Handling deviations & unexpected results during method validation


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This presentation from the Institute of Validation Technology's 7th Annual Method Validation covers regulatory expectations for deviations and out-of-specification results and protocol exceptions, change control, handing investigations and CAPAs, and avoiding common pitfalls.

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Handling deviations & unexpected results during method validation

  1. 1. Handling Deviations & Unexpected Results during Method Validation IVT – 7th Annual Method Validation at San Francisco July 29th 2010 Upen Shah, B.S, MBA Sr. Director, Quality Management Amneal Pharmaceuticals 1Handling Deviations & Unexpected Results during Method ValidationElements of Method Validation documents & deviationsRegulatory expectationsGuidance documents of regulatory agenciesProtocol & report evaluationsFDA proposal for validation in cGMPHandling OOS results and protocol exceptionsReview of protocols & compilation of dataReview reports - internal auditsReport findings and observationsDocumenting OOS and protocol exceptionsPreparing for and documenting Change ControlInvestigations & recordsFactors contributing deviations followed by investigationsNotes from industryHandling investigations & CAPA’sMethod transfer failuresPost validation failures & QC lifeAvoiding common pitfalls 2 1
  2. 2. Validation Deviations & OOS What are analytical method validation & deviations? How are validations performed? Protocols & Reports? Identification & Evaluations of deviations? MV the Proof of Method? 3 Guidance Documents for IndustryICH Q2A Text on Validation of Analytical Procedures – March 1995 Q2B Validation of Analytical Procedures: Methodology – Nov 1996USP Chapter <1225> Validation of Compendial Methods 4 2
  3. 3. 21 CFR PART 211 –CGMP for Finished Pharmaceuticals Subpart J-Records and Reports 211.194 Laboratory records (a) (2) method used in the testing meet proper standards of Accuracy and Reliability Current revision of the USP/NF AOAC or in other recognized Standard Ref. An approved New Drug Application and Suitability of methods under actual conditions 5 Subpart I--Laboratory Controls 211.165 Testing and release for distribution Accuracy, Sensitivity, Specificity, and Reproducibility to be established and documented. Such validation and documentation accomplished in accordance with 211.194(a)(2) 6 3
  4. 4. FDA Proposed New subpart L to 211,entitled “Validation” Subpart L-Validation 211.222 Methods validation The accuracy, sensitivity, specificity, and reproducibility of test methods used by a manufacturer shall be validated and documented. Such validation and documentation shall be accomplished in accordance with Sec. 211.194(a)(2). 7 21 CFR PART 210 - CGMP 210.3 Definitions (b) (25) Methods validation means establishing, thorough documented evidence, a high degree of assurance that an analytical method will consistently yield results that accurately reflect the quality characteristics of the product tested. 8 4
  5. 5. Guideline for Method Validation 1978 Current Good Manufacturing Practices (cGMPs) 1987 FDA Validation Guideline 1989 Supplement 9 to USP XXI 1994 FDA Reviewer Guidance 1995 ICH Validation Definitions 1997 ICH Validation Methodology 1999 Supplement 10 to USP 23 2000 FDA Draft Validation Guidance 9 Objective of Method Validations?To demonstrate suitability for its intended useTo design the experimental workfor evaluation of appropriate validationcharacteristics simultaneouslyTo provide a sound, overall knowledge of thecapabilities of the analytical procedure for: Specificity, Linearity, Range, Accuracy, and Precision 10 5
  6. 6. Protocol Details andEvaluation for Deviations & OOSValidation protocol – A written plan – how, parameters & characteristics, testing equipment & instruments, and decision points for acceptable test resultsDeviations from a written protocol should beidentified & evaluated thoroughly uponreviewing the data obtained during thetesting 11In a case “OOS” results obtained meaning NOT meeting acceptance criteriaThe protocol exceptions – To deal deviations & OOS results prior to final method validation report 12 6
  7. 7. Performance of ValidationAnalytical method validation performance should be meticulous could be tedious cost of not doing it right the first time? Waste of time, money, and resourcesThe characteristics of the validations should be well understood 13 Why Validate a Method?Fulfill FDA &/Or Other RegulatoryRequirementsEstablish Proof of Method Used for Decision MakingCritical Requirement in Risk Assessmentand Management: establishment of product-specific acceptance criteria & stability of APIs and FPs 14 7
  8. 8. Validation criteria Analytical Method Validation Specificity, Linearity, Precision, Accuracy/Recovery, Ruggedness What are the acceptance criteria of each parameter? 15 Verification vs. ValidationCompendial vs. Non-compendial Methods Compendial methods-Verification Non-compendial methods-ValidationCompendial Method Verification –USP Chapter <1226> 16 8
  9. 9. Which tests to Validate ?Testing IDAssay / Quantitation / Purity/Dissolution / Content Uniformity Could be HPLC, UV, GC etc.Biological activityTesting product Stability 17 Which Methods to Validate? In-Process testing methods Product Release methods Stability indicating methods Analytical methods for Cleaning Validation / Verifications 18 9
  10. 10. Contributing Factors of DeviationsMan ( Human factor )Method ( Procedures )Machine ( Lab Equip./ Instruments )Material ( Chemicals & Reagents ) 19FDA Validation Parameters 1987 FDA Guidelines Accuracy Precision Linearity & Range Specificity & LOD / LOQ Recovery Ruggedness 20 10
  11. 11. ICH/USP Validation ParametersICH USP Specificity Specificity Linearity Linearity and Range Range Accuracy Accuracy Precision Precision Limit of Detection Repeatability Limit of Quantitation Intermediate Ruggedness Precision Robustness Reproducibility Limit of Detection Limit of Quantitation 21 Analytical MV Overview GMP Consideration Validation SOP / Protocols Training Specifications / Acceptance criteria Sample preparation Ref. Standards Instrument Qualification and Calibrations & Maintenance Validation Reports 22 11
  12. 12. SOAR - GAS PRICES!! 23 Validation SOP & ProtocolsProcedure that describes: methods requiring validation? responsibility for performing validation? How much? How documented?Protocol: Needed in absence of a detailed SOP A specific procedure for a type of method under validation Plans, “Specifications” = acceptance criteria Data compilation & Final Report 24 12
  13. 13. Data Review & DeviationsCompilation and data Review Regulatory and Compliance Requirements ReviewExperimental data compiled, reviewed & a final Report is preparedDeviations, OOS & Exceptions Must be noted & investigated Any Deviations / Failures need to be identified 25 Extensive Investigation ?Rigorous OOS procedures – When applicable?How Deviations issued?Investigations? Reported?& True error? E.g : One data point of the standard curve of a linearity test is inconsistent with the other points (i.e., OOS because it fails acceptance criteria) E.g: Dilution by analyst. This should not be ignored to ensure someone doesnt use inappropriate procedures -- such as testing into compliance. 26 13
  14. 14. Root cause may be revealed e.g trends, such as a high error rate associated with particular analyst or a recurring instrument problemCAPA considered - Analyst training orInstrument maintenance & calibration 27 Case of Extensive Investigation NOT requiredExample Coeluted peaks – during specificity experiment ( e.g forced degradation, placebo/ matrix evaluation, analysis of known degradants/impurities ) The separation modified and the validation restarted No extensive Investigation required 28 14
  15. 15. Barr decision - QC release of drug substanceand products & testing of in-process samples Only validated release testing considered Applicability to unvalidated methods? US v. Barr did not deal with method development/validation? Validation protocol criteria? Based on experience gained in developing a new analytical method Analysts best guess at what to expect following a limited amount of experience with a new method 29 When the results obtained do not comply: investigation needs to be performed to determine whether method development done was sufficient? OR whether the criterion was simply too tight? 30 15
  16. 16. Deviation & OOS Handling NotesMethod validation - a recursive process Non-complying results means various possibilities: method improvement OR Criterion to be changed with proper justification Based on these, changes may be made through Change Control procedure, when required 31No system allows a company to openly deal withvalidation failuresNotes to be made: ICH Q8–10 guidelines and the US FDA (OOS) guidance document provide regulatory flexibility Current industry practice is that risks be managed - to the extent of validation studies executed but not so much by actually using risk-based acceptance criteria 32 16
  17. 17. Common Pitfalls:Calibration failure In which Performing Tests on System Components to Ensure Proper Functioning If the instrument is not calibrated, tests are invalidSystem Suitability failure S.S Tests to verify the proper functioning of the operating system If the system is not suitable, the tests are invalidUntrained analyst & or reviewerData obtained are not to be considered 33FDA – OOS Guidance document Very systematic approach for OOS investigation Identifying & assessing the deviation/OOS result, Investigating - Lab phase Retesting, Resampling and full scale investigation Averaging, Outlier test Conclusion & CAPA 34 17
  18. 18. Method Transfer FailuresValidated method when need to be transferred toQC routine lab or other site Concept of “abbreviated” or “limited” validation Identify the failures To verify the validation and transfer protocols Very systematic approach for investigation Treat failures as an OOS or OOT Explainable / logical OOS Unexplainable / illogical OOS 35 Post Validation Failures & QC Life QC daily routine worker - mostly not exposed to Validation QC method training an overview of the basis of the method the critical steps and materials the behavior of the method as reviewed in the method validation report – for their usefulness in QC 36 18
  19. 19. FDA references to use of the method validation along with historical trending data by QC to ensure that the test method is behaving as intended Why are these important? What are the implications? 37Method trending files to be reviewed on a routine basis by the Quality group with reference to the validation parameters the capability of the method to monitor? Method still behaving as intended when the specifications were set? has there been a drift? to what could this be attributed? and how can it be addressed? 38 19
  20. 20. FDA Form 483 Observations, Warning Letters & EIR’s483 Observations There was no adequate method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from its impurities and degradation products. Specificity studies did not include the minimum stress conditions of acid and base hydrolysis, oxidation, thermal degradation and photolysis, degradation schematic for the active ingredient that identifies the major degradation products was not included for each product. 39Stress studies conducted as part of methodvalidation do not target a minimum amountof degradation. … a standard period of twohours as commonly used for stress studieswith no justification…Spreadsheets used to calculate linearity,percent recovery, and final assay results forthe cleaning validation of …were notvalidated and the data transcribed fromchromatographs to the spreadsheets werenot checked for accuracy. 40 20
  21. 21. Warning letters & EIR’sA statement indicating that the method has notbeen validated in the particular formulation wasincluded in the certificate of analysis for…use ofthis statement does not absolve…from using valid,accurate and reproducible methods.There is no assurance that qualification ormaintenance of the laboratory equipment canconsistently produce valid and accurate analyticalresults in that numerous examples of test data wereinvalidated due to instrument malfunction. 41Change control procedures in the laboratoryfailed to document test method changes toassure accurate, reliable, and reproducibleresults. The test method did not statewhether a helix was to be used duringdissolution testing. A … was reportedly usedduring method development, validation anddaily method runs, but there is nodocumentation of a … being used in any ofthe documents. 42 21
  22. 22. Attempts to corroborate data in the validationreport with supporting raw data in the laboratorywere difficult and frustrating for the FDApersonnel conducting the inspection.OOS accuracy results reported by analyst 3 werenever submitted in the final report. Repeat analysisperformed in a different system passedspecifications and these results were submitted inthe report.Raw data and calculations were not checked by asecond responsible individuals required by yourprocedures. Inaccurate calculations were noted inthe report. 43The process validation samples wereassayed using an HPLC method that hadnot been validated. The method validationused for both products … did not include aprotocol that included specification andacceptance criteria. … The methodvalidation was not reviewed and approveduntil during the current inspection. Lots ofboth products were released for distributionprior to completion of the methodvalidation. 44 22
  23. 23. Compendial methods not verified, no systemsuitability testing performed .Insufficient documentation of methodvalidation, inadequate documentation oflaboratory equipment calibration,Method validation documentation did notinclude appropriate data to verify that theanalytical method produced accurate andreliable dataLaboratory equipment calibration was notadequately documented. 45Failure to validate changed USP standardmethods, missing validation for stabilityindicating methods, insufficientdocumentation of test methods, insufficientdocumentation of changes, no follow-up ofOOS situations, failure to release productsthat do not meet USP requirements,incomplete batch records 46 23
  24. 24. Inadequate validation of the analyticalmethod for detecting residual solvents inxxxx in that an unknown xxxx wasdetermined above the limitAccuracy of the test for xxxx was determinedat a higher concentration than the limitLinearity and limits of detection weredetermined above the limit of the test 47Extraneous HPLC peaks continuouslyexplained to be autoinjector contamination,no further investigationMissing acceptance criteria for validationtestingFailure to effectively train employees inlaboratory operations to assure that originalrecords are accurate, complete and incompliance with established specifications. 48 24
  25. 25. FDA Systems Based Inspection: Laboratory System - 477 Observations in a typical year Controls & General – 35% Inadequate Records – 27% Stability Program – 21% Method Validation – 13% &Training & Qualification – 4 Source – FDA, CDER Office of Compliance 49Most Common GMP Deficiencies by System Domestic Inspections by FDA Quality -47% Laboratory -19% Production – 11% Facility & Equipment – 8% Materials – 6% Packaging & Labeling – 0% 50 25
  26. 26. Important Check Points: Check whether any failures occurred in the past for similar methods? Review all the developmental work notebooks, data for such occurrences – Interview the Devp. Chemist/ Analysts Review the protocols again – to find out the justifications for acceptance criteria. Verify all the critical characteristics for OOS & deviations. Where do we stand with Regulatory agency for OOS dealing? 51 References• ‘Analytical Methods Validation for FDA Compliance’ Guideline for submitting samples and analytical data for methods validation (Feb. 1987)• ICH Q2A• ICH Q2B• 21 Code of Federal Registrations Part 210 and 211• USP – Current <1225>• FDA 483’s & Warning Letters 52 26
  27. 27. QUESTIONS????THANK YOU upen@amneal.com Branchburg Facility 131 Chambersbrook Road Branchburg, NJ 08876 908.231.1911 www.amneal.com 53 27