1、GUIDE TO INSPECTIONS OF PHARMACEUTICAL QUALITY CONTROL LABORATORIESNote: This document is reference material for investigators and other FDApersonnel. The document does not bind FDA, and does no confer any rights,privileges, benefits, or immunities for or on any person(s).1. INTRODUCTIONThe pharmace
2、utical quality control laboratory serves one of the mostimportant functions in pharmaceutical production and control. A significantportion of the CGMP regulations (21 CFR 211) pertain to the quality controllaboratory and product testing. Similar concepts apply to bulk drugs.This inspection guide sup
3、plements other inspectional information containedin other agency inspectional guidance documents. For example, ComplianceProgram 7346.832 requiring pre-approval NDA/ANDA inspections containsgeneral instructions to conduct product specific NDA/ANDA inspection auditsto measure compliance with the appl
4、ications and CGMP requirements. Thisincludes pharmaceutical laboratories used for in-process and finishedproduct testing.2. OBJECTIVEThe specific objective will be spelled out prior to the inspection. Thelaboratory inspection may be limited to specific issues, or the inspectionmay encompass a compre
5、hensive evaluation of the laboratorys compliance withCGMPs. As a minimum, each pharmaceutical quality control laboratory shouldreceive a comprehensive GMP evaluation each two years as part of thestatutory inspection obligation.In general these inspections may include- the specific methodology which
6、will be used to test a new product- a complete assessment of laboratorys conformance with GMPs- a specific aspect of laboratory operations3. INSPECTION PREPARATIONFDA Inspection Guides are based on the team inspection approach and ourinspection of a laboratory is consistent with this concept. As par
7、t of oureffort to achieve uniformity and consistency in laboratory inspections, weexpect that complex, highly technical and specialized testing equipment,procedures and data manipulations, as well as scientific laboratoryoperations will be evaluated by an experienced laboratory analyst withspecializ
8、ed knowledge in such matters.District management makes the final decision regarding the assignment ofpersonnel to inspections. Nevertheless, we expect investigators, analystsand others to work as teams and to advise management when additionalexpertise is required to complete a meaningful inspection.
9、Team members participating in a pre-approval inspection must read and befamiliar with Compliance Program 7346.832, Pre-ApprovalInspections/Investigations. Relevant sections of the NDA or ANDA should bereviewed prior to the inspection; but if the application is not availablefrom any other source, thi
10、s review will have to be conducted using thecompanys copy of the application.Team members should meet, if possible, prior to the inspection to discussthe approach to the inspection, to define the roles of the team members, andto establish goals for completion of the assignment. Responsibilities ford
11、evelopment of all reports should also be established prior to theinspection. This includes the preparation of the FDA 483.The Center for Drug Evaluation and Research (CDER) may have issueddeficiency letters listing problems that the sponsor must correct prior tothe approval of NDA/ANDAs and suppleme
12、nts. The inspection team is expectedto review such letters on file at the district office, and they are expectedto ask the plant for access to such letters. The team should evaluate thereplies to these letters to assure that the data are accurate and authentic.Complete the inspection even though the
13、re has been no response to theseletters or when the response is judged inadequate.4. INSPECTION APPROACHA. GeneralIn addition to the general approach utilized in a drug CGMP inspection, theinspection of a laboratory requires the use of observations of thelaboratory in operation and of the raw labora
14、tory data to evaluatecompliance with CGMPs and to specifically carry out the commitments in anapplication or DMF. When conducting a comprehensive inspection of alaboratory, all aspects of the laboratory operations will be evaluated.Laboratory records and logs represent a vital source of information
15、thatallows a complete overview of the technical ability of the staff and ofoverall quality control procedures. SOPs should be complete and adequate andthe operations of the laboratories should conform to the written procedures.Specifications and analytical procedures should be suitable and, asapplic
16、able, in conformance with application commitments and compendialrequirements.Evaluate raw laboratory data, laboratory procedures and methods, laboratoryequipment,including maintenance and calibration, and methods validation datato determine the overall quality of the laboratory operation and the abi
17、lityto comply with CGMP regulations.Examine chromatograms and spectra for evidence of impurities, poortechnique, or lack of instrument calibration.s use systems that provide for the investigation oflaboratory test failures. These are generally recorded in some type of log.Ask to see results of analy
18、ses for lots of product that have failed to meetspecifications and review the analysis of lots that have been retested,rejected, or reworked. Evaluate the decision to release lots of product whenthe laboratory results indicate that the lot failed to meet specificationsand determine who released them
19、.B. Pre-ApprovalDocuments relating to the formulation of the product, synthesis of the bulkdrug substance, product specifications, analysis of the product, and othersare examined during the review process in headquarters. However, thesereviews and evaluations depend on accurate and authentic data th
20、at trulyrepresents the product.Pre-approval inspections are designed to determine if the data submitted inan application are authentic and accurate and if the procedures listed inthe application were actually used to produce the data contained in theapplication. Additionally, they are designed to co
21、nfirm that plants(including the quality control laboratory) are in compliance with CGMPregulations.The analytical sections of drug applications usually contain only testresults and the methods used to obtain them. Sponsors are not required tofile all the test data because such action would require v
22、oluminoussubmissions and would often result in filing redundant information. Sponsorsmay deliberately or unintentionally select and report data showing that adrug is safe and effective and deserves to be approved. The inspection teammust decide if there is valid and scientific justification for the
23、failureto report data which demonstrates the product failed to meet itspredetermined specifications.Coordination between headquarters and the field is essential for a completereview of the application and the plant. Experienced investigators andanalysts may contact the review chemist (with appropria
24、te supervisoryconcurrence) when questions concerning specifications and standards arise.Inspections should compare the results of analyses submitted with results ofanalysis of other batches that may have been produced. Evaluate the methodsand note any exceptions to the procedures or equipment actual
25、ly used fromthose listed in the application and confirm that it is the same methodlisted in the application. The analyst is expected to evaluate rawlaboratory data for tests performed on the test batches (biobatches andclinical batches) and to compare this raw data to the data filed in theapplicatio
26、n.5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTSEvaluate the companys system to investigate laboratory test failures. Theseinvestigations represent a key issue in deciding whether a product may bereleased or rejected and form the basis for retesting, and resampling.In a recent court decision t
27、he judge used the term “out-of-specification“(OOS) laboratory result rather than the term “product failure“ which is morecommon to FDA investigators and analysts. He ruled that an OOS resultidentified as a laboratory error by a failure investigation or an outliertest. The court provided explicit lim
28、itations on the use of outlier testsand these are discussed in a later segment of this document., or overcome byretesting. The court ruled on the use of retesting which is covered in alater segment of this document. is not a product failure. OOS results fallinto three categories:- laboratory error-
29、non-process related or operator error- process related or manufacturing process errorA. LABORATORY ERRORSLaboratory errors occur when analysts make mistakes in following the methodof analysis, use incorrect standards, and/or simply miscalculate the data.Laboratory errors must be determined through a
30、 failure investigation toidentify the cause of the OOS. Once the nature of the OOS result has beenidentified it can be classified into one of the three categories above. Theinquiry may vary with the object under investigation.B. LABORATORY INVESTIGATIONSThe exact cause of analyst error or mistake ca
31、n be difficult to determinespecifically and it is unrealistic to expect that analyst error will alwaysbe determined and documented. Nevertheless, a laboratory investigationconsists of more than a retest. The inability to identify an errors causewith confidence affects retesting procedures, not the i
32、nvestigation inquiryrequired for the initial OOS result.The firms analyst should follow a written procedure, checking off each stepas it is completed during the analytical procedure. We expect laboratorytest data to be recorded directly in notebooks; use of scrap paper and loosepaper must be avoided
33、. These common sense measures enhance the accuracy andintegrity of data.Review and evaluate the laboratory SOP for product failure investigations.Specific procedures must be followed when single and multiple OOS resultsare investigated. For the single OOS result the investigation should includethe f
34、ollowing steps and these inquiries must be conducted before there is aretest of the sample:o the analyst conducting the test should report the OOS result to thesupervisoro the analyst and the supervisor should conduct an informal laboratoryinvestigation which addresses the following areas:1. discuss
35、 the testing procedure2. discuss the calculation3. examine the instruments4. review the notebooks containing the OOS resultAn alternative means to invalidate an initial OOS result, provided thefailure investigation proves inconclusive, is the “outlier“ test. However,specific restrictions must be pla
36、ced on the use of this test.1. Firms cannot frequently reject results on this basis.2. The USP standards govern its use in specific cases only.3. The test cannot be used for chemical testing results. An initial contentuniformity test was OOS followed by a passing retest. The initial OOS resultwas cl
37、aimed the result of analyst error based on a statistical evaluation ofthe data. The court ruled that the use of an outlier test is inappropriatein this case4. It is never appropriate to utilize outlier tests for a statisticallybased test, i.e., content uniformity and dissolution.Determine if the fir
38、m uses an outlier test and evaluate the SOP.Determine that a full scale inquiry has been made for multiple OOS results.This inquiry involves quality control and quality assurance personnel inaddition to laboratory workers to identify exact process or non processrelated errors.When the laboratory inv
39、estigation is inconclusive (reason for the error isnot identified) the firm:1. Cannot conduct 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 sampling or preparation error4. Can conduct a retest of different tablet
40、s from the same sample when aretest is considered appropriate (see criteria elsewhere)C. FORMAL INVESTIGATIONSFormal investigations extending beyond the laboratory must follow an outlinewith particular attention to corrective action. The company must:1. State the reason for the investigation2. Provi
41、de summation of the process sequences that may have caused theproblem3. Outline corrective actions necessary to save the batch and preventsimilar recurrence4. List other batches and products possibly affected, the results ofinvestigation of these batches and products, and any corrective action.Speci
42、fically:o examine other batches of product made by the errant employee or machineo examine other products produced by the errant process or operation5. Preserve the comments and signatures of all production and qualitycontrol personnel who conducted the investigation and approved anyreprocessed mate
43、rial after additional testingD. INVESTIGATION DOCUMENTATIONAnalysts mistakes, such as undetected calculation errors, should bespecified with particularity and supported by evidence. Investigations alongwith conclusions reached must be preserved with written documentation thatenumerates each step of
44、the investigation. The evaluation, conclusion andcorrective action, if any, should be preserved in an investigation orfailure report and placed into a central file.E. INVESTIGATION TIME FRAMESAll failure investigations should be performed within 20 business days ofthe problems occurrence and recorde
45、d and written into a failure orinvestigation report.6. PRODUCT FAILURESAn OOS laboratory result can be overcome (invalidated) when laboratory errorhas been documented. However, non-process and process related errorsresulting from operators making mistakes, equipment (other than laboratoryequipment)
46、malfunctions, or a manufacturing process that is fundamentallydeficient, such as an improper mixing time, represent product failures.Examine the results of investigations using the guidance in section 5 aboveand evaluate the decision to release, retest, or rework products.7. RETESTINGEvaluate the co
47、mpanys retesting SOP for compliance with scientificallysound and appropriate procedures. A very important ruling in one recentcourt decision sets forth a procedure to govern the retesting program. Thisdistrict court ruling provides an excellent guide to use in evaluating someaspects of a pharmaceuti
48、cal laboratory, but should not be considered as law,regulation or binding legal precedent. The court ruled that a firm shouldhave a predetermined testing procedure and it should consider a point atwhich testing ends and the product is evaluated. If results are notsatisfactory, the product is rejecte
49、d.Additionally, the company should consider all retest results in the contextof the overall record of the product. This includes the history of theproduct. The court ordered a recall of one batch of product on the basis ofan initial content uniformity failure and no basis to invalidate the testresult and on a history of content uniformity problems with the product.,type of test performed, and in-process test results. Failing assay resultscannot be disregarded simply on the basis of acceptable content uniformityresults.The number of retests performed before a firm concludes t
