Integrated Method Development and Validation

Integrated Method Development and Validation Dr. Ludwig Huber [email protected]

RACI Conference - Chemical Analyses

Copyright Ludwig Huber - LabCompliance

Slide *Todays AgendaLifecycle management of analytical procedures: development, validation and routine useUsing principles of Quality by Design to get most robust methodsDefining validation parameters, acceptance criteria and test procedures Templates and examples for efficient and consistent documentationsFDA 2014FDA 2013NATA 2013


Slide *FDA Guide Bioanalytical Method ValidationMajor differences to the 2001 GuideSection on System Suitability testingInclusion of incurred sample reanalysisLevel of details on LBA similar to chromatographic methodsConcentrations below the LLOQ should be reported as zerosSample Analysis Reporting should include: All accepted and rejected analytical runs


Slide *FDA Guide Analytical Method ValidationComponents of Quality by Design (QbD)Begin with an initial risk assessment and follow with multivariate experiments (design of experiments).Lifetime managementRequires submission of method development dataYou should submit development data within the method validation section if they support the validation of the method.


Official Guidelines for Method ValidationICH - Guidance for Industry - Q2 (R1) Text and Methodology Must be followed in US and EuropeFDA: Analytical Procedures and Methods Validation for Drugs and Biologics (Draft, Feb 2014)FDA - Industry Guidance Bioanalytical Method Validation (Draft, Nov 2013)USP : Validation of Compendial MethodsUSP : Verification of Compendial ProceduresUSP : Transfer of Analytical ProceduresICH = International Conference for HarmonizationUSP = United States PharmacopeiaSlide *QbD components


Slide *Method ValidationThe accuracy, sensitivity, specificity, and reproducibility of test methods have not been established and documented (W-187)Failure to validate analytical test methods used for API for potency testing. (W-259)For example, your firm failed to validate the xxx compound to quantify Peak A for potency and robustness. Your firm has been unable to determine why the chromatographic columns of the same make and model had variability and could not provide adequate separation (W-259)www.fdawarningletter.comSlide *


Slide *Method Validation Parameters for different Method Tasks (ICH Q2)

Analytical TaskIdentifi- cationImpurityQuantitativeImpurity QualitativeAssayAccuracyNoyesNoYesPrecisionRepeatabilityIntermediateReproducibilityNoNoNoYesYesYesNoNoNoYes YesYesSpecificityYesYesYesYesLimit of detectionNoNoYesNoLimit of quantitationNoYesNoNoLinearityNoYesNoYesRangeNoYesNoYes

RobustnessExpected to be done during Method Development


Slide *Parameters and Tests (ICH Q2)

ParameterTests (examples)AccuracyMinimum at 3 concentrations, 3 replicatesPrecisionRepeatabilityIntermediateReproducibilityMinimum of 9 determinations over the specified rangeOver 3 days, 2 operators, 2 instruments, Only required if testing is done in different laboratoriesSpecificityProve with specific methods: HPLC, DAD, MS, dif. columnsLimit of detectionVisual approach, S/N >= 3Limit of QuantitationS/N >= 10, Standard deviation of responseLinearityMin 5 concentrations: visual, correlation coefficient (r) Range80 to 120% of test concentration, from linearity tests


Slide *Why Should we Change the Traditional WayProblems in routine use, too many failuresDevelopers not end-usersLow emphasis on method robustness and ruggednessPoor knowledge on critical parameters problems during method transferNo or inadequate use of risk assessmentInvested time not very efficient


Slide *Possible Conflict of Interests

Development chemistShortest time possibleRoutine User / QC Director No problem during routine useNo out-of-specification situationsQuality AssuranceEnough documentation for inspections Regulatory AffairsEnough documentation for registrationFinanceLowest development and validation cost


Slide *Objectives of the New Approach

Efforts for method development and validation should be value adding: building knowledgeMethod will work consistently within its design spaceChanging peopleChanging material (e.g., chromatographic column)Environment (transfer)Focus on critical parameters using a risk based approachCompliance is still important !!!


Slide *What we really want

Design a method and validation procedures to ensure that the method works for the intended routine use, independently fromWhere it is being usedWho is using itSpecified instrumentationActual method parameters, as long as they are in the defined operating range

Trouble free operation transfer With no method specific OOS results


QbD - Background and regulatory SituationPrinciples widely applied in all industries, particularly in car industry Adopted by FDA in the 21st Century cGMP initiative Reference: Pharmaceutical Quality for the 21st Century: A Risk-Based Approach (2003)Adopted by ICH in Q8: Product Development, 2005, updated in Q8 (R2), 2009In 2006, Merck & Co.s Januvia became the first product.Starting to be adopted to analytical laboratories, e.g., used to design robustness into analytical methods with the Analytical Target Profile (ATP) concept2013: FDA/EMA Q&As on method validation by QbD2014: New FDA method validation guide with QbD components

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Slide *QbD in Laboratories: Key ApplicationsDevelopment and validation of analytical methods HPLC and othersTransfer or analytical proceduresVerification of compendial methodsAnalytical instrument qualificationDissolution testingNear Infrared Spectroscopy (NIR) methodWater analysis


Slide *EFPIA Positioning PaperEstablishment of Analytical Target Profile (method performance criteria, acceptance criteria) ATP defines what needs to be measured not howATP is submitted to regulatory agencies and approved instead of an analytical procedureAny analytical method conforming to the approved ATP can be usedAlternative methods, e.g., new technology, can be used through internal change control procedureIn line with FDAs general approach for QbD (no re-approval required as long as working in the approved design space) Also in line with the European Variation Guideline and with ICH Q8Reference: Ermer, European Pharmaceutical Review, Vol 10, Issue 3 (2011) EFPIA = European Federation of the Pharmaceutical Industries and Association


Slide *QbD in Laboratories Current Situation and key ApplicationsSituationNo formal regulations or guidelines, no FDA pilot projectQbD can be used for all critical analytical quality parametersSome laboratories are starting to adapt QbD for analytical method validation FDA/EMA address methods in Q&As sessions and guideEFPIA Positioning PaperKey ApplicationsDevelopment and validation of analytical methodsMethod transfer, disolution testingEFPIA = European Federation of the Pharmaceutical Industries and Association


Slide *Traditional Development & Validation of Analytical MethodsSelect preliminary method, scope & specificationsAssure performance of equipmentAssure that operators are qualififiedPreparationDevelopmentValidationRoutine OperationSelect and optimize method & parametersRobustness testingDefine operational limits and SST Preliminary validation experimentsDocument final acceptance criteriaDocument final scopePerform validation tests, incl. robustnessControlled transfer Regular reviewControlled changes & Revalidation


Slide *Quality by Design for Analytical MethodsSpecificationsAnalytical Target Profile, Quality Target Method ProfileControl Strategy for CMAsSystem SuitabilityMethod Qualification (ICH Q2)Design Space, Method Operational Ranges

Continuous Monitoring and ImprovementsQC TrackingMethod developmentCritical Method Parameters and Critical Attributes, Risk Assessment


Slide *QbD Terms in Method Development and Validation

Product DevelopmentMethod Development Method ValidationExamples for MethodsTarget product profile (TPP)Analytical target profile (ATP)Accurate quantitation of impurities in drugsQuality target product profile (QTPP)Quality target method profile (QTMP)LOQ 0.9900Rangeo.k. if accuracy, precision, linearity criteria are met


Slide *Example: Report Summary Table

Validation ParameterMeasureAcceptance criteriaResultsAccuracyRecovery Conc1Recovery Conc2Recovery Conc397 103 %97 103 %97 103 % 99%100%100%Method PrecisionRSD 1.5 %0.4%Intermediate PrecisionRSD 2.0 %0.8%SpecificityPeak Resolution Factor RR for all peaks >1.5 All peaks >2.0LinearityCorrelation CoefficientVisual inspection of plot 0.9900Linear response plot0.9900Shows linearityRangeCorrelation CoefficientPrecision at 3 concentrationsRecovery at 3 Conc. 0.9900 1.5 %97 103%0.99001.5R for all peaks >1.5Recovery in spec.2.0R for all l peaks >2.0Recovery in spec

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Integrated Method Development and Validation