官通常会从以下几点来评估：首先起始物料入库前是否有适当检查流程，是否有入库台帐，不同物料之间是否有物理隔离，仓库的温湿度是否有监控并能够达到物料所要求的存储温度，仓库是否有防虫和防鼠的措施(如窗户或风扇进风口是否装有纱窗，仓库内是否有灭蚊蝇灯，粘鼠板或电猫)，物料容器的标识(取样证、合格证或不合格者)，仓库是否有专门的区域存放不合格品、退货、召回产品，标签发放与控制等。

2.2 按照生产顺序，检查完仓库后，检查官将会去车间看生产，通常要求在检查期间车间处于动态生产的状态，通常检查官会对照着产品的生产工艺流程图，一步一步地了解整个生产过程，以便对GMP的执行过程进行深入的检查。FDA官员会关注每个重点操作岗位SOP是否在现场，原始记录是否与岗位SOP及实际运行情况一致以评估SOP的可操作性及员工的培训是否到位。除外，检查官会评估在整个生产过程中是否有物料污染或混淆的风险，如设备清洗是否足够、设备及标示牌与管道上的物料标记是否清晰准确，各种设备是否有醒目的编码便于操作，化学合成工艺中离心机滤袋的清洗及管理是否到位、不同房间及房间与走廊间的压差是否正常。

2.3 公用系统（纯化水、空调系统、压缩空气）

检查官主要评估公用系统能否有效地运行并满足产品生产所要求的条件，具体包括公用系统的日常维护保养、年度回顾与验证、在线监控，如纯水电导率超标如何处理，是否有报警装置及在线排放装置，过滤器更换频率，在线取样等），压缩空气是否进行水油检测、空调系统的过滤器更换等。

2.4 实验室

现场检查的重点之一是实验室，FDA检查至少会用半天甚至更多的时间检查实验室，通常由化学家或微生物学家进行。检查官到实验室时首先要了解的是样品的流向及管理，即样品接受、存放、分发及检验后的管理，是否有合理的台帐确保样品不会被混淆并可以追溯；空白检验记录的管理与控制，其它包括实验室仪器的合理使用及相应的记录，如：HPLC设备与色谱柱的使用台帐，二者是否可以相互追溯并；化学试剂的使用的管理(有效期，启用日期等)；配制试液的标签(试液名称，配制日期，配制人签字、复标日期及复标人，试液的效期规定等)和设备与仪器。FDA对设备与仪器的校验尤其重视，药厂需要定期进行校验的常用的测量仪表有温度计(包括自动记录温度计)，温湿度计，压差表，液体流速计，空气流量计，液位计等；计量设备和器具如磅称，粗天平，普通天平，分析天平以及高精密度天平等；工艺过程控制和质控试验室用的pH计，滴定管，移液管等；仪器分析用的UV，IR，HPLC和GC等设备。FDA检察官首先注意的是仪器设备上是否贴有校验合格的标志，查看有关设备仪器校验的SOP和使用与校验的原始记录。通常，我国的原料药厂的度量衡仪器都是由药厂专设的仪器计量室(大多是从属设备管理部门)负责定期校验并签发校验合格证。技术性高的仪器设备如UV，IR，HPLC和GC等设备则一般是委托地方政府的计量管理部门进行校验。凡是发现重要的仪器设备没有进行校验，或提供不出完整的文件记录说明，FDA检察官都认为是严重的问题，因为未经过合理校验的仪器无法确保其准确性，同样用该仪器检测所得数据的可靠性也无法保证。

微生物实验室包括培养基配制及适用性试验、菌种传代、工作服、工作鞋的清洗及器皿的灭菌等。

三、文件检查

在FDA通过现场检查之后，对工厂的布局及工艺流程有了一个具体的了解之后，便开始回到会议室集中看文件，通常两个检查官为分头进行，化学家或微生物学家会集中检查QC相关的文件。检查的文件涵盖生产系统、质量系统、厂房设施、实验室等。

3.1 生产系统

检查官在接到FDA对某个药厂进行现场检查的通知后，会从FDA文件管理处调出该药厂提交的DMF文件提前准备。到现场后通常会随机选一批或几批完整的批记录，然后对应DMF文件对应着检查，对关键的操作步骤一条一条核对，这就要求提交的DMF文件必须与现场的操作完全一致。在这过程中检查官会关注对关键的操作步骤的控制，涉及偏差时的相关调查记录。

3.2.质量体系

质量体系是FDA检查的核心，检查会涵盖关键的质量文件(偏差、投诉、OOS、召回、变更、自检、验证与确认、供应商管理等)，通常检查官会随机选取其中一个投诉或偏差，然后查看相关的调查记录及相应的SOP，一方面评估药厂的SOP是否合理，另一方面评估工厂能否够按照SOP对质量事件进行彻底的调查并采取有效的整改与预防措施（CAPA）以防止类似事件再次发生。

3.3 厂房与设施

这部分检查官会关注工厂是否有良好的厂房与设施维护计划并通过检查相关的记录来评估工厂能否按计划对厂房与设施进行很好的日常维护，包括仪器的校准与确认、设备与设施（水系统与空调系统、压缩空气）的3Q确认等。

3.4 实验室

QC文件检查通常包括产品的质量标准与检验方法确认与验证，检测记录、稳定性试验方案与相关记录以及其它检查官在现场检查时临时需要的文件。

四、检查的关键点

对任何公司来说，通过FDA验厂最重要的条件是自己要严格执行已经确立的程序和操作流程以及记录与数据的完整性与真实性，这两点最能反映工厂的GMP质量管理水平，而质量体系正是FDA检查的核心所在。这就要求记录的填写一定要规范可读，不得随意篡改记录，写错更改需要保证原输入的可读性，一旦检查官对记录的真实性产生质疑，那对药厂会非常的不利。另外，接待人员回答提问要有技巧，不清楚的事情切忌马上回答或者是使用“我记得、好像”之类的词汇，这样会给检查官留下很不专业的印象，不确定的可以先查文件，几个人商量定下来之后再回答。

五、总结会

检查官通常会留出一天时间来做总结，对整个检查期间的发现进行汇总，即483表，并现场宣读483上的每一条发现，并询问工厂对各条发现是否有异议，如果工厂有需要解释的地方，可以充分利用好此机会。如果FDA检查官认为解释有理，一般会对所提的问题进行修改或取消。如果对所发现的问题无异议，一般工厂代表人或公司总经理需要作出表态表示接受检查过程中的发现，然后双方在483表格上正式签字。FDA要求药厂对提出的问题尽快(一般在两周到一个月，根据情况而定)做出书面答复，其中要求提供明确的较详细的整改回复，在规定时间内递交到FDA地区办公室。FDA检查官在回国后根据药厂的整改报告写出一份非常详细的检查报告送交FDA有关主管部门(如新药评价中心，兽用药评价中心等)。

六、最后的决定——批准(或不批准)的通知函

按FDA的规定，FDA检查官无权对是否批准做出决定。FDA检查官在检查报告中非常客观地说明一切情况和存在问题，药厂的态度和整改措施，对该药厂是否可以得到批准会提出个人的建议，它对FDA做出批准或不批准的决定是具有关键性的影响的。

来源：HPC药闻药事/Joanna

第二篇：FDA是如何对原料药厂进行检查的（推荐）

(一)FDA是如何对原料药厂进行检查的

一、前言

本文作者从1981年起开始涉及原料药的FDA申请事务，从1992年一直专门从事这项专业工作至今。其间先后参与或主持了近20个原料药产品的FDA申请工作，制作归档了十几个DMF文件，与十多位美国代理商或美国终端用户的GMP符合及FDA申请顾问一起工作，九次参加FDA官员对我国一些制药企业进行的GMP符合性现场检查，其中8个品种通过了FDA的现场检查，从而积累了一些有益的经验。作者现任北京康利华公司咨询服务有限公司终身董事和监事，仍专门从事FDA的申请工作。本文就FDA对原料药管制的有关文件的学习了解，结合作者20年来的实际经验，对FDA官员对原料药厂如何进行现场检查作了简要的叙述，希望能给我国广大原料药企业提供有益的参考。1．定义 1．1原料药

通过化学合成、微生物发酵、天然物提取分离、酶工程、DNA重组等技术和手段得到的具有药物活性、符合一定质量标准的物质。原料药通常只供生产制剂之用，不可直接用于临床。欧美对原料药的称呼有以下几种：Bulk Pharmaceutical Chemical简称BPC。现常用：Active Pharmaceutical Ingredient简称API，或Drug Substance。

生产原料药的起始物料在生产过程中都要经历明显的化学变化，然后经分离纯化制成具有药物活性、且符合一定质量标准的原料药。

原料药又分为无菌(Sterile)和非无菌(Non—sterile)两种级别。前者常用于生产非消化道给药的制剂药，后者常用于生产口服制剂或外用制剂，或再经过无菌处理生产非消化道制剂药。

1．2制剂药

将原料药与辅料一起进一步加工，制成的适合临床应用的各种形式，所得到的产品为制剂药。欧美常把制剂药称作：

Finished Pharmaceutical，Finished Product，Dosage Form，Finished Dosage Form或Drug product。

在20世纪50年代中期，为了保证从国外进口的原料药的质量充分符合USP的要求，美国政府规定外国的药物生产商向美国出口药物产品，除了要对该产品的样品进行质量检查之外，还要对药物制造企业的相关设施进行检查才能做出批准与否的决定。2．FDA对国外原料药生产商的检查 2．1检查的历史

FDA从1955年开始进行第一次国外检查(抗生素)。1961年国外检查达13项，以后继续增加。1971年成倍增加，达到80项。此后，在整个70年代里不断增加。到了80年代及至90年代初，达到了每年检查160项之多。1993年FDA计划要进行340项检查·2000年进行的48项检查中，批准了28项。在未批准的项目中，有14个是问题很大的。发出了1l封警告信(2001年发出9封)。2002年和2003年FDA都派了检察官来我国检查一些药厂。2．2 FDA国外检查的范围

检查地域的面较广，主要有欧洲的意大利、荷兰、德国、俄罗斯、波兰、匈牙利等国，亚洲的中国、日本及印度等国。

只有加拿大，瑞典和瑞士与美国订有双边协议，美国不派员去检查，由他们自己的官员进行检查，FDA认可检查结果，并彼此交换检查信息。2．3 FDA国外检查的情况：

一美国制剂制药企业使用的原料药有70％来自国外。

一接受FDA检查的企业有三分之二是生产原料药的。

一有17％的原料药制药企业和11％的制剂制药企业不符合检查要求。

一外国接受检查的制药企业有六分之一不符合GMP要求。

一FDA向一些检查结果不能令人满意的制药企业发出了警告函。

一不合格的企业的医药产品被禁止进入美国。

一在欧洲拥有良好的符合要求记录国家是意大利。

一日本是接受FDA检查制药企业最多的国家，占总数的百分之十六。并有良好的符合要求的记录。

3．FDA对我国原料药厂的检查

自从八十年代初我国的原料药企业开始向美国FDA提出申请，接受FDA官员的检查，迄今，已有一些企业的生产原料药的设施通过了检查，得到FDA的认可，已有为数可观的各种原料药(如四环素，土霉素，庆大霉素，链霉素，金霉素，洁霉素，依维菌素，硫链丝菌素等抗生素，甲硝唑，扑热息痛等合成药)进入美国市场，占有了一定的份额。

自从八十年代初以来，我国药厂取得FDA批准出口美国的原料药主要还是非无菌级的原料药。

二、FDA对原料药管制的依据

原料药要接受什么法规管制?简单说来，就是要接受cGMP的管制。具体地说，就是要接受美国“食品、药物及化妆品法案”(FDCA)第501款(a)(2)(b)的管制，即所有药物的制造、加工和包装，均要严格符合cGMP的要求。

GMP制度在联邦法规(code 0f Federal Regulations)中的第210和第211条款中有具体规定。不过，自发布以来的GMP主要是为制剂药而制定的。在它的前言中说明：虽然它不是用于原料药，但有许多实例说明对原料药的GMP要求是与第211条款中所制定的要求很近似。因此，FDA就采用第2ll条款作为规范来对原料药厂进行检查。在这点上，FDA对原料药与制剂药的要求都是一样的严格，没有区别。1997年9月，国际协调会议(ICH：International Conference 0f Harmonization)公布了专为原料药制定的GMP草案，更切合原料药的生产实际。2001年8月，美国健康人类服务部 食品药物管理局 药物评价研究中心 和 生物制品评价研究中心 与国际协调会议联合发布了用于活性药物成分(原料药)生产的GMP指南：Guidance for Industry Q7A—Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients)，即Q7A GMP。此后，FDA宣布以这个指南文件为原料药生产的GMP统一标准，并以此对原料药厂进行符合性检查。

三、规章的实施与指导文件 1．法规的实施

*在美国，每个FDA的管辖区都有一套原料药制造商名单，一般对药物生产厂每两年要进行一次检查。由各辖区安排检查计划。FDA检查官是分地区的，美国各地区国内检查官也兼国外检查官的任务。这样就保证了国外的药物生产商也受到国内生产商同样要求的检查。*进行批准前的现场检查(Pre—approval inspection)，即我们通常说的“FDA检查”)一对新药和仿制药品的生产采取的检查行动。

*在有投诉、药源性伤亡或疾病发生时，FDA要进行专门的检查或监督。2．指导文件

FOAL公布了各种指导文件，其中有专供FDA检查官使用的关于原料药生产的“原料药生产检查指南”【The Guide for Inspection 0f Bulk Pharmaceutical Chemicals】。

四、FDA检查官检查的方式和重点 1．检查方式

FDA对我国原料药厂进行检查，在6年前，每次是派一位检查官到药厂进行2—3日的检查。此后，改为每次派两位检查官(确切地说，是一位检查官和一位药物审查化学家)到药 2 厂进行4—5日的检查，比过去的检查大为强化。其中：

*预备会议 约半日 *现场检查 约1.5-2日 *文件检查 约1-1.5日 总结会议 约1日

FDA检查官对药厂一般采用如下程序进行检查： 1．1预备性会谈

首先FDA官员作自我介绍，向我方出示FDA检查官身份证。我方负责人向对方介绍所有出席会议人员，出席人员一般包括：

*主谈人(1名)：由公司总经理(或厂长)，或负责生产技术的副总经理(或副厂长)，或总工程师担任，根据各药厂的具体情况而定。

*出席人员：总工程师，生产(或技术)部门负责人，申请产品的车间主任，车间工程师，QA及QC负责人，设备管理部门负责人，仓库主任，我方FDA申请顾问(一般都应兼任翻译)，英语翻译(2名)和联络员(1—2名，负责及时提交供检查的文件和与接受检查的各部门联系工作。可由生产技术管理部门人员或市场销售部门的外贸工作人员担任，最好熟悉英语)。*美方有美国代理人(有时还有美方FDA申请顾问)也出席会议和参与整个检查过程。1．2现场视察

包括(固体和液体)原材料，包装材料，标签和成品仓库；生产车间，用水供应设施(主要是纯化水制备车间)，质控实验室(QC)，以及FDA官员即兴提出要视察的任何地方(例如，三废处理设施，药厂自行加工的农产品原料的车间或无菌区的空气过滤系统等等)。FDA检查官一般不要求视察与申请产品无关的地方。1．3文件检查

a．DMF(药物主文件)一FDA检查官在接受检查任务后从文件管理办公室领取一份DMF文件，事先仔细阅读，熟悉接受检查的制药企业的全面情况。FDA官员到达药厂现场后，在整个的检查过程里不断地把DMF中所描述的情况和现场的实际情况进行核对。所以，DMF与现场实际的符合性或一致性是非常重要的。如果发现对不上号的地方太多，而且不能做出令人信服的解释，将会构成严重的问题。

b．重点检查的文件有：抽查近期的一个批的全套生产原始记录；有关生产工艺，质量控制，设备清洗，环境卫生，无菌区或洁净区的清洁和消毒等方面的标准操作规程(SOP)，工艺验证及设备的无菌度或清洁度的验证方案和记录；稳定性试验的方案和记录以及FDA检查官提出要查阅的任何文件。1．4会谈与总结：检查结束时与企业各有关负责人员会谈向企业发给FDA意见表483(FDA FORM 483)其中列出企业存在的问题。限期做出改进和答复。

1．5 FDA检查官向FDA总部提交检查结果的详细报告，由主管部门做出批准与否的决定。

2．现场检查的重点

原则上，FDA检查官是按照原料药的生产顺序，即从原料到成品包装及出厂的顺序来进行检查的。但根据环境条件和检查官个人的专业背景，习惯与判断方式的不同而从任何一个工序开始进行检查。以下是检查的重点： i．原材料(仓库管理)ii．生产工艺的执行：生产操作和工艺验证。iii．厂房、设备和设施 iv．设备的清洗 v．批成品的混合

vi．包装及贴签 vii．生产用水 viii质控实验室

*仪器配备和校验方法 *工艺过程的分析与控制 *试剂和试液的配制 *稳定性试验和留样制度

2．1 原材料(仓库管理)原材料是泛指从精细化学品到植物粗品及动物制品等用于生产原料药的所有物料，其中包括所用到的各种溶媒及辅助化学品。

FDA检查官最关心的是原材料的控制系统一仓库管理和质量控制。在大多数情况下都是先到仓库去检查原材料的管理情况，同时也检查成品，包装原材料和标签的仓储管理情况。FDA检查官要求进厂的原材料保证能符合要求的质量标准，并能良好地储存。这类控制系统一般包含一些临时隔离待验系统采用物理方法的分隔及识别标志。

FDA检查官对原材料的堆放要求符合“先进先出’’(First in and first out)的原则，对原材料包装容器上的贴签(诸如取样证，合格证及不合格证等)尤其重视。在固体原材料方面，抗生素生产的发酵用的原材料中的农产品原材料，例如黄豆粉，用粗麻布口袋包装，很难贴好标签，其它如装淀粉的棉布口袋和装化学品的塑料编织袋，由于重量大，堆放高，搬动不便，在取样检验合格后，很难做到每袋都贴上合格证。FDA检查官对此是讲情理的，例如在一次检查中对一批数量达2000个布袋的发酵原材料，不要求每袋都贴有待检验，合格或不合格的标签。但要求堆垛外围的袋上都贴有标签。

对仓库管理，有的FDA检查官着重检查管理的方法。在接收原材料时，对每一批原材料的条件，标签批号及有关信息的记录进行检查。在多数情况下，至少应有一项目测或化学鉴别实验。通常还附有一个合格的生产厂家的分析合格证(COA)，说明该原材料的质量规格均能符合标准的要求。对一些很关键的原材料和中间体则要求有全面的分析报告。

在液体原材料方面，有的FDA检查官对用于药物分离提取和纯化精制的溶媒原材料特别注意，因为在结晶过程和精制阶段，如果溶媒有污染，则成品会受到污染。对于桶装溶媒，更注意的是是否严格管理而不会混用。我国化学工业和制药业有个共同的缺点，就是对某些种类的溶媒或农产品原料(如玉米浆液)是利用其它原料用过的旧桶，而没有把原有的文字标记除去。钢桶容器由于没采取良好的方法，贴签非常不牢，常有脱落。对用槽车装运

溶媒也常有混用的现象，对此，FDA强调在取样检验时，要从输液管大量取样，而不是像有些企业那样，只从槽车的舱口取样100毫升进行检验。

FDA检查官要求企业对原材料供应商制定有整套的合格验证制度，根据供应商的分析合格证书和附有的鉴别试验来接收原材料。对原材料的批号的编制也有具体的要求。有时检查官会要求查看入库台帐。

FDA检查官对仓库的建筑结构和通风照明等条件没有具体的规定。一般说来，我国的一些老旧的未经改造的制药企业的仓库条件都较差，对此，他们只要求整个内部环境清洁整齐，没有空调设备的要求有通风设备(一般是采用排风扇)。室内有温度和湿度计，定时观察温湿度，要求有记录。要求有有效的防虫和防鼠的措施(如窗户或风扇进风口装有纱窗，仓库内有灭蚊蝇灯，粘鼠板或电猫，并要求有记录)。经验证明，企业改建或新建的仓库，特别是比较现代化的仓库结合较完善的管理能给予FDA检查官以良好的印象。2．2生产工艺规程的执行 2．2．1生产操作

FDA检查官一般不对生产工艺的先进或落后，高效率或低效率的水平进行评价。由于FDA 4 检查官不是全能的技术专家，不可能什么都懂，所以他们往往在检查本人不太熟悉的生产工艺过程时，更多的是向企业了解和弄清整个工艺过程。通常要求药厂出示该产品的生产工艺规程，以便对GMP的执行过程进行深入的检查。FDA官员要查看每个重点操作岗位上的原始记录并对现场生产的实际运行情况核对。

由于原料药的生产工艺范围极广，很难说FDA检查官主要检查哪一个步骤。对于合成药物，通常是把注意力集中在生产的起着活性作用的关键的中间体的第一次反应步骤上。对于非合成药物(如抗生素)则重点放在药物的分离和提取的第一步上。但FDA检查官通常从头到尾都要进行检查。特别是对生产开始的配料和后期的净化过程，干燥和包装等都很关注。2．2．2工艺验证

FDA重视对生产工艺的验证。在八十年代中期时FDA还没有对药物生产工艺的验证进行检查。直到1987年FDA才决定要对生产工艺的验证进行检查，并于1987年5月发布了一个有关原料药的生产工艺验证指南的文件：[工艺验证的总的原则指南](Guideline 0n General Principles 0f Process Validation)。

此后，FDA对工艺验证极为重视。

FDA认为，对一种已采用多年的生产工艺，企业应行一次回顾性的验证(Retrospective validation)。生产工艺即使通过一次验证，也不等于自动地永久性地验证合格。如工艺变动，还要重做验证。现在，制药企业都把工艺验证方案和当前三个连续批的验证结果作为一个独立的章节编入向FDA申报的DMF文件中以供审查。2．3厂房，设备和设施

FDA对生产车间的厂房，设备和设施的先进性不作评论，但重视厂房的清洁，通风和防虫措施(如所有窗户均有窗纱)。对洁净区(100，000或100，000加100级)则要求厂房密闭性良好。室内外保持内高外低的压差。对设备管理，其中尤其重视设备(如发酵罐，反应储罐，高压灭菌釜，各种物料及压缩空气，工艺用水，蒸汽等的运送管线等)上应有的醒目的编码号以保证操作工不会发生误操作。FDA官员非常重视设备上的生产运行状态标记牌和管线上的物料标记。

FDA官员进入生产车间，首先要检查的是配料间的设备和物料管理，其管理的原则要求是和仓库管理的要求一样的，这在我国许多原料药厂往往是个弱项。个别药厂(特别是合成药厂)，甚至没有配料间，配料就在反应器旁边进行，而且，往往比较凌乱，这是FDA所不能接受的。

其它检查的要点还有：发酵法生产的种子制备室(其中包括无菌室，摇瓶间等)，无菌室，杯碟法生物效价测定间，生产工艺控制间，属于手动控制的，重点检查仪表的校验和原始记录的准确性；属于半自动控制的，检查自控仪表的校验周期和记录；属于电脑系统全自动控制的，要对该系统的准确性的验证提供充分的说明。

2．4设备的清洗

FDA检查官对所有的生产关键设备，特别是反应器(如发酵罐，化学合成反应罐等)，容器(如中间体的转运容器，储罐，储槽等)，分离设备(如液体过滤器，气体过滤器，离心分离器，振动筛等)，结晶罐，干燥器和混合器等的清洗周期，清洗方法和清洗效果的验证都很关注。原则上是要防止不同批的残余物料和外来杂质对药物产品造成交叉污染或感染。

除了在现场一般地观察设备和容器的清洗情况外(一般无法在现场看到完整的清洗情况)FDA检查官重点是检查设备清洗的SOP，清洗验证方法的文件和清洗的记录，对于用同一套设备来进行周期性的交叉生产多种产品的生产设施，则要求更为严格。主要检查清洗规程是否制定得完善，还要询问这些清洗方法是否经过验证。

对于用水、洗涤剂或溶媒作为清洗剂清洗设备的效果，过去多是目测清洗液的澄清程度，或用TLC法测定洗液中残留物的含量。从而做出残留物是否洗净的结论。近年来，许多药厂 5 广泛采用HPLC仪器分析的手段来测定洗液的残留量。所以，现在不是有无残留物存在的问题，而是残留量的多少的问题。应根据具体情况，制定容许残留量的标准。2．5批成品的混合

制剂生产商通常要求原料药生产商的生产批量越大越好。他们认为，对两个500Kg 批量的产品进行制剂生产要比1000 Kg批量的产品的检验耗费更多的人力和物力。

通常，来自一个结晶周期的或其它提炼周期的批量的产品被认为具有良好的均一性。

批混合的数量取决于混合器的能力。如果FDA官员发现原料药生产商出厂产品的批量大于混合器的实际能力，则该药厂就不会被FDA所接受，得不到批准，进口就会被搁置。FDA禁止把不合格的产品与合格的产品进行混合以取得合格品。

拥有足够大的混合器的药厂还必须向FDA检查官显示它的混合工艺确能产生均匀的批量产品，必要时要出示混合器的均一性的验证记录。但要注意，由于多数情况下成品是在混合器里同时进行干燥的，混合时间不能太长，太长会造成药品的降解。2．6包装及贴签

FDA认为对原料药的包装和贴签的控制应与对制剂药的要求一样地严格。包装和贴签的操作人员应该训练有素并且可靠。如果，标签是由电脑控制的，则该控制系统应经过验证。虽然，原料药的贴签发生错误造成的危害与制剂药相比没有那么大的危害，但会损害原料药厂的声誉。因此对原料药成品包装容器进行最后的控制检查是十分必要的。2．7生产用水 2．7．1饮用水

用于抗生素原料药的发酵阶段或合成工艺的早期阶段不需要高化学纯度的条件下，采用从深井或地表的饮用水是可接受的。只要水质符合规定的标准。在美国，城市自来水必须符合联邦环保局的要求。可从自来水厂取得合格的饮用水。当然，原料药厂不可能去验证自来水厂。FDA希望药厂能提供定期检查水质是否符合质量标准的资料。我国的大多数药厂是使用城市自来水，一般都能从城市自来水厂取得定期的水质检验报告。FDA对水质的关注的重点是用水的微生物含量状况，特别是致病菌，如大肠杆菌的含量。2．7．2纯化水

纯化水也广泛用于原料药生产。FDA重视对纯化水系统的检查。由于脱离子器(装有离子交换树脂的离子交换柱)，超微过滤和反渗析系统都存在着细菌滋长的问题，对这些系统应进行验证和控制。控制的方法包括制定水质标准，当含菌量超标时采取的措施，完善的维修规程(如离子交换树脂的再生和灭菌)，对用水的化学物和细菌含量制定标准并定期进行检查。如果，水是用在工艺过程的较后的阶段，如最后清洗滤饼，或原料药是从水溶液中结晶析出，则对水质的要求要比对一般的纯化水为高。这对于将要作为注射剂的原料药厂来说是特别重要的。

FDA还认为大多数的纯化水及注射用水系统，包括反渗析和超微过滤系统都存在着产生内毒素的可能。如果要求原料药成品无热源或无菌，或是要用于制备注射剂产品，则应对工艺用水定期检验其内毒素的含量。只做终点检验是不够的。原料药厂还应对注射用水处理系统以控制内毒素的滋生。

FDA对用于生产兽用药，非无菌口服制剂，局部外用药如油膏剂，乳剂等制剂的原料药，对用水质量的仍要进行严格的检查。2．8质量控制实验室(QC Laboratory)2．8．1检查的重点中之重点一质量控制试验室 FDA检查官在为时4—5天的检查中，其中之一的药物审查化学家至少有3／5的时间用于对QC实验室的检查。

FDA对QC实验室的清洁程度，化学分析室，微生物分析室，种子室(包括无菌室的无菌状 6 况)，仪器分析室，稳定性试验和留样室等都很重视。2．8．2仪器配备和检验方法

从FDA立场看，在原料药厂中没有比质量控制试验室的管理更重要的了。事实上，在有些方面，它们对于原料药厂比对制剂厂更为重要。制剂厂一般的典型作法是只对进厂的批量的原料药按药典的规定标准进行检验。在多数情况下，不足以充分检查出可能存在的污染物。这些污染物因不同的药厂及采用不同的生产工艺而不同。所谓污染物包括合成过程中未经化学反应的起始物料，中间体，立体异构体，残留溶媒，交叉污染物，微生物污染物及从工艺设备上带下来的碎屑，通常看上去是黑色的斑点。原料药厂的试验室最了解污染物的种类和存在状况，并保证这些污染物不会超过规定含量而送入生产制剂的制药厂。如果送人了制药厂，就说明这些污染物未被发现。

FDA检察官对原料药厂生产进行视察的一个基本项目是弄清该药厂的试验室是否拥有该厂的DMF或USP对该产品所要求的足够的仪器设备。近年来，FDA对中国原料药药厂的检查，每次是派两名官员，其中一人是FDA有关部门的化学家(有时是美籍华人)，他的任务是对药厂的仪器使用方法及检验方法做出评价。对USP的实验方法，只要药厂是遵照USP的规程进行检验，FDA不要求药厂对分析方法进行验证。

但在这种情况下，药厂还是要做USP规定的有关验证，例如，在采用HPLC法时要进行HPLC设备适用性的验证。总的说来，因为原料药是单一的纯物质，对分析方法的验证并不具有制剂药所具有的同样的问题。制剂药常在药物活性物质之外含有几种不同的物质。有些物质会干扰分析的方法。不同的制剂药厂有不同的添加物质。因此同一种药物的USP分析方法或申请书上所采用的分析方法不能适用于所有的制剂药。通常原料药产品就没有这个问题。

2．8．3工艺过程的分析控制

我国的原料药厂的工艺过程分析一般是在生产该产品的车间里的试验室里进行的。有些药厂的工艺过程控制中要用HPLC设备进行分析的项目则是由车间取样送交质控试验室分析的。FDA认为，工艺过程分析可以在生产车间进行，也可以在质控实验室进行。但FDA要求这些分析应由称职的人员和采用完整的分析仪器来进行，并有完整的分析结果的记录．

在有些药物产品的生产工艺里，可能被带入成品的不纯物是在工艺过程中取样而不是从成品取样进行检查的。在这种情况下，较为恰当的办法是由质控试验室来做分析试验。对于一个一批又一批地接续生产同一个中间体，然后又生产另一个中间体的药厂，则较为恰当的做法仍是由车间控制试验室在放行到下一步工艺之前进行检验。FDA强调，不论由何单位进行检验。QC部门都应对工艺过程的每一个重要的步骤的物料的批准合格或不合格负责。2．8．4化学药品和试剂，试液的配制

FDA检查官注重检查化学品的使用的管理(有效期，开始使用日期等)；成品和原材料的样品的登记和管理；配制试液的标签(注明试液名称，配制日期，配制人签字等)；配制标准操作规程及原始记录等。还有微生物试验的培养基配置，灭菌记录等。2．8．5稳定性试验和留样制度

FDA要求原料药，特别是抗生素原料药必须规定有效期(或复验期)，并应编制有书面的稳定性试验方案和试验记录。现在，我国大多数原料药厂都为原料药产品制定了稳定性试验的制度并付诸实施。

FDA官员要查看加速稳定性试验和长期稳定性试验，作稳定性试验的样品的包装和储存的方式(它应模拟市场方式)，稳定性试验的温度和湿度的条件，测定的方法和原始记录。

我国原料药厂一般都在QC实验室里设有留样间。有的药厂是把长期稳定性试验的样品也放在留样间里。FDA检查官要检查留样的方式和记录。2．9设备和仪器的校验

FDA对药厂的设备和仪器的校验非常重视。

FDA认为如果一个原料药厂对工艺设备仪器和试验室设备仪器不进行校验，则说明该药厂对它的操作失控，因此是不符合要求的。何况，没有一套正规的校验控制系统，该药厂就不能对它的生产工艺做出符合要求的验证。凡是用于工艺验证的仪器本身就应该是经过校验和验证的。结果是该药厂对该原料药的申请有得不到批准的危险。

药厂需要定期进行校验的常用的测量仪表有温度计(包括自动记录温度计)，温湿度计，压力计(包括自动记录压力计)，液体流速计，空气流量计，液位计等；计量设备和器具如 地磅，磅称，粗天平，普通天平，分析天平以及高精密度天平等；工艺过程控制和质控试验室用的pH计，滴定管，移液管等；仪器分析用的UV，IR，HPLC和GC等设备。FDA检察官首先注意的是仪器设备上是否贴有校验合格的标志，查看有关设备仪器校验的SOP和使用与校验的原始记录。通常，我国的原料药厂的度量衡仪器都是由药厂专设的仪器计量室(大多是从属设备管理部门)负责定期校验并签发校验合格证。技术性高的仪器设备如UV，IR，HPLC和GC等设备则一般是委托地方政府的计量管理部门进行校验。凡是发现重要的仪器设备没有进行校验，或提供不出完整的文件记录说明，FDA检察官都认为是严重的问题。2．10电脑控制系统的验证

在发达国家的原料药厂里对生产的启动，监测，调节等生产工艺步骤都已普遍采用电脑控制系统来实现自动化操作。我国也有少数原料药厂采用了这种先进的手段。因此，电脑系统的工作准确性即可靠性是非常重要的。要保证不发生未经认可的或疏忽大意造成的变化，并能提供充分的工艺信息，FDA要求对电脑系统应进行验证以保证其运行的准确性及可靠性。

对电脑系统的硬件和软件都要进行以下五个方面的考虑：

ix．确定电脑系统要执行的任务，并将此任务配置人电脑系统。

x．鉴定电脑系统的操作限定值，并使其与标准操作法所规定的限定值一致。Xi．测试整个电脑系统。

Xii．做好文件记录，并建立起监测各种变化及重新验证的系统。

FDA认为电脑系统主要应由作为终端用户的药厂负责进行验证，并要保证它应用于原料药生产操作的适用性。但许多实际的测试工作和文件记录还是要由电脑系统供应商来做。电脑系统的验证记录数据应由终端用户提供。FDA检查官要检查这些记录数据。FDA为电脑控制系统的验证提供了以下一些文件指南： xiv．“药物生产采用电脑控制系统的检查指南”

(Guide t0 Inspection 0f Computerized System in Drag Processing)1983年2月公布。

XV．“符合性政策指南”中的7132a。07、08、ll、12及15章节(Compliance Policy Guide)1987年公布。Xvi．“软件发展活动的技术报告”

(Technical Report on Software Development Activities)1987年公布。3．会谈形式的检查

一般在进行约占总时间1／3的现场检查后(有时是会谈和现场检查交叉进行)FDA检查官与药厂的有关负责人员会谈。会谈检查的重点和需要提供的文件如下： 3．1批生产纪录

FDA检察官要随意抽查一个当前生产批的全套原始记录，并以该批记录作为判断药厂的GMP管理水平的重要依据。FDA要求原料药厂生产原料药制定有完整的工艺规程和操作规程。FDA检查官主要是通过批记录来了解药厂的工艺规程及操作规程的执行情况和对每一个生产步骤里的工艺参数和原料投人的控制情况进行追溯。

FDA十分重视在每一个步骤的记录上由操作者和监督人的签字的制度。认真检查原始记 8 录填写得是否清晰和正确。对任何不规范的数据的修改，一发现，就要作为问题记入483表。

3．2成品质量标准和检验方法

如果该申请产品原来就是采用USP当前版的标准和方法来进行检验，一般提供数批产品检验报告单(COA)和根据USP制定的质量检验的SOP文件给FDA检查官进行检查。如果原来是采用其它的药典标准如中国药典(CP)，英国药典(BP)或欧洲药典(EP)，则要提供有关检验方法和USP的对比验证资料和数据。由于我国的原料药厂的产品大量出口到世界各地，其质量标准大都是根据客户的要求而定，在许多情况下，并不是采用USP的标准和方法，或者是只采用USP的部分标准，或相同的标准但检验方法不同。FDA的原则是：希望申请方最好采用USP标准和方法，这有便于美方进行质量控制，FDA不规定一定要采用USP标准和方法。但要求提供充分的对比验证资料来说明其它的标准和方法能满足USP对产品质量的要求。

为了避免不必要的麻烦，我国药厂对申请出口美国的产品尽量采用USP当前版的标准和方法。

3．3验证文件

FDA要了解药厂的有关验证文件如下：

*工艺验证一工艺验证的方案和验证记录数据

*设备清洗的验证一重点设备(如发酵罐或反应器)的清洗验证方案和验证记录数据。*消毒(灭菌)的验证一重点是发酵罐或反应器，高压灭菌釜，无菌室，无菌区等的 消毒验证方案和验证记录数据。

*电脑制动控制系统的验证方案和验证记录数据。

*其它方面，如质控试验室的重点仪器分析设备(HPLC，GC，UV，IR等)的适合性试验，纯水制备系统的验证，发酵生产的空气过滤(超微)过滤器和无菌区的空调系统的空气过滤器的除菌效果验证，成品干燥混合器的混合均匀度的验证。3．4标准操作规程(SOP)FDA认为符合GMP要求的药厂应该制定有完整的SOP(以及SMP)文件。FDA可能只是重点检查几份与问题有关的文件，但药厂主动出示全套SOP及SMP的文件的目录清单(英文译文或中英对照)供FDA检查官审阅也有助于对药厂的管理水平的了解。

凡是在会谈中与上述的FDA检查所涉及的事项有关的SOP，一般FDA都要求我方提供SOP文件当场检查。某些重要的SOP如药厂职工的技术培训和GMP培训，药厂的对用户的投诉的处理，对不合格品的重加工的规程，药厂的自查制度等一般都已编人DMF(大多数是SOP的形式，英文译文或中英文对照)可供FDA检查官随时查阅。在检查中涉及的某些行政管理上的问题，还要提供有关的标准管理规程(SMP)文件。

五、总结会一发给483表

在全部检查结束后，FDA检查官用半天时间单方面对检查中发现的问题进行汇总，分析和研究。根据检查结果填写“FDA483表”，该表是FDA印制的表格式的文件。

从理论上说，如果一个问题都没有发现，FDA就不必发给此表，并预示着下一步的正式批准没问题了。这种情况是罕见的，只有极个别的制剂药厂在两年一度的复查时有过。通常FDA会提出不少的问题(作者所接触过的场合一般是10—20条问题)。问题提得越多，固然意味着药厂的缺点较多，获得批准的难度加大。但FDA主要看问题的大小和性质，一般说来，不能有严重的大问题，“致命性的问题”(Lethal problem)或“不可接受的问题”(unacceptable problem)。即使只有一个重大的问题也可能会导致通不过。

“FDA检查无小事”(这是作者的体会)。大的问题固然是大事，例如，没有做过工艺验证，没有制定SOP或消毒灭菌不彻底造成交叉感染，特别是某些文件被FDA发现弄虚作假，与实 9 际对不上号等等。但有些看起来似小事，却成为严重的问题，如对原始记录的不规范的改动(涂改)，没按照规定放置清洁工具，在配料间原料包装袋上的合格证脱落等。某药厂在向FDA检查官出示的工艺规程文件里的几个参数发现被手写涂改，尽管药厂作了种种解释并承认错误，但FDA检查官认为这是不可接受的问题，从而导致检查未能通过的恶果。

FDA检查官写好483表后召集我方人员开会。先把483表中列出的观察结果和问题，逐条逐字读给我方人员听。然后进行讨论，我方可以就不能接受的提法提出解释(看法，解说或辩解)，如果FDA检查官认为解释有理，一般会对所提的问题进行修改或取消。在双方取得一致意见后，我方做出接受观察结果的表态。FDA检查官在该表上签字。立即复印该文件，一份交给药厂，另一份他们回国后送交FDA主管部门。

FDA要求药厂对提出的问题尽快(一般在两周内，至多不超过一个月，根据情况而定)做出书面答复，其中要求提供明确的较详细的改进措施和解决问题的期限，及早报送FDA地区办公室。FDA检查官在回国后根据药厂的改进报告写出一份非常详细的检查报告送交FDA有关主管部门(如新药评价中心，兽用药评价中心等)。

六、最后的决定——批准(或不批准)的通知函

按FDA的规定，FDA检查官无权对是否批准做出决定。FDA检查官在给主管的报告中非常客观地说明一切情况和存在问题，药厂的态度和改正的措施，对该药厂是否可以得到批准会提出个人的建议。它对主管做出批准或不批准的决定是具有关键性的影响的。

在检查结束后FDA检查官不会向药厂表示生产设施是否合乎FDA要求和取得最后批准的可能性。只有极个别的例子，一位资深的年过古稀的FDA检查官在结束检查时，主动伸出手来与药厂主管握手并说该药厂是一个令人满意的药厂。表示祝贺。但那是20年前的事情(我国第二个申请得到批准的药厂)。近年来，FDA检查官至多是在药厂的美方代理人私下要求下，间接透露483表中没有不可接受的问题。提交报告后的3—6个月，FDA有关主管部门做出最后批准(或不批准)的决定，并给出书面通知函。

FDA要求得到批准的药厂在批准后每年一次向FDA提出报告，说明DMF中的任何可能发生的变动(如重要设备和厂房，原材料，工艺路线，工艺参数等的变动)，如果没有变动也要向FDA报告无变动。

一般在接到批准通知函后，得到批准的原料药产品就可以出口到美国，美国海关给予放行。

FDA规定，凡是第一次检查没有得到批准的药厂，要两年后才能再次提出申请检查。FDA规定，得到批准的药厂每两年要接受一次复查，复查的程序和初查是一样的。如果复查没有通过就要取消资格，又要等两年后才能申请检查。

第三篇：美国FDA关于制剂药厂cGMP的检查指南-93-10

Dosage Form Drug Manufacturers cGMPs(10/93)GUIDE TO INSPECTIONS OF DOSAGE FORM DRUG MANUFACTURER'S-CGMPR'S

Note: This document is reference material for investigators and other FDA personnel.The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I.INTRODUCTION

This document is intended to be a general guide to inspections of drug manufacturers to determine their compliance with the drug CGMPR's.This guide should be used with instructions in the IOM, other drug inspection guides, and compliance programs.A list of the inspection guides is referenced in Chapter 10 of the IOM.Some of these guides are:

o Guide to Inspections of Bulk Pharmaceutical Chemicals.o Guide to Inspections of High Purity Water Systems.o Guide to Inspections of Pharmaceutical Quality Control Laboratories.o Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.o Guide to Inspections of Lyophilization of Parenterals.o Guide to Inspections of Validation of Cleaning Processes.o Guide to Inspections of Computerized Systems in Drug Processing.o Guideline on General Principles of Process Validation.II.CURRENT GOOD

MANUFACTURING PRACTICE

REGULATIONS

Prescription vs.Non-prescription

All drugs must be manufactured in accordance with the current good manufacturing practice regulations otherwise they are considered to be adulterated within the meaning of the FD&C Act, Section 501(a)(2)(B).Records relating to prescription drugs must be readily available for review in accordance with Sec.704(a)(1)(B)of the FD&C Act.If the product is an OTC drug which is covered by an NDA or ANDA, FDA may review, copy and verify the records under Sec.505(k)(2)of the FD&C Act.However, if the product is an OTC drug for which there is no application filed with FDA, the firm is not legally required to show these records to the investigator during an inspection being conducted under Section 704 of the FD&C Act.Nonetheless, all manufacturers of prescription and OTC drugs must comply with the drug CGMPR requirements, including those involving records.The investigator should review these records as part of the inspection in determining the firm's compliance with the CGMP regulations.On rare occasions, a firm may refuse to allow review of OTC records stating they are not legally required to.While the firm may be under no legal obligation to permit review of such records, this does not relieve the firm of its statutory requirement to comply with the good manufacturing practices under section 501(a)(2)(B)of the Food Drug and Cosmetic Act, including the requirements for maintaining records.If a firm refuses review of OTC records, the investigator should determine by other inspectional means the extent of the firm's compliance with CGMPR's.Inspectional observations and findings that CGMPR's are not being followed are to be cited on a List of Inspectional Observations, FDA-483, for both prescription and non-prescription drugs.Organization and Personnel [21 CFR 211 Subpart B]

The firm must have a quality control department that has the responsibility and authority as described in the referenced CFR.The quality control department must maintain its independence from the production department, and its responsibilities must be in writing.Obtain the name, title and individual responsibilities of corporate officers and other key employees as indicated in the IOM.In the drug industry, an employee's education and training for their position has a significant impact on the production of a quality product.Report whether the firm has a formalized training program, and describe the type of training received.The training received by an employee should be documented.Quality control must do product annual review on each drug manufactured, and have written annual review procedures.Review these reports in detail.This report will quickly let you know if the manufacturing process is under control.The report should provide a summary all lots that failed in-process or finished product testing, and other critical factors.Investigate any failures.Quality control must validate the manufacturing process for each drug manufactured.Review and evaluate this data.Buildings and Facilities [21 CFR 211 Subpart C]

Review the construction, size, and location of plant in relation to surroundings.There must be adequate lighting, ventilation, screening, and proper physical barriers for all operations including dust, temperature, humidity, and bacteriological controls.There must be adequate blueprints which describe the high purity water, HEPA, and compressed air systems.The site must have adequate locker, toilet, and hand washing facilities.The firm must provide adequate space for the placement of equipment and materials to prevent mix-ups in the following operations:

o receiving, sampling, and storage of raw materials;

o manufacturing or processing;

o packaging and labeling;

o storage for containers, packaging materials, labeling, and finished products;

o production and control laboratories.Equipment [21 CFR 211 Subpart D]

Review the design, capacity, construction, and location of equipment used in the manufacturing, processing, packaging, labeling, and laboratories.Describe the manufacturing equipment including brief descriptions of operating principles.Consider the use of photographs, flow charts, and diagrams to supplement written descriptions.New equipment must be properly installed, and operate as designed.Determine if the equipment change would require FDA pre-approval and/or revalidation of the manufacturing process.The equipment must be cleaned before use according to written procedures.The cleaning must be documented and validated.The equipment should not adversely effect the identity, strength, quality, or purity of the drug.The material used to manufacture the equipment must not react with the drug.Also, lubricants or coolants must not contaminate the drug.The equipment should be constructed and located to ease cleaning, adjustments, and maintenance.Also, it should prevent contamination from other or previous manufacturing operations.Equipment must be identified as to its cleaning status and content.The cleaning and maintenance of the equipment are usually documented in a log book maintained in the immediate area.Determine if the equipment is of suitable capacity and accuracy for use in measuring, weighing, or mixing operations.If the equipment requires calibration, they must have a written procedure for calibrating the equipment and document the calibration.Components and Product Containers [21 CFR 211 Subpart E]

Inspect the warehouse and determine how components, drug product containers, and closures are received, identified, stored, handled, sampled, tested, and approved or rejected.They must have written procedures which describe how these operations are done.Challenge the system to decide if it is functioning correctly.If the handling and storage of components are computer controlled, the program must be validated.The receiving records must provide traceability to the component manufacturer and supplier.The receiving records for components should contain the name of the component, manufacturer, supplier if different from the manufacturer, and carrier.In addition, it should include the receiving date, manufacturer's lot number, quantity received, and control number assigned by the firm.Check sanitary conditions in the storage area, stock rotation practices, retest dates, and special storage conditions(protection from light, moisture, temperature, air, etc.).Inspect glandular and botanical components for insect infestation.Components or finished product adulterated by rodents, insects, or chemicals must be documented and submitted for seizure.Collect the evidence even if the firm plans to voluntarily destroy the product.Be alert for components, colors, and food additives that may be new drug substances, appear to have no use in the plant or appear to be from an unknown supplier.Check the colors against the Color Additives Status List in the IOM Determine if the color is approved for its intended use, and required statements are declared on the drug label.Components might be received at more than one location.Components must be handled in accordance with the drug CGMP's including components used in the research and development lab.Determine how components are identified after receipt and quarantined until released.Components must be identified so the status(quarantine, approved, or rejected)is known.Review the criteria for removing components from quarantine and challenge the system.Determine what records are maintained in the storage area to document the movement of components to other areas, and how rejected components handled.The component container has an identification code affixed to it.This unique code provides traceability from the component manufacturer to its use in the finished product.Review the sampling and testing procedures for components, and the process by which approved materials are released for use.Decide if these practices are adequate and followed.Determine the validity, and accuracy of the firm's inventory system for drug components, containers, closures and labeling.Challenge the component inventory records by weighing a lot and comparing the results against the quantity remaining on the inventory record.Significant discrepancies in these records should be investigated.Evaluate the following to determine whether the firm has shown that the containers and closures are compatible with the product, will provide adequate protection for the drug against deterioration or contamination, are not additive or absorptive, and are suitable for use:

o Specifications for containers, closures, cotton filler, and desiccant, etc.o What tests or checks are made(cracks, glass particles, durability of material, metal particles in ointment tubes, compliance with compendium specifications, etc.).o Cleaning procedures and how containers are stored.o Handling of preprinted containers.Are these controlled as labeling, or as containers? The firm must review the labeling for accuracy.Production and Process Controls [21 CFR Subpart F]

1.Critical Manufacturing Steps [21 CFR 211.101]

Each critical step in the manufacturing process shall be done by a responsible individual and checked by a second responsible individual.If such steps in the processing are controlled by automatic mechanical or electronic equipment, its performance should be verified.Critical manufacturing steps include the selection, weighing, measuring and identifying of components, and addition of components during processing.It includes the recording of deviations from the batch record, mixing time and testing of in-process material, and the determination of actual yield and percent of theoretical yield.These manufacturing steps are documented when done, and not before or after the fact.2.Equipment Identification [21 CFR 211.105]

All containers and equipment used in to manufacture a drug should be labeled at all times.The label should identify the contents of the container or equipment including the batch number, and stage of processing.Previous identification labels should be removed.The batch should be handled and stored to prevent mixups or contamination.3.In-Line and Bulk Testing [21 CFR 211.110]

To ensure the uniformity and integrity of products, there shall be adequate in-process controls, such as checking the weights and disintegration time of tablets, the fill of liquids, the adequacy of mixing, the homogeneity of suspensions, and the clarity of solutions.Determine if in-process test equipment is on site and the specified tests are done.Be alert for prerecording of test results such as tablet weight determinations.The bulk drug is usually held in quarantine until all tests are completed before it is released to the packaging and labeling department.However, the testing might be done after packaging.product.4.Actual Yield [21 CFR 211.103]

Determine if personnel check the actual against the theoretical yield of each batch of drug manufactured.In the event of any significant unexplained discrepancies, determine if there is a procedure to prevent distribution of the batch in question, and related batches.5.Personnel Habits

Observe the work habits of plant personnel.Determine:

Their attitudes and actions involving the jobs they perform.(Careless, lackadaisical, disgruntled, etc.).Their dress.(Clean dresses, coats, shirts and pants, head coverings, etc.If proper equipment is used for a given job or whether short cuts are taken(i.e.use of hands and arms to mix or empty trays of drug components).If there are significant written or verbal language barriers that could affect their job performance.Tablet and Capsule Products

Become familiar with the type of equipment and its location in the tableting operation.The equipment may include rotary tableting machines, coating and polishing pans, punches and dies, etc.The equipment should be constructed and located to facilitate maintenance and cleaning at the end of each batch or at suitable intervals in the case of a continuous batch operation.If possible, observe the cleaning and determine if the cleaning procedure is followed.The ingredients in a tablet are the active ingredient, binders, disintegrators, bases, and lubricants.The binder is added to the batch to keep the tablet together.Excess binder will make the tablet too hard for use.The disintegrator is used to help disintegration of the tablet after administration.The base should be an inert substance which is compatible with the active ingredient and is added to provide size and weight.The lubricant helps in the flow of granulated material, prevents adhesion of the tablet material to the surface of punches and dies, and helps in tablet ejection from the machine.Tablets and capsules are susceptible to airborne contamination because of the manipulation of large quantities of dry ingredients.To prevent cross-contamination in the tableting department, pay close attention to the maintenance, cleaning, and location of equipment, and the storage of granulations and tablets.To prevent cross-contamination, the mixing, granulation, drying and/or tableting operation should be segregated in enclosed areas with its own air handling system.Determine what precautions are taken to prevent cross-contamination.When cross-contamination is suspect, investigate the problem and collect in-line samples(INV)and official samples of the suspect product.Determine what temperature, humidity, and dust collecting controls are used by the firm in manufacturing operations.Lack of temperature and humidity controls can affect the quality of the tablet.Observe the actual operation of the equipment and determine whether powders or granulations are processed according to the firm's specifications.The mixing process must be validated.The drying ovens should have their own air handling system which will prevent cross-contamination.Does the firm record drying time/temperature and maintain recording charts including loss on drying test results? Review the in-line tests performed by production and/or quality control.Some in-process tests are tablet weight, thickness, hardness, disintegration , and friability.Evaluate the disposition of in-process samples.Capsules may be either hard, or soft type.They are filled with powder, beads, or liquid by machine.The manufacturing operation of powders for capsules should follow the same practice as for tablets.Determine manufacturing controls used, in-line testing, and basis for evaluating test results for the filling operations.Sterile Products

Typically, a sterile drug contains no viable microorganisms and is non-pyrogenic.Drugs for intravenous injection, irrigation, and as ophthalmic preparations, etc., meet this criteria.In addition, other dosage forms might be labeled as sterile.For instance, an ointment applied to a puncture wound or skin abrasion.Parenteral drugs must be non-pyrogenic, because the presence of pyrogens can cause a febrile reaction in human beings.Pyrogens are the products of the growth of microorganisms.Therefore, any condition that permits bacterial growth should be avoided in the manufacturing process.Pyrogens may develop in water located in stills, storage tanks, dead legs, and piping, or from surface contamination of containers, closures, or other equipment.Parenterals may also contain chemical contaminants that will produce a pyretic response in humans or animals although there are no pyrogens present.There are many excellent reference materials which should be reviewed before the inspection.Some of these are the “Guideline on Sterile Drug Products Produced by Aseptic Processing,” and chapter 84 on pyrogens in the Remington's Pharmaceutical Sciences.Determine and evaluate the procedures used to minimize the hazard of contamination with microorganisms and particulates of sterile drugs.o Personnel

Review the training program to ensure that personnel performing production and control procedures have experience and training commensurate with their intended duties.It is important that personnel be trained in aseptic procedures.The employees must be properly gowned and use good aseptic techniques.o Buildings

The non-sterile preparation areas for sterile drugs should be controlled.Refer to Subpart C of the proposed CGMPR's for LVP's;however, deviations from these proposed regulations are not necessarily deviations from the CGMPR's.Evaluate the air cleanliness classification of the area.For guidance in this area, review Federal Standard #209E entitled “Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones.” Observe the formulation practices or procedures used in the preparation areas.Be alert for routes of contamination.Determine how the firm minimizes traffic and unnecessary activity in the preparation area.Determine if filling rooms and other aseptic areas are constructed to eliminate possible areas for microbiological/particulate contamination.For instance, dust-collecting ledges, porous surfaces, etc.Determine how aseptic areas are cleaned and maintained.1.Air

Air supplied to the non-sterile preparation or formulation area for manufacturing solutions prior to sterilization should be filtered as necessary to control particulates.Air being supplied to product exposure areas where sterile drugs are processed and handled should be high efficiency particulate air(HEPA)filtered under positive pressure.Review the firm's system for HEPA filters, determine if they are certified and/or Dioctyl Phthalate(DOP)tested and frequency of testing.Review the compressed air system and determine if it is filtered at the point of use to control particulates.Diagrams of the HEPA filtered and compressed air systems should be reviewed and evaluated.2.Environmental Controls

Specifications for viable and non-viable particulates must be established.Specifications for viable particulates must include provisions for both air and surface sampling of aseptic processing areas and equipment.Review the firm's environmental control program, specifications, and test data.Determine if the firm follows its procedure for reviewing out-of-limit test results.Also, determine if review of environmental test data is included as a part of the firm's release procedures.Note: In the preparation of media for environmental air and surface sampling, suitable inactivating agents should be added.For example, the addition of penicillinase to media used for monitoring sterile penicillin operations and cephalosporin products.o Equipment

Determine how the equipment operates including the cleaning and maintenance practices.Determine how equipment used in the filling room is sterilized, and if the sterilization cycle has been validated.Determine the practice of re-sterilizing equipment if sterility has been compromised.Determine the type of filters used.Determine the purpose of the filters, how they are assembled, cleaned, and inspected for damage.Determine if a microbial retentive filter, and integrity testing is required.o Water for Injection

Water used in the production of sterile drugs must be controlled to assure that it meets U.S.P.specifications.Review the firm's water for injection production, storage, and delivery system.Determine that the stills, filters, storage tanks, and pipes are installed and operated in a manner that will not contaminate the water.Evaluate the firm's procedures and specifications that assure the quality of the water for injection.As reference material, review the “FDA Guide to Inspecteons of High Purity Water Systems” before initiating an inspection.o Containers and Closures

Determine how containers and closures are handled and stored.Decide if the cleaning, sterilization, and depyrogenization are adequate, and have been validated.o Sterilization

1.Methods

Determine what method of sterilization is used.A good source of reference material on validation of various sterilization processes is the Parenteral Drug Association Technical Reports.For instance, Technical Report #1 covers “Validation of Steam Sterilization Cycles.” Review and evaluate the validation data whatever the method employed.If steam under pressure is used, an essential control is a mercury thermometer and a recording thermometer installed in the exhaust line.The time required to heat the center of the largest container to the desired temperature must be known.Steam must expel all air from the sterilizer chamber to eliminate cold spots.The drain lines should be connected to the sewer by means of an air break to prevent back siphoning.The use of paper layers or liners and other practices which might block the flow of steam should be avoided.Charts of time, temperature, and pressure should be filed for each sterilizer load.If sterile filtration is used, determine the firm's criteria for selecting the filter and the frequency of changing.Review the filter validation data.Determine if the firm knows the bioburden of the drug, and examine their procedures for filter integrity testing.Filters might not be changed after each batch is sterilized.Determine if there is data to justify the integrity of the filters for the time used and that “grow through” has not occurred.If ethylene oxide sterilization is used, determine what tests are made for residues and degradation.Review the ETO sterilization cycle including preconditioning of the product, ETO concentration, gas exposure time, chamber and product temperature, and chamber humidity.2.Indicators

Determine the type of indicator used to assure sterility.Such as, lag thermometers, peak controls, Steam Klox, test cultures, biological indicators, etc.Caution: When spore test strips are used to test the effectiveness of ethylene oxide sterilization, be aware that refrigeration may cause condensation on removal to room temperature.Moisture on the strips converts the spore to the more susceptible vegetative forms of the organism which may affect the reliability of the sterilization test.The spore strips should not be stored where they could be exposed to low levels of ethylene oxide.If biological indicators are used, review the current U.S.P.on sterilization and biological indicators.In some cases, testing biological indicators may become all or part of the sterility testing.Biological indicators are of two forms, each of which incorporates a viable culture of a single species of microorganism.In one form, the culture is added to representative units of the lot to be sterilized or to a simulated product that offers no less resistance to sterilization than the product to be sterilized.The second form is used when the first form is not practical as in the case of solids.In the second form, the culture is added to disks or strips of filter paper, or metal, glass, or plastic beads.During the inspection of a firm which relies on biological indicators, review background data complied by the firm to include:

o Surveys of the types and numbers of organisms in the product before sterilization.o Data on the resistance of the organism to the specific sterilization process.o Data used for selecting the most resistant organism and its form(spore or vegetative cell).o Studies of the stability and resistance of the selected organism to the specific sterilization process.o Studies on the recovery of the organism used to inoculate the product.o If a simulated product or surface similar to the solid product is used, validation of the simulation or similarity.The simulated product or similar surface must not affect the recovery of the numbers of indicator organisms applied.o Validation of the number of organisms used to inoculate the product, simulated product, or similar surface, to include stability of the inoculum during the sterilization process.Since qualified personnel are crucial to the selection and application of these indicators, review their qualifications including experience dealing with the process, expected contaminants, testing of resistance of organisms, and technique.Review the firm's instructions regarding use, control and testing, of the biological indicator by product including a description of the method used to demonstrate presence or absence of viable indicator in or on the product.Review the data used to support the use of the indicator each time it is used.Include the counts of the inoculum used;recovery data to control the method used to demonstrate the sterilization of the indicator organism;counts on unprocessed, inoculated material to

indicate the stability of the inoculum for the process time;and

results of sterility testing specifically designed to demonstrate the presence or absence of the indicator organism for each batch or filling operation.In using indicators, you must assure yourself that the organisms are handled so they don't contaminate the drug manufacturing area and product.3.Filled Containers

Evaluate how the filled vials or ampules leave the filling room.Is the capping or sealing done in the sterile fill area? If not, how is sterility maintained until capped?

Review the tests done on finished vials, ampules, or other containers, to assure proper fill and seal.For instance, leak and torque tests.Review examinations made for particulcte contamination.You can quickly check for suspected particulate matter by using a polariscope.Employees doing visual examinations on line must be properly trained.If particle counts are done by machine, this operation must be validated.4.Personnel Practices

Check how the employees sterilize and operate the equipment used in the filling area.Observe filling room personnel practices.Are the employees properly dressed in sterile gowns, masks, caps, and shoe coverings? Observe and evaluate the gowning procedures, and determine if good aseptic technique is maintained in the dressing and filling rooms.Check on the practices after lunch and other absences.Is fresh sterile garb supplied, or are soiled garments reused?

Determine if the dressing room is next to the filling area and how employees and supplies enter the sterile area.o Laboratory Controls

For guidance on how to inspect micro and chemistry labs, review the “FDA Guide to Inspections of Pharmaceutical Quality Control Laboratories” and “FDA Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.”

1.Retesting for Sterility See the USP for guidance on sterility testing.Sterility retesting is acceptable provided the cause of the initial non-sterility is known, and thereby invalidates the original results.It cannot be assumed that the initial sterility test failure is a false positive.This conclusion must be justified by sufficient documented investigation.Additionally, spotty or low level contamination may not be identified by repeated sampling and testing.Review sterility test failures and determine the incidence, procedures for handling, and final disposition of the batches involved.2.Retesting for Pyrogens

As with sterility, pyrogen retesting can be performed provided it is known that the test system was compromised.It cannot be assumed that the failure is a false positive without documented justification.Review any initial pyrogen test failures and determine the firm's justification for retesting.3.Particulate Matter Testing

Particulate matter consists of extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions.Cleanliness specifications or levels of non-viable particulate contamination must be established.Limits are usually based on the history of the process.The particulate matter test procedure and limits for LVP's in the U.S.P.can be used as a general guideline.However, the levels of particulate contamination in sterile powders are generally greater than in LVP's.LVP solutions are filtered during the filling operation.However, sterile powders, except powders lyophilized in vials, cannot include filtration as a part of the filling operation.Considerable particulate contamination is also present in sterile powders which are spray dried due to charring during the process.Review the particulate matter test procedure and release criteria.Review production and control records of any batches for which complaints of particulate matter have been received.o Production Records

Production records should be similar to those for other dosage forms.Critical steps, such as integrity testing of filters, should be signed and dated by a second responsible person.Review production records to ensure that directions for significant manufacturing steps are included and reflect a complete history of production.Ointments, Liquids, and Lotions

Major factors in the preparation of these drugs are the selection of raw materials, manufacturing practices, equipment, controls, and laboratory testing.Following the basic drug inspection fundamentals, fully evaluate the production procedures.In addition, evaluate specific information regarding:

o The selection and compatibility of ingredients.o Whether the drug is a homogeneous preparation free of extraneous matter.o The possibility of decomposition, separation, or crystallization of ingredients.o The adequacy of ultimate containers to hold and dispense contents.o Procedure for cleaning the containers before filling.o Maintenance of homogeneity during manufacturing and filling operations.The most common problem associated with the production of these dosage forms is microbiological contamination caused by faulty design and/or control of purified water systems.During inspections, evaluate the adequacy of the water system.Review and evaluate the micro/chemistry test results on the routine monitoring of the water system including validation of the water system.Review any microbiological tests done on the finished drug including in-process testing.Some of these drugs have preservatives added which protect them from microbial contamination.The preservatives are used primarily in multiple-dose containers to inhibit the growth of microorganisms introduced inadvertently during or after manufacturing.Evaluate the adequacy of preservative system.Preservative effectiveness testing for these products should be reviewed.For additional information, review the “Antimicrobial Preservatives-Effectiveness” section of the U.S.P..Equipment employed for manufacturing topical drugs is sometimes difficult to clean.This is especially true for those which contain insoluble active ingredients, such as the sulfa drugs.The firm's equipment cleaning procedures including cleaning validation data should be reviewed and evaluated.Packaging and Labeling [21 CFR Subpart G]

Packaging and labeling operations must be controlled so only those drugs which meet the specifications established in the master formula records are distributed.Review in detail the packaging and labeling operations to decide if the system will prevent drug and label mix-ups.Approximately 25% of all drug recalls originate in this area.Evaluate what controls or procedures the firm has to provide positive assurance that all labels are correct.Determine if packaging and labeling operations include:

o Adequate physical separation of labeling and packaging operations from manufacturing process.o Review of:

1.Label copy before delivery to the printer.2.Printer's copy.3.Whether firm's representative inspects the printer.4.Whether or not gang printing is prohibited.5.Whether labels are checked against the master label before released to stock.Determine who is responsible for label review prior to release of the labels to production.Also, whether the labels are identical to the labeling specified in the batch production records.o Separate storage of each label(including package inserts)to avoid mixups.o Inventory of label stocks.Determine if the printer's count is accepted or if labels are counted upon receipt.o Designation of one individual to be responsible for storage and issuance of all labels.o Receipt by the packaging and labeling department of a batch record, or other record, showing the quantity of labels needed for a batch.Determine if the batch record is retained by the packaging supervisor or accompanies the labels to the actual packaging and labeling line.o Adequate controls of the quantities of labeling issued, used, and returned.Determine if excess labels are accounted for and if excess labels bearing specific control codes, and obsolete or changed labels are destroyed.o Inspection of the facilities before labeling to ensure that all previously used labeling and drugs have been removed.o Assurance that batch identification is maintained during packaging.o Control procedures to follow if a significant unexplained discrepancy occurs between quantity of drug packaged and the quantity of labeling issued.o Segregated facilities for labeling one batch of the drug at a time.If this is not practiced, determine what steps are taken to prevent mix-ups.o Methods for checking similar type labels of different drugs or potencies to prevent mixing.o Quarantine of finished packaged products to permit adequate examination or testing of a representative sample to safeguard against errors.Also, to prevent distribution of any batch until all specified tests have been met.o An individual who makes the final decision that the drug should go to the warehouse, or the shipping department.o Utilization of any outside firms, such as contract packers, and what controls are exercised over such operations.Special attention should be devoted to firms using “rolls” of pressure sensitive labels.Investigators have found instances where:

o Paper chips cut from label backing to help running the labels through a coder interfered with the code printer causing digits in the lot number to be blocked out.o Some rolls contained spliced sections resulting in label changes in the roll.o Some labels shifted on the roll when the labels were printed resulting in omitting required information.The use of cut labels can cause a significant problem and should be evaluated in detail.Most firms are replacing their cut labels with roll labels.Review prescription drugs for which full disclosure information may be lacking.If such products are found, submit labels and other labeling as exhibits with the EIR See 21 CFR 201.56 for the recommended sequence in which full disclosure information should be presented.Review labels of OTC products for warnings required by 21 CFR 369.A control code must be used to identify the finished product with a lot, or control number that permits determination of the complete history of the manufacture and control of the batch.Determine:

o The complete key(breakdown)to the code.o Whether the batch number is the same as the control number on the finished package.If not, determine how the finished package control number relates, and how it is used to find the identity of the original batch.Beginning August 3, 1994 the following new requirements will become effective:

o Use of gang-printed labels will be prohibited unless they are adequately differentiated by size, shape or color.(211.122(f))o If cut labels are used one of the following special control procedures shall be used(211.122(g)):

(1)Dedication of packaging lines.(2)Use of electronic or electromechanical equipment to conduct a 100-percent examination of finished product.(3)Use of visual inspection to examine 100-percent of the finished product for hand applied labeling.The visual examination will be conducted by one person and independently verified by a second person.o Labeling reconciliation required by 211.125 is waived for cut or roll labeling if a 100-percent examination is performed according to 211.22(g)(2).Holding and Distribution [21 CFR subpart H]

Check the finished product storage and shipping areas for sanitary condition, stock rotation, and special storage conditions needed for specific drugs.Evaluate any drugs that have been rejected, or are on hold for other than routine reasons.Laboratory Controls [21 CFR Subpart I]

Laboratory controls should include adequate specifications and test procedures to assure that components, in-process and finished products conform to appropriate standards of identity, strength, quality, and purity.In order to permit proper evaluation of the firm's laboratory controls, determine:

o Whether the firm has established a master file of specifications for all raw materials used in drug manufacture.This master file should include sampling procedures, sample size, number of containers to be sampled, manner in which samples will be identified, tests to be performed, and retest dates for components subject to deterioration.o The firm's policies about protocols of assay.These reports are often furnished by raw material suppliers;however, the manufacturer is responsible for verifying the validity of the protocols by periodically performing their own complete testing and routinely conducting identity tests on all raw materials received.o Laboratory procedure for releasing raw materials, finished bulk drugs or packaged drugs from quarantine.Determine who is responsible for this decision.Raw material specifications should include approved suppliers.For NDA or ANDA drugs, the approved suppliers listed in their specifications should be the same as those approved in the NDA or ANDA.o If the laboratory is staffed and equipped to do all raw material, in-process, and finished product testing that is claimed.o Whether drug preparations are tested during processing.If so, determine what type of tests are made and whether a representative sample is obtained from various stages of processing.o Specifications and description of laboratory testing procedures for finished products.o Procedures for checking the identity and strength of all active ingredients including pyrogen and sterility testing, if applicable.o If the laboratory conducts pyrogen tests, safety tests, or bioassays;determine the number of laboratory animals and if they are adequately fed and housed.Determine what care is provided on weekends and holidays.o Sterility testing procedures.Entries should be permanently recorded and show all results, both positive and negative.Examine representative samples being tested and their records.When checking the sterility testing procedures, determine:

1.Physical conditions of testing room.The facility used to conduct sterility testing should be similar to those used for manufacturing products.2.Laboratory procedures for handling sterile sample.3.Use of ultra-violet lights.4.Number of units tested per batch.5.Procedure for identifying test media with specific batches.6.Test media's ability to support growth of organisms.7.Length of incubation period.8.Procedure for diluting products to offset the effects of bacteriostatic agents.o Pyrogen testing procedures

Determine if animals involved in positive pyrogen tests are withdrawn from use for the required period.If the L.A.L.Test is used, review the FDA “Guideline on Validation of the Limulus Amebocyte Lysate Test ***.”

o If any tests are made by outside laboratories, report the names of the laboratories and the tests they perform.Determine what precautions the firm takes to insure that the laboratories' work is bona fide.o Methods used to check the reliability, accuracy, and precision of laboratory test procedures and instrumentation.o How final acceptance or rejection of raw materials, intermediates, and finished products is determined.Review recent rejections and disposition of affected items.o The provisions for complete records of all data concerning laboratory tests performed, including dates and endorsements of individuals performing the tests, and traceability.o For components and finished product, the reserve sample program and procedures should be evaluated.Challenge the system and determine if the samples are maintained and can be retrieved.The storage container must maintain the integrity of the product.o Whether stability tests are performed on:

1.The drug product in the container and closure system in which marketed.2.Solutions prepared as directed in the labeling at the time of dispensing.Determine if expiration dates, based on appropriate stability studies, are placed on labels.o If penicillin and non-penicillin products are manufactured on the same premises, whether non-penicillin products are tested for penicillin contamination.Obtain copies of laboratory records, batch records, and any other documents that show errors or other deficiencies.Control Records [21 CFR Subpart J]

1.Master Production and Control Records [21 CFR 211.186]

The various master production and control records are important because all phases of production and control are governed by them.Master records, if erroneous, may adversely affect the product.These records must be prepared according to the drug CGMPR's outlined in 21 CFR 211.186.These records might not be in one location, but should be readily available for review.2.Batch Production and Control Records [21 CFR 211.188]

The batch production and control records must document each significant step in the manufacture, labeling, packaging, and control of specific batches of drugs.21 CFR 211.188 provides the basic information the batch records must provide.A complete production and control record may consist of several separate records which should be readily available to the investigator.Routinely check the batch record calculations against the master formula record.Give special attention to those products on which there have been complaints.Be alert for transcription errors from the master formula record to the batch record.Be alert for transcription or photocopying errors involving misinterpretation of symbols, abbreviations, and decimal points, etc.It is important that batch production records be specific in terms of equipment(v-blender vs.ribbon blender)and processing times(mixing time and speed).The equipment should have its own unique identification number.The manufacturing process for these products must be standardized, controlled, and validated.3.Distribution [21 CFR 211.196]

Complete distribution records should be maintained per 21 CFR 211.196.Be alert for suspicious shipments of products subject to abuse or which have been targeted for high priority investigation by the agency.These include steroids, counterfeits, diverted drugs(i.e.;physician samples, clinical packs, etc.).Determine and evaluate if the firm checks on the authenticity of orders received.What references are used, e.g.current editions of the AMA Directory, Hays Directory, etc.4.Complaint Files [21 CFR 211.198] CFR 211.198 requires that records of all written and oral complaints be maintained.Although FDA has no authority to require a drug firm, except for prescription drugs, to open its complaint files, attempt to review the firm's files.The complaint files should be readily available for review.Do a follow-up investigation on all applicable consumer complaints in the firm's district factory jacket.Review and evaluate the firm's procedures for handling complaints.Determine if all complaints are handled as complaints and not inappropriately excluded.Review the complaints and determine if they were fully investigated.Evaluate the firm's conclusions of the investigation, and determine if appropriate corrective action was taken.Determine if the product should be recalled, or warrant a comprehensive investigation by FDA

Returned Drug Products [21 CFR Subpart K]

Returned drugs often serve as an indication that products may have decomposed during storage, are being recalled or discontinued.Determine how returned drug items are handled.For example, are they quarantined, destroyed after credit, or returned to storage?

If an abnormally large amount of a specific drug item is on hand, determine why.Check if returned drug items are examined in the laboratory, and who makes the ultimate decision as to the use of the returned drugs.Note: Dumping salvage drugs in the trash is a potentially dangerous practice.Advise management to properly dispose of the drugs to preclude salvage.Drugs should be disposed of in accordance with E.P.A.regulations.

第四篇：FDA工厂检查心得

FDA工厂检查心得

FDA工厂检查是美国FDA对医疗器械生产现场的调查。检查对象是所有在美国境内销售医疗器械的制造商，包括美国内和国外的制造商。由美国FDA派出检查官员到医疗器械实际生产场所，执行对工厂检查，以确定被检查的工厂是否符合QSR法规的要求。

在这里对FDA的工厂检查谈一点感受。

一、企业必须按FDA QSR的要求编制质量手册和相关的程序文件及第三层次文件，要充分了解和理解法规, 制定既符合要求又实用的体系文件。最最重要的是要切实地执行这些文件，整理相关的历史记录和资料，工作必须严谨，不得浮于表面。做一项工作，首先要问自己为什么做？怎么做？谁来做？什么时间做（包括完成的时间）？

二、FDA检查重点：评审文件；按QSIT方法——基于7个子系统

4个主要子系统（管理、设计、纠正预防、生产过程）；3个支持子系统（文件、物料、生产工具和设备控制）；FDA检查工作时会以点带面，抓住一点，可在一个问题上几个来回，也可能检查整个公司的质量管理体系。

三、在FDA官员来工厂检查前公司内部应进行多次的核查和确认；对任何公司来说，通过FDA验厂最重要的条件是自己要严格执行已经确立的程序和作业流程，文件编制合理性及可操作性当然重要，检查官员对有文件不执行最反感。这样的事情肯定会上Form483。

四、FDA对工艺过程特别是特殊过程中的一些关键步骤的操作条件、方法及设备进行的验证(Validation)非常重视。但他们更注重过程控制，应该有的作业指导书一定要准备好；至少要有懂行的人陪同，万一缺少文件，这时就*懂行的人员临场发挥，只要能说出你们实际操作、控制的方法，能说服检查官，一般也过得去，观察项可能会有，但不太会作为不符合项，这一点他们到不死板。

五、FDA非常重视对生产记录的检查，对原材料的入库、检验及发放、生产工艺过程的控制、成品的质量检验以及各项重点项目的验证等均要求有完整的原始记录及整套的批记录，FDA官员在工厂检查要任意取样抽查批记录，批记录的真实性与完整性能具体体现工厂的GMP管理的水平。

六、FDA检查官对不合格品和顾客投诉的控制及处理方法、过程及相关的记录非常关注。这方面的准备务必充分，来不得半点马虎，在这里利嘴巧舌不管用，必须得有真实的证据。

七、接待人员回答提问要有技巧，不清楚的事情切忌马上回答，可以先查文件，几个人商量定下来再回答。更不要“灵机一动”，以为自己应付得了，接下来的问题可能会让你目瞪口呆。我曾看到过报道： FDA检查官在工厂检查时问：你们的文件看起来怎么很新啊，回答人员灵机一动：哦，我们的文件均用塑料文件袋保管的。检查官也不再说什么了，可到了最后一天，检查官突然说：我在你们工厂检查了4天，可我从没有看见你们递给我的文件使用塑料文件袋保管的。到了这时你还有什么话说？

八、检查结果：什么都没有得到，这是最好的情况，但这恐怕不太可能。能接到无批评的483表（无不合格项，只有观察项）已经是相当不错；到于做得不够好的企业也许会接到有批评的483表，这就危险啦，它可能导致：警告信（Warning letter）、自动滞留（Automatic Detention）、QSR扣留、（QSR Hold）撤回（Recall）、直至永久不得进入美国市场。

所以，凡是接美国FDA通知要来工厂的企业务请注意，需要全公司员工的非常重视，全员动员，全力准备，将可能出现的不符合减到最少，才能避免接到警告信

第五篇：Peter Baker 和FDA 检查

Peter Baker 和FDA 检查---没啥秘密的揭秘

2016-11-03

Peter Baker，一个外国人，不远万里，来到东方，早期以志愿者身份暂居广西柳州，习得基本汉语，兼而了解炎黄子孙的秉性乃至思维习惯。后返美，在药厂实验室操练ＨＰＬＣ，据称对Ａｇｉｌｅｎｔ之Ｃｈｅｍｓｔａｔｉｏｎ了如指掌，猜测其亦顿悟实验室仪器数据处理的后门和漏洞。加入ＦＤＡ，后派驻印度，频发警告信，把印度各大药厂搅得鸡飞狗跳，把数据完整性问题（现曰数据可靠性）提到了前所未有的高度。现派驻中国北京办事处，每年执行约２０个检查，不少国内药厂亦频频中招，Peter B所到之处不免人心惶惶。细数Peter B的厉害之处在于: 精通实验室操作流程，也深谙数据“处理之道”，思维敏捷，检查过程直接“粗暴”，不留情面；还有，通中文。

现就Peter Baker采用的检查流程和可能的应对之策，作一简要汇总。由于信息来源有限，难免挂一漏万，权作参考吧。

检查通知：

由于是北京办公室派出的检查员，一般通知期较短。多数是周末通知（周四、周五），下周一即开始检查。若确定是Peter Baker，除了接机接站，不必费心思接风，安排游玩等等接待活动。该美国公务员廉洁奉公，不与公司餐聚，不接受礼物，不要求额外接待，所以好好准备业务检查就好。

检查准备：

若有一点时间，二三天也很宝贵呀！能做什么准备呢？电子数据真有问题，靠临时处理，早干嘛去了？不建议再做处理了，时间短，处理急，反而弄巧成拙。熟悉下目前的流程、数据情况，特别是缺陷情况非常重要，因为要准备解释呀，或者招供呀！

若时间还比较宽裕，目前FDA检查周期还是规律，所以一般工厂能预感FDA要来，那么建议整个自查报告，数据完整性专项自查吧。面对Peter Baker没有啥抹不开脸面的，勇敢自查，自爆短处，自揭伤疤。这样做，有利有弊。好处，下面详解，坏处是，风闻Peter Baker曾将自查结果直接写进了483缺陷中。但个未经授权许可，严禁转载 人判断还是自查报告写得有瑕疵，不深刻，遮遮掩掩，整改措施也不到位，一句话，打铁还需自己硬。

检查过程：

Peter Baker的检查，看时间吧，若有五天，那么P老兄会过一下实验室以外的系统；若时间短，譬如四天，乃至三天，那么，弃其他不顾直奔实验室而去，也是情理之中，确实也发生过的。举个极端例子：某次，暂定四天实则执行了三天的FDA检查，Peter 检查大员（仅Peter一位检查员），在换名片，介绍彼此，亮出FDA检查工作证后，便打断工厂意欲开场PPT介绍，PPT可以打出来，带回去看，咱们直接去QC开始工作吧。面面相觑哦，大家可以体会其中的感受吧！

谈谈见识过的Peter正常的检查流程。某次FDA检查（二位检查员，Peter是当仁不让的主角喽）。开幕会结束，言明去现场，在办公楼前，了解方向位置后，指向车库，先从门卫车库开始，然后基本溜边而行，钻厂区围墙，清洁工具存放间，废弃物存放间，锅炉房，外围的厕所，任何不明、没有标识的房间，统统打开，看啥？你懂的。。文件、物料嘛！

某次现场巡查，工厂声明某建筑物几间房是同场地兄弟公司的地盘，Peter B先和陪同管理层核实: 非工厂管辖，没有工厂任何文件、物料，不在工厂体系，有否书面协议证据，如何标识，如何分割。似乎工厂的表述没有漏洞。转过脸Peter B 坚决要求开门，一番磨蹭拖延。。开门后，文件。。物料。。Peter Baker的小数码相机“咔咔，咔咔”的同时，大家。。在数“草泥马”啦！然后，PeterB严斥工厂不诚实，并申明要中断检查。Peter B 的检查之道还有欲擒故纵哦。

基本的判断，Peter Baker走其他现场，除了暗查不该有的物料，文件外，主要在于了解实验室相关的样品取样、中控、结果报告的流程，更好地检查实验室数据问题。

下面说说Peter B 的兴奋点---实验室检查。首先，Peter B一般会事先询问，实验室有没有研发样品检测，小试样品检测等一切不必严格GMP条件下完成的操作。若承认有，下一个问题，如何区分? 如批号、文件名、操作记录、样品登记，等等。有时还会问，实验室是否还有专有的实验室“偏差”系统（针对有工厂专设实验室异常处理程序，游离于偏差系统之外）。这时，一定要如实回答啊！这时不实说，按Peter B的描述，就上纲上线到欺骗美国政府，有点狠哦！也见过Peter B直接问，工厂自己有没有发现不合规的数据处理操作，这时，自查报告可以适时登场，据个人的实际体验，凡是Peter B查出的数据问题，若自查报告中有体现，则他都没有写进483，还算有职业道德。

走实验室现场，一般常被Peter Baker深究的问题还有：

     天平称量的打印管理，紫外仪器的审计追踪功能，红外的使用前校准的记录和操作，样品的保存（特别是有小样、研发样品纳入GMP体系时），GMP放行实验室和研发实验室的关系（可能会特地去研发实验室，看看系统里的数据），仪器数量和实验员数量（亲见，4台GC，3个操作分析员，被Peter B 写上483，实验室人员配备不充分），主管的职责，只要是在数据、电子数据的审核方面（亲见，说实验室经理有上机复核的职责，则让经理演示上机，结果以经理操作不熟练，上483的）

走实验室现场也不会是个拖延时间的手段，因为往往没有等到走完整个实验室，Peter B 就已经迫不及待地坐在了电脑前，选择的对象，可能是最旧的那台仪器。坐定，一般就是一天哦。先问操作者，再问管理员权限，确认管理员权限可以查看任何数据。然后，请以管理员权限登入，以保证可以审核所有数据信息，开始了最激动人心的检查。

一般流程是：

问，操作系统工作站，数据存哪个盘符，哪个文件夹，如何命名，如何归档，如何备份。演示操作路径。

看，设备使用记录，选取个时间段，可能是近三年，每年选取几周，逐条上机核查。

核，书面的原始检验记录和数据。检验批记录，大家一定费心准备过的啦。调，备份数据。备份数据的恢复和完整性，大家自己心里掂掂分量啦。查，系统中数据和上述文件、记录、数据的一致性。

重点来了。。一般，初始，Peter检查员会请管理员权限人员操作，但不一会儿，便会亲自上阵，更具体的程序大致是：



  任意挑一天开始，工作站有操作，但设备使用记录没有登记的操作和数据，会优先关注先查。若设备使用记录登记在案，则核对是否登记信息完整（如产品、批号、人员）。即设备使用记录的信息和电脑中数据的一致性。任何一项电脑操作系统（审计追踪或日志）中有操作痕迹，但没有登入设备使用记录的，都会细问。譬如，系统中有积分处理的记录，但没有相应的人员登入记录，便顺藤摸瓜，先把当事分析员或操作者叫来，细问数据处理细节。这里提示大家，设备使用记录一定填写完整呀！包括不入账、不开报告的研发样品、小试样品（也该有记录啊，因为进入了GMP体系了），重复测试、重新处理这事就不赘述该不该记录了哈！

 查序列信息和报告数据，序列安排了7针，报告记录了6针? 那一针为什么不记录报告？SOP规定了吗？分析员你当时是啥考虑？序列中断，有偏差调查吗？调查结果拿来看看?  按照序列的提示，逐针核对审计追踪，先看进针顺序，后看每针间隔（基本一致，偶尔的序列中断或停顿都可能问理由和解释），再看存储路径，还看有么有异常出错信息。

 按照打印图谱和审计追踪提示的路径信息（不止一次发现有工厂二者显示的路径不一致，可想而知想干嘛呢），去对应路径查看图谱文件，先点数（文件少了，又想干嘛呢!），后看文件名，再看文件夹中有没有近似文件名（特别是批号相同的）。

 在工作站调看图谱，积分合理与否在放大缩小指指画画中比对进行，在上列路径中发现的任何有兴趣的图谱也一并调出审看。

再看审计追踪记录，是否有相同批号的检测，被发现没有原因的复测可是低级错误哦。一般，序列运行前的任何单针进样都值得审问，更别提相同批号乃至序列被发现重复进样，还没有调查和评估。

 有时，PeterBaker会要求把备份数据恢复，和工作站中的数据、纸质打印的数据一并核对，看备份的完整性(怎么完整的数据备份，大家看指南哈)

坦白说，我写烦了。还有未尽信息，也到此为止吧！

总结三句：打铁还靠自身硬，平日里合规，十个Peter 来也无妨。若有问题，数据完整性的专项自查、评估和整改报告很重要。诚信很重要，检查时的合作坦诚，至少对Peter有点效果。