1、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
2、 on any person(s).注:此指南是 FDA检查官和其他人员的参考资料,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 一、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
3、briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.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,简单的提出了清洁验证的这个话题后,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,都清楚的确定了对清洁工艺需要被验证的期望。This guide is designed to establish inspection consistency and u
4、niformity 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
5、 scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.通过讨论那些已经被认为可接受的(或不可接受的)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,清洁验证的方法不止一种。最后,所有过程验证的检查标准是:检查器科学数据能否证明该系统始终如一的达到预期目的,结果稳定的符合预先制定的标准。This guide is intended
6、to cover equipment cleaning for chemical residues only. 本指南仅适用于设备的化学残留物的清洁验证II. BACKGROUND 二、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 clean and orderly manner *.“ A very sim
7、ilar 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 cleani
8、ng 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 r
9、ecalled over the past decade due to actual or potential penicillin cross-contamination.1963年 GMP法规(133.4)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他物质。从历史事件看 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,或防尘控制系统的不当。过去 FDA更多的关注于
10、非青霉素类产品和青霉素类产品或药品与甾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 pr
11、oduce 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 la
12、ck 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 a
13、dequate 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现,那些召回的原因是用于生产制剂的原料药被农业除虫剂生产中低剂量的中间体和降解物污染,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,这些桶之前是用于除虫剂生产线产生的回收溶剂,之后又被重复的用于树脂生产线使用的回收溶剂储存,该公司对溶剂回收桶缺乏有效的管理控制,对于储存
14、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 facilitys fluid bed dryers with pesticide contamination. This in turn l
15、ed 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到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,从而最终导致该厂的生产的众多批次产品被污染,尽管他们并不生产杀虫剂。FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactur
16、ed 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 cl
17、eaning 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 p
18、resence of residues of reaction byproducts and degradants from the previous process.1992年 FDA对一家海外 API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,因此该公司是多品种 API生产厂家,FDA 认为潜在交叉污染的可能性很大,多公众健康造成很大的威胁,该公司只是在 FDA检查的近期蔡开展了清洁验证工作,而 FDA认为该清洁验证工作丝不当的,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
19、物。III. GENERAL REQUIREMENTS 三、基本要求FDA expects firms to have written procedures (SOPs) 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
20、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 proce
21、dure 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
22、 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 SOP,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
23、程序也应说明这两种情况,并清楚的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(如清洁剂、溶剂等),也必须被去除。FDA expects firms to have written general procedures on how cleaning processes will be validated. FDA期望公司建立书面的清洁工艺验证通则。FDA expects the general
24、 validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.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 expects firms to prepare specific written validation protocols in advance for t
25、he 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期望对于每一个生产系统或每一个设备,公司应预先制定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 expects firms
26、 to conduct the validation studies in accordance with the protocols and to document the results of studies.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 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 concl
27、usion that residues have been reduced to an “acceptable level.“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由有效,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 四、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 f
28、ailed 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 cl
29、eaning 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
30、 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
31、 for the company.第一步是明确验证目的,我们曾经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,而没有真正的评估各步骤清洁操作的有效性,在评估清洁工序时,有一系列的问题需要关注,比如:到达哪种程度或哪个点,一个设备或系统算是清洁了?是不是一定要用手擦洗?用手擦洗到达什么效果?而只用一种溶剂清洗是达不到的?批与批之间或产品与产品之间,人工清洁的差异有多大?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的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于的步骤,能更有效的工作,从而为公司节约资源。Determ
32、ine 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
33、 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 val
34、idation.检查每个设备有几种清洁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需要清洗的,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 1、设备的设计Examine the design of equipment, particularly in those large systems that may employ semi-automatic or f
35、ully 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
36、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球阀(这在 API 工业中普遍的)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
37、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
38、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 th
39、e operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.对于大型的系统,比如使用了很长的转移或输送管道的,要检查流程图和管道图纸从而确认需要清洁的阀门,和是否有书面的清洁规程。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,都会导致正确的清洁操作。Always check for the presen
40、ce 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 res
41、idues 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洗开始的时间间隔,这对于局部药物、悬浮剂和 API的生产尤其重要,因为残留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. Thi
42、s 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
43、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,都应该考虑设备清洁的微生物情况,这包括大量的预防性措施,而不只是在染菌之后在除菌,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 pro
44、cedures 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 cl
45、eaning 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 process
46、es 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,是对接下来的灭菌或消毒工序能够达到无菌水平的保证,从无菌工艺应控制热原的观点来说,这一点也非常重要,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 2、书面清洁程序Procedure and
47、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
48、 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.要检查验证后的清洁方法是否具体,详细,检查需要记录的项目,我们曾见过不少通用性的SOP,同时也见过其他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作出专门
49、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作出记录(如某些原料药合成工序),在这点上,应有专门的设备记录,包括清洗人员的姓名、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