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1、如有侵权，请联系网站删除，仅供学习与交流FDA 清洁验证审计指南【精品文档】第 9 页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, benef
2、its, 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
3、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 cleani
4、ng 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 specif
5、ications.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
6、 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 cl
7、eaning 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 be
8、en 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 c
9、hemical 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 contaminat
10、ed 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 d
11、rums, 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 ba
12、gs 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.FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured po
13、tent 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 cleanin
14、g 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 presen
15、ce of residues of reaction byproducts and degradants from the previous process.III. GENERAL REQUIREMENTSFDA 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
16、 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 proced
17、ure 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. Flui
18、d 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
19、 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 a
20、dvance 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 p
21、rotocols 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
22、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 evaluati
23、ng 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
24、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
25、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 thi
26、s 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
27、 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-
28、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 impor
29、tant 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
30、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 va
31、lves 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 cl
32、eaning 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 proces
33、s.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
34、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
35、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
36、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 s
37、ince 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
38、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
39、 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 whic
40、h 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 variabi
41、lity 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. Appropria
42、te 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 analy
43、tical 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 t
44、he 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%, e
45、tc. 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
46、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 inte
47、rfere 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 re
48、asonably 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 a
49、rea 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