FDA无菌原料药检查指南

FDA无菌原料药检查指南 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、利益或豁免权。 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. 多年来现场检查最难的、也是出现问题最多的领域就是无菌原料药的生产。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。 其它一些生产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， 再也没有别的处理来去除微粒、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，同时加上工艺的复杂性，审阅一些 报告 软件系统测试报告下载sgs报告如何下载关于路面塌陷情况报告535n,sgs报告怎么下载竣工报告下载 和总结，如验证研究、 拒绝(不合格批)清单、环境监控总结报告、质量保证调查 记录 混凝土 养护记录下载土方回填监理旁站记录免费下载集备记录下载集备记录下载集备记录下载 等就变得非常重 要。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，因为受时间所限。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). 1. 通过在溶媒中溶解，将非无菌原料药转换为无菌原料药。溶液通过过滤除菌 后收集在一个无菌反应罐中(即结晶罐)。 2. Aseptic precipitation or crystallization of the sterile drug substance in the sterile reactor. 2. 在无菌反应罐中进行无菌沉淀或结晶。 3. Aseptic isolation of the sterile substance by centrifugation or filtration. 3. 通过离心或过滤实现无菌分离。 4. Aseptic drying, milling and blending of the sterile substance. 4.无菌干燥、磨粉和混合。 5. Aseptic sampling and packaging the drug substance. 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. 这些操作应在密闭系统进行，尽可能少的人工参与。如果操作员在密闭系统之外 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非无菌 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，在对进行了大量非无菌原料药转变为无菌原料药试 验的制造商进行现场检查时，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变的验证(非无菌到无菌)，挑战性试验应放在实验室或中 试规模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， 只需对生产批做一些监控。如任何验证过程一样，每一步的目的和有效性均需 评估。例如，如果非无菌到无菌的转变(结晶)减少了1个log值的内毒素，那 么，应有数据支持该步骤。 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，监控灭菌中的非无菌原料药的生物负荷 也很重要。例如，应关注灭菌前非无菌原料药中的某些革兰氏阴性菌污染，特 别是如果灭菌(过滤)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施的 设计 领导形象设计圆作业设计ao工艺污水处理厂设计附属工程施工组织设计清扫机器人结构设计 应与SVP无菌设施具有相同的设计特征。这 包括温度、湿度和压力控制。由于原料药无菌设施通常较大，常常遇到压差和 消毒问题。例如，在现场检查中发现，一个生产商更衣区域的压力比临近无菌 区的压力更大。有时需要排除溶媒蒸汽也可能影响着洁净区域的压差。 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. 非必要设备和/或无法充分消毒的设备，如木质托盘和叉车，应当予以鉴定。询 问大量无菌原料药的转运和位于无菌核心区和非无菌区之间传递区域的位置。 观察这些区域，审阅环境监控结果和消毒程序。 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法规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。询问厂家石棉过滤器的使用。 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. 用于非无菌组分，如非无菌原料药的投料或加料的设施，应当与灭菌前注射液 的配料设施相同。需要关注的是可溶解的外来污染物，包括内毒素，它们可能 贯穿于生产过程。观察这个区域，审阅环境控制和标准，以确定可允许的活性 和非活性微粒水平。 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. 无菌粉的生产通常在有机溶媒中溶解非无菌物质或反应物并通过除菌过滤器过 滤。过滤后，无菌大宗物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，过滤除菌和通过过滤或结晶离析。水溶液也可以经无菌过滤、喷雾 干燥或冻干。 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，输送水溶液的管线被发现是无菌粉 中内毒素污染的来源。应当有管路系统的打印图纸。跟踪实际管路，与图纸相 对照，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。确定公司选择过滤器的标准以及更换 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，有一些需关注的问题。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，问题包括空气洁净级别，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变更的次数和频率。这可以表明在一些批中经历的 问题。短时间内出现的大量变更可以表明，该公司正经历着的问题。审阅工艺 变更SOP和变更记录，包括变更理由。 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无菌而且能够被灭菌。这包括结晶器，离心机和 干燥器。只对设备消毒而不灭菌是不能接受的。应当审阅设备、管线灭菌的灭 菌程序和验证文件。 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饱和纯蒸汽压力灭菌。在设备和管线的灭菌验证 中，生物指示剂和温度传感器应放在冷凝物聚集的冷点位置。这包括蒸汽注入 处和排放处，以及位置较低的冷点。例如，在最近的检查中，一个制造商使用 了在线灭菌系统(SIP)，只监排放点的温度，没监测系统中冷凝物聚集的较低 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。在检查使用甲醛作为灭 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。应通过直接从关键表面取样来检测甲醛含量。 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取样来 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系统需要大量的维护，它们的故障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，过氧化氢或环氧乙烷， 均导致过垫圈和密封出现问题。在两个案例中，不完善的操作程序甚至导致了 焊接失败。例如，水塔或池塘的水意外地留在夹套内而且阀门被关闭。此时对 罐施加1000磅的纯蒸汽压力，造成针孔形成和污染。审阅设备维护记录。审阅 非未列入计划的设备维护和可能对产品质量的影响。找出那些设备维修前被放 行的怀疑批次。 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 致湿度的增加和设备表面微生物的增加。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，如大宗非无菌原料药行业一样，通常是阶段性生产方式。 虽然系统灭菌可能是有效的，但当一个阶段性生产中间出现污染时，问题就出 现了。通常，一批产品出现问题时，该阶段性生产的全部批均被怀疑。审阅该 批失败的调查报告和放行其中任何一批的理由。一些非常重大的召回就是由于 生产商未能鉴定和分离出污染源。 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 接触平板和人员监控。如同SVP行业，应当建立警戒限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. 有些生产商在生产区域使用UV照明灯。这些灯没有什么价值。它们可能会掩 盖沉降碟的污染物。它们甚至可能产生有抵抗力的有机体。因此，使用Rodac 或接触平板将为污染水平提供更多的信息。 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。对关键表面的取样，如操作员的 手套，培养皿上的平均结果不能接受。主要的担心是任何有害污染物污染都可 能导致非无菌产品。 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，设备表面在蒸汽灭菌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水。 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表面和人员。 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. 有关设备和输送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，异物，粒径大小，溶剂残留，水分含量和混 合均一性。例如，如果原料药是由两种原料药或一种原料药、一种辅料混合而 成，应当对该过程进行评估，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. 和非无菌原料药一样，应建立杂质档案和具体的验证过的 分析 定性数据统计分析pdf销售业绩分析模板建筑结构震害分析销售进度分析表京东商城竞争战略分析 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. 生产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，例如一级反渗透系统。例如，一个国外原 料药生产商使用一级反渗透系统加反渗透后除菌过滤以将微生物污染减少到最 小。这个系统是不可接受的。反渗透系统不是完全的应当串联使用。而且，在 注射用水系统中使用除菌过滤器也是不可接受的，因为会掩盖微生物(内毒素) 问题。与环境监测一样，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，请参阅高纯水系统检查指南。 IX. TERMINAL STERILIZATION终端灭菌 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 使用备受质疑因为它无法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 重新加工/返工/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，返工的程序也应该通过验证。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. 对用于验证工艺的返工批次和数据进行审查。对要返工批次应该有详细的调查报 告，包括描述、原因和纠正行动。 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无菌测试进行观察。另外，还应该对任何无菌测试的失败 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 无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 菌剂型建立的法定限度要严格的多。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。如果没有建立法定限度，审查颗粒的 放行标准及限度制定的原则。 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. 无菌原料药被分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. 如果使用到多层无菌袋，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。一家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. 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、外来物质(颗粒)，无菌性和内毒素。刚性容器系统的重要方面 包括湿度、颗粒和无菌性。