Integrated Method Development and Validation

1. Integrated Method Development and Validation RACI Conference - Chemical Analyses Dr. Ludwig Huber Ludwig_huber@labcompliance.com

2. Today’s Agenda FDA 2014 • 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 2013 NATA 2013

3. FDA Guide – Bioanalytical Method Validation Major differencestothe 2001 Guide • Section on System Suitability testing • Inclusionofincurred sample reanalysis • Level ofdetails on LBA similartochromatographicmethods • Concentrations below the LLOQ should be reported as zeros • Sample Analysis Reporting should include: All accepted and rejected analytical runs

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.

5. Official Guidelines for Method Validation QbD components • ICH - Guidance for Industry - Q2 (R1)Text and MethodologyMust be followed in US and Europe • FDA: Analytical Procedures and Methods Validation for Drugs and Biologics (Draft, Feb 2014) • FDA - Industry GuidanceBioanalytical Method Validation (Draft, Nov 2013) • USP <1225>: Validation of Compendial Methods • USP <1226>: Verification of Compendial Procedures • USP <1224>: Transfer of Analytical Procedures ICH = International Conference for Harmonization USP = United States Pharmacopeia

6. WL/483Example 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

7. Method Validation Parameters for different Method Tasks (ICH Q2)

8. Parameters and Tests (ICH Q2)

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

10. Possible Conflict of Interests What is most important? • 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

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 !!!

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

13. QbD - Background and regulatory Situation • Principles widely applied in all industries, particularly in car industry • Adopted by FDA in the 21st Century cGMP initiativeReference: 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

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

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

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 addressmethods in Q&As sessionsandguide • EFPIA PositioningPaper Key Applications • Development andvalidationofanalyticalmethods • Methodtransfer, disolutiontesting EFPIA = European Federation of the Pharmaceutical Industries and Association

17. Traditional Development & Validation of Analytical Methods Not regulated Preparation • Select preliminary method, scope & specifications • Assure performance of equipment • Assure that operators are qualifified • Select and optimize method & parameters • Robustness testing • Define operational limits and SST • Preliminary validation experiments Development • Document final acceptance criteria • Document final scope • Perform validation tests, incl. robustness Validation Regulated • Controlled transfer • Regular review • Controlled changes & Revalidation Routine Operation

18. Quality by Design for Analytical Methods Specifications Analytical Target Profile, Quality Target Method Profile Method development Critical Method Parameters and Critical Attributes, Risk Assessment Continuous Monitoring andImprovements QC Tracking Design Space, Method Operational Ranges Control Strategyfor CMAs System Suitability MethodQualification(ICH Q2)

19. QbD Terms in Method Development and Validation

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 • Acceptancecriteriafor 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.

21. Determine Factors Impacting Critical Method Attributes (CMA) Factor3 Factor2 • 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 Factor1 MCA Factor1 Factor2 Factor3 Use Fishbone diagrams and risk assessment

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

23. Example Risk Prioritization Matrix Impact of Method Parameters on Performance 1 = low, 2= medium 3 = high impact RPN ≥ 9 included in DOE study

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)

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) Ludwig Huber

26. Simple DoE Example for HPLC Method- Impact on Selectivity - FDA: Need sufficient statistical power to support analytical “Design Space”

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

28. Examples for HPLC Robustness Testing • 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 • Deliberately change critical operational limits and evaluate impact on performance: precision, accuracy • Include sample preparation and testing parameters For reliability in routine - Avoid OOS - For revalidation criteria Define acceptable ranges !

29. Examples for Acceptance Criteria Quantitative Impurities in Finished Drugs

30. Example: Report Summary Table

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

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

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

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

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

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

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