Validation of Cleaning Processes
清洁工艺验证
GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES
清洁工艺验证检查指南
Mike Ma Sort out
Xiao Gang
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).
注意：本指南是审计官和其他FDA人员的参考资料。FDA不受本指南的约束，也没有授予任何人任何权利、特权、收益或豁免权。
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Content
I. INTRODUCTION 简介 (3)
II. BACKGROUND 背景 (3)
III. GENERAL REQUIREMENTS 常规要求 (5)
IV. EVALUATION OF CLEANING VALIDATION清洁验证的评估 (6)
V. ESTABLISHMENT OF LIMITS 确定限度 (11)
VI. OTHER ISSUES 其他问题 (12)
VII. REFERENCES 参考资料 (13)
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Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.
自从机构文件，包括化学原料药制剂检查指南和生物技术制剂检查指南简明的提及清洁验证规程以来，就对清洁规程验证产生了大量的讨论。这些机构的文件明确建立了清洁规程验证的预期结果。
This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.
设计本指南是为了通过讨论已发现的可接受（或不可接受）的实际操作来建立检查的一致性和统一性。同时必须认识到清洁验证和其他过程验证一样，某一过程的验证可能不止一种方式。最后，任何过程验证的检测是科学数据是否反映系统能始终如一按照既定标准运作并持续产生符合既定标准的结果。
This guide is intended to cover equipment cleaning for chemical residues only.
备***应该按照清洁和有序的方式来进行维护”。在1978 CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。当然，清洁设备的主要理由是防止药品被污染或掺假。在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。而且，从历史上来说，FDA更
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加关注非青霉素药品被青霉素污染、或药品中的活性激素或荷尔蒙交叉污染。由于实际或潜在的青霉素的交叉污染所致，在过去的十年中有很多药品被召回。
One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.
1998年消美国专利药消胆胺树脂制剂的召回，使FDA进一步认识到因不当规程而导致交叉污染的可能性。用于生产药品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。本案例中的交叉污染被认为是由于回收溶剂的重新使用。回收溶剂由于缺乏对溶剂桶的重新使用进行控制而被污染。用于储存杀虫剂生产过程中的回收溶剂的溶剂桶，后来又用于储存树脂生产过程的回收溶剂。公司未对这些溶剂桶进行适当的控制，也未对桶中的溶剂进行适当的测试，以及未对桶的清洗过程进行验证。
Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility's fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced.
部分被杀虫剂污染的原料药被运输到在其他地方的另外一家工厂进行最后加工。由于该工厂的流体床干燥器袋子被原料药中的杀虫剂污染，结果导致在该工厂地点生产的很多批次产品相应的被交叉污染，该地点在正常情况下是不生产杀虫剂的。
FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started a cleaning validation program at the time of the inspection and it was considered inadequate by FDA. One of the reasons it was considered inadequate was that the firm was only looking for evidence of the absence of the previous compound. The firm had evidence, from TLC tests on the rinse water, of the presence of residues of reaction byproducts and degradants from the previous process.
FDA在1992年对使用普通设备生产活性激素产品和非激素产品的国外原料药生产商提出了进口警告。该公司是多用途原料药制药工厂。FDA认为交叉污染的可能性非常大，并对公众健康产生严重威胁。公司只是在最近被检查的时候才开始进行清洗验证程序，FDA认为这是不够的。其中的一个原因是，公司只是收集
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了以前化合物不存在的证据。公司从冲洗水的TLC测试上有证据表明，来自以前的过程中反应副产品和降解物的残留物的存在。
different scenario. Similarly, if firms have one process for removing water soluble residues and another process for non-water soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed. Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment.
FDA要求公司应具有详细地记录设备各种零件的清洗过程的书面程序（SOP's）。如果公司在清洁不同批次的相同产品时使用一种清洗过程，而在清洗不同产品时使用一种不同的清洗过程，那么我们要求书面程序能包括这些不同的细节。相似地，如果公司在除掉可溶于水的残留物时使用某一种清洗过程，而对于不可溶于水的残留物时使用另外一种清洗过程，书面程序应当说明这两种过程，并且明确的阐述出何时应该遵守已知的过程。当生产过程会产生难以除去的焦油状或粘状残留物时，原料药公司也许会决定使用特定的设备来进行特定的化学生产步骤。流体床的干燥器袋是很难清洗的设备之一，经常用于特定的产品。清洗过程本身留下的任何残留物也必须清除掉（清洁剂、溶剂等）。
FDA expects firms to have written general procedures on how cleaning processes will be validated.
FDA要求公司应具有验证清洗过程的常规书面程序。
FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.
FDA要求常规验证程序说明负责执行和批准验证研究的负责人员、可接受标准以及再验证时间。
FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment which should address such issues as sampling procedures, and nalytical methods to be used including the sensitivity of those methods.
FDA要求公司在对每个生产系统或设备部件进行研究之前应准备具体的书面验证方案，验证方案中阐述取样程序、采用的分析方法以及这些方法的灵敏度等问题。
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FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.
FDA要求公司应按照方案来进行验证研究，并以书面形式记录这些研究结果。
FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an "acceptable level."
FDA要求应该有一份经管理部门批准的最终验证报告，并且该报告应指出该清洗过程是否有效。数据应当证明残留物已被减少到“可接受的水平”。
process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.
第一步应该集中在验证过程的目标上，而且FDA发现一些公司未能成功实现这样的目标。生产商在清洗过程中使用大量的样品和检测程序，而从未真正地对设备的清洗步骤进行有效性评估，这样的做法不足为奇。当对清洗规程进行评估时，应当阐明一些问题。例如，认为设备部件或系统是清洁的标准是什么？必须要用手擦洗吗？用手擦洗跟洗涤剂清洗相比应该伴随什么过程？从批次到批次的清洗过程与从产品到产品有什么样的变化？由于我们必须确定整个过程的有效性，所以在检查和评估清洗过程时，回答这些问题的重要性是显而易见的，应为我们必须要确定整个过程的有效性。对这些问题的回答也可能断定哪些步骤可以省略而采用更加有效的方法，来进行评估并为公司节省资源。
Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning, however this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process) the firm need only meet a criteria of, "visibly clean" for the equipment. Such between batch cleaning processes do not require validation.
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确定对每个设备部件的清洗过程的数量。在理想的情况下，每个设备或系统的部件都应该有相应的一种清洗过程。但是，这要取决于被生产的产品，以及清洗是否发生在同一产品的批次之间（如在较大的清洗规模中），还是发生在不同产品的批次之间。当在同一产品的批次之间进行清洗时（或者在原料药工艺中同一中间体的不同批次之间），公司只需要达到“设备目视清洁”的标准就行了。统一品种批间的清洗过程并不需要验证。
1. Equipment Design 设备设计
Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.
检查设备的设计。尤其是在那些大的系统中，其可能使用了半自动或全自动的在线清洗系统，这是非常令人担心的。例如，应当使用没有球阀的卫生级管道。当使用非卫生级别的球阀时（在原料药企业中很常见），清洗过程会更加困难些。
When such systems are identified, it is important that operators performing cleaning operations be aware of problems and have special training in cleaning these systems and valves. Determine whether the cleaning operators have knowledge of these systems and the level of training and experience in cleaning these systems. Also check the written and validated cleaning process to determine if these systems have been properly identified and validated.
当这些已明确时，执行清洗操作的人员应该知道问题所在，并且在清洗这些系统和阀门方面经过专项的训练。应该确定清洗工作人员是否具有清洗这些系统以及在清洗系统中的训练程度和经验。另外还要核对书面的经核实的清洗过程来确定这些系统是否被正确的鉴定和验证。
In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.
在一些更大的系统中，例如那些使用很长的传送带或管道的系统，应该检查流程图和管道系统图以确认阀门和书面的清洗程序。应当在管道和阀门应加以标识，并且可以被执行清洗过程的工作人员很容易地辨认出。有时，若对阀门的示意图和现场标识不当，会导致不正确的清洗操作。
Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.
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应该经常检查清洗过程的文档中通常关键的因素的记录情况；并识别和控制生产过程结束与每个清洗步骤之间的时间长度。这对于外用剂型产品、悬浮剂和原料药操作尤其重要。在这些操作中，残留物的干化将直接影响到清洗过程的效果。
Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.
无论是否使用CIP系统清洗工艺设备，都应该考虑设备清洗的微生概况。这主要是包括指预防措施，而不包括发生微生物污染后的再除掉。应该证据证实，设备的常规清洗和存储时不会有微生物繁殖。例如，设备在存储前应该被干燥，绝对不允许有污水留在清洗后的设备中。
Subsequent to the cleaning process, equipment may be subjected to sterilization or sanitization procedures where such equipment is used for sterile processing, or for nonsterile processing where the products may support microbial growth. While such sterilization or sanitization procedures are beyond the scope of this guide, it is important to note that control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.
在清洗完成之后，用于无菌过程，或产品有助于微生物繁殖的非无菌过程的设备可能会被灭菌或消毒。虽然灭菌和消毒程序已超出本指南的范围，但值得注意是通过设备的适当清洁和适当存储控制生物负荷对于保证接下来的灭菌或消毒程序达到必要的无菌保证是很重要的。因为设备杀菌过程不能够获得显著的失活或除去热原质，所以这对无菌处理热原控制的立场来看也特别重要。尤其是这也对于无菌工艺的热源控制非常重要，由于设备灭菌过程可能不会充分达到显著的热源灭活和去除。
2. Cleaning Process Written清洗过程记录
Procedure and Documentation 规程和记录
Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.
检查被验证的清洗工艺规程的细节和特性，以及必须的文件的数量。FDA官员已看过通常的SOPs,其余的则采用一份批记录或日志单系统，其规定了详细记录每一步操作的一些。执行不同清洁步骤或规程所必须的文件数量因系统和清洁工艺的复杂性以及操作人员的能力和培训而不同。
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When more complex cleaning procedures are required, it is important to document the critical cleaning steps (for example certain bulk drug synthesis processes). In this regard, specific documentation on the equipment itself which includes information about who cleaned it and when is valuable. However, for relatively simple cleaning operations, the mere documentation that the overall cleaning process was performed might be sufficient.
当需要更复杂的清洗规程时，记录关键清洗步骤（如某种原料药的合成工艺）是很重要的。这种情况下，设备本身的详细记录文档应包括谁清洗的和清洁有效时限的信息。然而，对于相关简易的清洗操作，只需已执行的完成清洁过程的记录可能就足够了。
Other factors such as history of cleaning, residue levels found after cleaning, and variability of test results may also dictate the amount of documentation required. For example, when variable residue levels are detected following cleaning, particularly for a process that is believed to be acceptable, one must establish the effectiveness of the process and operator performance. Appropriate evaluations must be made and when operator performance is deemed a problem, more extensive documentation (guidance) and training may be required.
其它因素，如清洗历史、清洗后发现的残留物水平、和测试结果的变化趋势，也可能决定所需要文件的数量。例如，如果在后续清洗中发现了不同的残留物水平，特别是对于被认为是可接受的清洗过程，那么就必须确定过程和操作员的执行的有效性。应该做适当的评估，如果认为操作员的执行有问题，就需要更多的文件（指南）和培训。
3. Analytical Methods 分析方法
Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).
应该确定用来检测残留物或污染物的分析方法的专属性和灵敏度。用先进的分析技术能检测生产和清洗过程中很低水平的残留物。如果污染或残留物水平不能被检测，并不意味着清洗后不存在残留物污染物。只能说明样品中不存在高于分析方法灵敏度或检测限度的污染物水平。公司应该通过结合从设备表面重新找回残留物及残留物回收率（如50％或者90％）的分析方法，对使用的分析方法进行挑战。这在根据取样结果下结论前是很必要的。不当的取样技术可能会导致阴性的测试结果（见下）。
4. Sampling 取样
There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.
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通常有两种可接受的取样方法。最适当的方法是从设备表面直接取样。另一种方法是使用淋洗溶液。
a. Direct Surface Sampling - Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to assure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.
a. 表面直接取样-确定使用的取样材料类型以及对测试数据产生的影响，因为取样材料可能会干扰测试。例如，发现药签上的粘合剂会干扰样品的分析。因此，在早期的确认程序中，确保取样媒介和溶剂（用于从媒介中萃取）的符合要求并容易使用是很重要的。
Advantages of direct sampling are that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination or residue per given surface area. Additionally, residues that are "dried out" or are insoluble can be sampled by physical removal.
直接取样的优点是清洗难点和容易接近的区域可以被评估，从而可确定每个已知表面区域的污染物或残留物的水平。另外，不能溶解的或已干透的残留物可以通过物理取除的方法来取样。
b. Rinse Samples - Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.
b.淋洗液样品-使用淋洗液样品的两个好处是可以大面积的取样，而且可以对人为不易接近或不能按照方
法拆卸的系统进行取样和评估。
A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the "dirty pot." In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.
取淋洗液样品的一个缺点是，残留物或污染物可能不溶解或被堵塞在设备中。可以推断“不干净的罐”可以被使用。在评价对不干净的药罐的清洗时，特别是那种有干透残留物的，不应该只看淋洗液样品是否干净，而应该看药罐是否干净。
Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.
在验证清洗过程时，要确保对淋洗液样品的残留物或污染物进行直接测量。例如，只简单检测淋洗液样品的质量（它是否符合测试纲要）而不检测所有潜在的污染物的，这种做法是不被认可的。
c. Routine Production In-Process Control 常规生产过程控制
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Monitoring - Indirect testing, such as conductivity testing, may be of some value for routine monitoring once a cleaning process has been validated. This would be particularly true for the bulk drug substance manufacturer where reactors and centrifuges and piping between such large equipment can be sampled only using rinse solution samples. Any indirect test method must have been shown to correlate with the condition of the equipment. During validation, the firm should document that testing the uncleaned equipment gives a not acceptable result for the indirect test.
监控，即间接检测，如导电率测试，在清洗过程取得验证之后，就可作为常规监控的数值。尤其对那些原料药生产商来说，反应釜、离心机或大设备间的管道系统可以只是取淋洗溶液样品，这样做法是正确的。任何间接测试方法必须表明与设备的状况的相关性。在验证期间，公司必须记录不干净设备的检测（间接
organoleptic levels such as no visible residue.
FDA并不想设定决定清洗过程是否有效的可接受标准或方法。因为原料药和成品剂型生产工业中使用的设备和产品的巨大差异，FDA如果设定标准或方法是不现实的。公司确定的残留物限度的理由应当合理的基于生产商对涉及的原料的知识，而且应当具有可操作性、可实现且可被证实。为了确立合理的限度，明确分析方法的灵敏度是很重要的。行业代表在著作或报告中提到的一些限度包括分析检测级别如10ppM，生物活性级别如1/1000的正常治疗剂量，器官感觉级别如无可见残留物。
Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents) bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable.
检查限度确立的方法。不像化学残留物（如活性成分，非活性成分和清洁剂）已经被清楚鉴定的成品药物，原料药生产工艺中也许还有一直未进行化学鉴定的部分反应物和多余的副产品。在确定残留物限度时，只集中关注主要的反应物也许是不够的，因为也许有其他的化学衍生产物更难以除去。有的情况下，除了进
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行化学分析，薄层色谱分析（TLC）也是必要的。在原料药生产工艺中，特别是某些如激素类的高活性化学制品生产中，如果设备不是专用的，必须要考虑副物的问题。检查的目的就是要保证任何限度的根据都具有科学道理。
placebo batch is then tested for residual contamination. However, we have documented several significant issues that need to be addressed when using placebo product to validate cleaning processes.
为了评估和验证清洗过程，有的生产商在设备中按照与加工成品完全相同的操作参数进行无效对照药批次生产。然后检测无效对照药批次的样品的残留物。然而，我们（FDA）有文件可以证明在使用无效药验证清洗过程时需要阐明的几个重要问题。
One cannot assure that the contaminate will be uniformly distributed throughout the system. For example, if the discharge valve or chute of a blender are contaminated, the contaminant would probably not be uniformly dispersed in the placebo; it would most likely be concentrated in the initial discharge portion of the batch. Additionally, if the contaminant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo.
任何人都不能保证污染物在整个系统中是均匀分布的。例如，如果下料阀或混合机的斜槽被污染，污染物就不可能均匀分布在无效批药品中，而是很可能集中在无效批药品在最初出料的部分。另外，如果污染物或残留颗粒物较大，它也不可能均匀分布在无效批药品中。
Some firms have made the assumption that a residual contaminant would be worn off the equipment surface uniformly; this is also an invalid conclusion. Finally, the analytical power may be greatly reduced by dilution of the contaminate. Because of such problems, rinse and/or swab samples should be used in conjunction with the placebo method.
有的公司假定某一残留的污染物均匀的覆盖在设备表面，这样的结论也是不正确的。最终，分析效果会因污染物被稀释而大大削弱。基于这些问题的存在，在使用无效药批次方法时应结合淋洗液样品或擦拭取样方法。
b. Detergent 清洁剂
If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning
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process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected.
如果在清洗中使用了清洁剂或肥皂，应该确定和考虑试图检测残留物时带来的难度。使用清洁剂的普遍问题就是其成分。许多清洁剂供应商不会提供清洁剂的具体成分信息，这使得使用者难以评估残留物。和产品残留物一样，生产商评估除去残留物的清洗过程的有效性也是必要的和重要的。然而，与产品残留物不同的是，在清洗后不希望有清洁剂存在（超灵敏度检测方法-量非常低）。清洁剂并不是生产工艺中的成分，加进去只是为了便于清洗。这样，它们就容易清除。另一方面，还要选择使用不同的清洁剂。
c. Test Until Clean 清洗前检测
Examine and evaluate the level of testing and the retest results since testing until clean is a concept utilized by some manufacturers. They test, resample, and retest equipment or systems until an "acceptable" residue level is attained. For the system or equipment with a validated cleaning process, this practice of resampling should not be utilized and is acceptable only in rare cases. Constant retesting and resampling can show that the cleaning process is not validated since these retests actually document the presence of unacceptable residue and contaminants from an ineffective cleaning process.
因为有的生产商在清洗前就进行检测，所以应当考察和评估检测和重测的结果。他们要检测，重新取样，重新检测设备或系统，直到达到被认可的残留物水平。因为系统或者设备的清洗过程已经被验证过，所以
4) W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng. 7(3), 29-33 (1987).
5) J.A. Smith, "A Modified Swabbing Technique for Validation of Detergent Residues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).
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6) Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations," Pharm. Technol. 17(4), 54-60 (1993).
7) McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2nd Ed., edited by I.R. Berry and R.A. Nash, 319-349 (1993)
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Welcome Speech Good morning, ladies and gentlemen: Welcome to China, welcome to our beautiful city Hangzhou! On behalf of China International Travel Service, Hangzhou Branch and our colleagues, please allow me to express our warm welcome to all of you. It is a great pleasure for me to meet you today and to be of service. Now we are heading to the hotel, let me introduce our team to you first. My name is Zhou Yujia, English name is Yoga, I will be your local guide for the next two days during your stay in Hangzhou. You can call me Yoga if you like. This is Mr. Zhang, our bus driver, who is an experienced driver and has a driving experience of more than 15 years. During your stay in our city, we will do everything possible to make your stay pleasant and enjoyable. If you have any problems or requests, please do not hesitate to let us know. We’ll try our best to help you. We really appreciate your understanding and cooperation. You are going to stay at the Zhejiang xizi hotel, a five-star hotel, which is located in West Lake Scenic Area. So you will have a very beautiful view from the room. Since you are to stay in our city for two days, you will do well to remember the number of our bus, it is ZheL39978. Let me repeat it, ZheL39978. Our dear friends, I sincerely wish you a pleasant and memorable trip inHangzhou! Hope you enjoy yourself. Thank you for your kind attention!
2020年度WHO清洁验证指南（中文版） 附录3 清洁验证 世界卫生组织药物制剂规范专家委员会第十四次报告。日内瓦，世界卫生组织；2006：附件4（世卫组织技术报告系列第937号） 1.原则 2.范围 3.概述 4.清洁验证方案和报告 5.人员 6.设备 7.清洁剂 8.微生物 9.取样 10.分析方法 11.确定可接受标准 （1）原则 1.1药品质量管理规范（GMP）的目标包括防止可能的污染、药物原料和产品的交叉污染。 1.2药品可能被各物质污染，如与微生物有关的污染物，产品（包括原料药和赋形剂残留）、清洁剂、空气传播的物料，如微尘和颗粒物。润滑剂和辅料材料，如消毒剂、残留降解产物：例如，在清洗的过程中使用强酸和强碱会导致产品残渣分解。洗涤剂、酸和碱的分解产物，可作为清洗工艺的一部分。 1.3适当的清洗程序对防止污染和交叉污染具有重要作用。清洗方法的验证需提供文件证明，经批准的清洗程序将提供与预期用途相适应的清洁设备。 1.4清洁验证的目的是证明设备对产品、洗涤剂和微生物残留物的清洗均能达到可接受水平，以防止可能的微生物污染和交叉污染。 1.5清洁验证对于非关键性的清洗并不一定是必须的，例如批次相同的产品（或散装过程中相同中间体的不同批次）、地板、墙壁、容器外部以及一些中间步骤
之间的清洗。 1.6清洁验证在多产品生产设备清洁中是很重要的，并应在设备、消毒程序和服装洗涤等方面进行验证。 2.范围 2.1指南里描述了清洁验证的一般方面，不包括可能需要的特殊清洁验证或灭活，例如，在生物制造业中去除病毒或支原体污染物。 2.2一般情况下，清洁验证适用于关键清洁，例如，在生产一种产品与另一种产品，与产品、药品和原料药接触的表面的清洗。 3.概述 3.1要有详细的书面标准操作规程（SOP），说明设备和仪器的清洗过程。清洗程序应该经过验证。 3.2制造商应制定清洗策略和一定的清洗验证程序，包括：与产品的接触表面；产品转换后的清洗（当一种药物配方被另一种完全不同的配方替换时）；在批次之间的活动（当同一配方是在一段时间内，在不同的日期生产）；用于清洁验证的产品组。（这种情况经常发生在产品中含有具有类似性质（如溶解度）或具有不同强度的相同物质的地方。一种可接受的策略是首先制造含量较低的剂型（不一定是最低剂量），然后是含量较高的形式。）有时产品的“组”在活性物质或赋形剂方面略有不同。需定期评估和再清洁验证之间生产的批次数。 3.3至少连续三次应用清洁程序，并证明是成功的，以证明该方法是有效的。 4.清洁验证方案和清洁验证报告 4.1清洁验证应在清洁方案中进行描述，该方案应得到正式批准，例由质量控制或质量保证部门批准。 4.2在制定清洁验证方案时，应考虑一下事项： 系统拆卸 预清洗 清洁剂、浓度、溶液体积、水的质量 时间和温度 流速、压力和冲洗 设备复杂性及设备设计
片剂生产线清洁验证方案（2010年） 编号：SVP-QJ-001-01
人员会签表 一、概述 固体口服制剂在生产过程中，由于存在粉尘和大量固体残留物，在每批生产结束时如果设备清洗不彻底，容易对下个批号的产品产生污染。因此，每批生产结束后必须按照相应的清洁规程对所用生产设备进行清洁。为评价设备清洁规程的效果，必须进行清洁验证。 口服固体制剂车间片剂生产线的主要设备有HLSG－200高效湿法制粒机、YK160-C摇摆式颗粒机、CT-C-Ⅱ热风循环烘箱、HD-800三维运动混合机、BG-150高效包衣机、STP-ZB35B压片机。 片剂生产线上生产的品种有，本方案中选用检测微生物限度和化学分析检测化学残留来检查设备清洁后残留的污染物，进行生产后的清洁效果验证。 二、验证目的 设备清洁验证采用化学分析和微生物检测方法，来检查该设备经清洗后所残留的污染物量是否符合规定的限度标准。本验证方案选择最不利清洁条件，对口服固体制剂片剂生产线主要设备的清洁程序进行验证。采用棉签擦拭法取样，对设备清洁后的残留进行化学检验和微生物检验，并将所得结果与可接受限量进行比较。若检测结果均低于其相应规定限量，则可证实设备清洁程序的有效性及稳定性。从而消除换品种或设备清洗不彻底而造成残留物对下一个生产药品污染的发生，有效地保证药品质量，防止交叉污染。因此，清洁验证不仅为设备清洁规程提供技术依据，同时也是设备清洁规程有效性评价的控制标准。这也是此次清洁验证的主要目的。 三、验证人员与职责： 四、验证的安排 进行设备清洁验证前，所有与验证有关的设备、仪器等均已经过验证，仪表、计量器具等已校验合格，检验方法经验证证明符合清洁验证对准确度、精密度、选择性的要求，设备、仪器等已建立相应的操作规程、维护保养规程，对验证试验的样品已建立相应的检验操作规程。对实验的取样方法（取样回收率实验）和设备的最低检测限度均已
f d a清洗验证指南中文 内部编号：（YUUT-TBBY-MMUT-URRUY-UOOY-DBUYI-0128）
FDA清洗验证检查指南 I．引言 自FDA各种文件（包括化学原料药检查指南、生物技术检查指南）首次提出这个问题之后，清洗过程的验证已经引发了很多讨论。FDA的文件明确指出要求对清洗过程进行验证。 本指南讨论了各种可接受（或不可接受）的验证方法，从而使FDA的检查具有一致性。但必须清楚地认识到：与其他工艺验证一样，清洗验证方法也不止一种。所有过程验证的检查标准是：检查其科学数据能否证明系统稳定一致地达到预期目的，系统结果稳定地符合预先制定的标准。 本指南仅适用于设备化学残留物的清洗验证。 II．背景 对于FDA而言，使用设备前进行清洗不是什么新要求。1963年GMP法（133.4）规定“设备应处于清洁、有序的状态”。1978年的cGMP中规定了设备清洗的章节（211.67）。要求清洗设备的主要目的还是防止污染或混料。由于设备清洗维护不当或防尘管理不当，FDA检查官曾十分注意检查卫生状况。过去FDA总是更注意检查青霉素类与非青霉素类药物之间的交叉污染、药品与甾类物质或激素之间的交叉污染问题。在过去二十年间，因实际或潜在的青霉素交叉污染问题已从市场上撤回了大量的药品。 另一个事件使FDA对交叉污染问题日益重视，即1988年从市场上撤回了消胆胺成品制剂，原因是规程不当。生产该制剂的原料药受到了农业杀虫剂生产中少量中间体和降解物质的污染。造成交叉污染的主要原因使用了回收溶媒。而回收溶媒受到了污染，原因是对溶媒桶的重复使用缺少监控。贮存杀虫剂产生的回收溶媒桶又重复地用于贮存该药品生产中的回收溶媒。而工厂没有对这些溶媒桶进行有效的监控，没有对其中的溶媒进行有效的检验，也没有对桶的清洗规程进行验证。 被杀虫剂污染的部份化学原料药运到了另一地点的第二家工厂生产制剂，使该工厂的流化床干燥器中物料袋受到了杀虫剂的污染，料造成各批产品受到污染，而该工厂根本就没有生产杀虫剂。 1992年，FDA对一家海外原料药生产厂发出了进口警告，该工厂使用同一设备生产强力甾类物质和非甾类物质。该工厂是多品种原料药生产厂。FDA认
欢迎词范文英文版 欢迎词大家是怎么样写的呢？这个时候，大家可以一起看看下面的欢迎词范文，欢迎各位阅读借鉴哦！ 篇一：欢迎词范文英文版 Welcome to my hometown Jilin city. And I am the tour guide of China National Tourism Administration you can call me Vera. or Miss Zhang , and on my left hand is our driver Mrs. Li he have more than 20 year driving experiences, he will keep our safe. There is a sentence in China as the saying goes regards: Construct such that the same boat spends for a century. Today we will be: Repair same car dealer s for a century. Everybody knows each other well from not being acquainted for to meeting in all of us being gone to from different place ride in in the same vehicle with a destination, this is really one kind of very marvellous and fine as well preordained relationship , lets us carry this fine preordained relationship through to the end so right away. That Little meng first here wish everybody trip to Dalian happy, hope we Dalian good mountain, good water, good tourist guide, good driver bring a portion to a portion good state of mind, make everybody with face to face Dalian expectation and
GUIDELINE ON GENERAL PRINCIPLES OF PROCESS VALIDATION May, 1987 Prepared by: Center for Drugs and Biologics and Center for Devices and Radiological Health Food and Drug Administration Maintained by: Division of Manufacturing and Product Quality (HFN-320) Office of Compliance Center for Drugs and Biologics Food and Drug Administration 5600 Fishers Lane Rockville, Maryland 20857 General Principles of Process Validation May 1987 GENERAL PRINCIPLES OF PROCESS VALIDATION I. PURPOSE This guideline outlines general principles that FDA considers to be acceptable elements of process validation for the preparation of human and animal drug products and medical devices. II. SCOPE This guideline is issued under Section 10.90 (21 CFR 10.90) and is applicable to the manufacture of pharmaceuticals and medical devices. It states principles and practices of general applicability that are not legal requirements but are acceptable to the FDA. A person may rely upon this guideline with the assurance of its acceptability to FDA, or may follow different procedures. When different procedures are used, a person may, but is not
英文商务会议欢迎词 篇一：招待晚会欢迎词中英文对照 第一届武汉总领馆美国国庆招待晚会欢迎词（中英对照）welcomingRemarksatFirstconGenwuhanJuly4thReception byUSconsulGeneraltowuhanwendyLyle July4th,20XX 在第一届武汉总领馆美国国庆招待晚会所致的欢迎词 美国驻武汉领事馆总领事白小琳 20XX年7月4日 GoodEvening,LadiesandGentlemen!iamwendyLyle,theU.S.consulGeneral inwuhanandthemoderatoroftonight’sreception. 大家好！我是白小琳，美国驻武汉总领事，也是今天晚上美国国庆招待会的主持人。onbehalfoftheU.S.consulateGeneralinwuhan,iwouldliketoextendaheartyw elcometoallofyou--ViceGovernorTianchengzhongofHubei;deputymayorY ueYongofwuhan;FrenchconsulGeneral;seniorofficialsfromallfourprovince softhewuhanconsulardistrict;mayorsanddeputymayorsandseniorgovernme ntofficialsof13citiesincentralchina；presidents,professorsandstudentsfrom14universities；membersofwuhanartcommunity;mydearfriendsfromShenzhen,HongKong
第四节设备的清洁验证 关于清洁验证的原理及方法将在第三篇第二章详细介绍，制剂生产验证各章亦对相应设备的清洗验证要点进行介绍，可以参阅这些章节的内容。 考虑到制药设备验证的完整性，应包括设备的确认，变动控制程序、仪器仪表的校准和清洗验证。在此对设备的清洁验证从方法上作简单介绍。 设备清洗有自动清洗和人工清洗两种方法，或者两种方法的结合。 所谓清洗是从工艺设备或贮存设备中清除污染物的工艺过程，以保证设备能够安全地进行下一步的产品生产，它包括清洗、消毒和贮存。 设备清洁验证的目的是通过测试证明该设备的自动清洗程序(CIP)或人工清洗程 序能够清除设备部件上的活性药物残留物，并达到可接受的合格标准，并证明此清洁程序具有稳定性和重演性。 一、设备清洁验证中常用的术语 ①人体接触剂量限度(SEL，Subject E×posure Limit)。指一个没有药理学和毒理 学经验的人可以接触的某一药物的暴露剂量。 ②允许残留浓度(ARL，Allowable Residual Limit)．指某一设备经清洗后，其表面残留的药物(或清洁剂)的最大允许量。 ③活性成分(API，Active Pharmaceutical lngredient；或ADS，Active Drug Substance)：指在某一药物中代表效用的物质。这种物质在制造、工艺或包装过程中就变成了一种活性成分或者药物的最终成型形式。活性成分在疾病诊断、治疗、缓解、处理或预防方面提供药理上的活力或其他直接的作用，以致影响人体或动物的组织和功能。 API 在工艺制造过程中产生，如：①化学合成；②发酵；③重组DNA 或其他 生物工艺；④从自然资源上分离或取得；⑤ 其他工艺的任何组合等。对设备清洁验证来说，API 包括中间体及成品。 一般来说，SEL、ARL 的允许值应从药物安全评价部门获取。 二、验证设计 在验证取样测试时，若发现洗过的设备明显不干净，应立即停止验证，有明显的残留物存在表明现有的清洁程序是不合适的，因此必须在验证开始前重新评价清洁程序。从某种意义上来说，清洁验证就是对清洗标准操作规程的验证。 清洁验证主要是通过擦拭取样法和冲洗取样法对活性成分APl 进行测试。另外可根据日常使用的需要，增加一些其他项目的测试，如清洁剂、酸液、溶剂、消毒剂等残留量的测试。 大部分企业在设备清洗中使用的清洁剂是水(包括饮用水、纯化水和注射用水)，原因之 一就是使用化学清洁剂要作清洁剂残留量的测试，从而增加清洗的难度。 制造部门在设备清洁程序中任何关于清洁剂、溶剂、添加剂的改变必须填写变动控制表， 得到批准后执行。并非所有的设备清洁验证需做活性成分APl 的测试。根据APl 是否在特殊的清洁剂或溶剂中溶解而使设备难以清洗的程度来对APl 的浓度作 出评价o APl 允许浓度可根据公式来计 算，如果人体接触剂量限度SEL 太低无法达到时，可用替代基质来覆盖所有的 产品。 (一)验证次数
英文欢迎词范文 英文欢迎词范文 英文欢迎词范文1 Ladies and gentlemen: On the occasion of the 30th anniversary anniversary of the XXX plant, please allow me to extend my warm welcome to the distinguished guests from all over the world on behalf of the XXX plant and in my own name. My friends have come to congratulate and discuss trade cooperation in spite of the distant journey. I feel happy for the 30th anniversary factory celebrations of our factory. I sincerely feel happy and express our sincere thanks to our friends for their efforts to promote friendly relations between the two sides. Many of you here today are our old friends, and we have good cooperative relations. Our factory has built up factories for 30 years and can achieve today’s results. We cannot do without our sincere cooperation and strong support from our old friends. In this regard, we express our sincere admiration and thanks. At the same time, we are very happy to have the opportunity to meet new friends from all over the country. Here, I would like to extend a warm welcome to our new friends again, and hope to work closely with new friends and develop friendly and cooperative relations with each other. “It’s not a pleasure to have friends coming from the distance.”On the occasion of the meeting of the new friends and old friends, I propose: For further cooperation between us, For the growing friendship between us, For the health and happiness of my friends, Cheers!英文欢迎词范文2 Leaders and teachers: Good morning, everybody! Today is another great event of our educational circles in Lu Kou Town. Today is full of the attention of all schools to teaching and research activities, which fully
Validation of Cleaning Processes (7/93) 清洁工艺验证 清洁工艺验证检查指南 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。 介绍 自从FDA 的各文件，包括化学原料药检查指南和生物技术检查指南简单地提出了清洁验证这个话题之后，关于清洁工艺的验证已经引发了相当多的讨论。这些官方的文件， 都清楚地确定了对于清洁工艺需要被验证的期望。 通过讨论那些已被认为可接受的（或者不可接受的）实际情况，此指南是为了建立检查 的连贯一致性。同时，必须意识到，与其他工艺验证一样，清洁验证的方法也不止一种。最后，所有过程验证的检查标准是，检查其科学数据能否证明该系统始终如一地达到预 期目的，结果稳定地符合预先制定的标准。 本指南仅适用于设备的化学残留物的清洁验证。 背景 1963 年GMP 法规（133.4 节）要求如下“设备需要被维持在一个清洁、有序的状态”。还有一个很相似的关于设备清洁的章节是在1978 年GMP 法规（211.67 节）。同这些法规相比，FDA对于设备在使用前应被清洁的要求并不是什么新要求。当然，对于设备 清洁的总的原则是为了防止产品污染或掺杂其它物质。从历史事件看来，FDA检查官发 现了一些明显的不卫生是由于设备的清洁和维护不到位，或防尘控制系统不当。过去 FDA 更多的关注于非青霉素类产品和青霉素类产品，或药品与甾类产品和激素类产品之 间的交叉污染问题。在过去的十年中，有大量的产品召回事件都是由于实际的或潜在的 青霉素交叉污染。 1988 年的召回消胆胺树脂事件，使FDA 对于潜在交叉污染的问题日益重视。那次召回 的原因是用于生产制剂的原料药被农业杀虫剂生产中低剂量的中间体和降解物给污染 了。造成这次交叉污染的原因是由于重复使用了回收溶剂引起的。而回收溶剂被污染的 原因是由于对重复使用的溶剂桶缺乏控制。这些桶之前是用于贮存杀虫剂生产线产生的 回收溶剂，之后又被重复地用于树脂生产线使用的回收溶剂贮存。该公司对于这些溶剂 桶缺乏有效的控制，对于贮存的溶剂缺少适当的检测，对于溶剂桶的清洁过程也没有进 行验证。 一部分被杀虫剂污染的原料药被供给了在另一地址的厂进行最后的制剂生产，这就导致 2
英文欢迎致辞 欢迎辞 Welcoming speech Ladies and gentlemen, Following the increasing rapidity of our communications with countries abroad, China is having a large number of visitors from different countries. Today, we feel very much honored to have [Prof. Martin. Wilson] with us. [Prof. Martin. Wilson] is well known to the world for his achievements in the field of [mathematics]. First of all, let me, on behalf of all present here, extend our warm welcome and cordial greetings to our distinguished guest. Now let us invite [Prof. Wilson] to give us a lecture. 女士们，先生们： 随着我国对外交往日益增多，中国每天要接待大量来自不同国家的贵客。今天，我们感到很荣幸能和[马丁·威尔逊教授]欢聚一堂。[威尔逊教授]在[数学]领域卓有成就，在世界上享有一定的威望。 首先，让我代表在座的各位向我们的贵宾表示热烈的欢迎和真挚的问候。现在请[威尔逊教授]做报告。 用英文欢迎新来的同事 I am Peter, Sales manager of the company. First of all, I would like to take this opportunity to welcome you to our company. As you are aware that our company is the one of the leading companies. I know you will be proud of you being a member of our company. It is always my great concern to keep the business going. We can never rest on our laurels. We need to set new goals for ourselves all the time. As you are equipped with new knowledge, new thoughts and new insights, make full use of them while they are still fresh in your minds.
APIC颁布原料药工厂清洁验证指南 An APIC multinational working group has compiled a new guidance on cleaning validation with the title "APIC Guidance on Aspects of Cleaning Validation in Active Pharmaceutical Ingredients Plants". Publication date is May 2014 and the document can be downloaded from the APIC website. The following is a summary description of the document. The document contains 55 pages and is subdivided into 13 chapters. APIC多国工作组汇编了新的清洁验证指南，题为“APIC原料药工厂清洁验证指南面面观”。颁布日期为2014年5月，文件可以从APIC官网下载。以下是该文件的摘要。文件包括55页，分为13章。 Foreword 前言 Objective 目的 Scope 范围 Acceptance Criteria 可接受标准 Levels of Cleaning 清洁水平 Control of Cleaning Process 清洁工艺控制 Bracketing and Worst Case Rating 括号法和最差情况分类法 Determination of the Amount of Residue 残留量的检测 Cleaning Validation Protocol 清洁验证方案 Validation Questions 验证问题 References 参考文献 Glossary 术语 Copyright and Disclaimer 版权和声明 The topic cleaning validation gained new importance in the EU with the publication of the EMA Guideline "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" and with the chapter Cleaning Validation in the draft of the revision of Annex 15. The foreword refers to the integration of cleaning validation within a quality system supported by quality risk management processes in order to protect the patients. According to the authors the document is aligned with ISPE Risk-MaPP
(1) 清洁验证的一般要求 清洁验证是通过文件证明清洁程序有效性的活动，它的目的是确保产品不会受到来自于同一设备上生产的其他产品的残留物、清洁剂以及微生物污染。 为了证明清洁程序的有效性，在清洁验证中应至少执行连续三个成功的清洁循环。 对于专用设备，清洁验证可以不必对活性成分进行考察，但必须考虑清洁剂残留以及潜在的微生物污染等因素，对于一些特殊的产品，还应考査降解产物。 对于没有与药物成分接触的设备（如加工辅料用的流化床或包衣片所使用的包装设备），清洁验证可以不必对活性成分进行考察，但必须考虑清洁剂残留及微生物污染等因素。 清洁验证中需对下列放置时间进行考察，进而确定常规生产中设备的放置时间： ? 设备最后一次使用与清洁之间的最大时间间隔（“待清洁放置时间”）； ? 设备清洁后至下一次使用的最大时间间隔（“清洁后放置时间”）。 (2) 清洁验证的前提条件 进行清洁验证的前提条件是: ? 清洁程序已批准，其中包括关键清洁程序的参数范围； ? 完成风险评估（对于关键操作、设备、物料包括活性成分、中间体、试剂、辅 料、清洁剂、以及其他可能影响到清洁效果的参数）； ? 分析方法经过验证； ? 取样方法已经批准，其中包括取样规程和取样点； ? 验证方案已经批准，其中包括接受标准（根据不同设备制定）。 (3) 测试项目 清洁验证中涉及的测试项目应根据产品的类型通过风险分析而定，通常需考虑以下 内容： 參目测检查； ? 活性成分残留； ? 清洁剂残留； ? 微生物污染； ? 难清洁并可能对后续产品造成不良影响的辅料（如色素或香料）。 ( 4 ) 取样 清洁验证中应用的取样方法应详细规定并且经过批准，选择取样方法时应考虑残留物和生产设备的特性。 3 产品质量实现的要素 化学成分残留取样：
FDA清洗验证检查指南 I．引言 自FDA各种文件（包括化学原料药检查指南、生物技术检查指南）首次提出这个问题之后，清洗过程的验证已经引发了很多讨论。FDA的文件明确指出要求对清洗过程进行验证。 本指南讨论了各种可接受（或不可接受）的验证方法，从而使FDA的检查具有一致性。但必须清楚地认识到：与其他工艺验证一样，清洗验证方法也不止一种。所有过程验证的检查标准是：检查其科学数据能否证明系统稳定一致地达到预期目的，系统结果稳定地符合预先制定的标准。 本指南仅适用于设备化学残留物的清洗验证。 II．背景 对于FDA而言，使用设备前进行清洗不是什么新要求。1963年GMP法（133.4）规定“设备应处于清洁、有序的状态”。1978年的cGMP中规定了设备清洗的章节（211.67）。要求清洗设备的主要目的还是防止污染或混料。由于设备清洗维护不当或防尘管理不当，FDA检查官曾十分注意检查卫生状况。过去FDA总是更注意检查青霉素类与非青霉素类药物之间的交叉污染、药品与甾类物质或激素之间的交叉污染问题。在过去二十年间，因实际或潜在的青霉素交叉污染问题已从市场上撤回了大量的药品。 另一个事件使FDA对交叉污染问题日益重视，即1988年从市场上撤回了消胆胺成品制剂，原因是规程不当。生产该制剂的原料药受到了农业杀虫剂生产中少量中间体和降解物质的污染。造成交叉污染的主要原因使用了回收溶媒。而回收溶媒受到了污染，原因是对溶媒桶的重复使用缺少监控。贮存杀虫剂产生的回收溶媒桶又重复地用于贮存该药品生产中的回收溶媒。而工厂没有对这些溶媒桶进行有效的监控，没有对其中的溶媒进行有效的检验，也没有对桶的清洗规程进行验证。 被杀虫剂污染的部份化学原料药运到了另一地点的第二家工厂生产制剂，使该工厂的流化床干燥器中物料袋受到了杀虫剂的污染，料造成各批产品受到污染，而该工厂根本就没有生产杀虫剂。
欢迎辞 金秋十月，丹桂飘香。蓉城日丽风和，柳林秋高气爽，欣逢2012全球化进程国际学术大会召开之际，我谨代表西南财经大学向远道而来的各位嘉宾致以最热烈的欢迎！ 本次全球化进程国际学术大会，以著名经济学家尼古拉·康德拉季耶夫诞生120周年、及其著作“The World Economy and its Conjunctures during and after the War”发表90周年为契机，由西南财经大学与莫斯科罗诺萦夫国立大学共同主办，中国世界经济学会和中国留美经济学会协办，同时，我们十分荣幸地邀请到了来自美国、俄罗斯、英国、德国、乌克兰、澳大利亚、新加坡、南非、瑞士等十多个国家的多名经济学者共聚西南财经大学，参加此次全球化进程国际学术大会。通过为国际范围内的学术对话与讨论搭建平台，全球化进程国际学术大会将成为一次影响范围广、学术水平高、社会意义大的经济学盛会。 全球化是本次会议的讨论主题，也是当今世界格局发展的必然趋势。经济全球化是全球化进程的主要方面，包括了金融全球化、生产全球化、贸易全球化、技术全球化等不同领域的经济现象。借助于经济全球化，世界经济活动超越国界，以对外贸易、资本流动、技术转移、提供服务的方式形成相互依存、相互联系的覆盖全球范围的有机经济整体。经济全球化发展的同时，也将伴随着政治、文化等诸多方面的全球化发展。因此，全球化的时代，是竞争与合作并存、机遇与挑战相倚的时代。对于正处在改革发展关键时期的中国，和其它世界各国，思考如何适应全球化大背景下的多元化发展趋势、如何应对全球化发展衍生出的经济与社会危机、如何在良性竞争的同时实现互利共赢等问题，有着巨大的现实意义。 本次全球化进程国际学术大会将从理论与实际的不同视角，探讨全球化——特别是经济全球化进程中的重点与热点问题，展示当前经济学界在相关领域的最新研究成果。通过对于热点学术问题的相互交流，以及对于当前经济现象的共同思考，必将推动全球化问题研究的进步，为中国改革开放、世界经济的复苏和进一步发展提供丰富的建议。 衷心祝愿各位领导、同僚，各位专家、学者，各位新老朋友们蓉城之行愉快！ 西南财经大学党委书记：赵德武 西南财经大学校长：张宗益 二零一二年十月十三日
APIC 201405原料药厂清洁验证指南：7.0 分组法（括号法）和最差情况分级（中英文） 2014-07-15julia翻译蒲公英 7.0 Bracketing and Worst Case Rating 分组法（括号法）和最差情况分级 7.1 Introduction 介绍 The cleaning processes of multiple product use equipment in API facilities are subject to requirements for cleaning validation. The validation effort could be huge. In order to minimize the amount of validation required, a worst case approach for the validation can be used. 原料药工厂中的多产品设备清洁要求进行清洁验证。清洁工作量会比较大。为了减少验证的工作量，可以采用最差情形方法进行验证。 By means of a bracketing procedure the substances are grouped. 采用分组法时，物质按类进行分组。 A worst case rating procedure is used to select the worst case in each group. 然后在每组中采用最差情形分级法选择各组中最差的情况。 Validation of the worst case situation takes place. However, it is of utmost importance that a documented scientific rational for the chosen worst cases exists. 对最差情形进行验证。至关重要的是，选择最差情形的科学合理性要进行记录。This chapter gives an overview of the suggested work to be carried out, the acceptance criteria and the methodology for evaluation of the data. It should be emphasized that this is only an example to give guidance. The equipment, the substances produced and the procedures in place may vary; and this results in other solutions than those given in this example.
DPP-250C平板式铝塑泡罩包装机 清洁验证方案 编号：SVP-QJ-1308-01 制订人：日期： 审核人：日期： 日期： 日期： 批准人：日期： 设备名称：平板式铝塑泡罩包装机 型号：DPP-250C 制造厂商：**** 出厂日期：2014年10月 使用部门：固体制剂车间 安装位置：铝塑包装间 设备编号：S-GT-011
目录 1. 概述 (4) 1.1 验证目的 (4) 1.2 设备简介 (4) 1.3 验证描述 (4) 1.4 验证小组组成及分工 (4) 1.5 验证培训 (4) 1.6 验证时间安排 (4) 2. 验证内容 (5) 2.1 主要检验仪器确认 (5) 2.2 关键部位、参照产品、残留限度 (5) 2.3 清洁验证 (6) 3. 再验证周期 (8) 4. 确认评价及建议 (8) 5. 最终审核意见 (8) 6. 附验证检查记录 (8)
验证项目小组会签单 职责姓名部门时间项目组长 QA QC 计量管理员 操作人员 操作人员 操作人员
1 概述： 1.1 验证目的：为了防止污染和交叉污染，确保清洁完全彻底，采用物理外观检查、活性成分残留检查、清洁剂残留、微生物限度检查，对清洁效果进行综合评价，确认清洁、消毒程序能符合生产工艺要求，没有来自上批产品及清洗过程所带来的污染风险。 1.2 设备简介：平板式铝塑泡罩包装机，用于片剂、胶囊剂等固体制剂的泡罩式密封包装生产。由机械传动装置，包材传送系统，电加热系统，热合、冲裁机构，控制系统及药品输送系统组成。PVC/PVDC经包材传送系统进入热合机构，药品通过输送系统进入泡罩后热压成型，经冲裁机构分成所需板块。 1.3 验证描述：目前该设备主要用于扎来普隆片、星瑙灵片的内包装。确认生产结束后至清洁进行时的放置时间DHT；按《平板式铝塑泡罩包装机清洁、消毒操作规程》进行清洁、消毒。对设备最难清洗部位进行擦拭取样、分析、评价，确认所制订的清洁消毒操作规程能满足工艺要求；确认清洁过程对产品生产无污染。若不能满足，则应及时进行方法的调整，同时提出修正方案，并重新验证。清洁消毒后， 48，72，96小时分别取样检测微生物，进行清洁有效期验证。若出现偏差，进行必要的偏差处理。清洗效果验证须连续进行3批。 1.4 验证小组组成及分工： 部门责任人职责 固体制剂车间车间主任验证方案的起草、实施，验证数据的收集，验证报告的起草 生产技术部负责人验证方案的审核，验证工作的协调 质量管理部负责人验证方案的审核，验证过程的监督，样品的采集、分析，验证报告的审核1.5 验证培训： 培训内容日期签名 平板式铝塑泡罩包装机清洁、消毒标准操作规程 清洁工具的使用和清洁消毒操作规程 消毒液配制、贮存、发放操作规程 平板式铝塑泡罩包装机清洁验证方案 设备清洁擦拭取样回收率验证方案 1.6 验证时间安排： 2014年··月20日～··月··日进行方案培训，进行技术准备。 2014年··月··日～··月··日进行方案实施。