FDA 制剂生产厂检查指南

FDA检查员指导手册：原料药生产检查（药品质量保证）第I部分――背景至八十年代后期以来，美国食品与药品管理局以强化了其对原料药(API)生产企业的检查内容。

从部分方面来说，这归咎于对原料药质量在制剂的质量、效力、和安全方面所起的重要作用认识的提高。

例如，在配制成固体口服制剂，混悬剂和局部用药时原料药的化学特性会对制剂的溶出度/生物利用度产生不利影响。

另外，原料中的少量没有鉴别出的杂质或其特性未知的杂质会给病人造成的严重不良反应。

FDA长期以来一直认为，收载在制剂药品生产质量管理规范规定(21 CFR 210 and211)中的CGMP概念对原料药生产工艺同样有效。

这些概念包括，与其他一起，产品质量是生产出来的，雇佣能够胜任和经过培训的员工，建立适宜的书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期的使用期内质量稳定。

FDA在1991年出版的化学原料药检查指南，在1994年经过少量的编辑变化，包含有原料药生产的GMP/验证概念应用和范围方面的基本指南，并包含了FDA对杂质和杂质专论方面的要求。

在对国内和国外原料药进行检查时均必须使用该指南，以促进检查的一致性和均一性。

目前，FDA希望生产企业在API生产的全过程实施CGMP，即从起始原料的使用开始，到对原料药质量和纯度产生影响的关键工艺步骤的验证。

该方法认为所需的控制方法完全依赖于实际的生产工艺且随着合成步骤从早期的中间阶段向最终分离和纯化步骤的延伸控制水平也在不断加强。

该方法允许依据工艺本身（即，化学合成工艺和发酵工艺）及特殊工艺步骤的风险性和关键性采取适宜水平的控制方法。

该“控制所有步骤，验证关键工艺步骤”方法包含在FDA的《原料药制造，加工和储存指南》草案内，其在1996年9月20日公布供公众讨论。

后者可以从CDER的网站下载：/cder/api.htm.。

第II部分实施目的：该符合性程序的主要目的是为对国内和国外各类原料药生产企业的检查提供一份综合性的CGMP检查指南。

FDA行业指南-药品现场检查中被认为是延迟、否认、限制或拒绝的情形一、介绍2012年7月9日，《美国食品和药物管理局安全及创新法案》（FDASIA）被签署成为法律。

FDASIA章节707添加了501（j）到《食品、药品和化妆品法令》（FD&C Act），认为“任何从事生产、加工、包装或持有的生产企业、库房造成现场检查的延迟、否认、限制或拒绝的情况均被认为该产品为假劣药品”。

该指南的目的是对“延迟、否认、限制或拒绝”的情形进行定义。

二、定义1、延迟A、检查计划安排的延迟FDA将会根据当地的情况对检查计划进行适当的调整，例如天气、安保、节假日、其他非工作日、企业的生产计划等。

以下延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●企业不同意建议的检查日期，但没有合理的解释。

●在检查安排后，企业要求延迟检查日期，但没有合理的解释。

●企业不能回答为什么FDA联系不上企业指定的联系人。

下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业没有正在生产，例如每个月只生产一次，企业要求检查日期另定，以便FDA检查时生产正在进行中。

B、检查期间的延迟以下检查期间的延迟情况将会被认为产品是假劣药品，包括但不仅限于：●企业不允许FDA检查官进入某个区域直至一段时间过去之后，即使这个区域是正在进行操作的并且是FDA有权检查的区域，对于这种行为没有合理的解释。

●企业长时间把FDA检查官单独撂在会议室，没有相应的文件或责任人供审查和询问，从而干扰检查官完成其相应的检查。

下面给出了将不会被认为是假劣药品的潜在合理解释的一个例子，但不仅限于：●企业不允许FDA检查官进入无菌工艺区域，直至检查官能满足企业的无菌更衣程序要求。

C、记录提供延迟以下记录提供延迟的情况将会被认为产品是假劣药品，包括但不仅限于：●在检查期间，FDA检查官要求在合理的时间内提供其有权查看的文件和记录，但是企业不能按时提供，且没有合理的解释。

FDA对制药企业文件的现场检查
一、文件的永久性
记录原始文件必须用黑色的墨水圆珠笔（有些公司也允许用蓝色的墨水圆珠笔）以确保文字的永久性。

当采用热敏性纸记录原始数据时，必须要另拷贝一份并与原始记录并行贴在一起，缩写签名和日期。

此外，原始文件绝对不允许用铅笔记录，也不允许用涂改液涂改文件。

二、文件的易读性
写了错字或不正确的信息，应将错误部分用单线划掉，然后补上正确的信息，缩写签名和日期。

特别不要涂改标准样品和分析样品的重量，因为实验的最终结果与标样和分析样品的重量直接相关，涂改这类数据具有很大的可疑性。

如果记录的数据确实有误，最好的改正的措施是将其数据划掉，注明记录的数据有误，样品将会重新称量。

三、文件的及时性
这一要求重点强调任何原始数据，生产过程中的具体操作指标，实验的程序，测试中标样和分析样品的信息，以及仪器型号和操作步骤都必须及时记录。

当原始记录（包括样品名称、来源、批号、有效日期、缓冲液的pH，有机溶剂的种类，来源和数量，稀释样品溶剂的制备步骤，所用仪器的型号及编号，液相柱子的种类，编号和尺度，标样和分析样品制备的步骤等）没有被及时记录下来时，原则上不可以补记。

四、文件的完整性
所有文件必须牢固附在正式的记录本上。

所有没有记录的空间必须用一单线划掉
引用的参考文献或操作步骤必须详细记录下来
五、文件的时间顺序性
文件记录的日期应与文件页码数相符合
还有就是不允许在正式文件上注明追溯日期或事后日期。

FDA检查员指导手册CP 7356.002:药品生产检查程序对现场报告的要求 (35)第一部分背景 (36)第二部分执行 (36)2.1. 目的 (36)22 策略 (36)221. 对生产企业两年一度的检查（包括重新包装商、合同实验室等） (36)2.2.2. 系统性检查 (37)2.2.3. 对原料药及制剂生产的系统性检查计划 (38)2.2.3.1. 质量系统 (38)2.2.32 厂房设施与设备系统 (38)2.2.33 物料系统 (38)2.2.34 生产系统 (38)2.2.3.5. 包装和贴签系统 (38)2.2.3.6. 实验室控制系统 (39)2.3. 程序管理指导 (39)2.3.1. 定义 (39)2.3.1.1. 监督性检查 (39)2.3.1.2. 达标检查 (40)2.3.1.3. 受控状态 (40)2.3.1.4. 药品工艺 (40)2.3.1.5. 药品生产检查 (41)第三部分检查 (41)3.1. 检查活动 (41)3.1.1. 总则 (41)3.1.2. 检查方法 (42)3.1.2.1. 全面性检查的选择 (43)3.1.2.2. 简略性检查的选择 (43)3.1.2.3. 综合性检查范围 (43)3.1.3. 系统性检查范围 (43)3.131. 质量系统 (44)3.1.32厂房设施与设备系统 (44)3.1.3.3. 物料系统 (45)3.1.3.4. 生产系统 (46)3.1.3.5. 包装和贴签系统 (47)3.1.3.6. 实验室控制系统 (48)3.1.4. 取样 (49)3.1.5. 检查组组成 (49)3.1.6. 报告 (49)第四部分分析 (50)第五部分法律性/行政性策略 (50)5.1. 质量系统 (51)5.2. 厂房设施和设备 (51)5.3. 物料系统 (51)5.4. 生产系统 (52)5.5. 包装和贴签系统 (52)5.6. 实验室控制系统 (52)对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR) 。

(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。

GUIDE(1) TO INSPECTIONSOF FOREIGN PHARMACEUTICAL MANUFACTURERS BACKGROUND背景There has been a significant increase in the number of foreign inspections of pharmaceutical manufacturing plants in the past few years. This trend is attributable mainly to the increase in the number of pre-approval inspections although the increase has been noted in other areas such as routine GMP inspections and compliance follow-up activities. Considering the resource-intensive nature of the foreign inspection program, it has become clear that effective and efficient inspectional coverage is crucial to the successful management of the program and that can be achieved only through maintenance of consistency and uniformity of inspection and enforcement activities.在最近几年医药制造厂外检查数量显著增加。

这一趋势主要是由增加的前置审批检查的次数虽然增加了在其他领域如日常GMP检查和合规性的后续活动记录。

美国FDA生产过程(工艺)验证总则指南1 9 8 7年I．目的 3II．范围 3III．序言 3Ⅳ. 总概念 4V．现行药品生产质量管理规范(CGMP)法规 6Ⅵ．医疗器械的生产质量管理规范法规7Ⅶ．验证预备阶段所需考虑的事情7Ⅷ．生产过程验证的内容8Ⅸ．产品检验的可接受性11I．目的本指南概述了人用和兽用药品和医疗器械的生产过程(工艺)验证的总则，其验证的基本原理是得到fdA认可的。

II．范围本指南是根据21CFR10-90颁布的，适用于药品和医疗器械的生产。

本指南阐述了一般适用范围的原则和方法，这些原则和方法在法律上未做规定要求，但是得到了fdA认可。

本指南可以作为依据，并保证可以得到FDA的批准，但也可以按照其他方法进行验证。

在使用不同方法进行验证时，可事前与(但也可以不与)fdA讨论所要进行的验证工作，以避免在以后被FDA认为不合格而浪费了财力和精力。

总而言之，本指南列述的有关药品和医疗器械的生产过程验证原则和方法，是得到FdA认可的。

但不是在所有情况下都必须使用本指南所列述的原则和方法以符合法律。

本指南是要经常进行修订的。

对此有兴趣的人士可对本文件及随后的任一版本提出意见。

书面意见应向FDA的Dockets Maragement Branch(HFA—305)上报。

地址为：Room 462，5600FishersLane，Rockville，Maryland20847。

在星期—至星期五，上午9：00到下午4：00可在该办公处查阅所收到的意见，III．序言生产过程验证是药品生产管理规范法规21CFR210•211和医疗器械生产管理规范法规21CFR820的规定要求，所以适用于药品和医疗器械的生产。

有些生产厂商曾向FDA要求提供具体的指导：关寸FDA要求生产商做些什么工作，以保证生产过程验证符合规定的要求。

本指南讨沦了生产过程验证的原理和概念，FDA认为这些原理和概念是符合验证方案要求的。

GUIDE TO INSPECTIONS ORAL SOLUTIONS AND SUSPENSIONSNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights,privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONThe manufacture and control of oral solutions and oral suspensions haspresented some problems to the industry. While bioequivalency concerns areminimal (except for the antiseptic products such as phenytoin suspension),there are other issues which have led to recalls. These includemicrobiological, potency and stability problems. Additionally, because thepopulation using these oral dosage forms includes newborns, pediatrics andgeriatrics who may not be able to take oral solid dosage forms and may becompromised, defective dosage forms can pose a greater risk because of thepopulation being dosed. Thus, this guide will review some of the significantpotential problem areas and provide direction to the investigator whengiving inspectional coverage.II. FACILITIESThe design of the facilities are largely dependent upon the type of productsmanufactured and the potential for cross-contamination and microbiologicalcontamination. For example, the facilities used for the manufacture of OTCoral products might not require the isolation that a steroid or sulfaproduct would require.Review the products manufactured and the procedures used by the firm for theisolation of processes to minimize contamination. Observe the addition ofdrug substance and powdered excipients to manufacturing vessels to determineif operations generate dust. Observe the systems and the efficiency of thedust removal system.The firm's HVAC (Heating Ventilation and Air Conditioning) system may alsowarrant coverage particularly where potent or highly sensitizing drugs areprocessed. Some manufacturers recirculate air without adequate filtration.Where air is recirculated, review the firm's data which demonstrates theefficiency of air filtration such should include surface and/or airsampling.III. EQUIPMENTEquipment should be of sanitary design. This includes sanitary pumps,valves, flow meters and other equipment which can be easily sanitized. Ballvalves, packing in pumps and pockets in flow meters have been identified assources of contamination.In order to facilitate cleaning and sanitization, manufacturing and filling lines should be identified and detailed in drawings and SOPs. In some cases, long delivery lines between manufacturing areas and filling areas have been a source of contamination. Also, SOPs, particularly with regard to timelimitations between batches and for cleaning have been found deficient inmany manufacturers. Review cleaning SOPs, including drawings and validation data with regard to cleaning and sanitization.Equipment used for batching and mixing of oral solutions and suspensions is relatively basic. Generally, these products are formulated on a weight basis with the batching tank on load cells so that a final Q.S. can be made byweight. Volumetric means, such as using a dip stick or line on a tank, have been found to be inaccurate.In most cases, manufacturers will assay samples of the bulk solution orsuspension prior to filling. A much greater variability has been found with batches that have been manufactured volumetrically rather than by weight.For example, one manufacturer had to adjust approximately 8% of the batches manufactured after the final Q.S. because of failure to comply with potency specifications. Unfortunately, the manufacturer relied solely on the bulkassay. After readjustment of the potency based on the assay, batchesoccasionally were found out of specification because of analytical errors.The design of the batching tank with regard to the location of the bottomdischarge valve has also presented problems. Ideally, the bottom discharge valve is flush with the bottom of the tank. In some cases valves, including undesirable ball valves, have been found to be several inches to a footbelow the bottom of the tank. In others, drug or preservative was notcompletely dissolved and was lying in the "dead leg" below the tank withinitial samples being found to be subpotent. For the manufacture ofsuspensions, valves should be flush. Review and observe the batchingequipment and transfer lines.With regard to transfer lines, they are generally hard piped and easilycleaned and sanitized. In some cases manufacturers have used flexible hoses to transfer product. It is not unusual to see flexible hoses lying on thefloor, thus significantly increasing the potential for contamination. Such contamination can occur by operators picking up or handling hoses, andpossibly even placing them in transfer or batching tanks after they had been lying on the floor. It is also a good practice to store hoses in a way that allows them to drain rather than be coiled which may allow moisture tocollect and be a potential source of microbial contamination. Observemanufacturing areas and operator practices, particularly when flexible hose connection are employed.Another common problem occurs when a manifold or common connections areused, especially in water supply, premix or raw material supply tanks. Such common connections have been shown to be a source of contamination.IV. RAW MATERIALSThe physical characteristics, particularly the particle size of the drugsubstance, are very important for suspensions. As with topical products in which the drug is suspended, particles are usually very fine to micronized(less than 25 microns). For syrups, elixir or solution dosage forms in which there is nothing suspended, particle size and physical characteristics ofraw materials are not that important. However, they can affect the rate of dissolution of such raw materials in the manufacturing process. Rawmaterials of a finer particle size may dissolve faster than those of alarger particle size when the product is compounded.Examples of a few of the oral suspensions in which a specific and welldefined particle size specification for the drug substance is importantinclude phenytoin suspension, carbamazepine suspension, trimethoprim andsulfamethoxazole suspension, and hydrocortisone suspension. Review thephysical specifications for any drug substance which is suspended in thedosage form.V. COMPOUNDINGIn addition to a determination of the final volume (Q.S.) as previouslydiscussed, there are microbiological concerns. For oral suspensions, there is the additional concern with uniformity, particularly because of thepotential for segregation during manufacture and storage of the bulksuspension, during transfer to the filling line and during filling. Review the firm's data that support storage times and transfer operations. Thereshould be established procedures and time limits for such operations toaddress the potential for segregation or settling as well as otherunexpected effects that may be caused by extended holding or stirring.For oral solutions and suspensions, the amount and control of temperature is important from a microbiological as well as a potency aspect. For thoseproducts in which temperature is identified as a critical part of theoperation, the firm's documentation of temperature, such as by controlcharts, should be reviewed.There are some manufacturers that rely on heat during compounding to control the microbiological levels in product. For such products, the addition ofpurified water to final Q.S., the batch, and the temperatures duringprocessing should be reviewed.In addition to drug substances, some additives, such as the parabens aredifficult to dissolve and require heat. The control and assurance of their dissolution during the compounding stage should be reviewed. From a potency aspect, the storage of product at high temperatures may increase the level of degradants. Storage limitations (time and temperature) should bejustified by the firm and evaluated during your inspection.There are also some oral liquids which are sensitive to oxygen and have been known to undergo degradation. This is particularly true of the phenothiazine class of drugs, such as perphenazine and chlorpromazine. The manufacture of such products might require the removal of oxygen such as by nitrogenpurging. Additionally, such products might also require storage in sealedtanks, rather than those with loose lids. Manufacturing directions for these products should be reviewed.VI. MICROBIOLOGICALQUALITYThere are some oral liquids in which microbiological contamination canpresent significant health hazards. For example, some oral liquids, such as nystatin suspension are used in infants and immuno-compromised patients, and microbiological contamination with organisms, such as Gram-negativeorganisms, is objectionable. There are other oral liquid preparations such as antacids in which Pseudomonas sp. contamination is also objectionable.For other oral liquids such as cough preparations, the contamination withPseudomonas sp. might not present the same health hazard. Obviously, thecontamination of any preparation with Gram-negative organisms is notdesirable.In addition to the specific contaminant being objectionable, suchcontamination would be indicative of a deficient process as well as aninadequate preservative system. The presence of a specific Pseudomonas sp. may also indicate that other plant or raw material contaminants couldsurvive the process. For example, the fact that a Pseudomonas putidacontaminant is present could also indicate that Pseudomonas aeruginosa, asimilar source organism, could also be present.Both the topical and microbiological inspection guides discuss the methods and limitations of microbiological testing. Similar microbiological testing concepts discussed apply to the testing of oral liquids for microbiological contamination. Review the microbiological testing of raw materials,including purified water, as well as the microbiological testing of finished products. Since FDA laboratories typically utilize more sensitive testmethods than industry, consider sampling any oral liquids in whichmanufacturers have found microbiological counts, no matter how low. Submit samples for testing for objectionable microorganisms.VII. ORAL SUSPENSIONSUNIFORMITYThose liquid products in which the drug is suspended (and not in solution) present manufacturer and control problems.Those liquid products in which the drug is suspended (and not in solution) present manufacture and control problems. Depending upon the viscosity, many suspensions require continuous or periodic agitation during the fillingprocess. If delivery lines are used between the bulk storage tank and thefilling equipment, some segregation may occur, particularly if the product is not viscous. Review the firm's procedures for filling and diagrams forline set-up prior to the filling equipment.Good manufacturing practice would warrant testing bottles from thebeginning, middle and end to assure that segregation has not occurred. Such samples should not be composited.In-process testing for suspensions might also include an assay of a sample from the bulk tank. More important, however, may be testing for viscosity.VIII. PRODUCTSPECIFICATIONSImportant specifications for the manufacture of all solutions include assay and microbial limits. Additional important specifications for suspensionsinclude particle size of the suspended drug, viscosity, pH, and in somecases dissolution. Viscosity can be important from a processing aspect tominimize segregation. Additionally, viscosity has also been shown to beassociated with bioequivalency. pH may also have some meaning regardingeffectiveness of preservative systems and may even have an effect on theamount of drug in solution. With regard to dissolution, there are at least three products which have dissolution specifications. These products include phenytoin suspension, carbamazepine suspension, and sulfamethoxazole andtrimethoprim suspension. Particle size is also important and at this point it would seem that any suspension should have some type of particle sizespecification. As with other dosage forms, the underlying data to supportspecifications should be reviewed.IX. PROCESS VALIDATIONAs with other products, the amount of data needed to support themanufacturing process will vary from product to product. Development (data) should have identified critical phases of the operation, including thepredetermined specifications, that should be monitored during processvalidation.For example, for solutions the key aspects that should be addressed during validation include assurance that the drug substance and preservatives are dissolved. Parameters, such as heat and time should be measured. Also,in-process assay of the bulk solution during and/or after compoundingaccording to predetermined limits are also an important aspects of process validation. For solutions that are sensitive to oxygen and/or light,dissolved oxygen levels would also be an important test. Again, thedevelopment data and the protocol should provide limits. Review firm'sdevelopment data and/or documentation for their justification of theprocess.As discussed, the manufacture of suspensions presents additional problems, particularly in the area of uniformity. Again, development data should have addressed the key compounding and filling steps that assure uniformity. The protocol should provide for the key in-process and finished product tests, along with their specifications. For oral solutions, bioequivalency studies<<< Continued to next message >>><<< This message is part 2 of a previous message >>>may not always be needed. However, oral suspensions, with the possibleexception of some of the antacids, OTC products, usually require abioequivalency or clinical study to demonstrate effectiveness. As with oral solid dosage forms, comparison to the biobatch is an important part ofvalidation of the process.Review the firm's protocol and process validation report and, ifappropriate, compare data for full scale batches to biobatch, data andmanufacturing processes.X. STABILITYOne area that has presented a number of problems includes the assurance of stability of oral liquid products throughout their expiry period. Forexample, there have been a number of recalls of the vitamins with fluoride oral liquid products because of vitamin degradation. Drugs in thephenothiazine class, such as perphenazine, chlorpromazine and promethazine have also shown evidence of instability. Good practice for this class ofdrug products would include quantitation of both the active and primarydegradant. Dosage form manufacturers should know and have specifications for the primary degradant. Review the firm's data and validation data formethods used to quantitate both the active drug and degradant.Because interactions of products with closure systems are possible, liquids and suspensions undergoing stability studies should be stored on their side or inverted in order to determine whether contact of the drug product with the closure system affects product integrity.Moisture loss which can cause the remaining contents to become superpotent and microbiological contamination are other problems associated withinadequate closure systems.XI. PACKAGINGProblems in the packaging of oral liquids have included potency (fill) ofunit dose products, accurate calibration of measuring devices such asdroppers that are often provided. The USP does not provide for doseuniformity testing for oral solutions. Thus, for unit dose solutionproducts, they should deliver the label claim within the limits described in the USP. Review the firm's data to assure uniformity of fill and testprocedures to assure that unit dose samples are being tested.Another problem in the packaging of Oral Liquids is the lack of cleanliness of containers prior to filling. Fibers and even insects have been identified as debris in containers, and particularly plastic containers used for these products. Many manufacturers receive containers shrink-wrapped in plastic to minimize contamination from fiberboard cartons. Many manufacturers utilize compressed air to clean containers. Vapors, such as oil vapors, from thecompressed air have occasionally been found to present problems. Review the firm's systems for the cleaning of containers.There are no references from this document.。

FDA迎查指南一、概述FDA检查工厂的背景：近年来，美国连续发生多起的污染事件，美国每年有4800万人感染食源性疾病，每6个人就有一人因食品危害受到感染，超过10万人住院，其中3000人死亡。

2011年1月4日，美国总统奥巴马签署了《FDA食品安全现代法案》，这是美国对《联邦食品药品化妆品安全法》的重大修订，根据现行法律，美国FDA有权对境外食品生产的厂家实施检查，以此提高供给美国的食品质量安全。

二、检查要点1、检查接受的重要性美国FDA在对被检查企业，接到通知后，必须24小时回复同意接受检查，否则将会列入FDA黑名单，该企业将不能对美国进行食品出口。

2、记录的检查FDA官员对工厂进行检查时，要求检查食品生产过程中的所有环节原料的种植、管理、收获、运输，环节控制，生产加工的质量控制措施，以及产品包装发货运输，同时需要提供原料的检验报告，半成品检验报告，成品检验报告以及辅助材料的检验报告，以此证明该批次产品质量每个环节都得到有效的控制。

要求记录必须严格一致，不得有造假现象（尤其是笔迹不得一样），尤其是公司有电子版的记录一定与纸质的记录一致。

3、检查依据FDA来厂检查时会拿着公司出口美国的通关单，根据通关单提供的信息，要求公司提供相关记录，所以要求所有出口到美国的产品，必须记录齐全，及时提供给FDA检查的官员。

4、沟通的重要性企业需要至少有一位精通外语并且熟悉公司质量控制体系的人，对FDA官员的检查给予合理的解释，如果解释的能让FDA官员所接受，对于检查的深度将会大大地减少，反之，FDA 官员将会对某一个问题刨根问底，直至查处问题。

5、产品标识的关注FDA来厂检查时，会重点关注产品的标识，所有标识必须严格与该产品的特性保持一致。

如果标识与产品不相符合，将严重影响检查结果。

6、制定计划的实施情况检查他们将会根据公司书面的监控计划，查验相关的检验记录，如果公司制定了计划，就必须有相关的记录来满足和支持计划的要求，否则将视为不符合项。

FDA检查员指导手册CP 7356.002：药品生产检查程序目录对现场报告的要求……………………………………………………3 5第一部分背景……………………………………………………………………36第二部分执行…………………………………………………………………362.1.目的……………………………………………………………………362.2.策略……………………………………………………………………362.2.1.对生产企业两年一度的检查（包括重新包装商、合同实验室等）…362.2.2.系统性检查……………………………………………………………372.2.3.对原料药及制剂生产的系统性检查计划……………………………382.2.3.1.质量系统………………………………………………………………382.2.3.2.厂房设施与设备系统…………………………………………………382.2.3.3.物料系统………………………………………………………………382.2.3.4.生产系统………………………………………………………………382.2.3.5.包装和贴签系统………………………………………………………382.2.3.6.实验室控制系统………………………………………………………392.3.程序管理指3导…………………………………………………………92.3.1.定义……………………………………………………………………392.3.1.1.监督性检查……………………………………………………………392.3.1.2.达标检查………………………………………………………………42.3.1.3.受控状态………………………………………………………………42.3.1.4.药品工艺………………………………………………………………42.3.1.5.药品生产检查…………………………………………………………41第三部分检查……………………………………………………………………413.1.检查活动………………………………………………………………413.1.1.总则……………………………………………………………………413.1.2.检查方法………………………………………………………………423.1.2.1.全面性检查的选择……………………………………………………433.1.2.2. 简略性检查的选择……………………………………………………433.1.2.3.综合性检查围………………………………………………………433.1.3.系统性检查围………………………………………………………433.1.3.1.质量系统………………………………………44………………………3.1.3.2. 厂房设施与设备系统…………………………………………………443.1.3.3.物料系统………………………………………………………………453.1.3.4.生产系统………………………………………………………………463.1.3.5.包装和贴签系统………………………………………………………473.1.3.6.实验室控制系统………………………………………………………483.1.4.取样……………………………………………………………………493.1.5.检查组组成……………………………………………………………493.1.6.报告……………………………………………………………………49第四部分分析……………………………………………………………………5第五部分法律性/行政性策略…………………………………………………55.1.质量系统………………………………………………………………515.2.厂房设施和设备………………………………………………………515.3.物料系统………………………………………………………………515.4.生产系统………………………………………………………………525.5.包装和贴签系统………………………………………………………525.6.实验室控制系统………………………………………………………52对现场报告的要求作为法律行动的一部分，所有针对因在执行cGMP方面有缺陷而采取的检查，均要向药品评价和研究中心的达标办公室呈交一份现场检查报告(EIR)。