FDA 制剂生产厂检查指南

Dosage Form Drug Manufacturers cGMPs (10/93)

FDA 制剂生产厂检查指南

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).

注：此指南是FDA检查官和其工作人员的参考资料。此文件不约束FDA，也不赋予任何人任何权利，特权，利益或豁免权。

I. 简介

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:

该文件旨在为检查药品生产厂家提供一个总体性的指导，以决定他们是否符合药物生产的cGMP法规。该指南应该与IOM(Investigations Operations Manual，即检查操作手册)，其他的药品检查指南，及法规符合性程序中的指导

一起使用。在IOM的第十章中提供了一个检查指南清单，其中有：

o Guide to Inspections of Bulk Pharmaceutical Chemicals.

o原料药检查指南

o Guide to Inspections of High Purity Water Systems.

o高纯水系统检查指南

o Guide to Inspections of Pharmaceutical Quality Control Laboratories.

o 药品QC实验室检查指南

o Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories.

o微生物药品QC实验室检查指南

o Guide to Inspections of Lyophilization of Parenterals.

o冻干注射剂检查指南

o Guide to Inspections of Validation of Cleaning Processes.

o清洁验证检查指南

o Guide to Inspections of Computerized Systems in Drug Processing.

o制药过程中的计算机化系统检查指南

o Guideline on General Principles of Process Validation.

o工艺验证总体原则指南

II. CURRENT GOOD MANUFACTURING PRACTICE REGULATIONS

II. CGMP

Prescription vs. Non-prescription

处方药和非处方药

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.

所有药物的生产过程都必须遵循cGMP原则，否则依据FD&C 法令, 501(a)(2)(B)将认定其为掺假行为。必须提供处方药的记录以便按照FD&C 法令第704（a）(1)(B)进行审核。如果药物是NDA或ANDA范围内的OTC药物，FDA可以根据505（k）(2)进行记录的审核，复制和确认。然而，如果该OTC药物并没有在FDA注册申请，在依据Section 704 of the FD&C 法规进行检查时将不会从法律上要求工厂必须提供给检查官这些记录。尽管如此，所有的处方药和OTC 生产商必须符合cGMP的要求，包括涉及的记录。检察官应当把对记录的审核作为决定生产商是否符合cGMP要求的一部分。偶尔会有公司可能拒绝提供OTC的记录，因为并没有法定要求他们这样做。工厂虽没有法律义务去提供这些记录以供审核，但是这并不减轻工厂仍需符合501（a）(2)(B)cGMP的法定要求，其中包括对记录保持的要求。

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.

如果一个工厂拒绝审核OTC的记录，检查官应当根据其他检查手段决定该公司对cGMP的符合程度。要把在检查处方药和非处方药时观察到的、发现的不遵循cGMP的地方援引到检查发现列表（即FDA-483）中。

Organization and Personnel [21 CFR 211 Subpart B] 组织和人员

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.

工厂必须有质量控制部门，其职责和权限应与CFR描述的一致。QC部门必须与生产部门保持独立，其职责必须有书面规定。要获取IOM中公司官员和其他关键人员的姓名，头衔和个人职责。

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.

在制药工业，员工的教育背景和岗位培训对于产品的质量有着非常重要的影响。

报告工厂是否有正式的培训计划，并描述接受的培训类型。培训应当有文件记录

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.

对每种生产的药品，QC都必须进行产品年度回顾，并有书面的年度回顾规程。详细审核这些报告。通过报告你将很快了解生产过程是否受控。报告必须要提供所有的中控或成品检测中失败的批次，和其他关键因素。调查所有的失败。

Quality control must validate the manufacturing process for each drug manufactured. Review and evaluate this data.

质量控制一定要对药品生产过程进行验证。审核并评估这些数据。

Buildings and Facilities [21 CFR 211 Subpart C] 建筑和厂房

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.

审核工厂的建筑，尺寸，位置及其周围的环境。对所有的操作，包括对尘埃、温湿度和细菌的控制，一定要有充足的照明、通风、屏蔽和合适的物理屏障。高纯水、HEPA和压缩空气系统必须要有足够的蓝图。厂房必须要有足够数量的更衣室，卫生间和洗手设备。

The firm must provide adequate space for the placement of equipment and materials to prevent mix-ups in the following operations:

工厂必须提供充足的空间存放设备和物料以防止下列操作出现混淆:

o receiving, sampling, and storage of raw materials;

原辅料的接收，取样和储存;

o manufacturing or processing;

生产或加工;

o packaging and labeling;

包装和贴签;

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

容器、包材、标签和成品的存放;

o production and control laboratories.

生产和实验控制；

Equipment [21 CFR 211 Subpart D] 设备

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.

审核生产、加工、包装、贴签和实验室中所用设备的设计，产能，建造和位置。描述生产设备包括对操作规程进行简要描述。考虑使用照片，流程图和图谱实施书面描述的操作。

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.

新设备一定要正确安装，并按设计进行操作。如果设备发生变更应决定是否需要FDA提前许可或对生产过程进行再验证。在使用前，设备一定要根据书面规程进行清洁。清洁必须被记录和验证。

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.

设备不应对药品的成分、含量、质量和纯度产生不利影响。设备不得与用于生产的物料发生反应。同时，润滑剂或制冷剂一定不能污染药品。

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.

设备的安装和位置应该便于清洗、调试和维护。同时应该能够阻止来自其他或先前生产操作的污染。设备必须有标识以注明清洁状态和内容物。设备的清洁和维护通常记录在一个放在现场的设备日志中。决定测量、称量或混合的设备是否有适当的产能和精度。如果设备需要校准，必须有书面校准规程和校准记录。

Components and Product Containers [21 CFR 211 Subpart E]

组分和容器

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.

检查仓库以确定组分、产品容器和包材是如何进行接收、鉴别、储存、使用、取样、检测、批准或拒收的。必须有书面规程来描述这些操作。对这个系统进行挑战以决定能否正确运行。如果组分的使用和储存采用计算机控制，必须要对程序进行验证。

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.

接收记录必须可追溯组分的生产商和供应商。记录必须包含组分的名称，生产商的名称，供应商的名称（如果和生产商不同）以及送货商的名称。此外，还应包括接收日期、生产商批号、接收数量和公司指定的控制编号。

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.

检查储存区的卫生条件，货物周转操作，复验日期和特殊的储存条件（避光、湿度、温度、空气等）。检查动物腺体和植物来源的组分未遭受虫害。

Components or finished product adulterated by rodents, insects, or chemicals must be documented and submitted for seizure.

被啮齿类动物，昆虫或化学品污染了的组分或最终产品一定要有记录并提交予以没收。

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.

即使公司计划自愿销毁产品也要收集证据。要警惕工厂里那些看起来无用或来源不明的但可能是新型原料药的组分、色素和食品添加剂。根据IOM中的《色素和添加剂状态表》查看色素是否经过批准用作预定用途，并在药品标签中作出声明。

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.

组分的接收可能不止在一个地点。组分(包括研发实验室使用的组分)必须按照药品cGMP进行操作。确定组分接收后处于待验直至放行的标识方式。组分必须进行标识（待验、批准或不合格）。审核从待验挪走组分的准则并挑战这个系统。确定需要在储存区做的记录以便记录各组分在不同区域间的移动，还有不合格组分的处理措施。组分的容器应粘贴一个识别码，这个唯一的编码可追溯组分从生产商一直到成品使用的整个过程。

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.

审核组分取样和检测的操作规程，以及经批准物料放行使用的流程。决定这些操作规程是否足够并被执行。

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.

确定公司药品组分、容器、密封件和标签的存货系统的有效性和准确度。通过对一批组分进行称量，将结果与存货记录中的数量相比较以对存货记录进行挑战。记录中出现的严重偏离应当调查。

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:

评估以下几个方面以确定公司所用的容器与密封件是否与产品相匹配，是否能够为药品提供足够的保护以阻止药品变质或污染，是否向产品释放物质或吸附产品，是否适合使用：

o Specifications for containers, closures, cotton filler, and desiccant, etc.

容器，密封件，绵纸，干燥剂等

o What tests or checks are made (cracks, glass particles, durability of material, metal particles in ointment tubes, compliance with compendium specifications, etc.).

检测和检查的内容（裂缝，玻璃微粒，物料的耐用性，膏管中的金属粒子，符合药典标准等）

o Cleaning procedures and how containers are stored.

清洁操作规程和容器的储存方式

o Handling of preprinted containers. Are these controlled as labeling, or as containers? The firm must review the labeling for accuracy.

预先印刷好的容器是按标签还是按容器控制？公司必须审核标签的准确性。

Production and Process Controls [21 CFR Subpart F]

生产和过程控制

1. Critical Manufacturing Steps [21 CFR 211.101]

关键生产步骤

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.

生产过程每一个关键步骤应当由一个责任人负责完成，并由另一个责任人进行复核。

如果是采用自动机器或电子设备控制，应当对其性能进行确认。

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.

关键生产步骤包括组分的选择，称量，度量，和鉴别，以及添加操作。包括批记录中记录的偏差，混合时间和中间产品的检测，实际收率和理论收率的确定。这些生产步骤的记录要在操作时进行，不能提前或延后。

2. Equipment Identification [21 CFR 211.105]

2设备标识

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.

生产某一药品中使用的所有容器和设备都应始终有标识。标识应能够鉴别容器或设备内的内容物的批号和加工阶段。以前的标识应予以清除。批产品的处理和存放应能防止混

淆与污染。

3. In-Line and Bulk Testing [21 CFR 211.110]

在线和批量检测

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.

为了保证产品的均一性和完整性，应当有充分的中控，例如片剂的重量和崩解时限的检查，液体灌装，混合的充分性，混悬液的均一性和溶液的澄清度。

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.

确定现场是否有中控的检测设备并做了某项特殊的检测。警惕检测结果的提前记录如片重的测定。

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.

大批量产品在检测完成前通常处于隔离状态直至放行到包装和贴标部门。然而，检测可以在产品包装完成后进行。

4. Actual Yield [21 CFR 211.103]

实际收率

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.

确定是否有人员检查每批生产药品的实际收率与理论收率比较。在出现严重的未经解释的偏差时，决定是否有规程阻止嫌疑批次和相关批次的发放。

5. Personnel Habits

人员习惯

Observe the work habits of plant personnel. Determine: Their attitudes and actions involving the jobs they perform. (Careless, lackadaisical, disgruntled, etc.).

观察工厂人员的工作习惯。确定：他们操作时的工作态度和行为（粗心，懒洋洋的，不满等）

Their dress. (Clean dresses, coats, shirts and pants, head coverings, etc.

他们的着装（服装，大衣，衬衫和裤子，头套等干净与否）

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).

对于给定的工作是否使用了正确的设备或是否采取了捷径（如：使用手和胳膊来混合或清空盛放药品组分的托盘）

If there are significant written or verbal language barriers that could affect their job performance.

是否有明显的书面或语言障碍影响他们的工作

Tablet and Capsule Products 片剂和胶囊

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.

熟悉压片设备的型号和地点。设备可能包括旋转压片机，包衣抛光锅，冲子，冲模等。设备的建造和安装应当方便在每批结束后或在连续生产合适的间隔时间对其进行维护和清洁。如果可能，观察清洁操作以判定是否遵循清洁规程。

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.

片剂的成分有活性成分（原料药），黏合剂，崩解剂，骨架和润滑剂。黏合剂加入到批中使片子成型。过多的黏合剂将会使片子太硬。崩解剂用于帮助片子在服用后崩解。骨架是能与活性成分相匹配的一种惰性物质，用于调整大小和重量。润滑剂促进粒子的流动，阻止黏附在打孔机和冲模的表面，帮助片子在从机器中分离。

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.

片子和胶囊容易被空气污染因为需要对大量的干燥成分进行处理。为预防片子系统中的交叉污染，需密切注意设备的维护保养，清洁和安装位置，以及微粒和片子的存放。为阻止交叉污染，混合，制粒，干燥和压片应当处于独立封闭区域，使用各自的空气处理系统。确定需要采取的措施以阻止交叉污染。当怀疑交叉污染发生时，调查问题，并收集在线的样品和怀疑对象的正式样品。在工厂的生产中确定需要如何控制温度，湿度，粉尘收集。缺少温湿度控制将会影响片剂的质量。

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.

观察设备的实际操作并决定是否药粉和制粒按照工厂的标准生产。混合过程一定要经过验证。干燥烘箱应有其独立的空气处理系统以防止交叉污染。工厂是否记录了干燥时间/温度以及保存含干燥失重测试结果的记录图表？审核生产或质量控制的在线测试。一些中间测试是片重，厚度，硬度，崩解和脆碎度。评估中控样品的处置方式。

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.

胶囊有硬或软两种类型。他们被机器充填入粉末，液珠，或液体。工厂制造胶囊用药粉的过程与片子操作相同。确定使用的生产控制，在线测试，评估填充操作测试的结果的原则。

Sterile Products 无菌产品

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.

通常，无菌药品不包含活的微生物和热源。用于静脉注射，灌肠，眼科等的药物，要符合这个标准。另外，其他的剂型也会被标注为无菌。例如，用于刺伤或皮肤磨损的膏剂。

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.

注射用药物一定要无热源，因为热源的存在会引起人体的发热反应。热源是微生物繁殖的产物。因此，在生产过程应该避免任何允许微生物生长的条件。热原可来自蒸馏器、储罐、盲管，管道的存水，或者来自容器、密封件和其他设备的表面污染。注射药物尽管没有任何热源的存在也会因为含有化学污染从而引起人和动物的发热。

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.

检查前有许多优秀的参考材料需要回顾复习，如“无菌过程中无菌产品的生产指南”和热源雷氏药物科学的84章关于热原的部分。决定和估计所使用的操作规程以尽量减小无菌药品遭受微生物和微粒污染的风险。

o Personnel

人员

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.

审核培训计划以保证从事生产和控制的人员具有与他们预定职责相适应的经验和培训经历。个人的无菌培训非常重要。职员一定要正确更衣并使用好的无菌技术。

o Buildings

建筑

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.

无菌药品的非无菌准备区域应当受控。参考CGMPR关于LVP的C章。然而，对拟定规定的偏离并不一定是对CGMP偏离。评估该区域的空气清洁度级别。可回顾联邦标准209E题为“洁净间和洁净区的空气尘埃粒子数”作为参考。观察处方配料区的配料操作或规程。警惕路线污染。确定准备区如何最大限度地减少交通和不必要的活动。确定灌装间和其他无菌区域的构造以消除可能被微生物和微粒污染的区域。例如，捕尘壁架，多孔表面等。确定无菌区域的清洁和保养方式。

1. Air

1 空气

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.

药液灭菌前非无菌准备区或配料区的空气应该经过过滤以对微粒进行控制。无菌药品加工和处理的产品暴露区域，空气应该在正压下经HEPA过滤。

Review the firm's system for HEPA filters, determine if they are certified and/or Dioctyl Phthalate (DOP) tested and frequency of testing.

审核工厂的HEPA系统，决定是否有证明文件，DOP测试以及测试的频率

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.

审核压缩空气系统和确定是否在使用点经过过滤以控制微粒。高效过滤系统和压缩空气系统应该被审核和评估。

2. Environmental Controls

2环境控制

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.

一定要建立活性微粒和非活性微粒的规格标准。活性微粒的规格标准必须包含无菌加工过程和设备的空气和表面取样。审核工厂的环境控制项目，质量标准和检测数据。审核超限检测结果时确定工厂是否遵循了相关规程。同时，确定工厂的放行程序中是否包含对环境检测数据的审核。

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.

注：在制备环境空气和表面取样的培养基时，要加入合适的灭活剂。例如，青霉素酶添加到培养基中用于监测无菌的青霉素操作和头孢菌素产品。

o Equipment

设备

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.

确定设备操作、清洁和保养方式。确定灌装间内设备的灭菌方式，灭菌循环是否经过验证。如果无菌性受到削弱，确定设备重新灭菌的操作方法。

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.

确定使用过滤器的类型。确定使用过滤器的目的，以及如何进行过滤器的装配、清洁和损伤检查。微生物截留过滤器还需要确定是否已进行完整性测试。

o Water for Injection

注射用水

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 Inspections of High Purity Water Systems\" before initiating an inspection.

在生产无菌产品时的水要得到控制以保证它能达到U.S.P的要求。审核工厂注射用水的生产，储存，和分配系统。确定蒸馏机，过滤器，储罐和管道安装和运行不会对水造成污染。评估工厂能确保注射用水的质量的操作规程和质量标准。作为参考材料，在进行检查前可回顾“FDA高纯水系统检查指南”。

o Containers and Closures

容器和密封件

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

确定容器和密封件的使用和储存方式。确定清洁、灭菌和除热原是否充分，并已经过验证。

o Sterilization

灭菌

1. Methods

1方法

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.

确定使用何种灭菌方法。“注射药物相关技术报告”是一个关于各种类型灭菌过程的很好的参考资料。例如，技术报告#包括：蒸汽循环灭菌的验证。无论使用何种方法都有审核并评估验证数据。

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.

如果使用蒸汽压力灭菌，必须有水银温度计和安装在排气管道上的自记式温度计。必须知道最大容器的中心温度被加热到所需温度的时间。蒸汽一定要排出灭菌柜腔室中的所有空气以消除冷点。排水管道与下水道之间的连接应该有空气隔断以防止倒虹吸的发生。应当避免使用纸片或衬垫和其他可能堵塞蒸汽的通道的操作。每次灭菌的时间，温度和压力图表都要存档。

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.

如果使用过滤除菌，确定公司过滤器的选型标准和更换频率。审核过滤器的验证数据。确定工厂是否知道药物的生物负载，检查过滤器完整性试验的规程。每一批除菌过滤完成后可能不会更换过滤器。确定是否有数据证明过滤器在使用时的完整性，以及没有“穿透”发生。

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.

如果使用环氧乙烷灭菌，确定残留和降解的测试方法。审核ETO的灭菌循环包括产品的预处理，ETO浓度，气体暴露时间，灭菌腔室温度和产品温度，灭菌腔室湿度

2. Indicators

2 指示剂

Determine the type of indicator used to assure sterility. Such as, lag thermometers, peak controls, Steam Klox, test cultures, biological indicators, etc.

确定用于无菌保证的指示剂类型。例如：？，？，？测试培养基，生物指示剂等。

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.

注意：当使用芽孢测试条测试环氧乙烷灭菌的有效性时，应注意冷却至室温时可能会造成冷凝。纸条上的湿气可能使芽孢变成比较脆弱的营养繁殖体，这可能影响灭菌测试的可靠性。芽孢测试条不应存放在可能有低水平环氧乙烷暴露的地点。

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.

如果使用生物指示剂，回顾目前的U.S.P.关于灭菌和生物指示剂的指导。在某些情况下，生物指示剂测试将成为无菌测试的全部或其中一部分。

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.

生物指示剂分为两种，每种都含有单一微生物的活培养。第一种指示剂加入到待灭菌的批产品或模拟产品作为代表单位，模拟产品不应比待灭菌产品更能抵抗灭菌。第二种指示剂是在第一种不能应用时比如在固体中，可被加入到培养皿、滤纸带中、金属、玻璃或塑料珠子中。

During the inspection of a firm which relies on biological indicators, review background data complied by the firm to include:

在检查依赖生物指示剂的工厂时，需要审核的工厂背景资料包括：

o Surveys of the types and numbers of organisms in the product before sterilization.

产品灭菌前的微生物种类和数量的调查。

o Data on the resistance of the organism to the specific sterilization process.

微生物对特殊灭菌过程的抵抗性数据。

o Data used for selecting the most resistant organism and its form (spore or vegetative cell).

用于选择最有抵抗性微生物和它的形态（芽孢或繁殖体）数据。

o Studies of the stability and resistance of the selected organism to the specific sterilization process.

所选微生物对特殊灭菌过程的稳定性和抵抗性研究。

o Studies on the recovery of the organism used to inoculate the product.

发现接种产品的微生物的研究。

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.

如果使用模拟的产品或固体产品的类似表面，验证模拟性或类似性。模拟的产品和类似表面一定不能影响到对使用指示微生物的计数。

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.

验证用于接种产品、模拟产品或类似表面的微生物数量，包含灭菌过程中接种体的稳定性。

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.

既然有资质的人员对选择和使用这些指示剂至关重要，那么审核他们的资质包含对灭菌过程、预期污染物、残留微生物测试的处理经验和技术。

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.

审核工厂关于产品生物指示剂的使用，控制，测试，包括用于证明产品中是否存在活的指示剂的方法描述。

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.

审核用于支持每次使用指示剂的数据。包括使用的接种量；回收的数据以控制用于证明指示剂灭菌的方法；计数未处理的已接种物料以表明接种的稳定性；特殊设计的无菌测试结果旨在证明每批灌装操作是否存在生物指示剂。

In using indicators, you must assure yourself that the organisms are handled so they don't contaminate the drug manufacturing area and product.

每次使用指示剂时，都必须确保微生物的处理不会污染药品和药品生产区域。

3. Filled Containers

灌装容器

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?

评估西林瓶或安瓿瓶退出灌装间的方式，轧盖或密封是否在无菌灌装区完成？如果不

是，如何维持轧盖前的无菌状态？

Review the tests done on finished vials, ampules, or other containers, to assure proper fill and seal. For instance, leak and torque tests.

审核对已密封完毕的西林瓶、安瓿瓶或其他容器的测试以保证恰当的灌装和封口。例如，检漏和扭力测试。

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.

审核对微粒污染的检查。使用偏光器可以很快对可疑微粒物质进行检查。在线目检的员工必须进行适当培训。如果使用机器对微粒计数，需要进行验证。

4. Personnel Practices

4 个人操作

Check how the employees sterilize and operate the equipment used in the filling area.

检查员工如何在灌装区域灭菌和操作机器。

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.

观察灌装区域的人员的操作情况。员工是否正确的穿着无菌服，面罩，帽子，鞋套？观察和评估更衣流程，确定更衣室和灌装间内是否维持良好的无菌技术。

Check on the practices after lunch and other absences. Is fresh sterile garb supplied, or are soiled garments reused?

检查饭后和其他离开后的操作。是提供的新的无菌服还是重新用脏的工作服？

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

确定更衣间是否与灌装间相邻，以及员工和物品如何进入无菌区。

o Laboratory Controls

实验室控制

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.\"

关于检查微生物和化学实验室的指南，回顾“FDA对药物QC控制实验室的指南”和“FDA对微生物药物质量控制的指南”

1. Retesting for Sterility

1 无菌再测试

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.

参考U.S.P中关于无菌测试的指导。当由于非无菌的原因已知并因此导致原始结果无效时，无菌再测试是可以接受的。不能认为原来无菌测试失败就得出假阳性的结论。这个结论一定要通过充分的调查文件予以证明。另外，通过反复取样和测试可能并不能鉴别出不均匀或低水平的污染。

Review sterility test failures and determine the incidence, procedures for handling, and final disposition of the batches involved.

审核无菌测试的失败批次，并确定相关批次受影响的范围，处理规程，及最终处理方式。

2. Retesting for Pyrogens

2 热原再测试

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.

和无菌性一样，当测试系统被削弱时可以进行热原再测试。没有文件证明不能假定测试失败就是假阳性。

Review any initial pyrogen test failures and determine the firm's justification for retesting.

审核所有原始热原测试失败，并确定公司进行再测试的充分理由。

3. Particulate Matter Testing

3 微粒测试

Particulate matter consists of extraneous, mobile, undissolved substances, other than gas bubbles, unintentionally present in parenteral solutions.

微粒是指在注射液中无意出现的物质，除了气泡，还包括外来、易变的不溶性异物。

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.

必须建立非活性微粒污染的洁净度标准或水平。限度通常基于过程的历史数据。USP中关于LVP的微粒测试规程和限度可作为一般的指导原则。然而，无菌粉末中的微粒污染水平通常比LVP要高。LVP的溶液通常在灌装的操作时经过过滤。然而，无菌的粉末，除西林瓶冻干粉末外，不能将过滤作为灌装操作的一部分。无菌粉末在进行喷雾干燥时，由于干燥过程中的碳化也会出现大量的微粒污染。

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.

审核微粒测试规程和放行标准。审核收到的关于微粒投诉的所有批次的生产和控制记录。

o Production Records

生产记录

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.

生产记录应当和其他剂型的记录相仿。关键步骤，如过滤器的完整性测试，应当由第二负责人签字并标注日期。

Review production records to ensure that directions for significant manufacturing steps are included and reflect a complete history of production.

审核批生产记录保证含有重要生产步骤的指令并能反映生产的完整历史。

Ointments, Liquids, and Lotions 膏剂，液体，和洗剂

Major factors in the preparation of these drugs are the selection of raw materials, manufacturing practices, equipment, controls, and laboratory testing.

制备这些药物主要的因素有原辅料的选择，生产过程，设备，控制，和实验室测试。

Following the basic drug inspection fundamentals, fully evaluate the production procedures. In addition, evaluate specific information regarding:

根据基本的药物视察原则，充分评估生产操作规程。另外，下面的相关信息也要评估：：

o The selection and compatibility of ingredients.

活性组分的选择和相容性

o Whether the drug is a homogeneous preparation free of extraneous matter.

药物是否是不含异物的均一性制剂

o The possibility of decomposition, separation, or crystallization of ingredients.

活性组分降解，分离或结晶的可能性

o The adequacy of ultimate containers to hold and dispense contents.

最终容器用于盛装和分散药物的充分性

o Procedure for cleaning the containers before filling.

灌装前容器的清洗规程

o Maintenance of homogeneity during manufacturing and filling operations.

生产和灌装操作均一性的维持

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.

这些剂型生产的最普遍的问题是由于纯化水系统的错误设计和/或控制导致的微生物污染。检查时要评估水系统的适合性。审核和评估水系统日常监测的生化测试结果，包括水系统的验证。审核所有成品的微生物测试包括中控测试在内。

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..

一些药物加入防腐剂来保护他们免受微生物污染。防腐剂主要在多剂量西林瓶中使用以抑制生产过程中或后来偶然引入的微生物的生长。评估防腐剂系统的是适当性。防腐剂对这些产品的有效性测试也要被审核。另外，可回顾U.S.P “抗微生物的防腐剂效果”一章。

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.

用于外用药物的设备清洗较困难，尤其是那些包含不溶性的活性组分药物，如磺胺类药物。应当审核和评估工厂的包括清洁验证的数据在在内的设备清洁规程。

Packaging and Labeling [21 CFR Subpart G] 包装和贴签

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.

包装和贴签操作必须进行控制以保证只有符合主处方记录中质量标准的药物被发放。详细审核包装和贴签操作以确定系统防止药物和标签的混淆。大约25%的药物召回起源于此。

Evaluate what controls or procedures the firm has to provide positive assurance that all labels are correct. Determine if packaging and labeling operations include:

评估工厂采取何种控制或操作规程对贴标的正确性提供积极地保障。确定是否包含以

下的包装和贴签操作：

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

贴标与包装操作与生产加工区是否有足够的物理隔离。

o Review of:

审核：

1. Label copy before delivery to the printer.

1分配到打印机前标签的复制

2. Printer's copy.

2 印刷品的复制

3. Whether firm's representative inspects the printer.

3 工厂是否对打印机进行了检查

4. Whether or not gang printing is prohibited.

4多项印刷标签是否被阻止 (空白标签等)

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.

5 在放行入库前标签是否与主标签进行了对照检查。确定标签放行至生产前由谁负责进行审核。同时，确定标签是否与批生产记录中要求的标签一致。

o Separate storage of each label (including package inserts) to avoid mixups.

每个标签的存放（包括包装说明书） 都要分开以阻止混淆

o Inventory of label stocks. Determine if the printer's count is accepted or if labels are counted upon receipt.

标签储存的目录。决定是接收印刷品的数目或标签接受时是否点清。

o Designation of one individual to be responsible for storage and issuance of all labels.

指定专人负责标签的存储和发放。

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.

包装和贴标部门对批记录或其他记录的收据要注明该批所需的标签数量。确定批记录是由包装主管保留还是与标签一起放在包装贴标线上。

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.

对标签发放、使用和回收的数量要有足够的控制。确定是否对剩余的标签进行计数，对印有特别控制编码的剩余标签，废弃标签或变更的标签进行销毁。

o Inspection of the facilities before labeling to ensure that all previously used labeling and drugs have been removed.

贴标签前对厂房设施进行检查以确保所有以前使用过的标签和药品已被清除。

o Assurance that batch identification is maintained during packaging.

确保包装过程中批的状态标识。

o Control procedures to follow if a significant unexplained discrepancy occurs between quantity of drug packaged and the quantity of labeling issued.

控制规程要检查已包装的药品数量和发放的标签数量是否发生了原因不明的偏差。

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.

在同一时间每批产品的贴签设施要互相隔离。否则，需要确定采取什么步骤防止混淆。

o Methods for checking similar type labels of different drugs or potencies to prevent mixing.

检查不同药品或规格的相似标签的方法以防止混淆。

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.

待验已完成包装的产品以便进行充分的检查或对代表性样品进行测试以预防错误发生。同时，在所有规定测试都符合前要防止任一批次的发放。

o An individual who makes the final decision that the drug should go to the warehouse, or the shipping department.

需有人最终决定药品应当运往仓库还是发运部门。

o Utilization of any outside firms, such as contract packers, and what controls are exercised over such operations.

与任何公司外公司的合作，如：合同包装商，需确定这些操作是如何进行控制的。

Special attention should be devoted to firms using \"rolls\" of pressure sensitive labels. Investigators have found instances where:

应当对公司使用滚动式压力敏感性标签给予特别关注，检察官已发现的例子如下：

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.

使用切割式标签会引起非常严重的问题，应对其进行详细评估。大多数的公司都在使用滚动式标签代替切割式标签。

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.

审核21CFR369中对OTC的产品标签的警告

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.

必须使用一个控制编码对某个特定批的成品进行识别，或控制号可确定该批完整的生产和控制历史。

Determine:

确定：

o The complete key (breakdown) to the code.

编码的完整元素（分项数字）

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.

在最终包装中的控制号码是否与批号相同。如果不是，确定最后的包装控制号码如何相关联，和如何被用于识别原始批。

Beginning August 3, 1994 the following new requirements will become effective:

在1994年8月3日，下面的新的要求将生效.

o Use of gang-printed labels will be prohibited unless they are adequately differentiated by size, shape or color. (211.122(f))

多项印刷标签将被禁止除非他们能从大小，形状或颜色上可以充分区别。

o If cut labels are used one of the following special control procedures shall be used (211.122(g)):

如果使用切割式标签，应使用下面的某项特殊控制规程：

(1) Dedication of packaging lines.

包装线专用。

(2) Use of electronic or electromechanical equipment to conduct a 100-percent examination of finished product.

使用电子或电动机械设备对最终产品进行100%的检查。

(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.

使用目检对于手工贴签的成品进行100%检查，目检由一人操作，另一人独立复核。

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).

如果切割式或滚动式标签根据211.22(g) (2) 100%全检，就可根据211.125的要求免除标签的物料衡算。

Holding and Distribution [21 CFR subpart H]

贮存和发放

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.

检查成品储存区和发运区的卫生条件，存货周转以及特殊药品的特殊储存条件。评估所有不合格的药品，或者包括常规原因在内的因素造成的暂停。

Laboratory Controls [21 CFR Subpart I]

实验室控制

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.

实验室控制应包含足够的质量标准和检测规程以确保组分，中控和成品符合相应的均一性、规格、质量和纯度的标准。

In order to permit proper evaluation of the firm's laboratory controls, determine:

为了对公司的实验室控制进行合适的评估，需确定：

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.

公司对生产中使用的所有原辅料是否建立了质量标准的主文件。该主文件应包含取样程序，取样量，被取样的容器数量，样品的鉴定方式，所进行的检测，以及组分在恶劣条件下的复验日期。

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.

公司关于鉴定方案的政策。这些报告通常由原辅料供应商提供。然而， 工厂要负责通过定期进行全检和对接收的所有原辅料进行日常鉴别来对这些方案进行确认。

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.

实验室对处于待验的原辅料、成品的放行规程。确定谁负责作出此决定。原辅料的质量标准应包含经批准的供应商。对于NDA或ANDA的药物，它们质量标准中列出的批准供应商应当与NDA或ANDA批准的一致。

o If the laboratory is staffed and equipped to do all raw material, in-process, and finished product testing that is claimed.

实验室的人员和设备是否能完成他们所声称的所有原辅料、中控和成品的检测。

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.

在加工过程中是否对药物制剂进行测试。如果是，确定所进行测试的类型，是否从各个不同的加工阶段获取代表性样品。

o Specifications and description of laboratory testing procedures for finished products.

成品的质量标准和实验室检测规程的描述

o Procedures for checking the identity and strength of all active ingredients including pyrogen and sterility testing, if applicable.

检查所有活性组分均一性和规格的规程，必要时应包括热原和无菌测试。

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.

如果实验室做热原测试，安全测试或生物鉴定。确定实验室动物的数量，以及它们的喂养和安置是否充分。确定周末和节假日需提供的照料方法。

o Sterility testing procedures.

无菌测试规程

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:

人员进入应当进行永久记录，无论阴性或阳性要显示所有的结果。检查经测试的代表性样品及其记录。当检查无菌测试规程时，确定：

1. Physical conditions of testing room. The facility used to conduct sterility testing should be similar to those used for manufacturing products.

测试房间的物理条件。用来进行无菌测试的设施应与生产药品时的设施类似。

2. Laboratory procedures for handling sterile sample.

无菌样品的实验室操作规程

3. Use of ultra-violet lights.

紫外灯的使用

4. Number of units tested per batch.

每批测试的数量

5. Procedure for identifying test media with specific batches.

使用特定批次鉴定测试培养基的规程

6. Test media's ability to support growth of organisms.

测试培养基支持微生物生长的能力

7. Length of incubation period.

培养时间

8. Procedure for diluting products to offset the effects of bacteriostatic agents.

稀释产品以抵消抑菌剂效果的规程

o Pyrogen testing procedures

热原测试规程

Determine if animals involved in positive pyrogen tests are withdrawn from use for the required period.

确定参与阳性热原测试的动物在要求的时间内不能使用。

If the L.A.L. Test is used, review the FDA \"Guideline on Validation of the Limulus Amebocyte Lysate Test ***.\"

如果使用LAL测试，回顾FDA的“鲎试剂测试验证指南”。

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.

如果由外部实验室进行测试，报告实验室的名称和他们所进行的测试。确定公司所采取的措施以确保外部实验室的工作真实可信。

o Methods used to check the reliability, accuracy, and precision of laboratory

test procedures and instrumentation.

用于检测实验室操作规程和仪器仪表可靠性、准确性和精度的方法。

o How final acceptance or rejection of raw materials, intermediates, and finished products is determined. Review recent rejections and disposition of affected items.

如何对原辅料、中间体和成品作出最终接受或拒绝的决定。审核最近的拒绝及受影响的物品的处置。

o The provisions for complete records of all data concerning laboratory tests performed, including dates and endorsements of individuals performing the tests, and traceability.

条文规定对设计实验室测试数据进行完整记录，包括日期和测试人员的签注，及可追溯性。

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.

对组分和成品，应评估留样程序和规程。挑战该系统，确定样品是否被保留并能够重新找回。储存容器必须能保持产品的完整性。

o Whether stability tests are performed on:

是否进行了如下的稳定性测试：

1. The drug product in the container and closure system in which marketed.

在市售容器和密封系统中的药品

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.

配料时根据标签指令配制的溶液。确定失效期（建立在相应稳定性研究基础上）是否含在标签中。

o If penicillin and non-penicillin products are manufactured on the same premises, whether non-penicillin products are tested for penicillin contamination.

如果青霉素和非青霉素产品在同一厂房内生产，非青霉素产品是否进行了青霉素污染的测试。

Obtain copies of laboratory records, batch records, and any other documents that show errors or other deficiencies.

获取实验室记录，批记录和任何显示错误或其他偏差的文件。

Control Records [21 CFR Subpart J]

控制记录

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

主生产和控制记录

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.

各种主生产和控制记录非常重要，因为它们管理着生产和控制所有阶段。主记录如果出错将会严重影响产品。这些记录必须根据CGMPR 的条文CFR211.186要求准备。这些记录可能不会放在同一个地点，但应当随时供审核。

2. Batch Production and Control Records [21 CFR 211.188]

批生产和控制记录

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.

批生产和控制记录必须记录生产、贴标、包装和特殊批的控制的每一个重要步骤。21CFR211.188提供了批记录必须提供的一些基础信息。一个完整的生产和控制的记录可能由多个不同的记录组成，这些记录应当随时提供给检察官。

Routinely check the batch record calculations against the master formula record. Give special attention to those products on which there have been complaints.

日常检查与主处方记录不同的批记录运算。对有投诉的产品给予特别关注。

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.

警惕从主处方记录到批记录转换时出现的错误。警惕转化或复印时的错误，如对符号，缩写和小数点的误解等等。

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.

重要的是，批生产记录在设备（V型混合器VS带式混合器等）和加工时间（混合时间

和速度）的记录上应具体。设备应有它自身独特的识别码。这些产品的生产过程必须标准化、可控并经过验证。

3. Distribution [21 CFR 211.196]

发放

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.).

应根据21CFR211.196保留完整的发放记录。警惕那些已被滥用的或被FDA当局列为优先调查目标的可疑产品的发运，包括类固醇，假药，转移药（如医师样品，临床包装用药等）。

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.

确定和评估公司是否检查订单的真实性。所用的参考，如AMA目录，Hays目录等的现行版本。

4. Complaint Files [21 CFR 211.198]

投诉文件

21 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.

21CFR211.198要求应该保存所有书面和口头的投诉记录。除了处方药，尽管FDA没有权利要求制药公司公开他们的投诉文件进行审核。

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.

投诉文件应当随时准备以供审核。对所有适用的顾客投诉都要做随访调查。审核和评估公司处理投诉的规程。确定是否所有的投诉都已处理，没有不适当的摒除。

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

审核投诉并确定是否经过了全面调查。评估公司的调查结论，并确定是否已采取了适当的纠正措施。确定产品是否应当召回，或者决定是否采取了正确的措施。决定是否产品应该被召回，或由FDA批准进行全面的检查。

Returned Drug Products [21 CFR Subpart K]

退货药品

Returned drugs often serve as an indication that products may have decomposed during storage, are being recalled or discontinued.

退货通常表示产品可能在储存过程中发生分解，正被召回或停止上市。

Determine how returned drug items are handled. For example, are they quarantined, destroyed after credit, or returned to storage?

确定退货药品的处理方式。例如，是待验，销毁，或者返回后储存？

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.

如果有一个异常大量的某种药品即将使用，找出原因。检查退货的药品是否在实验室检查，由谁做出使用这些退回药物的最终决定。

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.

注：倾销从废品中回收利用的药物是潜在的危险操作。建议管理部门适当处理药物阻

止回收利用。药物应按照E.P.A的规定来处置。