實(shí)驗(yàn)室檢查指南英文版

1、GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROLLABORATORIESNote: This docume nt is reference material for in vestigators and other FDA pers onn el. The docume nt does not bind FDA, and does no confer any rights, privileges, ben efits, or immu nities for or on any pers on(s).1. INTRODUCTIONThe

2、 pharmaceutical quality con trol laboratory serves one of the most importa nt fun cti ons in pharmaceutical producti on and con trol. A sig nifica nt portion of the CGMP regulations (21 CFR 211) pertain to the quality control laboratory and product testi ng. Similar con cepts apply to bulk drugs.Thi

3、s in specti on guide suppleme nts other in specti onal in formati on contained in other age ncy in specti onal guida nee docume nts. For example, Complia nee Program 7346.832 requiri ng pre-approval NDA/ANDA in specti ons contains gen eral in structi ons to con duct product specific NDA/ANDA in spec

4、ti on audits to measure complia nee with the applicati ons and CGMP requireme nts. This in cludes pharmaceutical laboratories used for in-process and fini shed product testi ng.2. OBJECTIVEThe specific objective will be spelled out prior to the in specti on. The laboratory inspection may be limited

5、to specific issues, or the inspection may en compass a comprehe nsive evaluati on of the laboratory's complia nee with CGMP's. As a mi ni mum, each pharmaceutical quality con trol laboratory should receive a comprehe nsive GMP evaluati on each two years as part of the statutory in specti on

6、obligati on.In gen eral these in specti ons may in clude-the specific methodology which will be used to test a new product-a complete assessme nt of laboratory's con forma nee with GMP's-a specific aspect of laboratory operati ons3. INSPECTION PREPARATIONFDA In specti on Guides are based on

7、the team in specti on approach and our in specti on of a laboratory is eon siste nt with this eon cept. As part of our effort to achieve uni formity and eon siste ncy in laboratory in specti ons, we expect that complex, highly tech ni cal and specialized test ing equipme nt, procedures and data man

8、ipulati ons, as well as scie ntific laboratory operati ons will be evaluated by an experie need laboratory an alyst with specialized kno wledge in such matters.District man ageme nt makes the final decisi on regard ing the assig nment of pers onnel to in specti ons. Nevertheless, we expect in vestig

9、ators, an alysts and others to work as teams and to advise man ageme nt whe n additi onal expertise is required to complete a meanin gful in specti on.Team members participati ng in a pre-approval in specti on must read and be familiar with Complia nee Program 7346.832, Pre-ApprovalIn specti on s/I

10、nvestigati ons. Releva nt secti ons of the NDA or ANDA should be reviewed prior to the inspection; but if the application is not available from any other source, this review will have to be eon ducted using the compa ny's copy of the applicati on.Team members should meet, if possible, prior to t

11、he inspection to discuss the approach to the in specti on, to defi ne the roles of the team members, and to establish goals for completi on of the assig nment. Resp on sibilities for development of all reports should also be established prior to the in specti on. This in eludes the preparati on of t

12、he FDA 483.The Cen ter for Drug Evaluati on and Research (CDER) may have issued deficiency letters listing problems that the sponsor must correct prior to the approval of NDA/ANDA's and suppleme nts. The in specti on team is expected to review such letters on file at the district office, and the

13、y are expected to ask the pla nt for access to such letters. The team should evaluate the replies to these letters to assure that the data are accurate and authentic. Complete the in specti on eve n though there has bee n no resp onse to these letters or whe n the resp onse is judged in adequate.4.

14、INSPECTION APPROACHA. Gen eralIn additi on to the gen eral approach utilized in a drug CGMP in specti on, thein specti on of a laboratory requires the use of observati ons of the laboratory in operati on and of the raw laboratory data to evaluate complia nee with CGMP's and to specifically carry

15、 out the commitme nts in an applicati on or DMF. When con duct ing a comprehe nsive in specti on of a laboratory, all aspects of the laboratory operati ons will be evaluated. Laboratory records and logs represe nt a vital source of i nformatio n that allows a complete overview of the tech ni cal abi

16、lity of the staff and of overall quality con trol procedures. SOPs should be complete and adequate and the operati ons of the laboratories should con form to the writte n procedures. Specificati ons and an alytical procedures should be suitable and, as applicable, in con forma nee with applicati on

17、commitme nts and compe ndial requireme nts.Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipme nt, in cludi ng maintenance and calibrati on, and methods validati on data to determ ine the overall quality of the laboratory operati on and the ability to comply with CGMP

18、 regulatio ns.Exam ine chromatograms and spectra for evide nee of impurities, poor tech ni que, or lack of in strume nt calibrati on.s use systems that provide for the in vestigati on of laboratory test failures. These are gen erally recorded in some type of log. Ask to see results of an alyses for

19、lots of product that have failed to meet specificati ons and review the an alysis of lots that have bee n retested, rejected, or reworked. Evaluate the decisi on to release lots of product whe n the laboratory results in dicate that the lot failed to meet specificati ons and determ ine who released

20、them.B. Pre-ApprovalDocume nts relati ng to the formulati on of the product, syn thesis of the bulk drug substa nee, product specificati ons, an alysis of the product, and others are exam ined dur ing the review process in headquarters. However, these reviews and evaluati ons depe nd on accurate and

21、 authe ntic data that truly represe nts the product.Pre-approval inspections are designed to determine if the data submitted in an application are authentic and accurate and if the procedures listed in the applicati on were actually used to produce the data contained in the applicati on. Additi on a

22、lly, they are desig ned to confirm that pla nts (in clud ing the quality eon trol laboratory) are in complia nee with CGMP regulati ons.The an alytical secti ons of drug applicati ons usually contain only test results and the methods used to obta in them. Spon sors are not required to file all the t

23、est data because such action would require voluminous submissions and would often result in filing redundant information. Sponsors may deliberately or uninten ti on ally select and report data show ing that a drug is safe and effective and deserves to be approved. The in specti on team must decide i

24、f there is valid and scientific justification for the failure to report data which dem on strates the product failed to meet its predeterm ined specificati ons.Coordination between headquarters and the field is essential for a complete review of the applicati on and the pla nt. Experie need in vesti

25、gators and an alysts may con tact the review chemist (with appropriate supervisory con curre nee) whe n questi ons con cer ning specificati ons and sta ndards arise. In specti ons should compare the results of an alyses submitted with results of an alysis of other batches that may have bee n produce

26、d. Evaluate the methods and note any excepti ons to the procedures or equipme nt actually used from those listed in the applicati on and con firm that it is the same method listed in the application. The analyst is expected to evaluate raw laboratory data for tests performed on the test batches (bio

27、batches and clinical batches) and to compare this raw data to the data filed in the applicati on.5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTS Evaluate the compa ny's system to in vestigate laboratory test failures. These in vestigati ons represe nt a key issue in decidi ng whether a prod

28、uct may be released or rejected and form the basis for retesti ng, and resampli ng.In a recent court decision the judge used the term "out-of-specification" (OOS) laboratory result rather than the term "product failure" which is more com mon to FDA in vestigators and an alysts. H

29、e ruled that an OOS result identified as a laboratory error by a failure investigation or an outlier test. The court provided explicit limitati ons on the use of outlier tests and these are discussed in a later segme nt of this docume nt., or overcome by retesti ng. The court ruled on the use of ret

30、est ing which is covered in a later segme nt of this docume nt. is not a product failure. OOS results fall into three categories:-laboratory error-non-process related or operator error-process related or man ufacturi ng process errorA. LABORATORY ERRORSLaboratory errors occur whe n an alysts make mi

31、stakes in followi ng the method of an alysis, use in correct sta ndards, an d/or simply miscalculate the data. Laboratory errors must be determ ined through a failure in vestigati on to iden tify the cause of the OOS. Once the n ature of the OOS result has bee n identified it can be classified into

32、one of the three categories above. The in quiry may vary with the object un der in vestigati on.B. LABORATORY INVESTIGATIONSThe exact cause of an alyst error or mistake can be difficult to determ ine specifically and it is unrealistic to expect that analyst error will always be determ ined and docum

33、e nted. Nevertheless, a laboratory in vestigati on con sists of more tha n a retest. The in ability to ide ntify an error's cause with con fide nee affects retest ing procedures, not the in vestigati on in quiry required for the in itial OOS result.The firm's analyst should follow a written

34、procedure, checking off each step as it is completed during the analytical procedure. We expect laboratory test data to be recorded directly in no tebooks; use of scrap paper and loose paper must be avoided. These com mon sense measures enhance the accuracy and in tegrity of data.Review and evaluate

35、 the laboratory SOP for product failure in vestigati ons. Specific procedures must be followed whe n sin gle and multiple OOS results are in vestigated. For the sin gle OOS result the in vestigati on should in clude the follow ing steps and these in quiries must be con ducted before there is a retes

36、t of the sample:o the an alyst con duct ing the test should report the OOS result to the supervisoro the an alyst and the supervisor should con duct an in formal laboratoryin vestigati on which addresses the follow ing areas:1. discuss the testi ng procedure2. discuss the calculati on3. exam ine the

37、 in strume nts4. review the notebooks containing the OOS resultAn alter native means to in validate an in itial OOS result, provided the failure investigation proves inconclusive, is the "outlier" test. However, specific restrictions must be placed on the use of this test.1. Firms cannot f

38、requently reject results on this basis.2. The USP standards govern its use in specific cases only.3. The test cannot be used for chemical testi ng results. An in itial content uni formity test was OOS followed by a pass ing retest. The in itial OOS result was claimed the result of analyst error base

39、d on a statistical evaluation of the data. The court ruled that the use of an outlier test is in appropriatein this case.4. It is n ever appropriate to utilize outlier tests for a statistically based test, i.e., content uni formity and dissoluti on.Determine if the firm uses an outlier test and eval

40、uate the SOP.Determ ine that a full scale in quiry has bee n made for multiple OOS results. This in quiry in volves quality con trol and quality assura nee pers onnel in additi on to laboratory workers to ide ntify exact process or non process related errors.When the laboratory investigation is inco

41、nclusive (reason for the error is not identified) the firm:1. Cannot con duct 2 retests and base release on average of three tests2. Cannot use outlier test in chemical tests3. Cannot use a re-sample to assume a sampli ng or preparati on error4. Can con duct a retest of differe nt tablets from the s

42、ame sample whe n a retest is con sidered appropriate (see criteria elsewhere)C. FORMAL INVESTIGATIONSFormal investigations extending beyond the laboratory must follow an outline with particular attention to corrective action. The company must:1. State the reason for the investigation2. Provide summa

43、ti on of the process seque nces that may have caused the problem3. Outl ine corrective acti ons n ecessary to save the batch and preve nt similar recurre nee4. List other batches and products possibly affected, the results ofin vestigati on of these batches and products, and any corrective acti on.

44、Specifically:o exam ine other batches of product made by the errant employee or machi ne o exam ine other products produced by the errant process or operati on5. Preserve the comments and sig natures of all production and quality con trol pers onnel who con ducted the in vestigati on and approved an

45、yreprocessed material after additi onal test ingD. INVESTIGATION DOCUMENTATIONAn alyst's mistakes, such as un detected calculati on errors, should be specified with particularity and supported by evide nee. In vestigati ons along with con clusi ons reached must be preserved with writte n docume

46、ntati on that en umerates each step of the in vestigati on. The evaluati on, con clusi on and corrective acti on, if any, should be preserved in an in vestigati on or failure report and placed into a central file.E. INVESTIGATION TIME FRAMESAll failure in vestigati ons should be performed with in 20

47、 bus in ess days of the problem's occurrence and recorded and written into a failure or investigation report.6. PRODUCT FAILURESAn OOS laboratory result can be overcome (in validated) whe n laboratory error has bee n docume nted. However, non-process and process related errors result ing from op

48、erators mak ing mistakes, equipme nt (other tha n laboratory equipme nt) malfu ncti ons, or a man ufacturi ng process that is fun dame ntally deficient, such as an improper mixing time, represent product failures.Exam ine the results of in vestigati ons using the guida nce in secti on 5 above and ev

49、aluate the decisi on to release, retest, or rework products.7. RETESTINGEvaluate the compa ny's retest ing SOP for complia nce with scie ntifically sou nd and appropriate procedures. A very importa nt ruli ng in one rece nt court decision sets forth a procedure to govern the retesting program. T

50、his district court ruli ng provides an excelle nt guide to use in evaluati ng some aspects of a pharmaceutical laboratory, but should not be con sidered as law, regulati on or binding legal precede nt. The court ruled that a firm should have a predetermined testing procedure and it should consider a

51、 point at which test ing ends and the product is evaluated. If results are not satisfactory, the product is rejected.Additi on ally, the compa ny should con sider all retest results in the con text of the overall record of the product. This in cludes the history of the product. The court ordered a r

52、ecall of one batch of product on the basis of an in itial content uni formity failure and no basis to in validate the test result and on a history of content uni formity problems with the product., type of test performed, and in-process test results. Fail ing assay results cannot be disregarded simp

53、ly on the basis of acceptable content uni formity results.The number of retests performed before a firm concludes that an unexplained OOS result is in valid or that a product is un acceptable is a matter of scientific judgment. The goal of retesting is to isolate OOS results but retesting cannot con

54、tinue ad infinitum.In the case of non process and process-related errors, retest ing is suspect. Because the in itial tests are genuine, in these circumsta nces, additi onal test ing alone cannot con tribute to product quality. The court ack no wledged that some retesti ng may precede a finding of n

55、on process or process-based errors. Once this determ in ati on is made, however, additi onal retest ing for purposes of testi ng a product into complia nce is not acceptable.For example, in the case of content uni formity testi ng desig ned to detect variability in the ble nd or tablets, faili ng an

56、d non-faili ng results are not in here ntly incon siste nt and pass ing results on limited retesti ng do not rule out the possibility that the batch is not uni form. As part of the investigation firms should consider the record of previous batches, since similar or related failures on different batc

57、hes would be a cause of con cer n.Retesting following an OOS result is ruled appropriate only after the failure investigation is underway and the failure investigation determines in part whether retesting is appropriate. It is appropriate when analyst error is documented or the review of analyst'

58、;s work is "inconclusive" , but it is not appropriate for known and undisputed non-process or process related errors.The court ruled that retesti ng:o must be done on the same, not a differe nt sampleo may be done on a sec ond aliquot from the same porti on of the sample that was the sourc

59、e of the first aliquoto may be done on a portion of the same larger sample previously collected for laboratory purposes8. RESAMPLINGFirms cannot rely on resampli ng. The court ordered the recall of one batch of product after hav ing con cluded that a successful resample result alone cannot in validate an in itial OOS result. to release a product that has failed testi ng and retesti ng unl ess the failure in vestigati on discloses evidence that the original sample is not representative or was impr