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Integrated Method Development and Validation Dr. Ludwig Huber Ludwig_huber@labcompliance.com RACI Conference - Chemical Analyses
© Copyright Ludwig Huber - LabCompliance Slide 2 Today’s Agenda Lifecycle management of analytical procedures: development, validation and routine use Using principles of Quality by Design to get most robust methods Defining validation parameters, acceptance criteria and test procedures Templates and examples for efficient and consistent documentations FDA 2014 FDA 2013 NATA 2013
© Copyright Ludwig Huber - LabCompliance Slide 3 FDA Guide – Bioanalytical Method Validation Major differences to the 2001 Guide Section on System Suitability testing Inclusion of incurred sample reanalysis Level of details on LBA similar to chromatographic methods Concentrations below the LLOQ should be reported as zeros Sample Analysis Reporting should include: All accepted and rejected analytical runs
© Copyright Ludwig Huber - LabCompliance Slide 4 FDA Guide – Analytical Method Validation Components of Quality by Design (QbD) –Begin with an initial risk assessment and follow with multivariate experiments (design of experiments). –Lifetime management Requires submission of method development data –You should submit development data within the method validation section if they support the validation of the method.
© Copyright Ludwig Huber - LabCompliance Official Guidelines for Method Validation ICH - Guidance for Industry - Q2 (R1) Text and Methodology Must be followed in US and Europe FDA: 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 Methods USP : Verification of Compendial Procedures USP : Transfer of Analytical Procedures ICH = International Conference for Harmonization USP = United States Pharmacopeia Slide 5 QbD components
© Copyright Ludwig Huber - LabCompliance Slide 6 Method Validation The 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.com Slide 6
© Copyright Ludwig Huber - LabCompliance Slide 7 Method Validation Parameters for different Method Tasks (ICH Q2) Analytical Task Identifi- cation Impurity Quantitative Impurity Qualitative Assay AccuracyNoyesNoYes Precision Repeatability Intermediate Reproducibility No Yes No Yes Yes SpecificityYes Limit of detectionNo YesNo Limit of quantitationNoYesNo LinearityNoYesNoYes RangeNoYesNoYes RobustnessExpected to be done during Method Development
© Copyright Ludwig Huber - LabCompliance Slide 8 Parameters and Tests (ICH Q2) ParameterTests (examples) AccuracyMinimum at 3 concentrations, 3 replicates Precision Repeatability Intermediate Reproducibility Minimum of 9 determinations over the specified range Over 3 days, 2 operators, 2 instruments, Only required if testing is done in different laboratories SpecificityProve with specific methods: HPLC, DAD, MS, dif. columns Limit of detectionVisual approach, S/N >= 3 Limit of QuantitationS/N >= 10, Standard deviation of response LinearityMin 5 concentrations: visual, correlation coefficient (r) Range80 to 120% of test concentration, from linearity tests
© Copyright Ludwig Huber - LabCompliance Slide 9 Why Should we Change the Traditional Way Problems in routine use, too many failures Developers not end-users Low emphasis on method robustness and ruggedness Poor knowledge on critical parameters – –problems during method transfer No or inadequate use of risk assessment Invested time not very efficient
© Copyright Ludwig Huber - LabCompliance Slide 10 Possible Conflict of Interests Development chemist –Shortest time possible Routine User / QC Director –No problem during routine use –No out-of-specification situations Quality Assurance –Enough documentation for inspections Regulatory Affairs –Enough documentation for registration Finance –Lowest development and validation cost
© Copyright Ludwig Huber - LabCompliance Slide 11 Objectives of the New Approach Efforts for method development and validation should be value adding: building knowledge Method will work consistently within its design space –Changing people –Changing material (e.g., chromatographic column) –Environment (transfer) Focus on critical parameters using a risk based approach Compliance is still important !!!
© Copyright Ludwig Huber - LabCompliance Slide 12 What we really want Design a method and validation procedures to ensure that the method works for the intended routine use, independently from –Where it is being used –Who is using it –Specified instrumentation –Actual method parameters, as long as they are in the defined operating range Trouble free operation – transfer – With no method specific OOS results
© Copyright Ludwig Huber - LabCompliance QbD - Background and regulatory Situation Principles widely applied in all industries, particularly in car industry Adopted by FDA in the 21 st 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), 2009 In 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) concept 2013: FDA/EMA Q&As on method validation by QbD 2014: New FDA method validation guide with QbD components Slide 13
© Copyright Ludwig Huber - LabCompliance Slide 14 QbD in Laboratories: Key Applications Development and validation of analytical methods –HPLC and others Transfer or analytical procedures Verification of compendial methods Analytical instrument qualification Dissolution testing Near Infrared Spectroscopy (NIR) method Water analysis
© Copyright Ludwig Huber - LabCompliance Slide 15 EFPIA Positioning Paper Establishment of Analytical Target Profile (method performance criteria, acceptance criteria) ATP defines ‘what’ needs to be measured not ‘how’ ATP is submitted to regulatory agencies and approved instead of an analytical procedure Any analytical method conforming to the approved ATP can be used Alternative methods, e.g., new technology, can be used through internal change control procedure In line with FDA‘s 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 Q8 Reference: Ermer, European Pharmaceutical Review, Vol 10, Issue 3 (2011) EFPIA = European Federation of the Pharmaceutical Industries and Association
© Copyright Ludwig Huber - LabCompliance Slide 16 QbD in Laboratories – Current Situation and key Applications Situation No formal regulations or guidelines, no FDA pilot project QbD can be used for all critical analytical quality parameters Some laboratories are starting to adapt QbD for analytical method validation FDA/EMA address methods in Q&As sessions and guide EFPIA Positioning Paper Key Applications Development and validation of analytical methods Method transfer, disolution testing EFPIA = European Federation of the Pharmaceutical Industries and Association
© Copyright Ludwig Huber - LabCompliance Slide 17 Traditional Development & Validation of Analytical Methods Select preliminary method, scope & specifications Assure performance of equipment Assure that operators are qualifified Preparation Development Validation Routine Operation Select and optimize method & parameters Robustness testing Define operational limits and SST Preliminary validation experiments Document final acceptance criteria Document final scope Perform validation tests, incl. robustness Controlled transfer Regular review Controlled changes & Revalidation Regulated Not regulated
© Copyright Ludwig Huber - LabCompliance Slide 18 Quality by Design for Analytical Methods Specifications Analytical Target Profile, Quality Target Method Profile Control Strategy for CMAs System Suitability Method Qualification (ICH Q2) Design Space, Method Operational Ranges Continuous Monitoring and Improvements QC Tracking Method development Critical Method Parameters and Critical Attributes, Risk Assessment
© Copyright Ludwig Huber - LabCompliance Slide 19 QbD Terms in Method Development and Validation Product DevelopmentMethod Development Method Validation Examples for Methods Target product profile (TPP) Analytical target profile (ATP) Accurate quantitation of impurities in drugs Quality target product profile (QTPP) Quality target method profile (QTMP) LOQ <0.05%, precision and accuracy at LOQ better than 15% Critical process parameters (CPP) Critical method parameters (CMP) Flow rate, temperature, pH of mobile phase Critical quality attributes (CQA) Critical Method attributes (CMA) Resolution, peak tailing Proven acceptable range (PAR) Method operational design range (MODR) pH ± 1, col temperature ± 2
© Copyright Ludwig Huber - LabCompliance Slide 20 Define the Analytical Target Profile Method operational intent (what the method has to measure) Inputs from end-user department –Ease of use, analysis cycle time, acceptable solvents, analysis cycle time Method performance characteristics, e.g., precision, accuracy, specificity, LOD/LOQ, linearity Acceptance criteria for method performance characteristics Which instruments will be used, where will the method be used (specific lab, specific site, global)? Example (incomplete): Quantitative impurity analysis compound at ≥0.05% with an accuracy and precision of 15% RSD at the limit of quantitation and 5% at 20x LOQ.
© Copyright Ludwig Huber - LabCompliance Slide 21 Determine Factors Impacting Critical Method Attributes (CMA) Test Conditions –HPLC Mobile phase composition, pH –Column Temperature, detector wavelength –Sample extraction time Material attributes –Matrix, sample stability, sample solubility, column batch –Reference standards, quality of reagents Environmental conditions –Humidity, room temperature, electromagnetic interference Random effects –Analysts, e.g., skill level, thoroughness –Timing, e.g., day and night shift –Instrument, e.g., performance, maintenance MCA Factor2 Factor3 Factor1 Use Fishbone diagrams and risk assessment
© Copyright Ludwig Huber - LabCompliance Slide 22 Apply Risk Assessment to Support Defined Criticality of Method Attributes Identify parameters with impact on the method’s performance (Risk Identification) –Rely on subject matter experts, Brainstorming meeting –May also go back to development experiments Develop a prioritization matrix (Risk Evaluation) –Look at factors with highest impact on method performance –Link at specified instrument functionality, performance and qualification –Rank, e.g., in three categories: high (3), medium (2), low (1) Determine risk priority numbers for individual parameters SeverityProbabilityDetectabilityRisk Number Factor 133218 Factor 22136
© Copyright Ludwig Huber - LabCompliance Slide 23 Example Risk Prioritization Matrix 1 = low, 2= medium 3 = high impact Method Parameter Method Attributes col. temp. flow ratepH %organic phase UV Wave- length LOQ 12132 Linearity 21132 Repeatability 21123 Accuracy 23131 Specificity 31132 Risk Priority Number (RPN) 10851410 Impact of Method Parameters on Performance RPN ≥ 9 included in DOE study
© Copyright Ludwig Huber - LabCompliance Slide 24 Determine the Method Operational Design Range (MODR) through DOE From the „Critical Method Attribute“ exercise, select factors that based on the risk assessment will impact method performance. Choose levels of each factor (two or higher) Select range over which factors will be varied, e.g., in two level study there will be a high and low level value –Requires good knowledge of the method Use the multivariate experimental design approach Define and perform experiments Perform statistical analysis of data Interpret the data Perform follow-up runs (if necessary)
© Copyright Ludwig Huber - LabCompliance Slide 25 Design of Experiments (DoE) Early DoE strategies began in 1920s Part of QbD Helps to understand the cause and effect relationship between input factors and output (e.g., test parameters vs. method performance) Most important to determine a method’s robustness Typically implemented through simultaneously changing two or more parameters, reducing the number of experiments Facilitated through availability of software, e.g., Design Expert (www.statease.com), Minitab (www.minitab.com)www.statease.comwww.minitab.com Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 26 Simple DoE Example for HPLC Method - Impact on Selectivity - Run # % Org.Phase pHCol. TempColumnFlow Rate 1 +1 2+1 +1 3+1+1 4 +1 5+1 +1 6+1 -1 =40 % ACN4.0 25 ºC10 cm2.0 ml/min +1 = 60% ACN 40% Water 6.0 40 ºC20 cm2.5 ml/min FDA: Need sufficient statistical power to support analytical “Design Space”
© Copyright Ludwig Huber - LabCompliance Slide 27 Validate the Method for Intended Use Formally validate the method following ICH Q2 Develop a method qualification plan Assure that equipment is formally qualified (specifically spelled out in the new FDA guide) Assure that personnel is formally trained Perform qualification experiments, including robustness testing Evaluate data and document results Write a validation report
© Copyright Ludwig Huber - LabCompliance Slide 28 Examples for HPLC Robustness Testing Deliberately change critical operational limits and evaluate impact on performance: precision, accuracy Include sample preparation and testing parameters Sample preparation (accuracy) Extraction time (-20% of target) Extraction temperature (± 5 ºC) HPLC Col Temperature (± 3 ºC) Mobile phase composition (± 2%) Buffer concentration (± 2%) Flow rate (± 0.3 mL/min) Detection wavelength (± 1 nm) Column Lot (quality, selectivity) Ambient temperature/humidity Stability of samples, standards Define acceptable ranges !
© Copyright Ludwig Huber - LabCompliance Slide 29 Examples for Acceptance Criteria ParameterTest Accuracy90 – 110%, 80 – 120% at specifications limit Precision Repeatability Intermediate Reproducibility <4 % RSD (up to 15% at LOQ) <5.0 % RSD (higher at LOQ) < 6% RSD (higher at LOQ) Specificity Peak resolution >1.5 (related substances) or >2 (main peak) Peak purity check with UV DAD or MS Limit of DetectionN/A Limit of Quantitation0.05% Linearity visual inspection of linearity curve, r>0.9900 Rangeo.k. if accuracy, precision, linearity criteria are met Quantitative Impurities in Finished Drugs
© Copyright Ludwig Huber - LabCompliance Slide 30 Example: Report Summary Table Validation Parameter MeasureAcceptance criteriaResults Accuracy Recovery – Conc1 Recovery – Conc2 Recovery – Conc3 97 – 103 % 99% 100% Method Precision RSD≤ 1.5 %0.4% Intermediate Precision RSD≤ 2.0 %0.8% SpecificityPeak Resolution Factor RR for all peaks >1.5 All peaks >2.0 Linearity Correlation Coefficient Visual inspection of plot ≥ 0.9900 Linear response plot 0.9900 Shows linearity Range Correlation Coefficient Precision at 3 concentrations Recovery at 3 Conc. ≥ 0.9900 ≤ 1.5 % 97 – 103% 0.9900 <1% 99.6% Robustness Column Temp. ±2 C Mobile Phase ±2 % Sample extraction time -20 % Compound stability 6 days R for all peaks >1.5 Recovery in spec. <3% degradation R for all peaks >2.0 R for all l peaks >2.0 Recovery in spec <2% degradation
© Copyright Ludwig Huber - LabCompliance Slide 31 Assure that the Method Remains in a State of Control Run system suitability tests –Select critical test parameters based on risk assessment and design space experiments Track quality control sample test results Thoroughly look at OOS results, and if method specific, implement a corrective action plan Apply rigorous change control procedures
© Copyright Ludwig Huber - LabCompliance Slide 32 Change Control Follow change control procedure Assess the impact of each change and perform risk assessment Take advantage of knowledge gained during robustness testing Evaluate if the method parameter change is within the defined and tested design space and boundaries (method operational design ranges) If not may have to revalidate the method
© Copyright Ludwig Huber - LabCompliance Slide 33 Coninually monitor and improve the Method Actively collect inputs from operators on reliability and performance of the method Evaluate customer complaints Conduct regular method review, e.g., yearly Track and trend system suitability Respond to adverse trends before they become problems Continually improvement through –Problem solving and corrective action –Preventive action –Verification of correctve and preventive actions
© Copyright Ludwig Huber - LabCompliance Slide 34 Benefits of QbD for Laboratories - Example: Analytical Method Validation - Facilitates technology innovation (new technology can be used without FDA re-approval, as long as the Analytical Target Profile (ATP) is the same (future thinking) Technology changes can be implemented without loss of time – facilitates continuous improvement Less analytical method related Out-of-Specification and failure investigations Lower failure rates for method transfer Allowed method changes without revalidation well defined through design space and robustness testing Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 35 Industry Barriers to QbD Current guidelines not in line with QbD approaches Registration currently not based on method performance but on method conditions Low motivation to change Only little experience in the industry Requires new tools and skills for analysts Implementation Challenges –Collaboration between functions –Experience with new concepts –Workload and resource limitations Ludwig Huber
© Copyright Ludwig Huber - LabCompliance Slide 36 FDA-EMA Collaborative Research on QbD for Analytical Methods: Q&As Question What are the Agencies’ views with respect to the use of analytical target profile (ATP) for analytical methods? Answer In general, an analytical process profile (ATP) can be acceptable as a qualifier of the expected method performance by analogy to the QTPP as defined in ICH Q8 (R2). However, the Agencies would not consider analytical methods that have different principles (e.g.,HPLC to NIR) equivalent solely on the basis of conformance with the ATP. An applicant should not switch between methods without appropriate regulatory submission and approval
© Copyright Ludwig Huber - LabCompliance Slide 37 FDA-EMA Collaborative Research on QbD for Analytical Methods: Q&As Question What are the Agencies expectations in regulatory submissions for Method Operational Design Ranges (MODR)? Answer For example, data to support an MODR could include: (a) appropriately chosen experimental protocols to support the proposed operating ranges/ conditions; and (b) demonstration of statistical confidence throughout the MODR. Issues for further reflection include the assessment of validation requirements as identified in ICH Q2(R1) throughout the MODR and confirmation of system suitability across all areas of the MODR
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