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”
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。
一，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，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。 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； 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。 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。 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 生产现场的标识不在乎以下几个方面： 1.1生产区域的标识。包括生产区域的总平面图，不同洁净级别区域的标志，按定置管理要求划分的 不同区域进入控制区的程序等 1.2生产设备容器和管线的标识，包括设备容器的名称、编号、型号规格和安装日期等，以及用不同 颜色区分不同类型的管线并标明流向。 1.3设备运转状态的标识、标明设备处于生产、清洗还是维修等。 1.4生产过程的各种物料的标识，包括原辅料、包装材料、半成品或中间体和成品的品名、批号、数 量、来源等标识及标明检验状态的标识（待验、合格或不合格） 2.仪器、仪表、量具和衡器的校验 生产和检验的仪器、仪表、量具和衡器等准备与否，关系到工艺参数的控制与检验结果的准确性，如其出现差错，在产品的生产和质量控制中操作者会产生错误的判断，产品质量难以保证，FDA官员对此非常重视，检查中特别关注厂房生产和检验的仪器、仪表、量具和衡器等的管理。
注意事项 永远要讲实话。 这是药厂在针对现场检查的公司声明材料中，必须强调的内容，任何人要回答FDA的问题，都需要进行事先培训知道这些程序和原则。 不要答非所问，超出提问要求回答的内容和范畴。 先考虑好如何回答问题，确信保您正确理解它，并知道如何给出你要的答案。如果您不能确定具体问的是什么，请与调查人员澄清。如果FDA的检查员没有反应，耐心等到他或她作出解释为止。如果FDA检查员对你的回答没有发表评论，等待其作出评论。正常的社交规则不适用现场考察过程。通常情况下，FDA检查员通常会让你等待不耐烦，试图提示您主动谈更多情况。不要中其诱饵。 澄清被要求回答的问题。如果你不明白FDA问什么，试图问清提问的含义或目的。如果这个问题似乎过于宽泛，可以要求FDA更明确具体为题所问。最重要 的是，如果所涉的问题有错误，与检查员澄清问题的范围或给出不妥的理由。 尽力限制钓鱼式的敏捷。美国FDA往往要求你回答很广泛的问题。尽力缩小回 答的范围。例如，如果现场考察人员说，“我想看看您的申诉材料和文件。”你可以回应说：“你要的是哪一年材料？”或想看哪类“产品？”或“您是否正在寻找一个特定类型的投诉？“ 在回答同问题的同时反问FDA检查员问题，可以在 两方面帮助您。首先，您表示出您愿意帮助查看FDA检查员寻找的申诉文件。 其次，检查员无法简单给你回复的是或否的答案，让你更加有数他们到底想看什么。请记住，现场考察人员有权要求所有的档案，但更多情况下是，提出你的问题将有助于完善你的理解和回答。 如果你不知道某一个问题的答案，就坦率这么说。一时不知道答案这没关系。最佳对策是要找到知道问题答案的人或发现这一问题答案，如果适合您这样做的话。
Food and Drug Administration Compliance Program Guidance Manual FDA检查员指导手册：7356.002F 56002F- Active Pharmaceutical Ingredient Process Inspections (Drug Quality Assurance) 56002F-原料药生产检查（药品质量保证）
目录 现场检查报告要求 (55) 第I部分背景 (56) 第II部分实施 (57) 第III部分检查 (58) 第IV部分分析 (63) 第V部分法规/行政策略 (65) 第VI部分参考资料，附件和联系接触方式 (68) 第VII部分中心的职责 (69) 附件A (69) 附件B (72)
现场检查报告要求 工艺专论报告 在API检查时，要使用下列的分类进行报告所检查的工艺情况1．Non Sterile API by Chemical Synthesis CSN 化学合成非无菌原料CSN 2．Sterile API by Chemical Synthesis CSS 化学合成无菌原料药CSS 3．Non Sterile API by Fermentation CFN 发酵生产的非无菌原料CFN 4．Sterile API by Fermentation CFS 发酵生产的无菌原料CFS 5．Plant/Animal Extraction API CEX 植物/动物提取原料药CEX 6．Biotechnology API CBI 生物技术生产的原料药CBI
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 and 211)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：https://www.doczj.com/doc/7715546343.html,/cder/api.htm.。
Guidance for Industry Container Closure Systems for Packaging Human Drugs and Biologics Chemistry, Manufacturing and Controls Documentation 行业指南 人用药品及生物制品的包装容器和封装系统：化学，生产和控制文件 指南发布者：美国FDA下属的CDER及CBER 发布日期：May 1999 TABLE OF CONTENTS目录 I. INTRODUCTION介绍 II. BACKGROUND 背景 A. Definitions 定义 B. CGMP, CPSC and USP Requirements on Containers and Closures. CGMP, CPSC和 USP对容器和密封的要求 C. Additional Considerations 其他需要考虑的事项 III. QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS包装组件的合格要求以及质量控制 A. Introduction 介绍 B. General Considerations 通常要求 C. Information That Should Be Submitted in Support of an Original Application for Any Drug Product 为支持任何药品的原始申请所必须提供的信息 D. Inhalation Drug Products 吸入性药品 E. Drug Products for Injection and Ophthalmic Drug Products 注射剂和眼科用药 F. Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems 液体口服 和外用药品和外用给药系统 G. Solid Oral Dosage Forms and Powders for Reconstitution 口服固体剂型和待重新溶解 的粉末 H. Other Dosage Forms 其他剂型 IV. POSTAPPROVAL PACKAGING CHANGES 批准后的包装变更 V. TYPE III DRUG MASTER FILES 药品主文件第III类 A. General Comments 总体评述 B. Information in a Type III DMF 第III类DMF中包括的信息 VI. BULK CONTAINERS 大包装容器 A. Containers for Bulk Drug Substances 用于原料药的容器 B. Containers for Bulk Drug Products 用于散装药品的容器 ATTACHMENT A 附件A REGULATORY REQUIREMENTS 药政要求
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 (35) 第一部分背景 (36) 第二部分执行 (36) 2.1.目的 (36) 2.2.策略 (36) 2.2.1.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） (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) 2.2.3.2.厂房设施与设备系统 (38) 2.2.3.3.物料系统 (38) 2.2.3.4.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)
3.1.3.1.质量系统 (44) 3.1.3.2. 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)
接受FDA 检查的几点体会 郝运杰 (河北省石家庄市华曙制药厂 050031) 摘要 本文简要叙述了我厂化学原料药接受FDA 检查的过程,对FDA 检查中特别重视的几个G MP 管理问 题进行了深入分析,从而为完善原料药G MP 管理,促进我国的原料药打入美国市场提供参考。关键词 化学原料药 FDA 检查 G MP 管理 中图分类号:R95 文献标识码:A 文章编号:1002-7777(2002)12-0745-03R ealizing form FDA I nspection Hao Y unjie (Shijiazhuang Huashu Pharmaceutical Factory ,Hebei Province ,050031)ABSTRACT The procedure for FDA inspection bulk pharmaceutical chemicals (BPCs )is briefly instructed.Several queations for G MP management from FDA inspection are described.This article provide a reference for strengthening the G MP management and for prom oting BPCs enter to US market. KE Y WOR DS bulk pharmaceutical chemical ;FDA inspection ;G MP management 在当前日益激烈的国际市场竞争中,医药产品如果能够打入美国市场,无疑是获得了一张竞争王牌,不仅药品的生产质量管理得到认可,产品的售价也会有所提高。而绝大多数医药产品进入美国前,必须通过美国FDA 的检查。FDA 是美国食品药品管理局(F ood and Drug Administration )的简称,是美国卫生和人类健康服务部下设的公共卫生署的 一个下属机构,其宗旨是确保工业产品完全符合联邦管理法的法规,以保证食品、药物(包括兽用药品、生物制品)、医疗器械、化妆品等安全、有效。药品进入美国市场首先要有美国用户,用户的需要是申请FDA 检查的必要条件。申请时,首先编写DMF (Drug Master File 药品管理档案),阐明产品制造的相关资料,包括工厂概况、成品质量标准、检验方法、产品的生产过程、生产设备、所用原辅材料和包装材料质量标准及检验方法、产品的稳定性试验、杂质论述、验证和厂区平面图等资料。FDA 接到DMF 后,将发函告知DMF 已收到,给定DMF 的分配号,同时提醒厂家对DMF 中变更的内容按年度通知FDA ,并作好接受FDA 现场检查的准备。 FDA 一般在现场检查前1～2个月通知生产厂, 时间非常紧。故一旦申报,生产厂应严格按照cG MP (Current G ood Manufacturing Practice )要求提 前作好各项基础管理工作,尤其要保证实际情况与DMF 声称的内容相一致。FDA 官员来厂后,常常以批为线索,对照DMF 和厂方的生产质量管理文件,通过查阅各种记录、查看现场、对操作人员或管理人员提出问题、让操作人员现场演示等方式进行检查并记录。在检查结束前,FDA 官员将一份Inspectional Observations 表,即我们通常所说的 “483文件”交给厂方,提出检查中发现的问题。厂方应及时整改并以书面的形式答复上述问题。FDA 对检查结果及提出问题的答复进行汇总和综合 评估,如认为该产品可以进入美国市场,会在给厂方的信中表明该产品的生产质量管理按cG MP 要求进行,并提醒厂方这并不意味着完全符合cG MP ,应不断加强管理。 产品进入美国市场后并不是一劳永逸,每2～3年还要进行一次复查,复查程序与初次检查程序 基本相同。 近年来,FDA 加强了对出口到美国药品的检查,到现场检查的官员和检查时间相应增加,由原来1人检查3天,改为2人检查5天。而且2人进行了明确分工,一人侧重于生产现场,另一人侧重于试验室控制。笔者经历了华曙药厂土霉素碱的1998年7月的初次检查和2001年5月的复查及盐 酸土霉素的初次检查,明显感觉到FDA 现场检查 ? 547?中国药事2002年第16卷第12期
备注： 本文件是供检查员和其他的FDA人员的参考。并不限制FDA，并不获取任何利益，义务，权利，或豁免某人 I简介 本文件旨对制药厂CGMP检查提供一个概括性指导。这个指导应该结合其它IOM（Investigations Operations Manual）的指南，其他的药物检查指导，和应遵循的规定。IOM的第十章，所列的一些指导如下： 1 原料药视察指导 2 高纯水系统视察的指导 3 QC实验室视察的指导 4 微生物QC实验室的指导 5 冻干注射剂视察的指导 6 清洁验证视察的指导 7 制药过程中的计算机系统的视察的指导 8 工艺过程验证通则的指导 II CGMP 处方和非处方 所有的药物的生产过程要遵守CGMP否则就被认为违反FD&C（食品药品化妆品法案） 501（a）(2)(B)条款。 依据704（a）(1)(B)章, 处方药物的记录一定要随时备查。如果是NDA或ANDA所列的OTC药物，根据FDC 505（k）(2)规定，FDA可以审查，复制，核对。然而，如果视察员是根据FDC 704条款到厂检查，则没有法律要求厂方，把那些在FDA没注册过的OTC 药物记录提供给视察者。所有的处方药和OTC 药的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
FDA检查员指导手册 7356.002F 原料药生产检查（药品质量保证）
第一部分背景 总则 法案的501(a)(2)(B)条款要求所有药品的生产都必须遵守现行GMP 的要求，而原料药也不例外。关于原料药和制剂这两者的要求，法案并没有区不对待，而任何原料药或制剂方面的GMP缺陷都构成了对法案的偏离。关于原料药或药物成分来讲，FDA并没有为此而专门公布cGMP法规文件（就像我们现在有的制剂cGMP法规一样）。因此，本文提到的“cGMP”指的是法案要求，而并非美国联邦法规（CFR）第21部分210和211条款中关于制剂的要求。 事实上，FDA早就意识到cGMP对制剂的要求（美国联邦法规第21部分210、211条款）在理念上关于原料药生产来讲同样适用且有效。这些理念包括使用合适的设备；聘用通过培训且通过资质确认的人员；建立充分合理的书面程序和操纵，确保生产工艺和操纵的有效性，从而保证产品质量；建立一套中间体和最终药品检测方法的体系，确保药品在规定的使用期限内保持质量的稳定性。2001年，FDA在人用药物注册技术要求国际协调会议（ICH）上与其他政府监管部门共同努力，采纳了针对API 行业cGMP的国际性指南，也确实是ICH Q7A，活性药物成分的药品质量治
理的指南。ICH Q7A正体现了FDA关于原料药现行GMP体系的要求。因此，遵循该指南要求的API及其相关生产和检验设施是符合法定cGMP要求的。然而，只要是能符合法案501(a)(2)(B)的要求，并能确保API符合其纯度、均一性和质量特性的方法都能够采纳。 在本程序中所使用的术语“活性药物成分”（原料药）的含义与ICH Q7A 中的定义一致。在ICH Q7A中活性药物成分被定义为“旨在用于药品生产的任何物质或混合物，当用于药品生产时，这些物质即成为药品中的活性成分。这种物质被用来提供药学活性或在诊断、治疗、止痛、缓解、处理或疾病预防中起着直接作用或用于阻碍机体结构和功能。”目前，FDA 和原料药行业也会采纳其它术语来表示原料药。“药物成分”和“BPC”最常用，而BPC则表示非活性成分。这些术语和那个地点所使用的“API”意义等同。 FDA希望API厂家从起始原料的使用开始，到对原料药质量和纯度产生阻碍的关键工艺步骤的验证，即在API生产的全过程实施cGMP。越接近API 最终成品工序，就越要加强对物料质量的操纵。所需的操纵程度要紧取决于生产过程，且随着生产过程从起始中间体到最终的分离和纯化步骤而逐渐加强。操纵的强度还需依照每一步具体工序的风险性或关键性而定。 为了在合适的系统下生产原料药，并做好原料药的质量治理工作，ICH
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)
1 QUALITY SYSTEM质量保证系统 1.1 Product reviews (annual) 产品审查(年度) 1.2 Complaint reviews (quality and medical) 投诉审查(质量和医疗) 1.3 Discrepancy and failure investigations 不一致和失败的调查 1.4 Document Control 文件控制 1.5 Batch release 批放行 1.6 Change Control变更控制 1.7 Reprocess/Rework再加工/返工 1.8 Returns/Salvages 退回/补救 1.9 Rejects 拒收 1.10 Stability Failures稳定性失败 1.11 Quarantine 待验 1.12 Validation: computer, equipment, process, laboratory methods, cleaning 验证：计算机、设备、工艺、实验方法、清洁 1.13 Training/qualification 培训/资质 1.14 internal Audit Program内审规程 1.15 Supplier Audit Program 供应商审计规程 2 FACILITIES AND EQUIPMENT SYSTEM 厂房设施与设备系统 I Facilities 厂房设施 2.1 cleaning and maintenance 清洁与维护保养 2.2 facility layout and air handling systems厂房设施布局与空气处理系统 2.3 general air handling systems 全面的空气处理系统 2.4 control system for implementing changes in the building实施在厂房方面变更的控制系统
资产财务检查工作指引 一、抽查事项 （一）行政、事业单位国有资产管理及财务管理情况。 （二）企业、社会团体财务管理情况。 二、检查内容和方法 （一）检查内容 1、是否制定单位国有资产管理具体办法或规章制度，并组织实施，制度包括对国有资产配置、使用、处置等环节的具体规定。 2、是否有专门部门、专人负责国有资产的管理工作，包括账卡管理、资产信息系统管理、财产清查登记、统计报告及日常监督检查等工作。 3、是否按规定出租、出借和处置国有资产。 4、是否定期处理往来账务(应收应付款项)和挂账业务(应列支出未列支挂往来账)、是否每年定期进行内部资产清查。 5、是否存在浪费、流失国有资产现象；是否存在超标准配置资产。
（二）检查方法 1、查看国有资产管理制度建立情况和执行情况； 2、国有资产台账和国有资产账簿记录是否一致； 3、查看资产信息系统的卡片是否规范，项目填写是否完整、真实与国有资产账簿记录是否一致； 4、查看国有资产会计处理是否有长期未处理的往来款项或挂账，行政事业单位是否按机关事务管理局批复处置资产，是否形成国有资产损失； 5、根据资产台账或卡片抽查单位实有资产是否存在，是否造成国有资产损失等。 三、检查依据 （一）《财政部门监督办法》（财政部令第69号） 第十六条财政部门依法对下列事项实施监督： （一）财税法规、政策的执行情况； （二）预算编制、执行、调整和决算情况； （三）税收收入、政府非税收入等政府性资金的征收、管理情况； （四）国库集中收付、预算单位银行账户的管理使用情况； （五）政府采购法规、政策的执行情况；
（六）行政、事业单位国有资产，金融类、文化企业等国有资产的管理情况； （七）财务会计制度的执行情况； （八）外国政府、国际金融组织贷款和赠款的管理情况； （九）法律法规规定的其他事项。 对会计师事务所和资产评估机构设立及执业情况的监督，由省级以上人民政府财政部门依法实施。 （二）《行政单位国有资产管理暂行办法》（财政部令第35号） 第八条各级财政部门是政府负责行政单位国有资产管理的职能部门，对行政单位国有资产实行综合管理。其主要职责是： （一）贯彻执行国家有关国有资产管理的法律、法规和政策； （二）根据国家国有资产管理的有关规定，制定行政单位国有资产管理的规章制度，并对执行情况进行监督检查； （三）负责会同有关部门研究制定本级行政单位国有资产配置标准，负责资产配置事项的审批，按规定进行资产处置和产权变动事项的审批，负责组织产权界定、产权纠纷调处、资产统计报告、资产评估、资产清查等工作； （四）负责本级行政单位出租、出借国有资产的审批，负责与行政单位尚未脱钩的经济实体的国有资产的监督管
中美药品检查员队伍情况 一、FDA的检查员队伍情况 （一）、FDA的基本情况 美国食品和药物管理局(Food and Drug Administration，简称FDA)，FDA 是美国政府在健康与人类服务部(DHHS) 和公共卫生部(PHS) 中设立的执行机构之一。在国际上FDA被公认为是世界上最大的食品与药品管理机构之一，世界许多国家都通过寻求协助或参考FDA 的先进经验以提高本国产品的质量和安全水平。 FDA有员工9000余人，遍及全国167个城市。整个FDA 按工作职能分为局长办公室、生物制品审评与研究中心、药品审评与研究中心、食品安全与营养中心、医疗器械与放射性产品健康中心、兽药中心、国家毒理学研究中心、监督管理办公室（ORA）等8个主要监管机构。 （二）、FDA药品检查员情况 作为FDA所有药品检查工作的主管部门，ORA的首要任务就是调查（investigation）和检查（inspect）被监管公司以确定它们对公众健康法律的遵守情况，保证在FDA监管下的产品符合相应的公众健康法律和规章。ORA监管工作原则为：向相关产业提供指导信息；指出显著违法的领域及其对公众健康的影响；优先考虑并将目标定位于高风险领域监管。
FDA通过ORA直接对药品进行日常监督管理，ORA对个FDA各大区分局实行垂直领导，这种对检查的统一组织及管理形式有助于统一药品监督管理的标准，提高工作效率。ORA下设立了4个中央办公室和5个地方大区办公室，分别为：资源管理办公室、执行办公室、地区运行办公室、犯罪案件调查办公室、中部地区办公室、东北部地区办公室、太平洋地区办公室、东南地区办公室、西南地区办公室，另外还有13个药品检验所。ORA 在全国各地建立了众多的派出机构，各派出机构的人员数量约占FDA总人数的三分之一（约3000人），是FDA履行职责和掌握情况的重要部门。 ORA作为FDA检查员队伍的核心，指导并派出药品检查员实施各项检查工作，并与各州和地方公众健康机构和监管者共同协作，为公众的用药安全建立了可靠的保障。 1、FDA药品检查员数量、分级和管理 FDA设立了一套完整的检查员评估体系对检查员的实际工作进行考核和评估，检查员根据上述的各系统的综合评定结果划分为三个级别： 一级药品检查员（Level I certification audits），FDA通过对检查员上一年的工作表现和能力体现进行评估，符合要求者评为该级检查员。授予此级检查员资格的目的是确保新入职的检查员能够胜任FDA各类检查工作的职能，目前此级药品检查员数量约为1700人。
CFR - Code of Federal Regulations Title 21
Page 1 of 6
U.S. Food & Drug Administration
CFR - Code of Federal Regulations Title 21
1
FDA Home3 Medical Devices4 Databases5
6
510(k)7|Registration & Listing8|Adverse Events9|Recalls10|PMA11|Classification12|Standards13 CFR Title 2114|Radiation-Emitting Products15|X-Ray Assembler16|Medsun Reports17|CLIA18|TPLC19
2
New Search
Help20 | More About 21CFR 21
[Code of Federal Regulations] [Title 21, Volume 1] [Revised as of April 1, 2011] [CITE: 21CFR11] TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERAL PART 11ELECTRONIC RECORDS; ELECTRONIC SIGNATURES Subpart A--General Provisions Sec. 11.1 Scope. (a) The regulations in this part set forth the criteria under which the agency considers electronic records, electronic signatures, and handwritten signatures executed to electronic records to be trustworthy, reliable, and generally equivalent to paper records and handwritten signatures executed on paper. (b) This part applies to records in electronic form that are created, modified, maintained, archived, retrieved, or transmitted, under any records requirements set forth in agency regulations. This part also applies to electronic records submitted to the agency under requirements of the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, even if such records are not specifically identified in agency regulations. However, this part does not apply to paper records that are, or have been, transmitted by electronic means. (c) Where electronic signatures and their associated electronic records meet the requirements of this part, the agency will consider the electronic signatures to be equivalent to full handwritten signatures, initials, and other general signings as required by agency regulations, unless specifically excepted by regulation(s) effective on or after August 20, 1997. (d) Electronic records that meet the requirements of this part may be used in lieu of paper records, in accordance with 11.2, unless paper records are specifically required. (e) Computer systems (including hardware and software), controls, and attendant documentation maintained under this part shall be readily available for, and subject to, FDA inspection. (f) This part does not apply to records required to be established or maintained by 1.326 through 1.368 of this chapter. Records that satisfy the requirements of part 1, subpart J of this chapter, but that also are required under other applicable statutory provisions or regulations, remain subject to this part. [62 FR 13464, Mar. 20, 1997, as amended at 69 FR 71655, Dec. 9, 2004] Sec. 11.2 Implementation. (a) For records required to be maintained but not submitted to the agency, persons may use electronic records in lieu of paper records or electronic signatures in lieu of traditional signatures, in whole or in part, provided that the requirements of this part are met. (b) For records submitted to the agency, persons may use electronic
https://www.doczj.com/doc/7715546343.html,/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11... 2012/05/30