FDA清潔驗證檢查指南-翻譯和解讀.pdf

翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)目的 1 Validation of Cleaning Processes 7 93 清潔工藝驗證清潔工藝驗證 GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES 清潔工藝驗證檢查指南清潔工藝驗證檢查指南 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 檢查官和其工作人員的參考資料 此文件不約束檢查官和其工作人員的參考資料 此文件不約束 FDA 也不賦予任 何人任何權(quán)利 特權(quán) 利益或豁免權(quán) 也不賦予任 何人任何權(quán)利 特權(quán) 利益或豁免權(quán) I INTRODUCTION 介紹介紹 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 自從 FDA 的各文件 包括化學(xué)原料藥檢查指南和生物技術(shù)檢查指南簡單地提出了清潔 驗證這個話題之后 關(guān)于清潔工藝的驗證已經(jīng)引發(fā)了相當多的討論 這些官方的文件 都清楚地確定了對于清潔工藝需要被驗證的期望 通過討論那些已被認為可接受的 或者不可接受的 實際情況 此指南是為了建立檢查 的連貫一致性 同時 必須意識到 與其他工藝驗證一樣 清潔驗證的方法也不止一種 最后 所有過程驗證的檢查標準是 檢查其科學(xué)數(shù)據(jù)能否證明該系統(tǒng)始終如一地達到預(yù) 期目的 結(jié)果穩(wěn)定地符合預(yù)先制定的標準 本指南僅適用于設(shè)備的化學(xué)殘留物的清潔驗證 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 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)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 法規(guī) 133 4 節(jié) 要求如下 設(shè)備需要被維持在一個清潔 有序的狀態(tài) 還有一個很相似的關(guān)于設(shè)備清潔的章節(jié)是在 1978 年 GMP 法規(guī) 211 67 節(jié) 同這些 法規(guī)相比 FDA 對于設(shè)備在使用前應(yīng)被清潔的要求并不是什么新要求 當然 對于設(shè)備 清潔的總的原則是為了防止產(chǎn)品污染或摻雜其它物質(zhì) 從歷史事件看來 FDA 檢查官發(fā) 現(xiàn)了一些明顯的不衛(wèi)生是由于設(shè)備的清潔和維護不到位 或防塵控制系統(tǒng)不當 過去 FDA 更多的關(guān)注于非青霉素類產(chǎn)品和青霉素類產(chǎn)品 或藥品與甾類產(chǎn)品和激素類產(chǎn)品之 間的交叉污染問題 在過去的十年中 有大量的產(chǎn)品召回事件都是由于實際的或潛在的 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 年的召回消膽胺樹脂事件 使 FDA 對于潛在交叉污染的問題日益重視 那次召回 的原因是用于生產(chǎn)制劑的原料藥被農(nóng)業(yè)殺蟲劑生產(chǎn)中低劑量的中間體和降解物給污染 了 造成這次交叉污染的原因是由于重復(fù)使用了回收溶劑引起的 而回收溶劑被污染的 原因是由于對重復(fù)使用的溶劑桶缺乏控制 這些桶之前是用于貯存殺蟲劑生產(chǎn)線產(chǎn)生的 回收溶劑 之后又被重復(fù)地用于樹脂生產(chǎn)線使用的回收溶劑貯存 該公司對于這些溶劑 桶缺乏有效的控制 對于貯存的溶劑缺少適當?shù)臋z測 對于溶劑桶的清潔過程也沒有進 行驗證 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 一部分被殺蟲劑污染的原料藥被供給了在另一地址的廠進行最后的制劑生產(chǎn) 這就導(dǎo)致 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)目的 3 了該廠的流化床干燥機的袋子被殺蟲劑污染了 轉(zhuǎn)而導(dǎo)致此廠生產(chǎn)的眾多批次產(chǎn)品被污 染 盡管該廠并不生產(chǎn)殺蟲劑 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 對一家海外原料藥生產(chǎn)商發(fā)出了進口警告 該廠使用相同設(shè)備生產(chǎn)強效 甾類產(chǎn)品和非甾類產(chǎn)品 因此公司是多品種原料藥生產(chǎn)廠家 FDA 認為潛在交叉污染的 可能性很大 對公眾健康造成了嚴重的威脅 該公司只是在 FDA 檢查的近期才開展了 清潔驗證工作 而 FDA 認為該清潔驗證工作是不當?shù)?理由之一是 工廠僅尋找沒有 前一種物質(zhì)存在的證據(jù) 但是用薄層法檢測洗滌水后 找到了設(shè)備中還殘留了前一產(chǎn)品 生產(chǎn)過程中反應(yīng)副產(chǎn)物和降解產(chǎn)物的殘留物 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 期望公司建立書面的程序 SOPs 用于詳細描述設(shè)備各部件的清潔的過程 如果 公司用同一程序進行相同產(chǎn)品不同批次之間的清洗 而使用不同程序進行轉(zhuǎn)產(chǎn)之間的清 洗 公司的書面程序應(yīng)明確說明這些不同的情況 同樣 若水溶性殘留物與非水溶性殘 留物的清洗方法不同 則公司的書面程序也應(yīng)說明兩種情況 并清楚地規(guī)定在何種情況 下執(zhí)行哪個程序 對于化學(xué)原料藥生產(chǎn)中會產(chǎn)生柏油狀或粘膠狀殘留物的生產(chǎn)工序 因 為這些物質(zhì)不容易被清除 公司可以決定使用專用設(shè)備 流化床干燥機的袋子 作為一 種不容易被清洗的設(shè)備 也通常只被專用于某一特定產(chǎn)品的生產(chǎn) 對于清潔過程本身留 下的殘留物 清潔劑 溶劑等 也必須被去除 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)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 期望公司建立書面的清潔工藝驗證通則 FDA 期望這個清潔工藝驗證通則規(guī)定 驗證執(zhí)行的負責人 批準驗證工作的負責人 接 受標準 再驗證時間 FDA 期望對于每一個生產(chǎn)系統(tǒng)或每一個設(shè)備 公司應(yīng)預(yù)先制訂具體的書面驗證方案 其 中應(yīng)明確規(guī)定如取樣方法 分析方法 包括方法靈敏度 等方面的問題 FDA 期望公司根據(jù)方案進行驗證工作 并記錄歸檔驗證的結(jié)果 FDA 期望形成一個最終的驗證報告 報告應(yīng)經(jīng)過管理層的批準 并說明該清洗方法是否 有效 數(shù)據(jù)應(yīng)該能夠支持如下結(jié)論 殘留物質(zhì)已經(jīng)被降低到一個 可接受的水平 IV EVALUATION OF CLEANING VALIDATION 清潔驗證的評估清潔驗證的評估 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 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)目的 5 第一步是明確驗證目的 我們曾發(fā)現(xiàn)有一些公司沒有建立驗證目的 如常見一些生產(chǎn)商 在清潔之后進行了大量的取樣和檢測程序 而沒有真正去評估各步清洗操作的有效性 在評估清潔工序時 有一系列的問題需要被關(guān)注 比如 到達哪個點 程度 一個設(shè)備 或者系統(tǒng)算是清潔了 是不是一定要用手擦洗 用手擦洗達到了什么效果 而只用一種 溶劑清洗是達不到的 批和批之間或者產(chǎn)品和產(chǎn)品之間 人工清洗的差異有多大 這些 問題的答案 對于檢查和評估清潔過程來說是非常重要的 因為檢查官必須要全面評估 該過程的有效性 而且這些問題的答案也有助于省去多余的步驟 能更有效地工作 從 而為公司節(jié)約資源 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 檢查每個設(shè)備有幾種清洗方法 理想的情況是一個設(shè)備或系統(tǒng)擁有一套清洗工藝 然而 這也取決于生產(chǎn)的品種 以及同一產(chǎn)品的不同批次之間 如大量生產(chǎn) 或者不同產(chǎn)品的 轉(zhuǎn)產(chǎn)之間是否需要清洗 當清洗方法只用于同一產(chǎn)品的不同批次之間 或同一中間體的 不同批次之間 公司僅需要建立 目視清潔 的標準 諸如此類的批與批之間的清潔 工藝 不需要被驗證 1 Equipment Design 設(shè)備的設(shè)計 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 檢查設(shè)備的設(shè)計 尤其是使用了半自動或全自動在場清洗系統(tǒng)的大型生產(chǎn)系統(tǒng) 需要重 點關(guān)注 比如 應(yīng)使用沒有球閥的衛(wèi)生型管道系統(tǒng) 當使用了那些非衛(wèi)生型的球閥 這 在原料藥工業(yè)中是普遍的 清潔工序就變的更困難 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 若在現(xiàn)場檢查中發(fā)現(xiàn)使用了上述類型的設(shè)備系統(tǒng) 執(zhí)行清潔程序的操作人員必須了解問 題的所在 并已進行了關(guān)于系統(tǒng)和閥門清潔的特殊培訓(xùn) 檢查該操作人員是否了解系統(tǒng) 培訓(xùn)的水平和清潔操作的經(jīng)驗 并檢查書面的已驗證過的清潔程序 判定系統(tǒng)是否已經(jīng) 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)目的 6 被適當?shù)拇_認和驗證過 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 對于大型系統(tǒng) 比如使用了很長的轉(zhuǎn)移 輸送管道的 要檢查流程圖和管道圖紙從而確認 需要清洗的閥門 和是否有書面清潔規(guī)程 管道和閥門應(yīng)標記 以便操作人員識別 有 時 閥門標識不當 無論在打印圖紙上和實物上 都會導(dǎo)致不正確的清潔操作 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 在清潔工序的相關(guān)文件中 必須檢查是否包含了關(guān)鍵因素 確認并控制每次生產(chǎn)結(jié)束后 至清潔開始的時間間隔 這對于局部用藥物 懸浮劑和原料藥的生產(chǎn)尤其重要的 因為 殘留物干燥后 會直接影響清潔的效果 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 無論是否使用了在線清潔系統(tǒng) 都應(yīng)考慮設(shè)備清潔的微生物情況 這包括大量的預(yù)防性 的措施 而不只是在染菌之后再除菌 應(yīng)有證明 常規(guī)清潔和設(shè)備保存不會有微生物的 繁殖 比如 設(shè)備在保存之前應(yīng)該干燥 清潔后不允許有任何積水殘留其中 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 對于無菌工藝的設(shè)備 或者非無菌的但有助于微生物增長的產(chǎn)品 清潔之后還可能需滅 菌或消毒 雖然滅菌或消毒程序已超出了本指南的范圍 但要注意的是 通過適當?shù)那?潔和設(shè)備保存來控制微生物 是對接下來的滅菌 消毒工序能夠達到無菌水平的保證 從 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)目的 7 無菌工藝應(yīng)控制熱原的觀點來說 這一點也特別重要 因為設(shè)備滅菌工藝不一定能夠取 得顯著的滅活或去除熱原的效果 2 Cleaning Process Written 書面清洗程序 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 要檢查驗證后的清洗方法是否具體 詳細 檢查需要記錄的項目 我們曾見過不少通用 性的 SOP 同時也見過其它使用批生產(chǎn)記錄或者記錄表格系統(tǒng)的 其要求對每一步操作 做出專門的文件記錄 根據(jù)系統(tǒng)的復(fù)雜程度 清洗方法以及操作人員培訓(xùn)程度和能力的 不同 各種清洗工作或規(guī)程所需的文件數(shù)量也會有所不同 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 當需要進行更為復(fù)雜的清洗過程時 必須對關(guān)鍵的清洗工序做出記錄 如某些原料藥合 成工序 在這點上 應(yīng)有專門的設(shè)備記錄 包括清洗人員姓名 評估時間 然而 對 于相對簡單的清洗工作 僅記錄 全部清洗工作已經(jīng)被執(zhí)行 就足夠了 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 諸如清洗歷史 清洗后測出的殘留物水平 檢驗結(jié)果的可變性等有時也要記 錄 例如 清洗之后的殘留物水平具可變性 而又認定該清洗方法是可接受的 則必須 證明清洗過程和工人操作的有效性 必須對清洗方法做出適當?shù)脑u價 尤其是當認為工 人操作有問題時 就要求有更為廣泛的文件 指導(dǎo) 和記錄 并進行更多的培訓(xùn) 3 Analytical Methods 分析方法 Determine the specificity and sensitivity of the analytical method used to detect 翻譯 Cuckoo cuckoo801002 校對并解讀 Chank chank2006 注 個人學(xué)習(xí) 交流使用 不得用于商業(yè)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 應(yīng)確定用于殘留物或污染物檢測的分析方法的專屬性和靈敏度 借助于先進的分析技 術(shù) 清洗和生產(chǎn)過程中極少的殘留物或污染物也能夠被檢測出來 即使檢測不出污染物 或殘留物水平 也并不能說明清洗之后不存在殘留污染物 而只說明樣品中沒有超過該 分析方法靈敏度或檢驗限之外的污染物 公司應(yīng)對分析方法進行挑戰(zhàn)性實驗 即證明取 樣方法能夠從設(shè)備表面取回污染物 其收率是多少 如 50 90 等 根據(jù)取樣結(jié)果再做 出結(jié)論是必須的 取樣技術(shù)不當也可能得出相反的結(jié)論 見下文 4 Sampling 取樣 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 可接受的通用取樣方法有兩種 最好是直接從設(shè)備表面取樣 另一種方法是取漂洗水樣 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