FDA无菌原料药检查指南-中英文版

GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERS

FDA无菌原料药检查指南

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：本文件是FDA现场检查官和其他FDA人员的参考资料。本文件并不束缚FDA，也不赋予任何人任何权利、特权、好处以便获得赦免。

One of the more difficult processes to inspect and one which has presented considerable problems over the years is that of the manufacture of sterile bulk drug substances. Within the past several years, there have been a number of batches of sterile bulk drug substances from different manufacturers which exhibited microbiological contamination. One manufacturer had approximately 100 batches contaminated in a 6 month time period. Another had approximately 25 batches contaminated in a similar period. Other manufacturers have had recalls due to the lack of assurance of sterility. Although the Inspection Guide for Bulk Drug Substances provides some direction for the inspection of the sterile bulk drug substance, it does not provide the detailed direction needed.

在过去多年中，现场检查最难的，也是出现问题最多的领域就是无菌原料药的制造。在过去几年中，有数批来自不同制造商的无菌原料药出现了微生物污染。一个制造商在6个月中有100批产品有污染。另一个在相同的时间内出现了25批污染。其它一些供应商由于缺少无菌保证而召回了产品。虽然大宗原料药的现场检查指南在对无菌原料药的检查上提供了一些指导，但它未能提供所需要的详细指导。

I. INTRODUCTION简介

In the manufacture of the sterile bulk powders, it is important to recognize that there is no further processing of the finished sterile bulk powder to remove contaminants or impurities such as particulates, endotoxins and degradants.

在大宗无菌粉的制造中，认识到下面一点很重要，即最终无菌粉生产出来之后，再也没有别的程序来去除微粒、内毒素和降解物。

As with other inspections, any rejected batches, along with the various reasons for rejection, should be identified early in the inspection to provide direction for the investigator. For example, lists of batches rejected and/or retested over a period of time should be obtained from the manufacturer to provide direction for coverage to be given to specific processes or systems. Because some of the actual sterile bulk

operations may not be seen, and because of the complexity of the process, it is particularly important to review reports and summaries, such as validation studies, reject lists, Environmental Monitoring Summary Reports, QA Investigation Logs, etc. These systems and others are discussed in the Basic Inspection Guide. This is particularly important for the foreign sterile bulk drug substance manufacturer where time is limited. In the preparation for a sterile bulk drug substance inspection, a flow chart with the major processing steps should be obtained. Generally, the manufacture of a sterile bulk substance usually includes the following steps:

与其它检查一样，在检查的早期，应向检查官提供拒绝使用的批（不合格批）及拒绝的各种

理由，以使检查官把握方向。例如，应从制造商处获得一段时间内拒绝的批（不合格批）清单，为检查具体的工艺或系统提供方向。由于某些实际无菌操作可能看不见，同时，工艺复杂，审阅报告和概括，如验证研究，拒绝（不合格批）清单，环境检测概括，质量保证调查记录等。这些系统和相关部分在基本现场检查指南中有论述。这对海外无菌原料药制造商尤其重要，因为时间有限，在准备无菌原料药现场检查时，应获得包含主要工艺步骤的流程图。通常，无菌原料药的生产包含如下步骤：

1. Conversion of the non-sterile drug substance to the sterile form by dissolving in a solvent, sterilization of the solution by filtration and collection in a sterilized reactor (crystallizer).

2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor.

3. Aseptic isolation of the sterile substance by centrifugation or filtration.

4. Aseptic drying, milling and blending of the sterile substance.

5. Aseptic sampling and packaging the drug substance.

1. 通过在溶媒中溶解，将有菌原料药转换为无菌原料药。通过无菌反应罐中的过滤和收集实现溶剂的灭菌。

2. 在无菌反应罐中进行无菌原料药的无菌沉淀或结晶。

3. 通过离心或过滤进行原料药的无菌离析。

4. 无菌原料药的干燥，磨粉和混合。

5.无菌抽样和包装。

These operations should be performed in closed systems, with minimal operator handling. Any aseptic operations performed by an operator(s) other than in a closed system should be identified and carefully reviewed.

这些操作应在封闭系统进行，尽可能少的人工参与。如果在密封系统之外的操作员进行无菌操作，应当标示出来并仔细审查。

II. COMPONENTS组成部分

In addition to the impurity concerns for the manufacture of bulk drug substances, there is a concern with endotoxins in the manufacture of the sterile bulk drug substances. The validation report, which demonstrates the removal, if present, of endotoxins to acceptable levels, should be reviewed. Some manufacturers have commented that since an organic solvent is typically used for the conversion of the non-sterile bulk drug substance to the sterile bulk drug substance, that endotoxins will be reduced at this stage. As with any operation, this may or may not be correct. For example, in an inspection of a manufacturer who conducted extensive studies of the conversion (crystallization) of the non-sterile substance to the sterile drug substance, they found no change from the initial endotoxin level. Organic solvents were used in this conversion. Thus, it is important to review and assess this aspect of the validation report.

除了担心无菌原料药的杂质之外，内毒素是无菌原料药生产中的另一担心。应当审阅去除内毒素的验证报告。一些制造商认为，由于使用了有机溶媒来把有菌原料药转换为无菌原料药，内毒素在此阶段已经减少。如其它操作一样，这可能正确，也可能不正确。例如，在对进行了大量有菌转换为无菌试验的制造商的现场检查中，他们发现内毒素的含量没有变化。转换中使用了有机溶媒。因此，审阅和评估此方面的验证报告很重要。

In the validation of this conversion (non-sterile to sterile) from an endotoxin perspective, challenge studies can be carried out on a laboratory or pilot scale to determine the efficiency of the step. Once it is established that the process will result in acceptable endotoxin levels, some monitoring of the production batches would be appropriate. As with any validation process, the purpose and efficiency of each step should be evaluated. For example, if the conversion

(crystallization) from the non-sterile to the sterile substance is to reduce endotoxins by one log, then data should support this step.

从内毒素角度来看该转换的验证(有菌到无菌)，重点应放在实验室或定点规模的研究来确定该步骤的有效性。一旦确定该工艺可以带来可接受的内毒素含量，只需监控批生产过程。如任何验证过程一样，每一步的目的和有效性均需证实。例如，如果一个记录显示有菌到无菌的转换（结晶）减少了内毒素，那么，该数据应支持该步骤。

Since endotoxins may not be uniformly distributed, it is also important to monitor the bioburden of the non-sterile substance(s) being sterilized. For example, gram negative contaminats in a non-sterile bulk drug substance prior to sterilization are of concern, particularly if the sterilization (filtration) and crystallization steps do not reduce the endotoxins to acceptable levels. Therefore, microbiological, as well as endotoxin data on the critical components and operational steps should be reviewed.

由于内毒素可能不是均匀分布，因此，监控灭菌中的有菌原料药的生物负荷也很重要。例如，有菌原料药中的某些污染在灭菌前会很严重，特别是如果灭菌和结晶过程不能减少内毒素含量。因此，应当审阅关键设备部分和操作环节的微生物和内毒素数据。

III. FACILITY设施

Facility design for the aseptic processing of sterile bulk drug substances should have the same design features as an SVP aseptic processing facility. These would include temperature, humidity and pressure control. Because sterile bulk aseptic facilities are usually larger, problems with pressure differentials and sanitization have been encountered. For example, a manufacturer was found to have the gowning area under greater pressure than the adjacent aseptic areas. The need to remove solvent vapors may also impact on area pressurization.

无菌原料药的无菌加工设备的设计应与SVP无菌设备具有相同的设计特征。这包括温度、湿度和压力控制。由于无菌设备通常更大，压力不均和清洁问题常常遇到。例如，在现场检查中发现，一个制造商在更衣区域的压力比临近的加工区域的压力更大。过滤和结晶过程使用的压缩空气也可能影响着洁净区域的压力。

Unnecessary equipment and/or equipment that cannot be adequately sanitized, such as wooden skids and forklift trucks, should be identified. Inquire about the movement of large quantities of sterile drug substance and the location of pass-through areas between the sterile core and non-sterile areas. Observe these areas, review environmental monitoring results and sanitization procedures.

不能充分清洗的非关键设备，如木刹车和叉车，应当标记。询问大量无菌原料药的流动和在有菌和无菌区域的穿行。观察这些区域，审阅环境监控结果和清洗程序。

The CGMP Regulations prohibit the use of asbestos filters in the final filtration of solutions. At present, it would be difficult for a manufacturer to justify the use of asbestos filters for filtration of air or solutions. Inquire about the use of asbestos filters.

cGMP条例禁止在溶液的最终过滤时使用石棉过滤器。目前，制造商很难找出使用石棉过滤器来过滤空气或溶液的理由，向FDA询问使用石棉过滤器的问题已无必要。

Facilities used for the charge or addition of non-sterile components, such as the non-sterile drug substance, should be similar to those used for the compounding of parenteral solutions prior to sterilization. The concern is soluble extraneous contaminants, including endotoxins, that may be carried through the process. Observe

this area and review the environmental controls and specifications to determine the viable and non-viable particulate levels allowed in this area.

用来运出或装入有菌成分的设备，如有菌原料药，应当与灭菌前生产注射制剂的设备相同。需要关注的是可溶解的外来污染物，包括内毒素，它们可能在生产过程传播。观察此领域，审阅环境控制和参数，以确定可允许的活性和非活性微粒标准。

IV. PROCESSING加工

Sterile powders are usually produced by dissolving the non-sterile substance or reactants in an organic solvent and then filtering the solution through a sterilizing filter. After filtration, the sterile bulk material is separated from the solvent by crystallization or precipitation. Other methods include dissolution in an aqueous solution, filtration sterilization and separation by crystallization/filtration. Aqueous solutions can also be sterile filtered and spray dried or lyophilized.无菌粉通常通过在有机溶媒中溶解有菌物质或反应物以及在灭菌过滤器中的溶液过滤来生产。过滤后，无菌大宗材料通过结晶或沉淀被分离出来。其它方法包括在水溶液中溶解，过滤灭菌和通过过滤或结晶离析。水溶液也可以是无菌过滤的，喷雾烘干或冻干。In the handling of aqueous solutions, prior to solvent evaporation (either by spray drying or lyophilization), check the adequacy of the system and controls to minimize endotoxin contamination. In some instances, piping systems for aqueous solutions have been shown to be the source of endotoxin contamination in sterile powders. There should be a print available of the piping system. Trace the actual piping, compare it with the print and assure that there are no "dead legs" in the system.

在水溶液的处理中，在溶液挥发前（喷雾烘干或冻干），检查系统的充足性和对减少内毒素污染的控制。在某些情况下，运送水溶液的管线被发现是无菌粉中内毒素污染的来源。应当有管线系统的照片。跟踪实际的使用，与照片比较，保证系统中没有“死角”。

The validation data for the filtration (sterilization) process should also be reviewed. Determine the firm's criteria for selection of the filter and the frequency of changing filters. Determine if the firm knows the bioburden and examine their procedures for integrity testing filters.

过滤（结晶）过程的验证数据应当审阅。确定公司选定过滤器的标准以及更换的频率。确定公司是否知道生物负荷并检查他们过滤器完整性检测的程序。

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 periods utilized and that "grow through" has not occurred.

过滤器在每批灭菌后不一定更换。确定在使用期内是否有数据证明过滤器的完整性以及“漏网”没有发生。In the spray drying of sterile powders, there are some concerns. These include the sterilization of the spray dryer, the source of air and its quality, the chamber temperatures and the particle residence or contact time. In some cases, charring and product degradation have been found for small portions of a batch.

在无菌粉的喷雾干燥中，有一些问题。这包括干燥器的灭菌，空气来源和质量，室内温度，颗粒存在或接触时间。有时，批产品中的部分中发现有色微粒和降解物。

With regard to bulk lyophilization, concerns include air classification and aseptic barriers for loading and unloading the unit, partial meltback, uneven freezing and heat transfer throughout the powder bed, and the additional aseptic manipulations required to break up the large cake. For bulk lyophilization, unlike other sterile bulk operations, media challenges can be performed. At this point in time, with today's level of technology, it would seem that it would be difficult to justify the bulk lyophilization of sterile powders (from a microbiological aspect). Refer to the Guide for the Inspection of a Lyophilization Process for additional direction regarding this process.

关于冻干，问题包括空气分类，装卸中的无菌保证、部分融化、粉床的冷热不均匀转移，额

外的无菌处理来打碎大块。对冻干，不象其它无菌操作可以用培养基测试。此时，依据今天的技术水平，很难证明大宗无菌粉的冻干（从微生物学的角度）是有保证的。额外的指导，参照冻干工艺现场检查指南。

Seek to determine the number and frequency of process changes made to a specific process or step. This can be an indicator of a problem experienced in a number of batches. A number of changes in a short period of time can be an indicator that the firm is experiencing problems. Review the Process Change SOP and the log for process changes, including the reason for such changes. 发现并确定具体工艺或步骤改变的次数和频率。这可以表明在一些批中经历的问题。短时间内出现的一些改变可以表明，该公司正经历着的问题。审阅工艺改变SOP和记录，包括改变理由。

V. EQUIPMENT设备

Equipment used in the processing of sterile bulk drug substances should be sterile and capable of being sterilized. This includes the crystallizer, centrifuge and dryer. The sanitization, rather than sterilization of this equipment, is unacceptable. Sterilization procedures and the validation of the sterilization of suspect pieces of equipment and transfer lines should be reviewed.

大宗无菌原料药使用的设备应灭菌而且能够被灭菌。这包括结晶器，离心机和烘干机。只对设备清洗而不灭菌是不能接受的。应当审阅灭菌程序和设备、管线灭菌的验证文件。

The method of choice for the sterilization of equipment and transfer lines is saturated clean steam under pressure. In the validation of the sterilization of equipment and of transfer systems, Biological Indicators (BIs), as well as temperature sensors (Thermocouple (TC) or Resistance Thermal Device (RTD)) should be strategically located in cold spots where condensate may accumulate. These include the point of steam injection and steam discharge, as well as cold spots, which are usually low spots. For example, in a recent inspection, a manufacturer utilized a Sterilize-In-Place (SIP) system and only monitored the temperature at the point of discharge and not in low spots in the system where condensate can accumulate.

设备和管线的首选灭菌方法是渗透压力的清洁蒸汽。在设备和管线的灭菌验证中，生物指示剂和温度感应器应策略的放在冷疑物聚集的地方。这包括蒸汽注入处和放出处，以及位置较低的冷的地方。例如，在最近的检查中，一个制造商使用了内部灭菌系统（SIP），只监控流出点的温度，没监测系统中冷疑物聚集的较低位置。

The use of formaldehyde is a much less desirable method of sterilization of equipment. It is not used in the United States, primarily because of residue levels in both the environment and in the product. A major problem with formaldehyde is its removal from piping and surfaces. In the inspection of a facility utilizing formaldehyde as a sterilant, pay particular attention to the validation of the cleaning process. The indirect testing of product or drug substance to demonstrate the absence of formaldehyde levels in a system is unacceptable. As discussed in the Cleaning Validation Guide, there should be some direct measure or determination of the absence of formaldehyde. Since contamination in a system and in a substance is not going to be uniform, merely testing the substance as a means of validating the absence of formaldehyde is unacceptable. Key surfaces should be sampled directly for residual formaldehyde.

使用甲醛对设备灭菌不是好方法。美国不用它，因为它在环境和产品中留下残留物。甲醛的主要问题是把它从管线和表面去除困难。在对使用甲醛作为灭菌物的设施时，重点对清洗过程的验证进行注意。仅间接通过测试产品或原料药中甲醛的含量是不能接受的。如清洗验证指南指出的，应当有直接的方法，确定没有甲醛。由于系统或原料药的污染可能不均匀分布，仅通过检验原料药来证明未含甲醛是不能接受的。应通过直接从表面抽样来检测甲醛含量。

One large foreign drug substance manufacturer, after formaldehyde sterilization of the system, had to reject the initial batches coming through the system because of formaldehyde contamination. Unfortunately, they relied on end product testing of the product and not on direct sampling to determine the absence of formaldehyde residues on equipment.

一个大型海外原料药制造商，在用甲醛对系统灭菌后，被迫拒绝随后的几批产品，因为有甲醛污染。不幸的是，他们通过最终产品的检验而不是直接抽样来确定甲醛残留量。

SIP systems for the bulk drug substance industry require considerable maintenance, and their malfunction has directly led to considerable product contamination and recall. The corrosive nature of the sterilant, whether it is clean steam, formaldehyde, peroxide or ethylene oxide, has caused problems with gaskets and seals. In two cases, inadequate operating procedures have led to even weld failure. For example, tower or pond water was inadvertently allowed to remain in a jacket and was valved shut. Clean steam applied to the tank resulted in pressure as high as 1,000 lbs., causing pinhole formation and contamination. Review the equipment maintenance logs. Review non-schedule equipment maintenance and the possible impact on product quality. Identify those suspect batches manufactured and released prior to the repair of the equipment. 大宗原料药的SIP系统需要相当的维护，它们的差错已经导致了相当多的产品污染和召回。灭菌物的腐蚀性，不论是清洁蒸汽，甲醛，过氧化氢或环氧乙烯，均导致过机器垫和密封问题。在两个案例中，不完善的操作程序甚至导致了焊接错误。例如，水塔或水坑的水意外流入套内并被封入。罐中的蒸汽导致1000磅的压力，造成针孔和污染。审阅设备维护记录。审阅非计划的设备维护和可能对产品质量的影响。找出那些怀疑的批次，它们是在设备维修前生产的，可能有问题。

Another potential problem with SIP systems is condensate removal from the environment. Condensate and excessive moisture can result in increased humidity and increases in levels of microorganisms on surfaces of equipment. Therefore, it is particularly important to review environmental monitoring after sterilization of the system.

SIP系统的另外一个问题是冷凝物从环境中不易去除。冷凝物和过多的潮湿会导致湿度的增加和机器表面微生物的增加。因此，审阅灭菌后对环境监测的记录特别重要。

The sterile bulk industry, as the non-sterile bulk industry, typically manufactures batches on a campaign basis. While this may be efficient with regard to system sterilization, it can present problems when a batch is found contaminated in the middle of a campaign. Frequently, all batches processed in a campaign in which a contaminated batch is identified are suspect. Review the failure investigation reports and the logic for the release of any batches in a campaign. Some of the more significant recalls have occurred because of the failure of a manufacturer to conclusively identify and isolate the source of a contaminant.

大宗无菌原料药行业，如大宗有菌原料药行业一样，通常是商业生产每批产品。虽然对系统灭菌可能是充分的，当生产过程中出现污染时，问题就出现了。通常，一批产品出现问题时，一个订单的全部批均被怀疑。审阅该批订单中的失败调查报告和放行该批的理由，制造商未能找出和分离污染源而导致了几次更为重大的召回

VI. ENVIRONMENTAL MONITORING环境监测The environmental monitoring program for the sterile bulk drug substance manufacturer should be similar to the programs employed by the SVP industry. This includes the daily use of surface plates and the monitoring of personnel. As with the SVP industry, alert or action limits should be established and appropriate follow-up action taken when they are reached.

大宗无菌原料药行业的环境监测项目应当与SVP行业相同。这包括每天使用表面皿和有具体

监测人员。如同SVP行业，应当建立预警或行动限和在行动限达到时的适当后续行动。There are some bulk drug substance manufacturers that utilize UV lights in operating areas. Such lights are of limited value. They may mask a contaminant on a settling or aerobic plate. They may even contribute to the generation of a resistant (flora) organism. Thus, the use of Rodac or surface plates will provide more information on levels of contamination.

有些制造商在生产区域使用UV照明灯。这些灯没有什么价值。它们可能会掩盖沉淀物中或培养皿中的污染物。它们甚至可能产生有抵抗力的有机体。因此，使用Rodac或培养皿可能产生更多污染机会。

There are some manufacturers that set alert/action levels on averages of plates. For the sampling of critical surfaces, such as operators' gloves, the average of results on plates is unacceptable. The primary concern is any incidence of objectionable levels of contamination that may result in a non-sterile product.

一些制造商设置培养皿的平均预警或行动限。对关键表面的抽样，如操作员的手套，培养皿上的平均结果不能接受。主要的担心是任何可能导致无菌产品的有害污染物污染。

As previously discussed, it is not unusual to see the highest level of contamination on the surfaces of equipment shortly after systems are steamed. If this occurs, the cause is usually the inadequate removal of condensate.

如前所述，设备表面在蒸汽清洗后不太能发现很高程度的污染。如果出现，原因通常是未充分去除冷凝物。Since processing of the sterile bulk drug substance usually occurs around the clock, monitoring surfaces and personnel during the second and third shifts should be routine.

由于无菌原料药的加工通常24小时生产，应经常在二班和三班监测环境和人员。

In the management of a sterile bulk operation, periodic (weekly/monthly/quarterly) summary reports of environmental monitoring are generated. Review these reports to obtain those situations in which alert/action limits were exceeded. Review the firm's investigation report and the disposition of batches processed when objectionable environmental conditions existed.

在无菌原料药生产的管理中，应定期（周/月/季度）出具环境监测报告。审阅这些报告，以发现超出预警线/行动限的情况。审阅公司的调查报告以及当出现有害环境条件时所生产的批产品的处理。

VII. VALIDATION验证

The validation of the sterilization of some of the equipment and delivery systems and the validation of the process from an endotoxin perspective have been discussed.

有关设备和生产系统的灭菌验证和从内毒素角度进行的工艺验证已经讨论过。

In addition to these parameters, demonstration of the adequacy of the process to control other physicochemical aspects should also be addressed in a validation report. Depending upon the particular substance, these include potency, impurities, particulate matter, particle size, solvent residues, moisture content, and blend uniformity. For example, if the bulk substance is a blend of two active substances or an active substance and excipient, then there should be some discussion/evaluation of the process for assuring uniformity. The process validation report for such a blend would include documentation for the evaluation and assurance of uniformity. A list of validation reports and process variables evaluated should be reviewed.

除这些参数外，验证报告还应当证明对其它物理化学方面控制的充足性。依据具体原料药，这包括效价，杂质，专项问题，颗粒大小，残留溶媒，温度含量和混合批的均一性。例如，如果原料药是由两种原料药或一种原料药、一种铺料混合而成，应当对该过程进行论述，以确保均一性。该混合工艺的验证报告将包括均一性的保障和评估。应审阅验证报告和评估过

的工艺要素清单。

As with a non-sterile bulk drug substance, there should be an impurity profile and specific, validated analytical methods. Those should also be reviewed.

如有菌原料药，应建立杂质挡案和具体的验证过的分析方法。应当审阅这些。Manufacturers are expected to validate the aseptic processing of sterile BPCs. Such validation must encompass all parts, phases, steps, and activities of any process where components, fluid pathways, in-process fluids, etc., are expected to remain sterile. Furthermore, such validation must include all probable potentials for loss of sterility as a result of processing. Validation must also account for all potential avenues of microbial ingress associated with the routine use of the process.

制造商应验证无菌原料药的工艺。此验证必须报告所有部件，阶段，步骤和这些方面的全部活动。不仅如此，该验证必须包括所有因加工而可能失去无菌性的方面。还必须验证日常使用该工艺所带来的微生物进入问题。

The validation procedure should approximate as closely as possible all those processing steps, activities, conditions, and characteristics that may have a bearing on the possibility of microbial ingress into the system during routine production. In this regard, it is essential that validation runs are as representative aspossible of routine production to ensure that the results obtained from validation are generalizable to routine production.

验证程序应当尽量模仿实际生产下的加工步骤、活动、条件和可能带来微生物污染的工艺特征。在此方面，验证运行要能代表实际生产状况，以便使结论可以用于日常生产。Validation must include the 100% assessment of sterility of an appropriate material that is subjected to the validation procedure. Culture media is the material of choice. whenever feasible. Where not feasible, non-media alternatives would be acceptable. Where necessary, different materials can be used in series for different phases of a composite aseptic process incapable of accommodating a single material. In any event, some material simulating the sterile BPC, or the sterile BPC itself, must pass through the entire system that is intended to be sterile. Any material used for process validation must be microbiologically inert.

验证必须包含对验证程序覆盖的相关材料的100%的无菌性评估。如可能，可以选用培养基模拟。如不可行，非培养基方法也可接受。如有必要，对一个无菌处理工艺的各个环节可以使用不同材料。在任何情况下，一些模仿无菌原料药的材料必须其本身通过全部无菌系统的检验。如用于工艺验证的材料必须在微生物学上没有活性。

Environmental and personnel monitoring must be performed during validation, in a manner and amount sufficient to establish appropriate monitoring limits for routine production.

在验证时必须进行环境和人员监测，其方式和数量必须足以为日常生产建立适当限度。

At least three consecutive, successful validation runs are necessary before an aseptic process can be considered to be validated.

在无菌工艺被认为经过了验证之前，至少应进行连续三批的、成功的运转。

Alternative proposals for the validation of the aseptic processing of bulk pharmaceuticals will be considered by FDA on a case-by-case basis. For example, it may be acceptable to exclude from the aseptic processing validation procedure certain stages of the post-sterilization bulk process that take place in a totally closed system. Such closed systems should be sterilized in place by a validated procedure, integrity tested for each lot, and should not be subject to any intrusions whereby there may be the likelihood of microbial ingress. Suitable continuous system pressurization would be considered an appropriate means for ensuring system integrity.

替代的无菌工艺验证方法FDA将根据个案而考虑。例如，在验证程序中，可以排除部分灭菌加工环节，因为它们处于封闭系统。这样的封闭系统应有验证过的程序进行灭菌，每批检查完整性，不能有任何可能产生微生物污染的接触。适当的连续压力系统可以保证系统完整性的方法。

VIII. WATER FOR INJECTION注射用水

Although water may not be a component of the sterile drug substance, water that comes in contact with the equipment or that enters into the reaction can be a source of impurities (e.g., endotoxins). Therefore, only water for injection should be utilized.

虽然水可能不是无菌原料药的组成成分，但是水因为流入并接触到设备或参与反应可能成为杂质的来源（例如，内毒素）。因此，只能使用注射用水。

Some manufacturers have attempted to utilize marginal systems, such as single pass Reverse Osmosis (RO) systems. For example, a foreign drug substance manufacturer was using a single pass RO system with post RO sterilizing filters to minimize microbiological contamination. This system was found to be unacceptable. RO filters are not absolute and should therefore be in series. Also, the use of sterilizing filters in a Water for Injection system to mask a microbiological (endotoxin) problem has also been unacceptable. As with environmental monitoring, periodic reports should be reviewed.

一些生产商已经尝试使用边缘系统，例如单向流反渗透系统。例如，一个原料药生产商正在使用带有柱状反渗透无菌过滤器的单向流反渗透系统来把微生物污染减少到最小。人们发现这个系统是不可接受的。反渗透过滤器并不是单独使用的而应该配套使用。而且，用来屏蔽微生物（内毒素）问题，而在注射用水系统中使用的无菌过滤器也是不可接受的。作为环境监测措施，应该审查定期的报告。

If any questionable conditions are found, refer to the Inspection Guide for High Purity Water Systems.

如果发现任何问题，请参阅高纯度水系统检查指南。

IX. TERMINAL STERILIZATION终端杀菌

There are some manufacturers who sterilize bulk powders after processing, by the use of ethylene oxide or dry heat. Some sterile bulk powders can withstand the lengthy times and high temperatures necessary for dry heat sterilization. In the process validation for a dry heat cycle for a sterile powder, important aspects that should be reviewed include: heat penetration and heat distribution, times, temperatures, stability (in relation to the amount of heat received), and particulates.

一些生产商通过使用环氧乙烷或干热灭菌来对处理后的原料药进行杀菌。一些无菌的原料药应该通过必要的长时间和高温的杀菌过程。在对无菌粉末的干热灭菌周期的工艺验证中，有几个重要的方面应该被审查：热穿透和热分布、时间、温度、稳定性（跟接受的热量有关）和颗粒。

With regard to ethylene oxide, a substantial part of the sterile bulk drug industry has discontinued the use of ethylene oxide as a "sterilizing" agent. Because of employee safety considerations, ethylene oxide residues in product and the inability to validate ethylene oxide sterilization, its use is on the decline. As a primary means of sterilization, its utilization is questionable because of lack of assurance of penetration into the crystal core of a sterile powder. 对环氧乙烷来说，很大部分的无菌原料药企业已经停止使用环氧乙烷作为“灭菌”剂。因为出于员工安全性的考虑，环氧乙烷会在产品中残留，从而不能验证环氧乙烷的灭菌性，所以对它的使用正在下降。作为灭菌的主要手段，对它的使用令人怀疑因为它不能保证杀菌效果

能够穿透无菌粉末的晶体核心。

Ethylene oxide has also been utilized in the treatment of sterile powders. Its principal use has been for surface sterilization of powders as a precaution against potential microbiological contamination of the sterile powder during aseptic handling.

环氧乙烷还已经被用来进行对无菌粉末的处理。它的主要用途是对无菌粉末的表面进行处理，作为在杀菌过程中对无菌粉末的潜在微生物污染的预防措施。

There are some manufacturers of ophthalmics that continue to use it as a sterilant for the drug used in the formulation of sterile ophthalmic ointments and suspensions. If used as a primary sterilant, validation data should be reviewed. Refer to the Inspection Guide for Topical Products for further discussion.

有很多眼科药物生产商还在继续使用它，作为用在杀菌类眼用药膏和悬浊液配方中的杀菌剂。如果它用作主要的杀菌剂，那么就应该对其验证数据进行审查。更深入的讨论请参阅局部产品审查指南。

X. REWORK/REPROCESSING/RECLAMATION 返工/重新处理/回收As with the principal manufacturing process, reprocessing procedures should also be validated. Additionally, these procedures must be approved in filings.

在主要的生产工艺中，重新处理的过程也应该通过验证。另外，必须记录这些被批准的过程。Review reprocessed batches and data that were used to validate the process. Detailed investigation reports, including the description, cause, and corrective action should be available for the batch to be reprocessed.

对用于验证工艺的重新处理的批次和数据进行审查。对要重新处理的批次应该有详细的调查报告，包括描述、重新处理原因和修正措施。

XI. LABORATORY TESTING AND SPECIFICATIONS实验室测试和质量标准

The sterility testing of sterile bulk substances should be observed. Additionally, any examples of initial sterility test failures should be investigated. The release of a batch, particularly of a sterile bulk drug substance, which fails an initial sterility test and passes a retest is very difficult to justify. Refer to the Microbiological Guide and Laboratory Guide for additional direction.

应该对无菌原料药的杀菌测试进行观察。另外，还应该对任何杀菌测试的失败案例进行调查。对已经放行的批次，特别是无菌原料药，如果没有通过开始的杀菌测试而通过了重新测试，对其的验证是非常困难的。额外的指导请参阅微生物指导和实验室指南。

Particulate matter is another major concern with sterile powders. Specifications for particulate matter should be tighter than the compendial limits established for sterile dosage forms. The subsequent handling, transfer and filling of sterile powders increases the level of particulates. It is also important to identify particulates so that their source can be determined. Review the firm's program for performing particulate matter testing. If there are no official limits established, review their release criteria for particulates, and the basis of their limit.

颗粒的问题是对无菌粉末的另一个主要的考虑。对颗粒物质的参数应该比对无菌剂型建立的概要限制要严格的多。后期的处理、转移和无菌粉末的填充增加了颗粒的水平。对颗粒的鉴定也是非常重要的，以便可以确定他们的来源。对公司执行颗粒物质测试的程序进行审查。如果没有建立的官方限制，那么对颗粒的放行条件进行审查，并建立相应的限制标准。With regard to residues, since some sterile powders are crystallized out of organic solvents, low levels of these solvents may be unavoidable. In addition to evaluation of the process to assure that minimal levels are established, data used by the firm to establish a residue level should be reviewed. Obviously, each batch should be tested for conformance with the residue specification.

Refer to the Inspection Guide for Bulk Drug Substances for additional direction regarding limits for impurities.

对残留物来说，因为一些无菌粉末是从有机溶剂中结晶出来的，这些溶剂的低含量的残留物是不可避免的。在对工艺评估来保证建立最低的残留物等级之外，还应该对公司建立残留物等级的数据进行审查。很明显，对每个批次都应该按照残留物标准进行审查。对额外的指导请参见原料药关于杂质限度的审查指导。

XII. PACKAGING包装

Sterile bulk drug substances are filled into different type containers which include sterile plastic bags and sterile cans. With regard to sterile bags, sterilization by irradiation is the method of choice because of the absence of residues. There are some manufacturers, particularly foreign, which utilize formaldehyde. A major disadvantage is that formaldehyde residues may and frequently do appear in the sterile drug substance. Consequently, we have reservations about the acceptability of the use of formaldehyde for, container sterilization because of the possibility of product contamination with formaldehyde residues.

无菌原料药被填装到不同种类的容器中，包括无菌塑料袋和无菌罐。对无菌袋来说，通过辐射来杀菌是一种可供选择的方法，因为里面没有残留物。有些生产商，尤其是国外的生产商，都使用甲醛。主要的缺点就是甲醛的残留物可能或经常出现在无菌原料药中。因此，我们对使用甲醛作为无菌罐的可接受性有所保留，因为有甲醛的残留物有可能把产品污染。

If multiple sterile bags are used, operations should be performed in aseptic processing areas. Since the dosage form manufacturer expects all inner bags to be sterile, outer bags should be applied over the primary bag containing the sterile drug in an aseptic processing area. One large manufacturer of a sterile powder only applied the immediate or primary bag in an aseptic processing area. Thus, the outer portion of this primary bag was contaminated when the other bags were applied over this bag in non-sterile processing areas.

如果使用到很多无菌袋，那么包装过程应该在无菌处理区进行。因为剂型生产商希望所有的内部包装袋是无菌的，外部包装袋也应该在无菌处理区包装含有无菌原料药的主要包装袋。大型的无菌粉末生产商在无菌处理区只包装中间的或主要包装袋。因此，主要包装袋的外面部分就在非无菌处理区被其它袋包装时被污染。

With regard to sterile cans, a concern is particulates, which can be generated due to banging and movement. Because of some with trace quantities of aluminum, companies have moved to stainless steel cans.

无菌罐来说，主要应该考虑颗粒问题，颗粒主要是在移动和碰撞中产生的。因为其中一些含有痕量的铝，所以很多公司已经换成不锈钢罐。

The firm's validation data for the packaging system should be reviewed. Important aspects of the sterile bag system include residues, pinholes, foreign matter (particulates), sterility and endotoxins. Important aspects of the rigid container systems include moisture, particulates and sterility.

对应该对公司的包装系统验证数据进行审查。关于无菌袋系统的重要方面包括残留物、小孔、外部物质（颗粒），无菌性和内毒素。对严格的储藏系统的重要方面包括湿度、颗粒和无菌性。

FDA检查员指导手册

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.wendangku.net/doc/e811284524.html,/cder/api.htm.。

FDA 行业指南 中英对照 待完成

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--中文译

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)

2007 FDA固体制剂制造商cGMP的检查指南02

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检查员指导办法

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--药品生产检查程序(doc75页)(1)

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)

资产财务检查工作指引

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

FDA 11

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.wendangku.net/doc/e811284524.html,/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11... 2012/05/30

FDA检查员指导手册药品生产检查程序

FDA检查员指导手册CP ：药品生产检查程序

目录 对现场报告的要求……………………………………………………3 5 第一部分背 景…………………………………………………………………… 3 6 第二部分执 行………………………………………………………………… 3 6 .目 的…………………………………………………………………… 3 6 . 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）… 3 6 2.2.2.系统性检查…………………………………………………………… 3 7 2.2. 3.对原料药及制剂生产的系统性检查计划…………………………… 3 8 2.2. 3.1.质量系统……………………………………………………………… 3 8 2.2. 3.2.厂房设施与设备系统………………………………………………… 3 8 2.2. 3.3.物料系统……………………………………………………………… 3 8 2.2. 3. 4.生产系统……………………………………………………………… 3 8 2.2. 3.5.包装和贴签系统……………………………………………………… 3 8 2.2. 3.6.实验室控制系统……………………………………………………… 3 9

.程序管理指导………………………………………………………… 3 9 2.3.1.定 义…………………………………………………………………… 3 9 2.3.1.1.监督性检查…………………………………………………………… 3 9 2.3.1.2.达标检查……………………………………………………………… 4 2.3.1.3.受控状态……………………………………………………………… 4 2.3.1.4.药品工艺……………………………………………………………… 4 2.3.1.5.药品生产检查………………………………………………………… 4 1 第三部分检 查…………………………………………………………………… 4 1 .检查活动……………………………………………………………… 4 1 3.1.1.总 则…………………………………………………………………… 4 1 3.1.2.检查方法……………………………………………………………… 4 2 3.1.2.1.全面性检查的选择…………………………………………………… 4 3 3.1.2.2.简略性检查的选择…………………………………………………… 4 3 3.1.2.3.综合性检查范围……………………………………………………… 4 3 3.1.3.系统性检查范围……………………………………… 4 3

FDA 行业指南 中英对照 待完成

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 https://www.wendangku.net/doc/e811284524.html,rmation 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

瓦斯检查员安全操作规程标准版本

文件编号：RHD-QB-K8003 （操作规程范本系列） 编辑：XXXXXX 查核：XXXXXX 时间：XXXXXX 瓦斯检查员安全操作规 程标准版本

瓦斯检查员安全操作规程标准版本操作指导：该操作规程文件为日常单位或公司为保证的工作、生产能够安全稳定地有效运转而制定的，并由相关人员在办理业务或操作时必须遵循的程序或步骤。，其中条款可根据自己现实基础上调整，请仔细浏览后进行编辑与保存。 ㈠安全规定 ⒈必须按规定对所分管的采掘作业地点进行巡回瓦斯检查或专人定点检查。 ⒉要严格按照确定的地点、次数、检查方式进行检查，严禁空班漏检和假检。 ⒊采煤工作面需测定甲烷和二氧化碳的地点有： ⑴工作面进风流（指进风顺槽至工作面煤壁线以外的风流）。 ⑵工作面风流（指距煤壁、顶、底板各20厘米和以采空区切顶线为界空间风流）。 ⑶上隅角（指采煤工作面回风侧最后一架棚向上

1米处）。 ⑷工作面回风流（指距采煤工作面10米以外的回风巷不与其他风流汇合的一段风流）。 ⒋掘进工作面需测定甲烷及二氧化碳的地点有： ⑴掘进工作面风流（指风筒出口到掘进工作面的一段风流）。 ⑵掘进工作面回风流（指风筒出口到巷口一段风流）。 ⑶局部通风机前后各10米以内的风流。 ⑷局部高冒区。 ⒌放炮地点检查甲烷的部位有： ⑴采煤工作面放炮点的瓦斯检查应在工作面煤壁上、下各20米范围内的风流中进行。 ⑵掘进工作面放炮地点的瓦斯检查应在该地点向外20米范围内的巷道风流中进行。

⒍检查瓦斯的次数为：高瓦斯矿井的采掘工作面，瓦斯检查次数为每班不少于3次。采掘工作面瓦斯坚持巡回检查的时间间隔要均匀。 ⒎瓦斯检查牌板的设置位置以及需填写的内容，要符合有关规定。要求位置显眼、内容齐全，检一次，填一次。 ⒏瓦斯检查时，要严格按规定操作，发现不安全隐患，要先消除隐患再进行检查。 ⒐经分析确定的不宜安排瓦斯检查员检查的地点，不得擅自安排瓦斯检查员进入检查瓦斯。 ⒑实行现场指定地点（回采面在回风巷巷口、掘进面在风机边）的交接班制度。下一班人员不到，上一班人员不走，以防空班。 ㈡操作准备 ⒈准备仪器：下井要带齐瓦斯检测仪、温度计、

安全员手册最新版

安全员手册（2021版） 2021-1-11发布2021-3-1 实施 XXX有限责任公司发布

安全员手册 前言 《安全员手册》的编制是遵照“安全发展、预防为主、综合治理”的方针，目的是不断增强各级专兼职安全员、群安员的安全生产观念，提高安全管理业务素质和能力，打造项目安全文化，实现我公司的健康发展和安全生产。 《安全员手册》集知识性、实用性于一体，它贴近生产，具有较强的指导性和可操作性，是安全工作的得力"助手"，是广大安全工作者的必备手册。希望每位安全员都能从中有所裨益。 本手册适用于公司机关、项目安全管理人员以及普通员工阅读使用。 安全工作宗旨 关爱生命安全第一 遵章守纪从我做起

要我安全我要安全 我懂安全我会安全 目录 一、安全员的基本任职条件 (5) 二、安全员的检查权、奖惩权和否决权 (5) 三、安全员的职责 (6) 四、安全员的日常工作 (6) （一）建立并落实企业安全生产规章制度 (6) （二）对安全检查发现的问题作出处理 (7) （三）主要内业工作 (7) 五、安全员工作中应注意的问题 (8) 六、安全管理基本知识 (9) 1、如何层层签订安全生产协议书 (9) 2、安全生产责任制的考核工作 (10) 3、安全生产管理“五同时”原则 (10) 4、安全生产“一票否决”原则 (10) 5、如何建立项目安全生产领导组 (10) 6、项目安全总监设置要求 (11) 7、特种作业人员管理 (11)

8、特种作业人员资格 (11) 9、三级安全教育培训的内容 (12) 10、安全生产费用管理 (12) 11、安全生产费用帐目分类 (13) 12、安全生产费用提取标准 (13) 13、专项方案编制的内容 (13) 14、安全专项施工方案审批程序 (14) 15、如何进行日常安全检查工作 (14) 16、如何进行专项检查工作 (14) 17、如何进行定期检查工作 (15) 18、如何上报安全生产事故 (15) 19、事故处理“四不放过”原则 (15) 20、火灾处置的原则和要点 (15) 21、如何应对用电安全事故 (16) 22、专项应急预案编制的主要内容 (16) 23、应急物资的储备与管理 (16) 24、如何正确佩戴安全帽 (16) 25、漏电保护器的选择与使用标准 (17) 26、如何存放易燃、易爆、有毒等危险品 (17) 27、火工品仓库的规定 (17) 28、各种气瓶的运输、存放、使用规定 (17) 29、起重设备钢丝绳的使用规定 (18)

FDA制剂厂检查指南(英译)

对制剂企业的检查-CGMP 备注：这个文件是对检查者和其他的FDA官员的参照。这份文件并不限制FDA，并不获取任何利益，义务，权利，或豁免某人 1简介 这个文件介绍到一个大约的药厂检查指导他们是否符合药物的CGMP。这个指导应该被用来作IOM的介绍，其他的药物检查指导，和复核项目。这个检查的指导相对于IOM的第十章，一些指导是： a 原料药视察指导 b 高纯水系统视察的指导 C QC实验室视察的指导 D 微生物QC实验室的指导 E 冻干注射剂视察的指导 F 清洁验证视察的指导 G 制药过程中的计算机系统的视察的指导 H 一般工艺过程验证的指导 2 CGMP 处方和非处方 所有的药物的生产过程要对应于CGMP否则就被认为在FDC实施中掺假。501（a）(2)(B) 依据处方药物的记录一定要对照于704（a）(1)(B)章。如果药物是OTC药物被NDA或ANDA覆盖，FDA可以回顾，复制，验证在505（k）(2)章下的FDC。然而，如果产品是在FDA没注册过的OTC药

物。并没有法定的严格要求在视察过程中给视察者看的的记录要按704章FDC的要求。而且，所有的处方药和OTC 药的生产必须符合CGMP的要求，包括那些记录。视察者应该回顾这些记录作为决定是否符合CGMP要求的一部分。在很少的场合，可以拒绝回顾OTC的记录因为并没有法定要求这样做。当工厂在没有法定义务去提供回顾这些记录时，没有减轻需要符合在501（a）(2)(B)CGMP的要求，包括对主体文件的要求。 如果一个工厂拒绝回顾OTC的记录，视察者应该被其他的视察方法决定特别符合CGMP的要求。视察者观察和查找对于处方药和非处方药并不根据FDA-483确定的检查表中做的行为。 组织和人员 工厂一定要有QC控制文件描述CFR的责任和权威。QC文件一定要在表明它的相对于生产文件的独立性，在书面表明它的责任权属。 表明操作者的官员的名字，头衔和内在的责任，其他的主要的职员在IOM中列出。 在制药工业，一个职员的受教育和培训对于质量产品的位置很有用。报道是否这个工厂有一个严格的培训计划，描述培训接受的类型。一个职员的接受的培训应当被记录 QC在每个产品的生产过程中要有日常记录，有一个书写的日常流程。详细的回顾这些记录。这个报道将会很快让你了解生产过程在控制中。这个报告一定要提供所有的在中控中或最终产品测试中失败的批次，检查这些失败。