FDA清洁验证检查指南-翻译和解读.pdf

翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 1 Validation of Cleaning Processes 7 93 清洁工艺验证清洁工艺验证 GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES 清洁工艺验证检查指南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 也不赋予任 何人任何权利 特权 利益或豁免权 I INTRODUCTION 介绍介绍 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 a 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 2 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 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 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 3 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 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 1992 年 FDA 对一家海外原料药生产商发出了进口警告 该厂使用相同设备生产强效 甾类产品和非甾类产品 因此公司是多品种原料药生产厂家 FDA 认为潜在交叉污染的 可能性很大 对公众健康造成了严重的威胁 该公司只是在 FDA 检查的近期才开展了 清洁验证工作 而 FDA 认为该清洁验证工作是不当的 理由之一是 工厂仅寻找没有 前一种物质存在的证据 但是用薄层法检测洗涤水后 找到了设备中还残留了前一产品 生产过程中反应副产物和降解产物的残留物 III GENERAL REQUIREMENTS 基本要求基本要求 FDA 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 期望公司建立书面的程序 SOPs 用于详细描述设备各部件的清洁的过程 如果 公司用同一程序进行相同产品不同批次之间的清洗 而使用不同程序进行转产之间的清 洗 公司的书面程序应明确说明这些不同的情况 同样 若水溶性残留物与非水溶性残 留物的清洗方法不同 则公司的书面程序也应说明两种情况 并清楚地规定在何种情况 下执行哪个程序 对于化学原料药生产中会产生柏油状或粘胶状残留物的生产工序 因 为这些物质不容易被清除 公司可以决定使用专用设备 流化床干燥机的袋子 作为一 种不容易被清洗的设备 也通常只被专用于某一特定产品的生产 对于清洁过程本身留 下的残留物 清洁剂 溶剂等 也必须被去除 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 4 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 FDA 期望公司建立书面的清洁工艺验证通则 FDA 期望这个清洁工艺验证通则规定 验证执行的负责人 批准验证工作的负责人 接 受标准 再验证时间 FDA 期望对于每一个生产系统或每一个设备 公司应预先制订具体的书面验证方案 其 中应明确规定如取样方法 分析方法 包括方法灵敏度 等方面的问题 FDA 期望公司根据方案进行验证工作 并记录归档验证的结果 FDA 期望形成一个最终的验证报告 报告应经过管理层的批准 并说明该清洗方法是否 有效 数据应该能够支持如下结论 残留物质已经被降低到一个 可接受的水平 IV EVALUATION OF CLEANING VALIDATION 清洁验证的评估清洁验证的评估 The 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 Does it have to be scrubbed by hand What is accomplished by hand scrubbing rather than just a solvent wash How variable are manual cleaning processes from batch to batch and product to product 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 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 5 第一步是明确验证目的 我们曾发现有一些公司没有建立验证目的 如常见一些生产商 在清洁之后进行了大量的取样和检测程序 而没有真正去评估各步清洗操作的有效性 在评估清洁工序时 有一系列的问题需要被关注 比如 到达哪个点 程度 一个设备 或者系统算是清洁了 是不是一定要用手擦洗 用手擦洗达到了什么效果 而只用一种 溶剂清洗是达不到的 批和批之间或者产品和产品之间 人工清洗的差异有多大 这些 问题的答案 对于检查和评估清洁过程来说是非常重要的 因为检查官必须要全面评估 该过程的有效性 而且这些问题的答案也有助于省去多余的步骤 能更有效地工作 从 而为公司节约资源 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 检查每个设备有几种清洗方法 理想的情况是一个设备或系统拥有一套清洗工艺 然而 这也取决于生产的品种 以及同一产品的不同批次之间 如大量生产 或者不同产品的 转产之间是否需要清洗 当清洗方法只用于同一产品的不同批次之间 或同一中间体的 不同批次之间 公司仅需要建立 目视清洁 的标准 诸如此类的批与批之间的清洁 工艺 不需要被验证 1 Equipment Design 设备的设计 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 尤其是使用了半自动或全自动在场清洗系统的大型生产系统 需要重 点关注 比如 应使用没有球阀的卫生型管道系统 当使用了那些非卫生型的球阀 这 在原料药工业中是普遍的 清洁工序就变的更困难 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 若在现场检查中发现使用了上述类型的设备系统 执行清洁程序的操作人员必须了解问 题的所在 并已进行了关于系统和阀门清洁的特殊培训 检查该操作人员是否了解系统 培训的水平和清洁操作的经验 并检查书面的已验证过的清洁程序 判定系统是否已经 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 6 被适当的确认和验证过 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 对于大型系统 比如使用了很长的转移 输送管道的 要检查流程图和管道图纸从而确认 需要清洗的阀门 和是否有书面清洁规程 管道和阀门应标记 以便操作人员识别 有 时 阀门标识不当 无论在打印图纸上和实物上 都会导致不正确的清洁操作 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 在清洁工序的相关文件中 必须检查是否包含了关键因素 确认并控制每次生产结束后 至清洁开始的时间间隔 这对于局部用药物 悬浮剂和原料药的生产尤其重要的 因为 残留物干燥后 会直接影响清洁的效果 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 无论是否使用了在线清洁系统 都应考虑设备清洁的微生物情况 这包括大量的预防性 的措施 而不只是在染菌之后再除菌 应有证明 常规清洁和设备保存不会有微生物的 繁殖 比如 设备在保存之前应该干燥 清洁后不允许有任何积水残留其中 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 对于无菌工艺的设备 或者非无菌的但有助于微生物增长的产品 清洁之后还可能需灭 菌或消毒 虽然灭菌或消毒程序已超出了本指南的范围 但要注意的是 通过适当的清 洁和设备保存来控制微生物 是对接下来的灭菌 消毒工序能够达到无菌水平的保证 从 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 7 无菌工艺应控制热原的观点来说 这一点也特别重要 因为设备灭菌工艺不一定能够取 得显著的灭活或去除热原的效果 2 Cleaning Process Written 书面清洗程序 Procedure and Documentation 程序和文件 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 要检查验证后的清洗方法是否具体 详细 检查需要记录的项目 我们曾见过不少通用 性的 SOP 同时也见过其它使用批生产记录或者记录表格系统的 其要求对每一步操作 做出专门的文件记录 根据系统的复杂程度 清洗方法以及操作人员培训程度和能力的 不同 各种清洗工作或规程所需的文件数量也会有所不同 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 当需要进行更为复杂的清洗过程时 必须对关键的清洗工序做出记录 如某些原料药合 成工序 在这点上 应有专门的设备记录 包括清洗人员姓名 评估时间 然而 对 于相对简单的清洗工作 仅记录 全部清洗工作已经被执行 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 其他因素 诸如清洗历史 清洗后测出的残留物水平 检验结果的可变性等有时也要记 录 例如 清洗之后的残留物水平具可变性 而又认定该清洗方法是可接受的 则必须 证明清洗过程和工人操作的有效性 必须对清洗方法做出适当的评价 尤其是当认为工 人操作有问题时 就要求有更为广泛的文件 指导 和记录 并进行更多的培训 3 Analytical Methods 分析方法 Determine the specificity and sensitivity of the analytical method used to detect 翻译 Cuckoo cuckoo801002 校对并解读 Chank chank2006 注 个人学习 交流使用 不得用于商业目的 8 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 应确定用于残留物或污染物检测的分析方法的专属性和灵敏度 借助于先进的分析技 术 清洗和生产过程中极少的残留物或污染物也能够被检测出来 即使检测不出污染物 或残留物水平 也并不能说明清洗之后不存在残留污染物 而只说明样品中没有超过该 分析方法灵敏度或检验限之外的污染物 公司应对分析方法进行挑战性实验 即证明取 样方法能够从设备表面取回污染物 其收率是多少 如 50 90 等 根据取样结果再做 出结论是必须的 取样技术不当也可能得出相反的结论 见下文 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 可接受的通用取样方法有两种 最好是直接从设备表面取样 另一种方法是取漂洗水样 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 f