美国FDA药品质量控制微生物实验室检查指南

GUIDE TO INSPECTIONS OF MICROBIOLOGICAL 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).I. INTRODUCTIONThe Guide to the Inspection of Pharmaceutical Quality Control Laboratoriesprovided very limited guidance on the matter of inspection ofmicrobiological laboratories. While that guide addresses many of the issuesassociated with the chemical aspect of laboratory analysis ofpharmaceuticals, this document will serve as a guide to the inspection ofthe microbiology analytical process. As with any laboratory inspection, itis recommended that an analyst (microbiologist) who is familiar with thetests being inspected participate in these inspections.II. MICROBIOLOGICAL TESTING OF NON-STERILE PRODUCTSFor a variety of reasons, we have seen a number of problems associated withthe microbiological contamination of topical drug products, nasal solutionsand inhalation products. The USP Microbiological Attributes Chapter <1111>provides little specific guidance other than "The significance ofmicroorganisms in non-sterile pharmaceutical products should be evaluated interms of the use of the product, the nature of the product, and thepotential hazard to the user." The USP recommends that certain categories beroutinely tested for total counts and specified indicator microbialcontaminants. For example natural plant, animal and some mineral productsfor Salmonella, oral liquids for E. Coli, topicals for P. aeruginosa and S.Aureus, and articles intended for rectal, urethral, or vaginaladministration for yeasts and molds. A number of specific monographs alsoinclude definitive microbial limits.As a general guide for acceptable levels and types of microbiologicalcontamination in products, Dr. Dunnigan of the Bureau of Medicine of the FDAcommented on the health hazard. In 1970, he said that topical preparationscontaminated with gram negative organisms are a probable moderate to serioushealth hazard. Through the literature and through our investigations, it hasbeen shown that a variety of infections have been traced to the gramnegative contamination of topical products. The classical example being thePseudomonas cepacia contamination of Povidone Iodine products reported by ahospital in Massachusetts several years ago.Therefore, each company is expected to develop microbial specifications fortheir non-sterile products. Likewise, the USP Microbial Limits Chapter <61>provides methodology for selected indicator organisms, but not allobjectionable organisms. For example, it is widely recognized thatPseudomonas cepacia is objectionable if found in a topical product or nasal solution in high numbers; yet, there are no test methods provided in the USP that will enable the identification of the presence of this microorganism.A relevant example of this problem is the recall of Metaproterenol Sulfate Inhalation Solution. The USP XXII monograph requires no microbial testingfor this product. The agency classified this as a Class I recall because the product was contaminated with Pseudomonas gladioli/cepacia. The healthhazard evaluation commented that the risk of pulmonary infection isespecially serious and potentially life-threatening to patients with chronic obstructive airway disease, cystic fibrosis, and immuno-compromisedpatients. Additionally, these organisms would not have been identified bytesting procedures delineated in the general Microbial Limits section of the Compendia.The USP currently provides for retests in the Microbial Limits section <61> however there is a current proposal to remove the retest provision. As with any other test, the results of initial test should be reviewed andinvestigated. Microbiological contamination is not evenly dispersedthroughout a lot or sample of product and finding a contaminant in onesample and not in another does not discount the findings of the initialsample results. Retest results should be reviewed and evaluated, andparticular emphasis should be placed on the logic and rationale forconducting the retest.In order to isolate specific microbial contaminants, FDA laboratories, aswell as many in the industry, employ some type of enrichment mediacontaining inactivators, such as Tween or lecithin. This is essential toinactivate preservatives usually present in these types of product andprovides a better medium for damaged or slow growing cells. Other growthparameters include a lower temperature and longer incubation time (at least 5 days) that provide a better survival condition for damaged or slow-growing cells.For example, FDA laboratories use the test procedures for cosmetics in the Bacteriological Analytical Manual (BAM), 6th Edition, to identifycontamination in non-sterile drug products. This testing includes anenrichment of a sample in modified letheen broth. After incubation, further identification is carried out on Blood Agar Plates and MacConkey AgarPlates. Isolated colonies are then identified. This procedure allows FDAmicrobiologists to optimize the recovery of all potential pathogens and to quantitate and speciate all recovered organisms. Another important aspect of procedures used by FDA analysts is to determine growth promotioncharacteristics for all of the media used.The selection of the appropriate neutralizing agents are largely dependent upon the preservative and formulation of the product under evaluation. Ifthere is growth in the enrichment broth, transfer to more selective agarmedia or suitable enrichment agar may be necessary for subsequentidentification.Microbiological testing may include an identification of colonies foundduring the Total Aerobic Plate Count test. Again, the identification should not merely be limited to the USP indicator organisms.The importance of identifying all isolates from either or both Total Plate Count testing and enrichment testing will depend upon the product and itsintended use. Obviously, if an oral solid dosage form such as a tablet istested, it may be acceptable to identify isolates when testing shows highlevels. However, for other products such as topicals, inhalants or nasalsolutions where there is a major concern for microbiological contamination, isolates from plate counts, as well as enrichment testing, should beidentified.III. FACILITIES, EQUIPMENT, ANDMEDIABegin the inspection with a review of analyses being conducted and inspect the plates and tubes of media being incubated (caution should be exercised not to inadvertently contaminate plates or tubes of media on test). Beparticularly alert for retests that have not been documented and "specialprojects" in which investigations of contamination problems have beenidentified. This can be evaluated by reviewing the ongoing analyses (product or environmental) for positive test results. Request to review the previous day's plates and media, if available and compare your observations to therecorded entries in the logs. Inspect the autoclaves used for thesterilization of media. Autoclaves may lack the ability to displace steamwith sterile filtered air. For sealed bottles of media, this would notpresent a problem. However, for non-sealed bottles or flasks of media,non-sterile air has led to the contamination of media. In addition,autoclaving less than the required time will also allow media associatedcontaminants to grow and cause a false positive result. These problems may be more prevalent in laboratories with a heavy workload.Check the temperature of the autoclave since overheating can denature andeven char necessary nutrients. This allows for a less than optimal recovery of already stressed microorganisms. The obvious problem with potential false positives is the inability to differentiate between inadvertent mediumcontamination and true contamination directly associated with the sampletested.IV. STERILITY TESTINGOn 10/11/91, the Agency published a proposed rule regarding the manufacture of drug products by aseptic processing and terminal sterilization. A list of contaminated or potentially contaminated drug products made by asepticprocessing and later recalled was also made available. Many of theinvestigations/inspections of the recalled products started with a list of initial sterility test failures. FDA review of the manufacturer'sproduction, controls, investigations and their inadequacies, coupled withthe evidence of product failure (initial sterility test failure) ultimately led to the action.The USP points out that the facilities used to conduct sterility testsshould be similar to those used for manufacturing product. The USP states,"The facility for sterility testing should be such as to offer no greater a microbial challenge to the articles being tested than that of an asepticprocessing production facility". Proper design would, therefore, include a gowning area and pass-through airlock. Environmental monitoring and gowning should be equivalent to that used for manufacturing product.Since a number of product and media manipulations are involved in conducting a sterility test, it is recommended that the inspection include actualobservation of the sterility test even though some companies have tried to discourage inspection on the grounds that it may make the firm's analystnervous. The inspection team is expected to be sensitive to this concern and make the observations in a manner that will create the least amount ofdisruption in the normal operating environment. Nevertheless, such concerns are not sufficient cause for you to suspend this portion of the inspection.One of the most important aspects of the inspection of a sterilityanalytical program is to review records of initial positive sterility test results. Request lists of test failures to facilitate review of production and control records and investigation reports. Particularly, for the highrisk aseptically filled product, initial positive sterility test results and investigations should be reviewed. It is difficult for the manufacturer to justify the release of a product filled aseptically that fails an initialsterility test without identifying specific problems associated with thecontrols used for the sterility test.Examine the use of negative controls. They are particularly important to a high quality sterility test. Good practice for such testing includes the use of known terminally sterilized or irradiated samples as a system control.Alternatively, vials or ampules filled during media fills have also beenused.Be especially concerned about the case where a manufacturer of aseptically filled products has never found an initial positive sterility test. Whilesuch situations may occur, they are rare. In one case, a manufacturer'srecords showed that they had never found a positive result; their recordshad been falsified. Also, the absence of initial positives may indicate that the test has not been validated to demonstrate that there is no carryover of inhibition from the product or preservative.Inspect robotic systems or isolation technology, such as La Calhene unitsused for sterility testing. These units allow product withdrawal in theabsence of people. If an initial test failure is noted in a sample tested in such a system, it could be very difficult to justify release based on aretest, particularly if test controls are negative.Evaluate the time period used for sterility test sample incubation. Thisissue has been recently clarified. The USP states that samples are to beincubated for at least 7 days, and a proposal has been made to change theUSP to require a period of 14 days incubation. You are expected to evaluate the specific analytical procedure and the product for the proper incubation period. Seven days may be insufficient, particularly when slow growingorganisms have been identified. Media fill, environmental, sterility testresults and other data should be reviewed to assure the absence of slowgrowing organisms. Also, you should compare the methods being used forincubation to determine if they conform to those listed in approved orpending applications.V. METHODOLOGY ANDDetermine the source of test procedures. Manufacturers derive testprocedures from several sources, including the USP, BAM and othermicrobiological references. It would be virtually impossible to completely validate test procedures for every organism that may be objectionable.However, it is a good practice to assure that inhibitory substances insamples are neutralized.During inspections, including pre-approval inspections, evaluate themethodology for microbiological testing. For example, we expect test methods to identify the presence of organisms such as Pseudomonas cepacia or other Pseudomonas species that may be objectional or present a hazard to the user. Where pre-approval inspections are being conducted, compare the method being used against the one submitted in the application. Also verify that thelaboratory has the equipment necessary to perform the tests and that theequipment was available and in good operating condition on the dates ofcritical testing.The USP states that an alternate method may be substituted for compendialtests, provided it has been properly validated as giving equivalent orbetter results.You may find that dehydrated media are being used for the preparation of<<< Continued to next message >>><<< This message is part 2 of a previous message >>>media. Good practice includes the periodic challenge of prepared media with low levels of organisms. This includes USP indicator organisms as well asnormal flora. The capability of the media to promote the growth of organisms may be affected by the media preparation process, sterilization(overheating) and storage. These represent important considerations in any inspection and in the good management of a microbiology laboratory.VI. DATA STORAGEEvaluate the test results that have been entered in either logbooks or onloose analytical sheets. While some manufacturers may be reluctant toprovide tabulations, summaries, or printouts of microbiological testresults, this data should be reviewed for the identification of potentialmicrobial problems in processing. When summaries of this data are notavailable the inspection team is expected to review enough data to construct their own summary of the laboratory test results and quality controlprogram.Some laboratories utilize preprinted forms only for recording test data.Some laboratories have also pointed out that the only way microbiologicaltest data could be reviewed during inspections would be to review individual batch records. However, in most cases, preprinted forms are in multiplecopies with a second or third copy in a central file. Some companies uselog-books for recording data. These logbooks should also be reviewed.Additionally, many manufacturers are equipped with an automated microbialsystem, such as a Vitek, for the identification of microorganisms. Logs of such testing, along with the identification of the source of the sample, are also of value in the identification of potential microbial problems inprocessing.The utilization of automated systems for the identification ofmicroorganisms is relatively common in the parenteral manufacturer whereisolates from the environment, water systems, validation and people areroutinely identified.Microbiologists in our Baltimore District are expert on the use of automated microbic analytical systems. They were the first FDA laboratory to use such equipment and have considerable experience in validating methods for these pieces of equipment. Contact the Baltimore District laboratory forinformation or questions about these systems. Plants with heavy utilization of these pieces of equipment should be inspected by individuals from theBaltimore District laboratory.VII. MANAGEMENT REVIEWMicrobiological test results represent one of the more difficult areas for the evaluation and interpretation of data. These evaluations requireextensive training and experience in microbiology. Understanding themethodology, and more importantly, understanding the limitations of the test present the more difficult issues. For example, a manufacturer found highcounts of Enterobacter cloacae in their oral dosage form product derivedfrom a natural substance. Since they did not isolate E. coli, they released the product. FDA analysis found E. cloacae in most samples from the batchand even E. coli in one sample. In this case management failed to recognize that microbiological contamination might not be uniform, that otherorganisms may mask the presence of certain organisms when identificationprocedures are performed, and that microbiological testing is far fromabsolute. The inspection must consider the relationship between theorganisms found in the samples and the potential for the existence of other objectionable conditions. For example, it is logical to assume that if the process would allow E. cloacae to be present, it could also allow thepresence of the objectionable indicator organism. The microbiologist should evaluate this potential by considering such factors as methodology, and the growth conditions of the sample as well as other fundamental factorsassociated with microbiological analysis.Evaluate management's program to audit the quality of the laboratory workperformed by outside contractors.VIII. CONTRACT TESTINGLABORATORIESMany manufacturers contract with private or independent testing laboratories to analyze their products. Since, these laboratories will conduct only thetests that the manufacturer requests, determine the specific instructionsgiven to the contractor. Evaluate these instructions to assure thatnecessary testing will be completed. For example, in a recent inspection of a topical manufacturer, total plate count and testing for the USP indicator organisms were requested. The control laboratory performed this testing only and did not look for other organisms that would be objectionable based onthe product's intended use.Analytical results, particularly for those articles in which additional or retesting is conducted, should be reviewed. Test reports should be provided to the manufacturer for tests conducted. It is not unusual to see contract laboratories fail to provide complete results, with both failing as well as passing results.Bacteriostasis/fungiostasis testing must be performed either by the contract lab or the manufacturer. These test results must be negative otherwise any sterility test results obtained by the contractor on the product may not be valid.There are no references from this document.。

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 pharmaceutical 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 supplements 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 applications 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 comprehensive evaluation of the laboratory's compliance withCGMP's. 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 will be used to test a new product-- a complete assessment of laboratory's conformance with GMP's-- 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 part 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 withspecialized 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.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, this review will have to be conducted using thecompany's 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 fordevelopment 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/ANDA's and supplements. The inspection team is expected to 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 there 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 laboratory data to evaluatecompliance with CGMP's 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 thatallows a complete overview of the technical ability of the staff and ofoverall quality control procedures. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures.Specifications and analytical procedures should be suitable and, asapplicable, in conformance with application commitments and compendialrequirements.Evaluate raw laboratory data, laboratory procedures and methods, laboratoryequipment,including maintenance and calibration, and methods validation data to determine the overall quality of the laboratory operation and the abilityto 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 analyses 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.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 that 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 confirm 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 voluminoussubmissions and would often result in filing redundant information. Sponsors may deliberately or unintentionally select and report data showing that adrug is safe and effective and deserves to be approved. The inspection team must decide if there is valid and scientific justification for the 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 appropriate supervisoryconcurrence) when questions concerning specifications and standards arise.Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. Evaluate the methods and note any exceptions to the procedures or equipment actually 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 theapplication.5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTSEvaluate the company's system to investigate laboratory test failures. These investigations 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 the 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 limitations 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-- 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 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 can 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 error's causewith confidence affects retesting procedures, not the investigation inquiryrequired for the initial OOS result.The firm's 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. These common sense measures enhance the accuracy and integrity 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 following 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 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 placed 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 result was claimed 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 case..4. It is never appropriate to utilize outlier tests for a statisticallybased test, i.e., content uniformity and dissolution.Determine if the firm 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 investigation 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 tablets from the same sample when aretest is considered 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 summation of the process sequences that may have caused the problem3. 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.Specifically:o examine other batches of product made by the errant employee or machine o 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 material after additional testingD. INVESTIGATION DOCUMENTATIONAnalyst's mistakes, such as undetected calculation errors, should bespecified with particularity and supported by evidence. Investigations alongwith conclusions reached must be preserved with written documentation that enumerates each step of 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 problem's occurrence and recorded and written into a failure orinvestigation report.6. PRODUCT FAILURESAn OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. However, non-process and process related errorsresulting from operators making mistakes, equipment (other than laboratoryequipment) 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 company's 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 pharmaceutical 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 rejected.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 uniformity results.The number of retests performed before a firm concludes that an unexplained OOS result is invalid or that a product is unacceptable is a matter ofscientific judgment. The goal of retesting is to isolate OOS results butretesting cannot continue ad infinitum.In the case of nonprocess and process-related errors, retesting is suspect.Because the initial tests are genuine, in these circumstances, additionaltesting alone cannot contribute to product quality. The court acknowledgedthat some retesting may precede a finding of nonprocess or process-based errors. Once this determination is made, however, additional retesting forpurposes of testing a product into compliance is not acceptable.For example, in the case of content uniformity testing designed to detectvariability in the blend or tablets, failing and non-failing results are notinherently inconsistent and passing results on limited retesting do not ruleout the possibility that the batch is not uniform. As part of theinvestigation firms should consider the record of previous batches, sincesimilar or related failures on different batches would be a cause ofconcern.Retesting following an OOS result is ruled appropriate only after thefailure investigation is underway and the failure investigation determinesin part whether retesting is appropriate. It is appropriate when analysterror is documented or the review of analyst's work is "inconclusive" , butit is not appropriate for known and undisputed non-process or processrelated errors.The court ruled that retesting:o must be done on the same, not a different sampleo may be done on a second aliquot from the same portion of the sample that was the source of the first aliquoto may be done on a portion of the same larger sample previously collectedfor laboratory purposes8. RESAMPLINGFirms cannot rely on resampling. The court ordered the recall of one batchof product after having concluded that a successful resample result alonecannot invalidate an initial OOS result. to release a product that hasfailed testing and retesting unless the failure investigation disclosesevidence that the original sample is not representative or was improperlyprepared.Evaluate each resampling activity for compliance with this guidance.9. AVERAGING RESULTS OF ANALYSISAveraging can be a rational and valid approach when the object underconsideration is total product assay, but as a general rule this practiceshould be avoided. The court ruled that the firm must recall a batch thatwas released for content uniformity on the basis of averaged test results.because averages hide the variability among individual test results. Thisphenomenon is particularly troubling if testing generates both OOS andpassing individual results which when averaged are within specification.Here, relying on the average figure without examining and explaining theindividual OOS results is highly misleading and unacceptable.Content uniformity and dissolution results never should be averaged toobtain a passing value.In the case of microbiological turbidimetric and plate assays an average ispreferred by the USP. In this case, it is good practice to include OOSresults in the average unless an outlier test (microbiological assays)suggests the OOS is an anomaly.10. BLEND SAMPLING AND TESTINGThe laboratory serves a vital function in blend testing which is necessaryto increase the likelihood of detecting inferior batches. Blend uniformitytesting cannot be waived in favor of total reliance on finished producttesting because finished product testing is limited.One court has ruled that sample size influences ultimate blend test resultsand that the sample size should resemble the dosage size. Any other practice would blur differences in portions of the blend and defeat the object of thetest. If a sample larger than the unit must be taken initially, aliquotswhich resemble the dosage size should be carefully removed for the test,retests, and reserve samples. Obviously, the initial larger sample shouldnot be subjected to any additional mixing or manipulation prior to removingtest aliquots as this may obscure non-homogeneity.Multiple individual blend uniformity samples taken from different areascannot be composited. However when variation testing is not the object ofassay testing, compositing is permitted.If firms sample product from sites other than the blender, they mustdemonstrate through validation that their sampling technique isrepresentative of all portions and concentrations of the blend. This meansthat the samples must be representative of those sites that might beproblems; e.g. weak or hot spots in the blend.11. MICROBIOLOGICALThe review of microbiological data on applicable dosage forms is bestperformed by the microbiologist (analyst). Data that should be reviewedinclude preservative effectiveness testing, bioburden data, and productspecific microbiological testing and methods.Review bioburden (before filtration and/or sterilization) from both anendotoxin and sterility perspective. For drug substance labs evaluatemethods validation and raw data for sterility, endotoxin testing,environmental monitoring, and filter and filtration validation. Also,evaluate the methods used to test and establish bioburdens.Refer to the Microbiological Inspection Guide for additional informationconcerning the inspection of microbiological laboratories.12. SAMPLINGSamples will be collected on pre-approval inspections. Follow the samplingguidelines in CP 7346.832, Part III, pages 5 and 6.13. LABORATORY RECORDS AND DOCUMENTATIONReview personal analytical notebooks kept by the analysts in the laboratoryand compare them with the worksheets and general lab notebooks and records. Be prepared to examine all records and worksheets for accuracy andauthenticity and to verify that raw data are retained to support theconclusions found in laboratory results.Review laboratory logs for the sequence of analysis versus the sequence ofmanufacturing dates. Test dates should correspond to the dates when thesample should have been in the laboratory. If there is a computer data base,determine the protocols for making changes to the data. There should be anaudit trail for changes to data.We expect raw laboratory data to be maintained in bound, (not loose or scrapsheets of paper), books or on analytical sheets for which there isaccountability, such as prenumbered sheets. For most of those manufacturerswhich had duplicate sets of records or "raw data", non-numbered loose sheetsof paper were employed. Some companies use discs or tapes as raw data andfor the storage of data. Such systems have also been accepted provided theyhave been defined (with raw data identified) and validated.Carefully examine and evaluate laboratory logs, worksheets and other recordscontaining the raw data such as weighings, dilutions, the condition ofinstruments, and calculations. Note whether raw data are missing, if recordshave been rewritten, or if correction fluid has been used to conceal errors.Results should not be changed without explanation. Cross reference the datathat has been corrected to authenticate it. Products cannot be "tested intocompliance" by arbitrarily labeling out-of-specification lab results as"laboratory errors" without an investigation resulting in scientificallyvalid criteria.Test results should not have been transcribed without retention of theoriginal records, nor should test results be recorded selectively. Forexample, investigations have uncovered the use of loose sheets of paper withsubsequent selective transcriptions of good data to analyst worksheetsand/or workbooks. Absorbance values and calculations have even been found on desk calendars.Cut charts with injections missing, deletion of files in direct data entrysystems, indirect data entry without verification, and changes tocomputerized programs to override program features should be carefullyexamined. These practices raise questions about the overall quality of data.The firm should have a written explanation when injections, particularlyfrom a series are missing from the official work-sheets or from files andare included among the raw data. Multiple injections recorded should be inconsecutive files with consecutive injection times recorded. Expect to seewritten justification for the deletion of all files.Determine the adequacy of the firm's procedures to ensure that all validlaboratory data are considered by the firm in their determination ofacceptability of components, in-process, finished product, and retainedstability samples. Laboratory logs and documents when cross referenced may show that data has been discarded by company officials who decided torelease the product without a satisfactory explanation of the resultsshowing the product fails to meet the specifications. Evaluate thejustification for disregarding test results that show the product failed tomeet specifications.14. LABORATORY STANDARD SOLUTIONSAscertain that suitable standards are being used (i.e. in-date, storedproperly). Check for the reuse of stock solutions without assuring theirstability. Stock solutions are frequently stored in the laboratoryrefrigerator. Examine the laboratory refrigerators for these solutions andwhen found check for appropriate identification. Review records of standardsolution preparation to assure complete and accurate documentation. It ishighly unlikely that a firm can "accurately and consistently weigh" to thesame microgram. Therefore data showing this level of standardization orpattern is suspect and should be carefully investigated.15. METHODS VALIDATIONInformation regarding the validation of methods should be carefullyevaluated for completeness, accuracy and reliability. In particular, if acompendial method exists, but the firm chooses to use an alternate methodinstead, they must compare the two and demonstrate that the in-house method is equivalent or superior to the official procedure. For compendial methodsfirms must demonstrate that the method works under the actual conditions of use.Methods can be validated in a number of ways. Methods appearing in the USP are considered validated and they are considered validated if part of anapproved ANDA. Also a company can conduct a validation study on theirmethod. System suitability data alone is insufficient for and does notconstitute method validation.In the review of method validation data, it is expected that data forrepetitive testing be consistent and that the varying concentrations of testsolutions provide linear results. Many assay and impurity tests are nowHPLC, and it is expected that the precision of these assays be equal or lessthan the RSD's for system suitability testing. The analytical performanceparameters listed in the USP XXII, <1225>, under the heading of Validationof Compendial Methods, can be used as a guide for determining the analytical parameters (e.g., accuracy, precision, linearity, ruggedness, etc.) neededto validate the method.16. EQUIPMENTLaboratory equipment usage, maintenance, calibration logs, repair records,and maintenance SOPs also should be examined. The existence of the equipment specified in the analytical methods should be confirmed and its conditionnoted. Verify that the equipment was present and in good working order atthe time the batches were analyzed. Determine whether equipment is beingused properly.In addition, verify that the equipment in any application was in goodworking order when it was listed as used to produce clinical or biobatches.One would have to suspect the data that are generated from a piece ofequipment that is known to be defective. Therefore, continuing to use andrelease product on the basis of such equipment represents a seriousviolation of CGMP's.17. RAW MATERIAL TESTINGSome inspections include the coverage of the manufacturer of the drugsubstance. The safety and efficacy of the finished dosage form is largelydependent on the purity and quality of the bulk active drug substance.Examine the raw data reflecting the analysis of the drug substance includingpurity tests, charts, etc.Check the impurity profiles of the BPC used in the biobatch and clinicalproduction batches to determine if it is the same as that being used tomanufacture full scale production batches. Determine if the manufacturer hasa program to audit the certificate of analysis of the BPC, and, if so, checkthe results of these tests. Report findings where there is substantialdifference in impurity profiles and other test results.Some older compendial methods may not be capable of detecting impurities asnecessary to enable the control of the manufacturing process, and newermethods have been developed to test these products. Such methods must bevalidated to ensure that they are adequate for analytical purposes in thecontrol and validation of the BPC manufacturing process. The drug substancemanufacturer must have complete knowledge of the manufacturing process and the potential impurities that may appear in the drug substance. Theseimpurities cannot be evaluated without a suitable method and one that hasbeen validated.Physical tests such as particle size for raw materials, adhesion tests forpatches, and extrusion tests for syringes are essential tests to assureconsistent operation of the production and control system and to assurequality and efficacy. Some of these tests are filed in applications andothers may be established by the protocols used to manufacture the product.The validation of methods for such tests are as important as the test forchemical attributes.Physical properties tests often require the use of unique equipment andprotocols. These tests may not be reproducible in other laboratories,therefore, on site evaluation is essential.。

GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICALQUALITY CONTROL LABORATORIES制药行业微生物实验室现场检查指南Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does not confer any rights, privileges, benefits, or immunities for or on anyperson(s).注：该指南是检察官和其他FDA人员的参考材料。

该指南不约束FDA，也不授予任何权利，特权，利益或者任何人的豁免权。

I. INTRODUCTION介绍The Guide to the Inspection of Pharmaceutical Quality Control Laboratories provided very limited guidance on the matter of inspection of microbiological laboratories. While that guide addresses many of the issues associated with the chemical aspect of laboratory analysis of pharmaceuticals, this document will serve as a guide to the inspection of the microbiology analytical process. As with any laboratory inspection, it is recommended that an analyst (microbiologist) who is familiar with the tests being inspected participate in these inspections.“制药行业分析实验室现场检查指南”对如何进行微生物实验室的检查仅提供了非常有限的指导，那份指南文件主要涉及医药行业分析实验室化学分析方面的很多内容，而本指南主要讨论的是微生物分析过程的现场检查指导。

清洁验证中的微生物问题------设备表面微生物限度的制定及其检验陈雯秋½-ËÕÎÞÎý 214092¶ÔÖÆÒ©É豸½øÐÐÇåÏ´ÊÇ·ÀÖ¹Ò©Æ·ÎÛȾºÍ½»²æÎÛȾµÄ±ØÒªÊֿɽ«É豸±íÃæµÄ²ÐÁôÎï¼õÉÙµ½²»»áÓ°ÏìÏÂÅú²úÆ·µÄÁÆЧÇå½àÑéÖ¤¾ÍÊÇͨ¹ý¿ÆѧµÄ·½·¨²É¼¯×ã¹»µÄÊý¾ÝÄÜʼÖÕÈçÒ»µØ´ïµ½Ô¤¶¨µÄÇå½à±ê×¼[1]¿É·ÖΪ»¯Ñ§ÎïÖʺÍ΢ÉúÎïÁ½´óÀà化学物质一般有活性药物成分制药企业一般能够根据最低日治疗剂量成品的杂质限量等参数制定出适宜的限度对于产品质量虽然多数法规也强调了其重要性清洁验证的文件指南设备清洁的微生物问题都必须加以考虑特别要采取措施防止在设备存放期间的微生物繁殖[2]È´ÉÙÓÐÎÄÏ×Ìá³öºÏÀíµÄÖƶ¨·½·¨ÆäÏ޶ȵÄÖƶ¨µÄÈ·ÓÐÒ»¶¨ÄѶȶøÔÚʵ¼ÊµÄÇå½àÑéÖ¤Öл¹ÐèÒª½áºÏ²úÆ·ÒªÇóºÍÉú²úÇé¿ö×ÃÇéÖƶ¨»¯Ñ§ÎïÖʾßÓÐÊýÁ¿ÉϵĶø¶ÔÓÚ΢ÉúÎïÀ´Ëµ±íÃæ²ÐÁôµÄ΢ÉúÎï»áÓÐÊýÁ¿Éϵı仯´ÓÉ豸±íÃæ»ãÈëÏÂÅú²úÆ·µÄ΢ÉúÎïÀýÈç»òÕßÏÂÅú²úÆ·Ô-ÁÏÖк¬ÒÖ¾ú¼Á¶øÈç¹ûÉ豸´æ·ÅÆÚ¼äÓÐÊÊÒ˵ÄÉú³¤Ìõ¼þÔò»áʹ֮¼±ËÙÔöÖ³¼´±ãÔÚ¸ÉÔïµÄÉ豸±íÃæÒàÄÜ´æ»î»òÕßÏÂÅú²úÆ·ÊǸÉÆ·1. 微生物限度的制定方法1-1 微生物限度的理论推导[3]由于微生物的特殊性本文分三种情况来讨论微生物限度的制定方法下批产品的原料及其生产过程既不引起微生物的增殖第二种情况而产品将接受最终灭菌下批产品生产前设备需灭菌因下批产品的原料和生产过程不引起微生物数量的变化首先确定下批产品的成品微生物限度CFUÖ®ºó¼ÆË㵥λÃæ»ýµÄ΢ÉúÎïÏÞ¶ÈÓÐÁ½¸öÏà¹ØÐÅÏ¢Ô´一般会有微生物限度的要求非无菌药品的微生物要求例如然后要考虑该限度中究竟有多少该于设备表面的微生物残留内包装材料等也是成品中微生物的来源举例来说算得由原料造成的最高的微生物污染为27CFU/g那么允许由设备表面造成的污染限度为70CFU/g¼ÙÉèÈ¡5也可以采用更高的安全因子当确定了下批产品中由设备表面造成的微生物污染限度之后CFU/cm2这就和化学残留物的计算方法完全一样了LSPÀ´×ÔÉ豸±íÃæµÄ²ÐÁô΢ÉúÎïÏÞ¶ÈMBS Minimum batch size产品接触的设备表面积　假设某产品的批量为200kg由刚才推导出的LSP 计算所得的限度值为11CFU/cm2ÏÂÅú²úÆ·Éú²úÇ°É豸²»Ãð¾úÕâÖÖÇé¿öϲúÆ·ÎÞ¾ú±£Ö¤ÖµµÄ´óСÓëÃð¾ú¹¤ÒÕµÄF0值以及灭菌前微生物的含量有关即N0知晓这个限度后确定该限度中于清洁后设备表面的比例然后以最小批量和接触面积算出最终的限度值设备清洁非常重要以保证灭菌或消毒能够达到一定的无菌保证值[2]第三种情况因此设备本身将接受灭菌因为在做该设备的灭菌验证时已经制定了表面微生物的限度只须以该限度值除以某安全因子1-2 结合实际情况制定微生物限度通常理论推导出的微生物限度往往大大高于实际可达到的清洁水平良好的清洁规程应能使接触碟每碟小于25CFUÒ»°ãÿµú»á´óÓÚ100CFU¼ÆËãËùµÃÏÞ¶ÈֵΪ11CFU/cm2ÔòÏ൱ÓÚÿµú275CFU显然太宽因为一般每碟最多只能数清250CFUÈçºÎÖƶ¨Ï޶ȲÅËãºÏÀíÄØ×ÛºÏȨ衡举例来说则应予以考虑无菌药品的生产对不同洁净区的动态微生物水平提出了建议值如静态关键表面和一般表面分别制定所谓关键表面显然设备表面是属于关键表面而该企业对十万级区的关键表面要求动态不大于每碟10CFU二者取其低另外例如如管路而这些地方正是最不易清洁的此时淋洗水样品的限度值就未必适用于擦拭样品宜将设备分为不同的表面分别制定合理的限度值未必从一开始就能制定出合理的限度限度也是需要验证的过宽的限度会给产品质量带来风险从验证过程中积累的数据会发现原定限度的不合理性但是无论限度的制定还是修改2. 设备表面残留微生物的取样及检验方法传统的测量表面微生物的取样及检验方法都可使用通常用膜过滤棉签擦拭然后用倾注平皿法以及接触碟等一般来说比较关注需氧菌三种取样方法应视情况结合使用但难以反应真实的污染情况能弥补淋洗水取样的不足但是如每碟微生物计数超过250CFU3. 结束语微生物的残留问题在设备清洁验证中不容忽视除使用清洁剂和充分淋洗外以及保证设备存放期间的环境微生物水平等应自设备刚刚清洁完毕起在整个存放期间评价微生物随时间的增殖情况确保设备表面微生物在存放期间不进入快速增殖期应该满足生产和质量控制的要求并且是检验方法能够检验的制药企业应该根据具体的产品和生产情况在验证方案中阐述合理的微生物限度参考文献。

FDA 制剂厂检查指南对制剂企业的检查-CGMP备注：这个文件是对检查者和其他的FDA 官员的参照。

这份文件并不限制FDA，并不猎取任何利益，义务，权利，或豁免某人1简介这个文件介绍到一个大约的药厂检查指导他们是否符合药物的CGMP。

这个指导应当被用来作IOM 的介绍，其他的药物检查指导，和复核工程。

这个检查的指导相对于IOM 的第十章，一些指导是：A 原料药视察指导B 高纯水系统视察的指导C QC 试验室视察的指导D 微生物QC 试验室的指导E 冻干注射剂视察的指导F清洁验证视察的指导G 制药过程中的计算机系统的视察的指导H 一般工艺过程验证的指导2CGMP处方和非处方全部的药物的生产过程要对应于CGMP 否则就被认为在FDC 实施中掺假。

501(a)(2)(B)依据处方药物的记录肯定要比照于704(a)(1)(B)章。

假设药物是OTC 药物被NDA 或ANDA 掩盖，FDA 可以回忆，复制，验证在505(k)(2)章下的FDC。

然而，假设产品是在FDA 没注册过的OTC 药物。

并没有法定的严格要求在视察过程中给视察者看的的记录要按704 章FDC 的要求。

而且，全部的处方药和OTC 药的生产必需符合CGMP 的要求，包括那些记录。

视察者应当回忆这些记录作为打算是否符合CGMP 要求的一局部。

在很少的场合，可以拒绝回忆OTC 的记录由于并没有法定要求这样做。

当工厂在没有法定义务去供给回忆这些记录时，没有减轻需要符合在501(a)(2)(B)CGMP的要求，包括对主体文件的要求。

假设一个工厂拒绝回忆OTC 的记录，视察者应当被其他的视察方法打算特别符合CGMP 的要求。

视察者观看和查找对于处方药和非处方药并不依据FDA-483 确定的检查表中做的行为。

组织和人员工厂肯定要有QC 把握文件描述CFR 的责任和权威。

QC 文件肯定要在说明它的相对于生产文件的独立性，在书面说明它的责任权属。

说明操作者的官员的名字，头衔和内在的责任，其他的主要的职员在IOM 中列出。

美国药典微生物检测精要引言微生物检测在药品生产中起着至关重要的作用。

药品的微生物污染可能对患者的健康造成严重威胁。

为了确保药品的安全性、可靠性和有效性，美国药典（United States Pharmacopeia, USP）制定了一系列用于微生物检测的指南和标准。

本文将概述美国药典微生物检测的精要内容。

检测方法目视法目视法是最简单、最常用的微生物检测方法之一。

该方法通过对样品进行肉眼观察，检验人员可以检测到样品中是否存在明显的微生物污染。

目视法的优点是操作简单，不需要特殊的设备和试剂，适用于多种药品和原料的微生物检测。

然而，目视法存在主观性和局限性，无法检测到微生物的低水平污染。

营养物质法营养物质法是一种常用的培养基法。

该方法以适宜的培养基为基础，通过对样品进行培养，利用微生物的生长特性来检测样品中是否存在微生物污染。

营养物质法可以检测到微生物的低水平污染，并且可以进一步鉴定和计数微生物。

然而，营养物质法需要一定的培养时间，且存在一定的培养基选择性和适应性的局限性。

生物化学法生物化学法是一种通过检测微生物代谢产物来判断样品中是否存在微生物污染的方法。

该方法利用微生物的代谢反应，检测样品中的特定代谢产物的存在与否。

生物化学法可以快速、准确地检测微生物污染，并且不受培养基选择性和适应性的限制。

然而，生物化学法需要特定的试剂和设备，并且对检测人员的技术要求较高。

检测标准美国药典对药品的微生物检测制定了一系列的标准和要求。

这些标准主要包括微生物限度试验、总微生物数试验、鉴别试验和特定微生物试验等。

微生物限度试验微生物限度试验旨在确定样品中存在的微生物数量的限度。

该试验要求将样品接种在适当的培养基中，经过一定的培养时间后，观察并计数生长的微生物数量。

美国药典针对不同类型的药品和原料制定了不同的微生物限度指标，以确保药品的微生物安全性。

总微生物数试验总微生物数试验用于确定样品中所有可培养的微生物的数量。

该试验要求将样品接种在适当的培养基中，经过一定的培养时间后，观察并计数生长的微生物数量。

FDA微生物学手册6非灭菌产品的微生物检查第二章：非灭菌产品的微生物检查本节包含了对活性微生物的定量计数和成品药品和原料中缺少指定微生物的确定的补充信息，以前称为微生物限度检测（MLT）o这些测试的详细程序不在本PMM章节中说明，因为它们在以下USP中查阅：USPv60＞非无菌产品的微生物检验:洋葱伯克霍尔德氏菌检验；USPv 61＞非无菌产品微生物检验:微生物计数检验；USP＜62＞非无菌产品的微生物检验:对指定微生物的检验。

＜60＞是一种检测制剂或水系辅用制剂中是否存在洋葱伯克霍尔德氏菌的试验。

吸入使用产品或口服、口腔粘膜、皮肤或鼻腔的水溶液辅用制剂。

＜61〉描述了从药品中计数微生物的方法，包括膜过滤、常规平板计数（包括倾注平板法、表面铺开法）和最可能数法（MPN）o ＜62＞描述了特定的富集程序，取决于产品专论要求的必须缺少的目标指定微生物（不得检出的控制菌）。

不溶于水或不分散于水的产品必须经过适当处理，以获得适合于试验程序的悬浮液。

＜1111＞被推荐用于各种药物剂型微生物的鉴定，这对解决问题是有益的。

注意这一点很重要：即使USP根据各论的要求描述了特定微生物的回收和鉴定方法，通常需要确定产品中是否也存在其他有害微生物，并在工作表上报告这些微生物。

在许多情况下，这些可能是机会性的或新出现的病原体，而不是USP＜62＞针对性回收的目标。

鉴别方法，如VITEK,应用于鉴别在USP＜62＞实验中回收的微生物。

替代方法，先进的分子方法（即PCR,测序等）或使用附加的通用富集琼脂平板或无选择性的肉汤，可能更适合检测样品的筛选。

这些附加琼脂或方法的应用可能需要根据分析中药物或产品的目标人群来考虑, 并可能需要与实验室主管进行沟通以获得附加说明。

A.产品的储存和处理样品应在包装标签或说明书规定的存储条件下保存。

1.在产品测试前，单元容器的外部应进行消毒，然后转移到工作站或HEPA过滤层流罩。

如果产品容器不是密封的，不要将产品容器浸泡在消毒溶液中，这样可能会使杀菌溶液进入产品。

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 pharmaceutical 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 supplements 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 applications 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 comprehensive evaluation of the laboratory's compliance withCGMP's. 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 will be used to test a new product-- a complete assessment of laboratory's conformance with GMP's-- 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 part 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 withspecialized 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.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 be reviewed prior to the inspection; but if the application is not availablefrom any other source, this review will have to be conducted using thecompany's 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, and to establish goals for completion of the assignment. Responsibilities fordevelopment 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 to the approval of NDA/ANDA's and supplements. The inspection team is expected to review such letters on file at the district office, and they are expected to 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 there 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, the inspection of a laboratory requires the use of observations of thelaboratory in operation and of the raw laboratory data to evaluatecompliance with CGMP's and to specifically carry out the commitments in an application 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 thatallows a complete overview of the technical ability of the staff and ofoverall quality control procedures. SOPs should be complete and adequate and the operations of the laboratories should conform to the written procedures. Specifications and analytical procedures should be suitable and, asapplicable, in conformance with application commitments and compendialrequirements.Evaluate raw laboratory data, laboratory procedures and methods, laboratory equipment,including maintenance and calibration, and methods validation data to determine the overall quality of the laboratory operation and the ability to 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 analyses for lots of product that have failed to meet specifications and review the analysis of lots that have been retested,rejected, or reworked. Evaluate the decision to release lots of product when the laboratory results indicate that the lot failed to meet specifications and determine who released them.B. Pre-ApprovalDocuments relating to the formulation of the product, synthesis of the bulk drug substance, product specifications, analysis of the product, and others are examined during the review process in headquarters. However, thesereviews and evaluations depend on accurate and authentic data that trulyrepresents 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 inthe application were actually used to produce the data contained in theapplication. Additionally, they are designed to confirm 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 voluminoussubmissions and would often result in filing redundant information. Sponsors may deliberately or unintentionally select and report data showing that adrug is safe and effective and deserves to be approved. The inspection team must decide if there is valid and scientific justification for the failure to report data which demonstrates the product failed to meet itspredetermined specifications.Coordination between headquarters and the field is essential for a complete review of the application and the plant. Experienced investigators andanalysts may contact the review chemist (with appropriate supervisoryconcurrence) when questions concerning specifications and standards arise.Inspections should compare the results of analyses submitted with results of analysis of other batches that may have been produced. Evaluate the methods and note any exceptions to the procedures or equipment actually 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 theapplication.5. FAILURE (OUT-OF-SPECIFICATION) LABORATORY RESULTSEvaluate the company's system to investigate laboratory test failures. These investigations 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 the 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 limitations on the use of outlier testsand these are discussed in a later segment of this document., or overcome by retesting. The court ruled on the use of retesting which is covered in alater segment of this document. is not a product failure. OOS results fall into three categories:-- laboratory error-- non-process related or operator error-- process related or manufacturing process errorA. LABORATORY ERRORSLaboratory errors occur when analysts make mistakes in following the method of analysis, use incorrect standards, and/or simply miscalculate the data. Laboratory errors must be determined through a 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. The inquiry may vary with the object under investigation.B. LABORATORY INVESTIGATIONSThe exact cause of analyst error or mistake can be difficult to determinespecifically and it is unrealistic to expect that analyst error will always be determined and documented. Nevertheless, a laboratory investigationconsists of more than a retest. The inability to identify an error's cause with confidence affects retesting procedures, not the investigation inquiry required for the initial OOS result.The firm's analyst should follow a written procedure, checking off each step as it is completed during the analytical procedure. We expect laboratorytest data to be recorded directly in notebooks; use of scrap paper and loose paper must be avoided. These common sense measures enhance the accuracy and integrity 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 include the following steps and these inquiries must be conducted before there is a retest 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 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 placed 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 content uniformity test was OOS followed by a passing retest. The initial OOS result was claimed the result of analyst error based on a statistical evaluation of the data. The court ruled that the use of an outlier test is inappropriate in this case..4. It is never appropriate to utilize outlier tests for a statisticallybased test, i.e., content uniformity and dissolution.Determine if the firm 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 investigation is inconclusive (reason for the error is not 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 tablets from the same sample when aretest is considered 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 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.Specifically: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 material after additional testingD. INVESTIGATION DOCUMENTATIONAnalyst's mistakes, such as undetected calculation errors, should bespecified with particularity and supported by evidence. Investigations along with conclusions reached must be preserved with written documentation that enumerates each step of 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 problem's occurrence and recorded and written into a failure orinvestigation report.6. PRODUCT FAILURESAn OOS laboratory result can be overcome (invalidated) when laboratory error has been documented. However, non-process and process related errorsresulting from operators making mistakes, equipment (other than laboratory equipment) 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 above and evaluate the decision to release, retest, or rework products.7. RETESTINGEvaluate the company's 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. This district court ruling provides an excellent guide to use in evaluating some aspects of a pharmaceutical 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 rejected.Additionally, the company should consider all retest results in the context of 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 of an 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 results cannot be disregarded simply on the basis of acceptable content uniformity results.The number of retests performed before a firm concludes that an unexplained OOS result is invalid or that a product is unacceptable is a matter ofscientific judgment. The goal of retesting is to isolate OOS results butretesting cannot continue ad infinitum.In the case of nonprocess and process-related errors, retesting is suspect. Because the initial tests are genuine, in these circumstances, additionaltesting alone cannot contribute to product quality. The court acknowledged that some retesting may precede a finding of nonprocess or process-basederrors. Once this determination is made, however, additional retesting for purposes of testing a product into compliance is not acceptable.For example, in the case of content uniformity testing designed to detectvariability in the blend or tablets, failing and non-failing results are not inherently inconsistent and passing results on limited retesting do not rule out the possibility that the batch is not uniform. As part of theinvestigation firms should consider the record of previous batches, sincesimilar or related failures on different batches would be a cause ofconcern.Retesting following an OOS result is ruled appropriate only after thefailure investigation is underway and the failure investigation determines in part whether retesting is appropriate. It is appropriate when analysterror is documented or the review of analyst's work is "inconclusive" , but it is not appropriate for known and undisputed non-process or processrelated errors.The court ruled that retesting:o must be done on the same, not a different sampleo may be done on a second aliquot from the same portion of the sample that was the source of the first aliquoto may be done on a portion of the same larger sample previously collectedfor laboratory purposes8. RESAMPLINGFirms cannot rely on resampling. The court ordered the recall of one batch of product after having concluded that a successful resample result alonecannot invalidate an initial OOS result. to release a product that hasfailed testing and retesting unless the failure investigation disclosesevidence that the original sample is not representative or was improperlyprepared.Evaluate each resampling activity for compliance with this guidance.9. AVERAGING RESULTS OF ANALYSISAveraging can be a rational and valid approach when the object underconsideration is total product assay, but as a general rule this practiceshould be avoided. The court ruled that the firm must recall a batch thatwas released for content uniformity on the basis of averaged test results. because averages hide the variability among individual test results. Thisphenomenon is particularly troubling if testing generates both OOS andpassing individual results which when averaged are within specification.Here, relying on the average figure without examining and explaining theindividual OOS results is highly misleading and unacceptable.Content uniformity and dissolution results never should be averaged toobtain a passing value.In the case of microbiological turbidimetric and plate assays an average is preferred by the USP. In this case, it is good practice to include OOSresults in the average unless an outlier test (microbiological assays)suggests the OOS is an anomaly.10. BLEND SAMPLING AND TESTINGThe laboratory serves a vital function in blend testing which is necessary to increase the likelihood of detecting inferior batches. Blend uniformity testing cannot be waived in favor of total reliance on finished producttesting because finished product testing is limited.One court has ruled that sample size influences ultimate blend test results and that the sample size should resemble the dosage size. Any other practice would blur differences in portions of the blend and defeat the object of the test. If a sample larger than the unit must be taken initially, aliquotswhich resemble the dosage size should be carefully removed for the test,retests, and reserve samples. Obviously, the initial larger sample shouldnot be subjected to any additional mixing or manipulation prior to removing test aliquots as this may obscure non-homogeneity.Multiple individual blend uniformity samples taken from different areascannot be composited. However when variation testing is not the object ofassay testing, compositing is permitted.If firms sample product from sites other than the blender, they mustdemonstrate through validation that their sampling technique isrepresentative of all portions and concentrations of the blend. This means that the samples must be representative of those sites that might beproblems; e.g. weak or hot spots in the blend.11. MICROBIOLOGICALThe review of microbiological data on applicable dosage forms is bestperformed by the microbiologist (analyst). Data that should be reviewedinclude preservative effectiveness testing, bioburden data, and productspecific microbiological testing and methods.Review bioburden (before filtration and/or sterilization) from both anendotoxin and sterility perspective. For drug substance labs evaluatemethods validation and raw data for sterility, endotoxin testing,environmental monitoring, and filter and filtration validation. Also,evaluate the methods used to test and establish bioburdens.Refer to the Microbiological Inspection Guide for additional informationconcerning the inspection of microbiological laboratories.12. SAMPLINGSamples will be collected on pre-approval inspections. Follow the sampling guidelines in CP 7346.832, Part III, pages 5 and 6.13. LABORATORY RECORDS AND DOCUMENTATIONReview personal analytical notebooks kept by the analysts in the laboratory and compare them with the worksheets and general lab notebooks and records. Be prepared to examine all records and worksheets for accuracy andauthenticity and to verify that raw data are retained to support theconclusions found in laboratory results.Review laboratory logs for the sequence of analysis versus the sequence of manufacturing dates. Test dates should correspond to the dates when thesample should have been in the laboratory. If there is a computer data base, determine the protocols for making changes to the data. There should be an audit trail for changes to data.We expect raw laboratory data to be maintained in bound, (not loose or scrap sheets of paper), books or on analytical sheets for which there isaccountability, such as prenumbered sheets. For most of those manufacturers which had duplicate sets of records or "raw data", non-numbered loose sheets of paper were employed. Some companies use discs or tapes as raw data andfor the storage of data. Such systems have also been accepted provided they have been defined (with raw data identified) and validated.Carefully examine and evaluate laboratory logs, worksheets and other records containing the raw data such as weighings, dilutions, the condition ofinstruments, and calculations. Note whether raw data are missing, if records have been rewritten, or if correction fluid has been used to conceal errors. Results should not be changed without explanation. Cross reference the data that has been corrected to authenticate it. Products cannot be "tested into compliance" by arbitrarily labeling out-of-specification lab results as"laboratory errors" without an investigation resulting in scientificallyvalid criteria.Test results should not have been transcribed without retention of theoriginal records, nor should test results be recorded selectively. Forexample, investigations have uncovered the use of loose sheets of paper with subsequent selective transcriptions of good data to analyst worksheetsand/or workbooks. Absorbance values and calculations have even been found on desk calendars.Cut charts with injections missing, deletion of files in direct data entry systems, indirect data entry without verification, and changes tocomputerized programs to override program features should be carefullyexamined. These practices raise questions about the overall quality of data.The firm should have a written explanation when injections, particularlyfrom a series are missing from the official work-sheets or from files andare included among the raw data. Multiple injections recorded should be in consecutive files with consecutive injection times recorded. Expect to see written justification for the deletion of all files.Determine the adequacy of the firm's procedures to ensure that all validlaboratory data are considered by the firm in their determination ofacceptability of components, in-process, finished product, and retainedstability samples. Laboratory logs and documents when cross referenced may show that data has been discarded by company officials who decided torelease the product without a satisfactory explanation of the resultsshowing the product fails to meet the specifications. Evaluate thejustification for disregarding test results that show the product failed to meet specifications.14. LABORATORY STANDARD SOLUTIONSAscertain that suitable standards are being used (i.e. in-date, storedproperly). Check for the reuse of stock solutions without assuring theirstability. Stock solutions are frequently stored in the laboratoryrefrigerator. Examine the laboratory refrigerators for these solutions and when found check for appropriate identification. Review records of standard solution preparation to assure complete and accurate documentation. It ishighly unlikely that a firm can "accurately and consistently weigh" to the same microgram. Therefore data showing this level of standardization orpattern is suspect and should be carefully investigated.15. METHODS VALIDATIONInformation regarding the validation of methods should be carefullyevaluated for completeness, accuracy and reliability. In particular, if acompendial method exists, but the firm chooses to use an alternate methodinstead, they must compare the two and demonstrate that the in-house method is equivalent or superior to the official procedure. For compendial methods firms must demonstrate that the method works under the actual conditions of use.Methods can be validated in a number of ways. Methods appearing in the USP are considered validated and they are considered validated if part of anapproved ANDA. Also a company can conduct a validation study on theirmethod. System suitability data alone is insufficient for and does notconstitute method validation.In the review of method validation data, it is expected that data forrepetitive testing be consistent and that the varying concentrations of test solutions provide linear results. Many assay and impurity tests are nowHPLC, and it is expected that the precision of these assays be equal or less than the RSD's for system suitability testing. The analytical performanceparameters listed in the USP XXII, <1225>, under the heading of Validation of Compendial Methods, can be used as a guide for determining the analytical parameters (e.g., accuracy, precision, linearity, ruggedness, etc.) needed to validate the method.16. EQUIPMENTLaboratory equipment usage, maintenance, calibration logs, repair records, and maintenance SOPs also should be examined. The existence of the equipment specified in the analytical methods should be confirmed and its conditionnoted. Verify that the equipment was present and in good working order atthe time the batches were analyzed. Determine whether equipment is beingused properly.In addition, verify that the equipment in any application was in goodworking order when it was listed as used to produce clinical or biobatches. One would have to suspect the data that are generated from a piece ofequipment that is known to be defective. Therefore, continuing to use andrelease product on the basis of such equipment represents a seriousviolation of CGMP's.17. RAW MATERIAL TESTINGSome inspections include the coverage of the manufacturer of the drugsubstance. The safety and efficacy of the finished dosage form is largelydependent on the purity and quality of the bulk active drug substance.Examine the raw data reflecting the analysis of the drug substance including purity tests, charts, etc.Check the impurity profiles of the BPC used in the biobatch and clinicalproduction batches to determine if it is the same as that being used tomanufacture full scale production batches. Determine if the manufacturer has a program to audit the certificate of analysis of the BPC, and, if so, check the results of these tests. Report findings where there is substantialdifference in impurity profiles and other test results.Some older compendial methods may not be capable of detecting impurities as necessary to enable the control of the manufacturing process, and newermethods have been developed to test these products. Such methods must bevalidated to ensure that they are adequate for analytical purposes in thecontrol and validation of the BPC manufacturing process. The drug substance manufacturer must have complete knowledge of the manufacturing process and the potential impurities that may appear in the drug substance. Theseimpurities cannot be evaluated without a suitable method and one that hasbeen validated.Physical tests such as particle size for raw materials, adhesion tests for patches, and extrusion tests for syringes are essential tests to assureconsistent operation of the production and control system and to assurequality and efficacy. Some of these tests are filed in applications andothers may be established by the protocols used to manufacture the product. The validation of methods for such tests are as important as the test forchemical attributes.Physical properties tests often require the use of unique equipment andprotocols. These tests may not be reproducible in other laboratories,therefore, on site evaluation is essential.。

GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICAL QUALITY CONTROL LABORATORIES微生物实验室检查指南Note: This document is reference material for investigators and other FDA personnel.The document does not bind FDA, and does not confer any rights, privileges, benefits,or immunities for or on any person(s).I. INTRODUCTION 介绍The Guide to the Inspection of Pharmaceutical Quality Control Laboratories provided very limited guidance on the matter of inspection of microbiological laboratories. While that guide addresses many of the issues associated with the chemical aspect of laboratory analysis of pharmaceuticals, this document will serve as aguide to the inspection of the microbiology analytical process. As with any laboratory inspection, it is recommended that an analyst (microbiologist) who is familiar with the tests being inspected participate in these inspections.质检化验室的检查指南重点强调了有关化学分析方面的内容，对于微生物检查的内容涉及比较少，本文将作为化验室检查中对微生物检查方面的指南。

美国FDA药品质量控制微生物实验室检查指南1993年I．导言《药品质量控制实验室检查指南》主要涉及许多有关药品实验室分析的化学方面的问题，对微生物实验室的检查仅提供了有限的指导，而本指南则是微生物分析检查过程的指导。

本指南建议，如同对任何实验室检查—样，在检查微生物实验室时，应有—名熟悉检验的分析学家(微生物学家)参与。

II．非无菌药品的微生物检验由于种种原因，局部药品、滴鼻剂和吸入剂存在许多微生物污染方面的问题.美国药典‘‘微生物属性”章(1111)指出“应该从药品用法、药品性质及时患者的潜在危害等方面评价微生物在非无菌药品中的重要性”，除此之外，没有提供具体的指导。

美国药典还建议应对某些种类的非无菌药品做常规的总菌数检验及某些特定的污染指示微生物的检验：例如：植物、动物和某些矿物质中的沙门氏菌属；口服液体中的大肠杆菌；局部用药品小的金黄色倘萄球菌和绿脓杆菌污染；以及：自肠、尿道、阴道用药中的酵母菌和霉菌：大量的专题文章还沦及厂微生物的限度。

作为非无菌药品受微生物污染的可接受程度和类型的—般性指导，美国食品和药品管理局药品分局的邓尼根博士曾强调其对健康的危害问题。

1970年他提出被革兰氏阴性细菌污染的局部制剂可能引起中度至重度的健康危害：文献和调查表明，许多感染都源于这种局部药品的革兰氏阴性细菌污染。

几年前马萨诸塞州的—家医院就报道过—宗络合碘(Povidonelodine)被洋葱假恤孢菌(Pseudomonas cepacia)污染的典型病例。

因此，每家公司都希望为自己的非无菌药品制订出一种关于微生物限度的标准，美国药典中“微生物限度”(USP61)提供了检验几种指示微生物的方法，但并末涉及所有有害微生物。

例如医药界普遍认为，洋葱假中孢菌在局部药品或滴鼻剂斗，大量存在是有害的，但美国药典没有提供证明这种微生物存在的检验方法。

间羟异丙肾上腺素硫酸盐吸入剂溶液的收回就是这方面的—个例子。

美国药典第XⅫ版各论部分没有要求对这种药品进行微生物检验。

美国FDA药品质量控制微生物实验室检查指南
钱维清;潘有友
【期刊名称】《中国药品标准》
【年(卷),期】2001(002)002
【摘要】@@ 译者按:rn值此2000年版药典出版发行、执行之际,为了更好地理解药典中无菌和微生物限度检查法的增、修订内容;了解药品微生物质量控制在制药行业及质量检验中的重要性;以及今后发展的方向,特将美国FDA<药品质量控制微生物实验室检查指南>一文翻译推荐给大家.通过该文,可以了解和借鉴FDA的一些先进的观点.如:对化学、生化药品是否需要进行微生物限度检查?如何评价微生物污染在非无菌药品中的重要性.制订非无菌药品微生物限度的原则.无菌和微生物限度检查的培养时间、初试阳性结果后,是否复试及如何复试的规定.微生物实验中建立阳性、阴性对照的重要性.参加检查或验收微生物实验室时应重视和注意的问题等.
【总页数】4页(P60-62,64)
【作者】钱维清;潘有友
【作者单位】上海市药品检验所,上海,200233;无锡华瑞制药有限公司,无
锡,214000
【正文语种】中文
【中图分类】R9
【相关文献】
1.对美国FDA《植物药品企业指南》(草案)几点剖视 [J], 祝国光
2.美国FDA公布药品安全信息沟通指南 [J], 郑晓红（摘）
3.美国FDA关于《由生物工程操作的植物来源的人与动物用药品、生物制品和医疗器械工业生产指南(草案)》(讨论稿)介绍 [J], 张雪梅
4.美国FDA公布了最新版《医疗器械、药品以及其他产品分类指南》 [J],
5.美国FDA发布3个药品风险管理指南 [J],
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原料药生产检查（药物质量保证）目录现场检查汇报规定 (55)第I部分背景 (56)第II部分实行 (57)第III部分检查 (58)第IV部分分析 (63)第V部分法规/行政方略 (65)第VI部分参照资料，附件和联络接触方式 (68)第VII部分中心旳职责 (69)附件A (69)附件B (72)现场检查汇报规定工艺专论汇报在API检查时，要使用下列旳分类进行汇报所检查旳工艺状况1．Non Sterile API by Chemical Synthesis CSN化学合成非无菌原料CSN2．Sterile API by Chemical Synthesis CSS化学合成无菌原料药CSS3．Non Sterile API by Fermentation CFN发酵生产旳非无菌原料CFN4．Sterile API by Fermentation CFS发酵生产旳无菌原料CFS5．Plant/Animal Extraction API CEX植物/动物提取原料药CEX6．Biotechnology API CBI生物技术生产旳原料药CBI第I部分――背景至八十年代后期以来，美国食品与药物管理局以强化了其对原料药(API)生产企业旳检查内容。

从部分方面来说，这归咎于对原料药质量在制剂旳质量、效力、和安全面所起旳重要作用认识旳提高。

例如，在配制成固体口服制剂，混悬剂和局部用药时原料药旳化学特性会对制剂旳溶出度/生物运用度产生不利影响。

此外，原料中旳少许没有鉴别出旳杂质或其特性未知旳杂质会给病人导致旳严重不良反应。

FDA长期以来一直认为，收载在制剂药物生产质量管理规范规定(21 CFR 210 and 211)中旳CGMP概念对原料药生产工艺同样有效。

这些概念包括，与其他一起，产品质量是生产出来旳，雇佣可以胜任和通过培训旳员工，建立合适旳书面程序和管理规定，建立一套在线测试和产品测试系统，工艺验证，和保证原料药在预期旳有效期内质量稳定。