FDA清洁验证审计指南Word文件下载.docx

1、TWEETLINKEDINPIN ITMORE SHARING OPTIONSEMAILPRINTGUIDE 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, benefits, or immunities for or on any

2、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 Agency documents clearly establis

3、h 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

4、 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 t

5、o 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 similar section on equipment cle

6、aning （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 equipme

7、 nt an d/or poor dust con trol systems. Also, historically speak ing, FDA was more concerned about the con tam in ati on of nonpenicillin drug products with penicillins or the cross-contamination of drug products with pote nt steroids or horm on es. A nu mber of products have bee n recalled over the

8、 past decade due to actual or pote ntial peni cilli n cross-c on tam in ati on.One eve nt which in creased FDA aware ness of the pote ntial for cross con tam in ati on due to in adequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chem

9、ical used to produce the product had become con tam in ated with low levels of in termediates and degrada nts from the producti on of agricultural pesticides. The cross-c on tam in ati on in that case is believed to have bee n due to the reuse of recovered solve nts. The recovered solve nts had bee

10、n con tam in ated because of a lack of con trol over the reuse of solve nt drums. Drums that had bee n used to store recovered solve nts from a pesticide producti on process were later used to store recovered solve nts used for the res in manu facturi ng process. The firm did not have adequate con t

11、rols over these solve nt drums, did not do adequate testi ng of drummed solve nts, and did not have validated clea ning procedures for the drums.Some shipme nts of this pesticide con tam in ated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This result

12、ed 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 no rmally produced. FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical

13、 manu facturer which manu factured pote nt steroid products as well as non-steroidal products using com mon equipme nt. This firm was a multi-use bulk pharmaceutical facility. FDA con sidered the pote ntial for cross-contamination to be significant and to pose a serious health risk to the public. Th

14、e firm had only recently started a cleaning validation program at the time of the in spect ion and it was con sidered in adequate by FDA. One of the reas ons it was con sidered in adequate was that the firm was only look ing for evide nee of the abse nee of the previous compo und. The firm had evide

15、nee, from TLC tests on the rinse water, of the presence of residues of react ion byproducts and degrada nts from the previous process.III. GENERAL REQUIREMENTSFDA expects firms to have writte n procedures （SOPs） detaili ng the clea ning processes used for various pieces of equipme nt. If firms have

16、one clea ning process for clea ning betwee n differe nt batches of the same product and use a differe nt process for clea ning betwee n product cha nges, we expect the written procedures to address these different scenario. Similarly, if firms have one process for rem oving water soluble residues an

17、d ano ther process for non-water soluble residues, the writte n procedure should address both sce narios and make it clear whe n a give n procedure is to be followed. Bulkpharmaceutical firms may decide to dedicate certa in equipme nt for certa in chemical manu facturi ng process steps that produce

18、tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are ano ther example of equipme nt that is difficult to clea n and is ofte n dedicated to a specific product. Any residues from the clea ning process itself （detergents, solvents, etc.） also have to be remo

19、ved from the equipme nt.FDA expects firms to have writte n gen eral procedures on how clea ning processes will be validated.FDA expects the gen eral validati on procedures to address who is resp on sible for perform ing and appro ving the validati on study, the acceptance criteria, and when revalida

20、tion will be required.FDA expects firms to prepare specific writte n validati on protocols in adva nce for the studies to be performed on each manu facturi ng system or piece of equipme nt which should address such issues as sampli ng procedures, and an alytical methods to be used in clud ing the se

21、n sitivity of those methods. FDA expects firms to con duct the validati on studies in accorda nce with the protocols and to docume nt the results of studies.IV.FDA expects a final validati on report which is approved by man ageme nt and which states whether or not the clea ning process is valid. The

22、 data should support a con clusi on that residues have bee n reduced to an acceptable level.EVALUATION OF CLEANING VALIDATIONThe first step is to focus on the objective of the validation process, and we have see n that some compa nies have failed to develop such objectives. It is not unu sual to see

23、 manu facturers use exte nsive sampli ng and testi ng programs follow ing the clea ning process without ever really evaluati ng the effective ness of the steps used to clea n the equipme nt. Several questi ons n eed to be addressed whe n evaluat ing the clea ning process. For example, at what point

24、does a piece of equipme nt or system become clea n? Does it have to be scrubbed by hand? What is accomplished by hand scrubb ing rather tha n just a solve nt wash? How variable are manual clea ning processes from batch to batch and product to product? The an swers to these questions are obviously im

25、portant to the inspection and evaluation of the clea ning process since one must determ ine the overall effective ness of the process. An swers to these questi ons may also ide ntify steps that can be elimi nated for more effective measures and result in resource sav ings for the compa ny.Determ ine

26、 the nu mber of clea ning processes for each piece of equipme nt. Ideally, a piece of equipment or system will have one process for cleaning, however this will depe nd on the products being produced and whether the clea nup occurs betwee n batches of the same product （as in a large campaig n） or bet

27、wee n batches of differe nt products. Whe n the clea ning process is used only betwee n batches of the same product （or differe nt lots of the same in termediate in a bulk process） the firm n eed only meet a criteria of, visibly clea n for the equipme nt. Such betwee n batch clea ning processes do n

28、ot require validati on.1. Equipme nt Desig nExam ine the desig n of equipme nt, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place （CIP） systems since they represe nt sig nifica nt concern. For example, san itary type pip ing without ball valves shou

29、ld be used. Whe n such nonsan itary ball valves are used, as is com mon in the bulk drug in dustry, the clea ning process is more difficult.When such systems are ide ntified, it is importa nt that operators perform ing clea ning operatio ns be aware of problems and have special trai ning in clea nin

30、g these systems and valves. Determ ine whether the clea ning operators have kno wledge of these systems and the level of training and experie nee in clea ning these systems. Also check the writte n and validated clea ning process to determ ine if these systems have been properly identified and valid

31、ated.In larger systems, such as those employi ng long tran sfer lines or pipi ng, check the flow charts and pip ing diagrams for the ide ntificati on of valves and writte n clea ning procedures. Pip ing and valves should be tagged and easily identifiable by the operator performing the cleaning funct

32、ion. Sometimes, in adequately ide ntified valves, both on prints and physically, have led to in correct clea ning practices.Always check for the prese nee of an ofte n critical eleme nt in the docume ntati on of the clea ning processes; ide ntify ing and con troll ing the len gth of time betwee n the end of process ing and each clea ning step. This is especially importa nt for topicals, suspe nsions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficie ncy of a clea ning process.Whether or