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1、FDAFDA 清洁验证指南清洁验证指南 （转载中英文）（转载中英文） 2013-01-09 16:52:25| 分类： FDA|字号 订阅ValidationValidation ofof CleaningCleaning ProcessesProcesses 清洁工艺验证清洁工艺验证 GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES Note: This document is reference material for investigators and other FDA personnel. The document does
2、 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.I. INTRODUCTIONINTRODUCTION 简介简介 Validation of cleaning procedures has generated considerable discussion since agency documents, i
3、ncluding 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
4、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
5、more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications. 设计本指南是为了通过讨论已发现的可接受（或不可接受）的实际操作来建立 检查的一致性和统一性。同时必须认识到清洁验证
6、和其他过程验证一样，某一 过程的验证可能不止一种方式。最后，任何过程验证的检测是科学数据是否反 映系统能始终如一按照既定标准运作并持续产生符合既定标准的结果。This guide is intended to cover equipment cleaning for chemical residues only. 本指南只适用于化学残留物的设备清洁。II.II. BACKGROUNDBACKGROUND 背景背景 For FDA to require that equipment be clean prior to use is nothing new, the 1963 GMP Regula
7、tions (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 adultera
8、tion 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 penicill
9、ins 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. 对于 FDA 来说，要求对设备在使用前进行清洁并不是稀奇的事情，1963 年 GMP 法规（133.4 部分）指出“设备*应该按照清洁和有序的方式来进行维护”。 在 1978 CGMP 法规中也
10、包含了非常相似的有关设备清洗的章节(211.67)。当然， 清洁设备的主要理由是防止药品被污染或掺假。在历史上，FDA 检查官寻找由 于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。 而且，从历史上来说，FDA 更加关注非青霉素药品被青霉素污染、或药品中的 活性激素或荷尔蒙交叉污染。由于实际或潜在的青霉素的交叉污染所致，在过 去的十年中有很多药品被召回。One event which increased FDA awareness of the potential for cross contamination due to inadequate procedures
11、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 belie
12、ved 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 use
13、d for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums. 1998 年消美国专利药消胆胺树脂制剂的召回，使 FDA 进一步认识到因不当规程 而导致交叉污染的可能性。用于生产药品的原料药被生产农用杀虫剂中产生的 中间体和降解物污
14、染。本案例中的交叉污染被认为是由于回收溶剂的重新使用。 回收溶剂由于缺乏对溶剂桶的重新使用进行控制而被污染。用于储存杀虫剂生 产过程中的回收溶剂的溶剂桶，后来又用于储存树脂生产过程的回收溶剂。公 司未对这些溶剂桶进行适当的控制，也未对桶中的溶剂进行适当的测试，以及 未对桶的清洗过程进行验证。Some shipments of this pesticide contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted
15、in the contamination of the bags used in that facilitys fluid bed dryers with pesticide contamination. This in turn led to cross contamination of lots produced at that site, a site where no pesticides were normally produced. 部分被杀虫剂污染的原料药被运输到在其他地方的另外一家工厂进行最后加工。 由于该工厂的流体床干燥器袋子被原料药中的杀虫剂污染，结果导致在该工厂 地点生产
16、的很多批次产品相应的被交叉污染，该地点在正常情况下是不生产杀 虫剂的。FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started
