FDA清洗验证检查指南-翻译和解读
[VIP专享]FDA清洁验证指南
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Validation of Cleaning Processes清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSESNote: 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。
本指南不约束FDA，也没有授予任何人任何权利、特权、收益或豁免权。
I. INTRODUCTION 简介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。
准备FDA认证前检查中英文对照文档
? When is the ANDA reviewed by FDA?
FDA什么时候审查ANDA
? After the ANDA holder files the ANDA ANDA 持有人将 ANDA归档后
? Because of backlogs, expect at least 6 month delay before reviewing 由于积压，预计至少延迟 6个月才能被审查
? Ensure that the ANDA or DMF submission is an accurate reflection of what is being done at the facility
确保ANDA或DMF中提交的是设施正在进行的情况的准确反应
Richard Needham, RFL Associates
? Ensure that data submitted in the ANDA or DMF submission is supported by raw data at the facility
确保在ANDA或DMF文件中提交的数据以设施的原始数据为依据
? Data and original records must be documented according to cGMP standards 原始数据和记录必须根据cGMP标准进行
? Two adjacent conference rooms 两个相邻的会议室
配备两个人通常是指
? Two Interpreters (provided by the firm, at present) 两名翻译员（目前由公司提供的）
? The interpreters are extremely important to the smooth running of the inspection 翻译员对于检查顺利进行是非常重要的
FDA指南中文版
目录表I. 导言 (1)II. 背景 (2)III. 分析方法的类型 (3)A. 法定分析方法 (3)B. 可选择分析方法 (3)3 C. 稳定性指示分析 (3)IV. 对照品 (4)A. 对照品的类型 (4)B. 分析报告单 (4)C. 对照品的界定 (4)V. IND中的分析方法验证 (6)VI. NDA, ANDA, BLA 和PLA中分析方法验证的内容和格式 (6)A. 原则 (6)B. 取样 (7)C. 仪器和仪器参数 (7)D. 试剂 (7)E. 系统适应性实验 (7)F. 对照品的制备 (7)G. 样品的制备 (8)H. 分析方法 (8)L. 计算 (8)J. 结果报告 (8)VII. NDA，ANDA,BLA和PLA中的分析方法验证 (9)A． 非法定分析方法 (9)1．验证项目 (9)2. 其它分析方法验证信息 (10)a. 耐用性 (11)b. 强降解实验 (11)c. 仪器输出/原始资料 (11)3．各类检测的建议验证项目 (13)B． 法定分析方法 (15)VIII. 统计分析 (15)A. 总则 (15)B. 比较研究 (16)C. 统计 (16)IX. 再验证 (16)X. 分析方法验证技术包：内容和过程 (17)A. 分析方法验证技术包 (17)B. 样品的选择和运输 (18)C. 各方责任 (19)XI. 方法 (20)A. 高效液相色谱(HPLC) (20)B. 气相色谱(GC) (22)C. 分光光度法，光谱学，光谱法和相关的物理方法 (23)D. 毛细管电泳 (23)E. 旋光度 (24)F. 粒径相关的分析方法 (25)G. 溶出度 (26)H. 其它仪器分析方法 (27)附件 A：NDA，ANDA，BLA和PLA申请的内容 (28)附件 B：分析方法验证的问题和延误 (29)参考文献 (30)术语表 (32)I. INTRODUCTIONThis guidance provides recommendations to applicants on submitting analyticalprocedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.1. 绪论本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。
准备FDA认证前检查中英文对照PPT课件
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Purpose of a pre-Approval Inspection
认证前检验的目的
Ensure that data submitted in the ANDA or DMF submission is supported by raw data at the facility
确保在ANDA或DMF文件中提交的数据以设施的原始数据为依据
Preparation for two people generally means:
配备两个人通常是指
Two Interpreters (provided by the firm, at present) 两名翻译员（目前由公司提供的） The interpreters are extremely important to the smooth running of the inspection 翻译员对于检查顺利进行是非常重要的
然而，DMF持有人仍应通过年度报告和DMF修订将更新提交给FDA
This way, the DMF will be up-to-date when reviewed这样， DMF被审查时将是最新的
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The Pre-Approval Inspection (PAI) 认证前检查（PAI）
When is the ANDA reviewed by FDA?
Data and original records must be documented ng to cGMP standards 原始数据和记录必须根据cGMP标准进行
Ensure that the ANDA or DMF submission is an accurate reflection of what is being done at the facility
FDA清洁验证
Validation of Cleaning Processes (7/93)GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSESNote: 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. INTRODUCTIONValidation 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.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.This guide is intended to cover equipment cleaning for chemical residues only.II. BACKGROUNDFor FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillinsor the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.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.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.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 forcross-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.III. GENERAL REQUIREMENTSFDA expects firms to have written procedures (SOP's) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address these 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 expects firms to have written general procedures on how cleaning processes will be validated.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 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 analytical methods to be used including the sensitivity of those methods.FDA expects firms to conduct the validation studies in accordance with the protocols and to document the results of studies.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."IV. EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process. For example, at what point does a piece of equipment or system become clean?（何种情况下1台设备或系统已经被清洁干净？）Does it have to be scrubbed by hand?（需要用手工来擦洗吗？） What is accomplished by hand scrubbing rather than just a solvent wash?（哪些是手工擦洗完成，而不是溶剂清洗完成的？）How variable are manual cleaning processes from batch to batchand product to product?（产品之间和批之间的手工清洁如何不同？） The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the 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.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.1. Equipment DesignExamine 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.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.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.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 drugoperations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.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.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.2. Cleaning Process WrittenProcedure and DocumentationExamine 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.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.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.3. Analytical MethodsDetermine 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).4. SamplingThere 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.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.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.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.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.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.c. Routine Production In-Process ControlMonitoring - 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.V. ESTABLISHMENT OF LIMITSFDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm's rationale for the residue limits established should be logical based on the manufacturer's knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue.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 partialreactants 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.VI. OTHER ISSUESa. Placebo ProductIn order to evaluate and validate cleaning processes some manufacturers have processed a placebo batch in the equipment under essentially the same operating parameters used for processing product. A sample of the 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.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.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.b. DetergentIf 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 process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitiveanalytical 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.c. Test Until CleanExamine 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.。
FDA清洗验证检查
FDA清洗验证检查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(13 3.4)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( 21 1. 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。
WHO：清洁验证新指南（中英文对照版）！
WHO：清洁验证新指南（中英文对照版）！Points to consider when including Health-Based Exposure Limits(HBELs) in cleaning validation清洁验证使用基于健康的暴露限（HBEL）的考量1. Introduction andbackground介绍和背景2. Scope范围3. Glossary术语4. Historical approach传统方法5. New approaches新的方法5.1Documentation文件5.2 Equipment设备5.3 Cleaningagents清洁剂5.4 Sampling取样5.5Cleanability studies清洁能力研究5.6 Riskmanagement风险评估5.7 Guidancefor Health-BasedExposure Limits (HBELs) setting基于健康的暴露限设定的指南5.8Acceptance criteria接受标准5.9Analytical procedures分析方法5.10 Dataintegrity数据完整性5.11 Cleaningvalidation andcleaning verification清洁验证和清洁确认5.12 Visuallyclean目视干净5.13 Cleaningprocess capability清洁工艺能力5.14Personnel人员5.15 Qualitymetrics andperformance indicators质量量度和性能指标5.16 Lifecycle生命周期References参考文献Furtherreading扩展阅读Annex 1附录11. Introductionand background介绍及背景The World HealthOrganization (WHO) has published the guideline entitled Good manufacturing practicesfor pharmaceutical products: main principles in the WHO Technical ReportSeries, No. 986, Annex 2, 2014 (1).WHO 于 2014 年 TRS 986 附录2 发布了题为“药品 GMP：主则”的指南。
FDA清洁验证审计指南
Validation of Cleaning Processes(7/93)SHARETWEETLINKEDINPIN ITMORE SHARING OPTIONSLINKEDINPIN ITEMAILPRINTGUIDE TO INSPECTIONS VALIDATION OF CLEANINGPROCESSESNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s).I. INTRODUCTIONValidation of cleaning procedures has generated considerable discussionsince agency documents, including the Inspection Guide for BulkPharmaceutical Chemicals and the Biotechnology Inspection Guide, havebriefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.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 withvalidation 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 scientificdata shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.This guide is intended to cover equipment cleaning for chemical residuesonly.II. BACKGROUNDFor FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shallbe maintained in a clean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to preventcontamination or adulteration of drug products. Historically, FDAinvestigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipme nt an d/or poor dust con trol systems. Also,historically speak ing, FDA was more concerned about the con tam in ati onof nonpenicillin drug products with penicillins or the cross-contamination ofdrug products with pote nt steroids or horm on es. A nu mber of productshave bee n recalled over the past decade due to actual or pote ntial peni cilli n cross-c on tam in ati on.One eve nt which in creased FDA aware ness of the pote ntial for cross con tam in ati on due to in adequate procedures was the 1988 recall of afinished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become con tam in ated with low levels of in termediates and degrada nts from the producti on of agricultural pesticides. The cross-c on tam in ati on in that case is believed to have bee n due to the reuse of recovered solve nts. The recovered solve nts had bee n con tam in ated because of a lack of con trol over the reuse of solve ntdrums. Drums that had bee n used to store recovered solve nts from apesticide producti on process were later used to store recovered solve ntsused for the res in manu facturi ng process. The firm did not have adequate con trols over these solve nt drums, did not do adequate testi ng ofdrummed solve nts, and did not have validated clea ning procedures for the drums.Some shipme nts of this pesticide con tam in ated 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 withpesticide contamination. This in turn led to cross contamination of lotsproduced at that site, a site where no pesticides were no rmally produced.FDA instituted an import alert in 1992 on a foreign bulk pharmaceuticalmanu facturer which manu factured pote nt steroid products as well as non-steroidal products using com mon equipme nt. This firm was a multi-usebulk pharmaceutical facility. FDA con sidered the pote ntial for cross-contamination to be significant and to pose a serious health risk to thepublic. The firm had only recently started a cleaning validation program atthe time of the in spect ion and it was con sidered in adequate by FDA. One of the reas ons it was con sidered in adequate was that the firm was onlylook ing for evide nee of the abse nee of the previous compo und. The firm had evidenee, from TLC tests on the rinse water, of the presence ofresidues of react ion byproducts and degrada nts from the previous process. III. GENERAL REQUIREMENTSFDA expects firms to have writte n procedures (SOP's) detaili ng the cleaning processes used for various pieces of equipme nt. If firms have one clea ning process for clea ning betwee n differe nt batches of the same productand use a differe nt process for clea ning betwee n product cha nges, weexpect the written procedures to address these different scenario. Similarly, if firms have one process for rem oving water soluble residues and ano ther process for non-water soluble residues, the writte n procedure shouldaddress both sce narios and make it clear whe n a give n procedure is to be followed. Bulkpharmaceutical firms may decide to dedicate certa in equipme nt for certa in chemical manu facturi ng process steps that produce tarry or gummyresidues that are difficult to remove from the equipment. Fluid bed dryerbags are ano ther example of equipme nt that is difficult to clea n and is ofte n dedicated to a specific product. Any residues from the clea ning processitself (detergents, solvents, etc.) also have to be removed from the equipme nt.FDA expects firms to have writte n gen eral procedures on how clea ningprocesses will be validated.FDA expects the gen eral validati on procedures to address who is resp onsible for perform ing and appro ving the validati on study, the acceptancecriteria, and when revalidation will be required.FDA expects firms to prepare specific writte n validati on protocols in advance for the studies to be performed on each manu facturi ng system or piece of equipme nt which should address such issues as sampli ng procedures,and an alytical methods to be used in clud ing the sen sitivity of thosemethods. FDA expects firms to con duct the validati on studies in accordance with the protocols and to docume nt the results of studies.FDA expects a final validati on report which is approved by man ageme ntand which states whether or not the clea ning process is valid. The datashould support a con clusi on that residues have bee n reduced to an"acceptable level."IV.EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and wehave see n that some compa nies have failed to develop such objectives. It is not unu sual to see manu facturers use exte nsive sampli ng and testi ngprograms follow ing the clea ning process without ever really evaluati ng the effective ness of the steps used to clea n the equipme nt. Several questi ons n eed to be addressed whe n evaluat ing the clea ning process. Forexample, at what point does a piece of equipme nt or system become clean? Does it have to be scrubbed by hand? What is accomplished by handscrubb ing rather tha n just a solve nt wash? How variable are manual cleaning processes from batch to batch and product to product? The an swers to these questions are obviously important to the inspection and evaluation ofthe clea ning process since one must determ ine the overall effective ness of the process. An swers to these questi ons may also ide ntify steps that canbe elimi nated for more effective measures and result in resource sav ingsfor the compa ny.Determ ine the nu mber of clea ning processes for each piece of equipme nt.Ideally, a piece of equipment or system will have one process for cleaning,however this will depe nd on the products being produced and whether theclea nup occurs betwee n batches of the same product (as in a largecampaig n) or betwee n batches of differe nt products. Whe n the clea ningprocess is used only betwee n batches of the same product (or differe nt lotsof the same in termediate in a bulk process) the firm n eed only meet a criteria of, "visibly clea n" for the equipme nt. Such betwee n batch clea ning processes do not require validati on.1. Equipme nt Desig nExam ine the desig n of equipme nt, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represe nt sig nifica nt concern. For example, sanitary type pip ing without ball valves should be used. Whe n suchnonsan itary ball valves are used, as is com mon in the bulk drug industry, the clea ning process is more difficult.When such systems are ide ntified, it is importa nt that operatorsperform ing clea ning operatio ns be aware of problems and havespecial trai ning in clea ning these systems and valves. Determ inewhether the clea ning operators have kno wledge of these systems and the level of training and experie nee in clea ning these systems. Alsocheck the writte n and validated clea ning process to determ ine if these systems have been properly identified and validated.In larger systems, such as those employi ng long tran sfer lines or pipi ng, check the flow charts and pip ing diagrams for the ide ntificati on of valves and writte n clea ning procedures. Pip ing and valves should be tagged and easily identifiable by the operator performing the cleaningfunction. Sometimes, in adequately ide ntified valves, both on prints and physically, have led to in correct clea ning practices.Always check for the prese nee of an ofte n critical eleme nt in thedocume ntati on of the clea ning processes; ide ntify ing and con troll ing the len gth of time betwee n the end of process ing and each clea ning step. This is especially importa nt for topicals, suspe nsions, and bulkdrug operations. In such operations, the drying of residues will directly affect the efficie ncy of a clea ning process.Whether or not CIP systems are used for clea ning of process ingequipme nt, microbiological aspects of equipme nt clea ning should be con sidered. This con sists largely of preve ntive measures rather tha n removal of con tam in ati on once it has occurred. There should besome evide nee that rout ine clea ning and storage of equipme nt does not allow microbial proliferation. For example, equipment should bedried before storage, and un der no circumsta nces should stag nantwater be allowed to rema in in equipme nt subseque nt to clea ningoperati ons.Subseque nt to the clea ning process, equipme nt may be subjected to sterilizati on or san itizati on procedures where such equipme nt is used for sterile process ing, or for non sterile process ing where the products may support microbial growth. While such sterilizatio n or san itizati on procedures are bey ond the scope of this guide, it is importa nt to note that con trol of the bioburde n through adequate clea ning and storageof equipme nt is importa nt to en sure that subseque nt sterilizati on orsanitization procedures achieve the necessary assuranee of sterility.This is also particularly important from the standpoint of the control ofpyroge ns in sterile process ing since equipme nt sterilizati on processes may not be adequate to achieve sig nifica nt in activati on or removal of pyroge ns.2. Clea ning Process Writte nProcedure and Docume ntati onExam ine the detail and specificity of the procedure for the (clea ning)process being validated, and the amount of docume ntati on required.We have see n gen eral SOPs, while others use a batch record or logsheet system that requires some type of specific docume ntati on forperform ing each step. Depe nding upon the complexity of the systemand cleaning process and the ability and training of operators, theamount of docume ntati on n ecessary for executi ng various clea ningsteps or procedures will vary.When more complex clea ning procedures are required, it is importa nt to docume nt the critical clea ning steps (for example certa in bulk drug syn thesis processes). I n this regard, specific docume ntati on on theequipme nt itself which in cludes in formati on about who clea ned it and when is valuable. However, for relatively simple cleaning operations, the mere docume ntati on that the overall clea ning process was performed might be sufficie nt.Other factors such as history of clea nin g, residue levels found aftercleaning, and variability of test results may also dictate the amount ofdocume ntati on required. For example, whe n variable residue levelsare detected follow ing clea ning, particularly for a process that isbelieved to be acceptable, one must establish the effective ness of the process and operator performa nee. Appropriate evaluati ons must bemade and whe n operator performa nee is deemed a problem, moreexte nsive docume ntati on (guida nee) and training may be required. 3. Analytical MethodsDetermine the specificity and sensitivity of the analytical method used to detect residuals or con tam inan ts. With adva nces in an alytical tech no logy, residues from the manu facturi ng and clea ning 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 con tam inant prese nt after clea nin g. It only means that levels of con tam inant greaterthan the sensitivity or detection limit of the analytical method are notpresent in the sample. The firm should challenge the analytical method in comb in ati on with the sampli ng method(s) used to show that contam inants can be recovered from the equipme nt surface and at whatlevel, i.e. 50% recovery, 90%, etc. This is n ecessary before any conclusi ons can be made based on the sample results. A n egative testmay also be the result of poor sampli ng tech nique (see below).4. Sampli ngThere are two gen eral types of sampli ng that have bee n foundacceptable. The most desirable is the direct method of sampling thesurface of the equipme nt. Ano ther method is the use of rinse soluti ons.a. Direct Surface Sampli ng - Determi ne the type of samplingmaterial used and its impact on the test data since the sampli ngmaterial may in terfere with the test. For example, the adhesiveused in swabs has been found to interfere with the analysis ofsamples. Therefore, early in the validation program, it is importantto assure that the sampli ng medium and solve nt (used for extraction from the medium) are satisfactory and can be readily used.Advantages of direct sampling are that areas hardest to clean andwhich are reas on ably accessible can be evaluated, lead ing toestablish ing a level of con tam in ati on or residue per give nsurface area. Additi on ally, residues that are "dried out" or are insoluble can be sampled by physical removal.b.systems or ones that cannot be routi nely disassembled can besampled and evaluated.A disadva ntage of rinse samples is that the residue or con tam inantmay not be soluble or may be physically occluded in the equipme nt. An an alogy that can be used is the "dirty pot." In the evaluatio n of cleaning of a dirty pot, particularly with dried out residue, one does no t look at the rinse water to see that it is clea n; one looks at the pot.Check to see that a direct measureme nt of the residue or con tam inant has bee n made for the rinse water whe n 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.c. Rout ine Producti on In-Process Con trolMon itori ng - In direct test ing, such as con ductivity testi ng, may be of some value for rout ine mon itori ng once a clea ning process has bee n validated. This would be particularly true for the bulk drug substa neemanu facturer where reactors and cen trifuges and pip ing betwee nsuch large equipme nt can be sampled only using rinse soluti onsamples. Any in direct test method must have bee n show n to correlate with the condition of the equipment. During validation,the firm should docume nt that test ing the un clea ned equipme nt givesa not acceptable result for the in direct test.ESTABLISHMENT OF LIMITSFDA does not intend to set accepta nee specificati ons or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variati on in equipme nt and products used throughout the bulk and fini shed dosage form in dustries. The firm's rati on ale for the residue limitsestablished should be logical based on the manu facturer's kno wledge of the materials invo Ived and be practical, achievable, and verifiable. It is important to define the sensitivity of the an alytical methods in order to set reas on able limits. Some limits that have bee n men tio ned by in dustry represe ntatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1/1000 of the normal therapeutic dose, and orga no leptic levels such as no visible residue.Check the manner in which limits are established. Uni ike fini shedpharmaceuticals where the chemical ide ntity of residuals are known (i.e., from actives, in actives, deterge nts) bulk processes may have partial reacta nts and unwan ted by-products which may n ever have bee n chemically identified. In establishing residual limits, it may not be adequate to focus only on the prin cipal reacta nt since other chemical variati ons may be more difficult to remove. There are circumsta nces where TLC scree ning, in additi on to chemical an alyses, may be n eeded. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products n eeds to be con sidered if equipme nt is not dedicated. The objective of the inspection is to ensure that the basis for any limits is scie ntifically justifiable.OTHER ISSUESa. Placebo ProductIn order to evaluate and validate clea ning processes some manu facturers have processed a placebo batch in the equipme nt un der esse ntially the same operat ing parameters used for process ing product. A sample of the placebo batch is then tested for residual contamination. However, we have docume nted several sig nifica nt issues that n eed to be addressed whe n using placebo product to validate clea ning processes.One cannot assure that the con tam in ate will be uniformly distributedthroughout the system. For example, if the discharge valve or chute of a ble nder are con tam in ated, the con tam inant would probably not be uni formly dispersed in the placebo; it would most likely be concen trated in the in itial discharge portion of the batch. Additi on ally, if the con tam inant or residue is of a larger particle size, it may not be uniformly dispersed in the placebo. V. VI.Some firms have made the assumpti on that a residual con tam inant would be worn off the equipme nt surface uniformly; this is also an inv alid con clusi on.Fin ally, the an alytical power may be greatly reduced by diluti on of the contam in ate. Because of such problems, rinse an d/or swab samples should beused in conj un cti on with the placebo method.b. Deterge ntIf a deterge nt or soap is used for clea ning, determ ine and con sider thedifficulty that may arise whe n attempti ng to test for residues. A com monproblem associated with deterge nt use is its compositi on. Many deterge ntsuppliers will not provide specific compositi on, which makes it difficult for theuser to evaluate residues. As with product residues, it is importa nt and it isexpected that the manu facturer evaluate the efficie ncy of the clea ningprocess for the removal of residues. However, un like product residues, it isexpected that no (or for ultra sen sitive an alytical test methods - very low)deterge nt levels remai n after clea ning. Deterge nts are not part of the manufacturi ng process and are only added to facilitate clea ning duri ng the cleaning process. Thus, they should be easily removable. Otherwise, a differe ntdeterge nt should be selected.c. Test Until CleanExamine and evaluate the level of testing and the retest results since testinguntil clean is a concept utilized by some manufacturers. They test, resample,and retest equipme nt or systems un til an "acceptable" residue level isattained. For the system or equipment with a validated clea ning process, thispractice of resampli ng should not be utilized and is acceptable only in rarecases. Constant retesting and resampling can show that the clea ning processis not validated since these retests actually docume nt the prese nee of unacceptable residue and con tam inants from an in effective clea ning process.REFERENCES0. J. Rodehamel, "Cleaning and Maintenance," Pgs 82-87, University of Wisc VII.onsin's Con trol Procedures in Drug Productio n Sem inar, July 17-22, 1966,William Blockstein, Editor, Published by the University of Wisco nsi n,L.O.C.#66-64234.1. J.A. Constanee, "Why Some Dust Control Exhaust Systems Don't Work,"Pharm. Eng., January-February, 24-26 (1983).2. S.W. Harder, "The Validation of Cleaning Procedures," Pharm. Technol. 8 (5),29-34 (1984)3. W.J. Mead, "Maintenance: Its Interrelationship with Drug Quality," Pharm. Eng.7(3), 29-33 (1987).4. J.A. Smith, "A Modified Swabb ing Tech ni que for Validati on of Deterge ntResidues in Clean-in-Place Systems," Pharm. Technol. 16(1), 60-66 (1992).5. Fourman, G.L. and Mullen, M.V., "Determining Cleaning Validation Acceptanee Limits for Pharmaceutical Manu facturi ng Operati on s," Pharm. Tech nol.17(4), 54-60 (1993).6. McCormick, P.Y. and Cullen, L.F., in Pharmaceutical Process Validation, 2ndEd., edited by I.R. Berry and R.A. Nash, 319-349 (1993)。
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Validation of Cleaning Processes (7/93) 清洁工艺验证GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES清洁工艺验证检查指南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：此指南是FDA检查官和其工作人员的参考资料。
此文件不约束FDA，也不赋予任何人任何权利，特权，利益或豁免权。
I. INTRODUCTION 介绍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.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.This guide is intended to cover equipment cleaning for chemical residues only.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。
II. BACKGROUND 背景For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regulations (Part 133.4) stated as follows "Equipment *** shall be maintained in aclean and orderly manner ***." A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillin cross-contamination.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。
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.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。
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.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，这就导致了该厂的流化床干燥机的袋子被杀虫剂污染了。
转而导致此厂生产的众多批次产品被污染，尽管该厂并不生产杀虫剂。