1.FDA 483s in the LabFDA 483s in the LabCurrent IssuesCurrent IssuesCopyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013

2. FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues483 Observation Ratesfor ALL SystemsRecent FDA Documents: 216 inspections: 2,221 observationsCopyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 3. FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory IssuesLABORATORY System483 Observation Rates: 216 inspections; 477 observationsCopyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 4. FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues71 ObservationsContract LaboratoriesContract LaboratoriesLaboratory53%Material6%Other4%Production1%Quality21%Packaging/Label.1%Facilities/Equip.14%Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 5. FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory Issues%Citations by System26 warning letters over a three year periodCopyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 6. FDA 483s - Quality and Laboratory IssuesFDA 483s - Quality and Laboratory IssuesWarning Letter Summary 26 Warning Letters issued Quality or Production or Laboratorycited in every letter, 26 of 26 Quality cited in 20 of 26 Production cited in 18 of 26 Laboratory cited in 17 of 26 Quality & Production & Laboratory cited in10 of 26Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 7. FDA 483s and Warning LettersFDA 483s and Warning LettersWarning Letter A (Drug Product Manufacturer)Warning Letter A (Drug Product Manufacturer)Failure to conductFailure to conduct performance qualificationperformance qualification on the laboratory instruments (HPLCon the laboratory instruments (HPLCand GC) that are used to analyze raw materials and finished products.and GC) that are used to analyze raw materials and finished products.Failure toFailure to validatevalidate software programs used to run HPLC equipment. Software usedsoftware programs used to run HPLC equipment. Software useddoesnt secure data from alterations, loss, or erasures and allow for overwriting ofdoesnt secure data from alterations, loss, or erasures and allow for overwriting oforiginal data.original data.Warning Letter B (Drug Product Manufacturer)Warning Letter B (Drug Product Manufacturer)Failure toFailure to calibrate HPLCcalibrate HPLC used for testing in-process lots.used for testing in-process lots.Performance qualifications didnt include critical chromatographic specificationsPerformance qualifications didnt include critical chromatographic specificationsNo SOP requiringNo SOP requiring calibrationcalibration of laboratory equipment.of laboratory equipment.Warning Letter C (Drug Product Manufacturer)Warning Letter C (Drug Product Manufacturer)Failure to establish SOPs orFailure to establish SOPs or document the performance qualificationsdocument the performance qualifications andandmaintenance of analytical equipment used in the testing and release of drugmaintenance of analytical equipment used in the testing and release of drugproduct.product.Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 8. FDA 483s and Warning LettersFDA 483s and Warning LettersWarning Letter D (Drug Product Manufacturer)Warning Letter D (Drug Product Manufacturer)Failure toFailure to validatevalidate the Dissolution Test Method used to test the drug product.the Dissolution Test Method used to test the drug product.There is no assurance thatThere is no assurance that qualification or maintenance of laboratory equipmentqualification or maintenance of laboratory equipmentcan consistently produce valid and accurate analytical results because ofcan consistently produce valid and accurate analytical results because ofnumerous instrument malfunction.numerous instrument malfunction.Warning Letter E (Contract laboratory)Warning Letter E (Contract laboratory)No established procedure for theNo established procedure for the qualification of analytical instrumentsqualification of analytical instruments for drugfor drugtesting, when purchased and installed in this laboratory.testing, when purchased and installed in this laboratory.483 Observations A (Drug Product Manufacturer)483 Observations A (Drug Product Manufacturer)Several major laboratory instruments (HPLC, AA/AE/GC, etc,..)Several major laboratory instruments (HPLC, AA/AE/GC, etc,..) have not beenhave not beenqualified (installational, operational and performance qualificationqualified (installational, operational and performance qualification).).System suitability tests are not performedSystem suitability tests are not performed for several methods.for several methods.Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 9. FDA 483s and Warning LettersFDA 483s and Warning Letters483 Observations B (Contract Test Laboratory)483 Observations B (Contract Test Laboratory)RoutineRoutine calibrationcalibration, inspection, and checking of equipment is not performed, inspection, and checking of equipment is not performedaccording to a written program designed to assure proper performance.according to a written program designed to assure proper performance.Major laboratory equipment have not beenMajor laboratory equipment have not been qualified (installation, operational andqualified (installation, operational andperformance qualificationperformance qualification).).483 Observations C (Contract Test Laboratory)483 Observations C (Contract Test Laboratory)No performance qualificationNo performance qualification conducted on several instruments (HPLC, UV/VISconducted on several instruments (HPLC, UV/VISand AA Spectrometer).and AA Spectrometer).GMP vs non-GMP laboratory studies.GMP vs non-GMP laboratory studies.483 Observations A (Drug Product Manufacturer)483 Observations A (Drug Product Manufacturer)For HPLC instrumentation used for drug product testing, there was noFor HPLC instrumentation used for drug product testing, there was nodocumentation available which was approved by appropriate personnel showingdocumentation available which was approved by appropriate personnel showingthat HPLC was fully qualified. This includes lack ofthat HPLC was fully qualified. This includes lack of written and approvedwritten and approvedinstallation and operational qualification documentationsinstallation and operational qualification documentations..Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 10. FDAs ExpectationsFDAs ExpectationsICH-Q2A Guideline for Industry Text on Validation ofICH-Q2A Guideline for Industry Text on Validation ofAnalytical ProceduresAnalytical ProceduresICH-Q2B Guideline for Industry Validation ofICH-Q2B Guideline for Industry Validation ofAnalytical Procedures: MethodologyAnalytical Procedures: MethodologyFDA Guidance for Industry Analytical Procedures andFDA Guidance for Industry Analytical Procedures andMethods Validation Chemistry, Manufacturing andMethods Validation Chemistry, Manufacturing andControls DocumentationControls DocumentationReviewer Guidance Validation of ChromatographicReviewer Guidance Validation of ChromatographicMethods Nov.94Methods Nov.94U.S. Pharmacopeia/National Formulary (Chapters U.S. Pharmacopeia/National Formulary (Chapters and )and )Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 11. FDAs ExpectationsFDAs ExpectationsEach NDA and ANDA must include the analytical procedures necessary toEach NDA and ANDA must include the analytical procedures necessary toensure the identity, strength, quality, purity, and potency of the drugensure the identity, strength, quality, purity, and potency of the drugsubstance and drug product, including bioavailability of the drug product (21substance and drug product, including bioavailability of the drug product (21CFR 314.50(d)(1) and 314.94(a)(9)(i)).CFR 314.50(d)(1) and 314.94(a)(9)(i)). Data must be available to establish thatData must be available to establish thatthe analytical procedures used in testing meet proper standards of accuracythe analytical procedures used in testing meet proper standards of accuracyand reliability (21 CFR 211.165(e) and 211.194(a)(2)).and reliability (21 CFR 211.165(e) and 211.194(a)(2)).All analytical procedures are of equal importance from a validationAll analytical procedures are of equal importance from a validationperspective. In general,perspective. In general, validated analytical procedures should be usedvalidated analytical procedures should be used,,irrespective of whether they are for in-process, release, acceptance, orirrespective of whether they are for in-process, release, acceptance, orstability testing. Each quantitative analytical procedure should be designedstability testing. Each quantitative analytical procedure should be designedto minimize assay variation.to minimize assay variation.ValidationValidation should not be a one-timeshould not be a one-time situation to fulfill agency filingsituation to fulfill agency filingrequirement.requirement.Applicants should submit information on the validation characteristics ofApplicants should submit information on the validation characteristics oftheir proposed analytical procedures (see ICHtheir proposed analytical procedures (see ICH Q2AQ2A and ICHand ICH Q2BQ2B). Although). Althoughnot all of the validation characteristics are needed for all types of tests (seenot all of the validation characteristics are needed for all types of tests (seesection VII.A.3),section VII.A.3), typical validation characteristics are: Accuracy, Precisiontypical validation characteristics are: Accuracy, Precision(repeatability and intermediate precision), Specificity, Detection limit,(repeatability and intermediate precision), Specificity, Detection limit,Quantitation limit, Linearity, Range, and RobustnessQuantitation limit, Linearity, Range, and RobustnessCopyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 12. FDAs ExpectationsFDAs ExpectationsAll chromatographic analytical proceduresAll chromatographic analytical procedures should include system suitabilityshould include system suitabilitytestingtesting and criteria. Parameters typically used in system suitabilityand criteria. Parameters typically used in system suitabilityevaluations are defined and discussed in the CDER Reviewer Guidance onevaluations are defined and discussed in the CDER Reviewer Guidance onValidation of Chromatographic MethodsValidation of Chromatographic Methods (November 1994).(November 1994).A listing of all equipment (e.g., instrument type, detector, column type,A listing of all equipment (e.g., instrument type, detector, column type,dimensions) should be included, as well as a list of equipment parametersdimensions) should be included, as well as a list of equipment parameters(e.g., flow rate, temperatures, run time, wavelength settings).(e.g., flow rate, temperatures, run time, wavelength settings).VALIDATION OF COMPENDIAL METHODSVALIDATION OF COMPENDIAL METHODS Compendial procedures vary from highly exacting analyticalCompendial procedures vary from highly exacting analyticaldeterminations to subjective evaluation of attributesdeterminations to subjective evaluation of attributes Performance characteristics meet the requirements for the intendedPerformance characteristics meet the requirements for the intendedanalytical applicationsanalytical applications Equipment, electronics, analytical operations, and samples to beEquipment, electronics, analytical operations, and samples to beanalyzed constitute an integral system that can be evaluated as suchanalyzed constitute an integral system that can be evaluated as suchSystem suitability tests verify that the resolution and reproducibility of theSystem suitability tests verify that the resolution and reproducibility of thechromatographic system are adequate for the analysis to be done.chromatographic system are adequate for the analysis to be done.Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 13. ConclusionsConclusionsDo your homework prior to method development and instrumentsDo your homework prior to method development and instrumentspurchase:purchase: Method validation and instrument qualification shouldMethod validation and instrument qualification shouldfocus on suitability for intended usefocus on suitability for intended useInstallation Qualification should clearly identify calibration,Installation Qualification should clearly identify calibration,maintenance, SOP and training needsmaintenance, SOP and training needsOperational Qualification should ensure proper function of allOperational Qualification should ensure proper function of allsystem componentssystem componentsPerformance Qualification should ensure suitability of entirePerformance Qualification should ensure suitability of entireHPLC systemHPLC systemDevelop and validate methods using appropriate system suitabilityDevelop and validate methods using appropriate system suitabilityteststestsSST failures? Go back to PQ (holistic), if necessary OQ (modular)toSST failures? Go back to PQ (holistic), if necessary OQ (modular)toidentify problems, initiate repairs, etc.identify problems, initiate repairs, etc.Copyrighted Compliance Insight, Inc.Copyrighted Compliance Insight, Inc.20132013 14. www.Compliance-Insight.comwww.Compliance-Insight.comCall us at 513-860-3512Call us at 513-860-3512Email us atEmail us atFDAWarningLetterTeam@Compliance-Insight.comFDAWarningLetterTeam@Compliance-Insight.comFDA483Team@Compliance-Insight.comFDA483Team@Compliance-Insight.comFDATrainingTeam@Compliance-Insight.comFDATrainingTeam@Compliance-Insight.comQuestions?Questions?Comments?Comments?We are happy toWe are happy tohelp you!help you!