Quality By Design (QbD) Solutions For Analytical Method .
Quality by Design (QbD) Solutionsfor Analytical Method DevelopmentA systematic approach to reducingvariabilityAndreas TeiPharmaceutical Segment ManagerAgilent CrossLab Group
Content Introduction- Traditional approach of method development and transfer- QbD approach for method development Agilent solutions for method development-Agilent method development systems-Intelligent system emulation technology (ISET)-Method scouting wizard software-Third party QbD software A practical approach of method development under QbD principles-ScreeningOptimizationRobustness study, Design of ExperimentsTransfer & Verification
Quality by Design - A systematic approach to obtain a“consistent quality” ableoutputConsistentoutputICH Q8-Q11ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human UseJune 8, 20153
QbD in analytical method development Analytical method development is an important part of the drugdevelopment process therefore the quality principles whichhave been described in the ICH guideline Q8 (R2) should beimplemented to eliminate risks or failures 3507.pdf(ICH International Conference of Harmonization of Technical Requirementsfor Registration of Pharmaceuticals for Human Use, Founded in 1990 by an FDA initiative)4
Traditional Development and Transfer of MethodsA chromatographic challenge !DevelopTransferValidateQA / QCR&D 50%Parameters determinedby the trial-and error andOFAT approach. 0.2TransferSlope 14.5% min MeOHpH 7 /- 0.245oC /- 21.0 mL/min /- 0.1Transfer 10% 10% 10oC5
OFAT Approach: Method Transfer is a balancing actDifferent results on different systemsVariability of critical methodattributes (resolution, tailing, etc)DevelopmentSystemTarget QA/QCSystemsSmall changes in pH, temperatureor flow rate shows a large effectEven buffer solutions from differentoperators deliver different results10% of analytical methods are discarded per year to avoid high revalidation costsafter the method showed instabilities on the QC system6
QbD Approach for Method Development Analytical QbD begins by defining goals (Analytical TargetProfile, ATP) and identifying potential method variables andresponses that affect method quality A list of critical method parameters (CMPs- flow rate,temperature etc.) and critical method attributes (CMAsresolution, peak tailing etc.) has to be determined Key is the statistical “Design of Experiment” (DoE) wheremultiple CMPs will be varied in each experiment with the goalto create a Design Space The meaning of a Design Space has been defined in the ICHQ8 (R2) guideline7
One-Factor-At-The-Time (OFAT) vs. DoE ApproachDoEVariable 2Variable 2Classic Approach (OFAT)Variable 1Variable 1Impact of CMPs (e.g., %org phase, col temp, pH) on CMAs (e.g.peak resolution, symmetry, tailing factor) is measured8
DoE: Modifying different variables while keeping other set pointsInj. Volume (µl)0.63.020% organic phase(methanol)101.6Flow rate (ml/min)0.830Col temp (C)40CMAsSurface Plot to visualize the locationof the optimum parameter setResolutionMax number of peaksASP tailing factorSymmetry9
Creating a Design SpaceThe Design Space as a result of a multivariate analysisThe contour plot indicates the robust region based on the results of the multivariate study(example data: Fusion QbD Software (S-Matrix)Contour PlotList of CMPs and CMAs forrobustness testing* The coded names are used in robustness model displays
Advantages of the QbD approach DoE is leading to process and method understanding as therelationship between the different critical method parameterswill be described and visualized in surface or contour plots DoE is increasing the efficiency by avoiding unnecessaryexperiments during the method development process as oftenoptimized and robust conditions are only found by chanceusing the classic trial-and-error and OFAT approaches11
POLLINGJune 8, 201512
Content Introduction- Traditional approach of method development and transfer- QbD approach for method development Agilent solutions for method development-Agilent method development systemsIntelligent system emulation technology (ISET)Method scouting wizard softwareThird party QbD software A practical approach of method development under QbD principles-ScreeningOptimizationRobustness study, Design of ExperimentsTransfer & Verification
Agilent Solutions for QbD Method DevelopmentMethod DevelopmentSystem & Method Scouting SWISETIntelligent System Emulation TechnologyHarmonized QualificationACERARemote Advisor
Agilent Method Development Systems 1352 different combinations of column chemistries and eluents A nearly infinite number of separation conditions is created by includingdifferent temperature and flow rates as variable parameters15
1290 Infinity II Method Development SolutionNew: Multi Column ThermostatMulti Column ThermostatMCTAutosamplerdetectorpump1290 Infnity I System1290 Infnity II System16
Intelligent System Emulation Technology (ISET)- Seamless transfer of methods between LCs, regardless of the brandPO-Nr. G2197AA17
Method Transfer Between Different LC InstrumentsMethod transfer from a UHPLC system with a minimized dwellvolume and optimized mixing behavior to any other LC system isoften challenging and affects retention time and resolutionExample: Method Transfer from a 1290 UHPLC to a 1100 HPLC systemmAU1751501251001290 Infinity LC75501100 Series Binary System25034567891011 min18
Approach # 1: Applying Isocratic Holding StepsResults1260 Infinity LC1290 Infinity LC 900 µl hold Results show still inconsistent results Requires a manual determination of the dwell volume/ isocratic hold(in solvent delivery systems equipped with dampeners the dwell volume ispressure dependent and variable) Requires modification of the methods(should be avoided in validated environment,but doesn’t require revalidation USP Chapter 621 )19
Approach # 2: Adding a Physical Void VolumeResults1290 1000 μL dwell vol.1100/1200 Quat Pump Results show a good consistency Requires a manual determination of dwell volumes (issues of a variabledwell volumes when membrane dampeners are present) All mechanical changes are laboriously not flexible20
Agilent Solution:Intelligent System Emulation Technology (ISET)mAU400350300InjectionSoftware controlled compensationof dwell volume differences andsynchronization of mixingbehaviors250200150Programmed gradient1001290 gradient501200 gradient000.511.522.533.5min21
Agilent Solution: Method Transfer by ISETParacetamolResults: 1260 Infinity Binary LC to 1290 Infinity LCImp FImp K30 Consistency of resultsImp H40Imp JmAUImp BImp A20101290 Infinity LC with ISET01260 Infinity Binary LC123456789min22
Practical aspects how to measure dwell volumes, transfer & optimize methods23June 8, 2015
Automated Method Development SoftwareAgilent Chemstation Method Scouting Wizard Software Define projectChoose scouting combinations andbase method Select columnsAll installed columns are shown automatically Select solventsPump types and valves are automaticallydetected Define gradientsSelect between different gradients andtemperatures Review and select screening methodsCheck for incompatible combinations Check results at a glanceIntegrated browser to view all results at a glancePO-Nr.G2196AA24
Method Transfer from UHPLC to HPLCAgilent Method Translatorwww.agilent.com/chem/1200calculatorHPLC Calculator telechargement.htmCrawford Scientific Calculatorhttp://www.crawfordscientific.com/HPLC Method Transfer On-line.htm25June 8, 2015
Add-on Software Options for QbD Method DevelopmentChromSwordAutoChrom (ACD Labs)Fusion QbD (S-Matrix)
POLLING27June 8, 2015
Content Introduction– Traditional approach of method development and transfer– QbD approach for method development Agilent solutions for method development–Agilent method development systems–Intelligent system emulation technology (ISET)–Method scouting wizard software–Third party QbD software A practical approach of method development under QbDprinciples– Screening– Optimization– Robustness study, Design of Experiments– Transfer & Verification
QbD Method Development & Method Transfer WorkflowFrom UHPLC to HPLC in a MethodtransferMethod developmentSystemUse of 1.8 µ particlesand QbD softwareTarget SystemEmulation byISETTarget SystemsinQA/QC labsRobustness studyby QbD software29
QbD Based Method Development WorkflowOverall workflow whichconsists of four main stepsnamely Step # 1: ScreeningScreeningAgilentMethodScoutingWizard Column ChemistrypH conditionsOrganic SolventSelectionGradients, temperatures30
Step # 1: ScreeningResultsBubble size represents the number of integrated peaks and, consequently, bestmobile and stationary phase combinationFor more details please see Agilent Application Note 5991-0989EN31
QbD Based Method Development WorkflowOverall workflow whichconsists of four main stepsnamely Step # 1: Screening Step # 2: OptimizationAgilentMethodScoutingWizardScreening Column ChemistrypH conditionsOrganic SolventSelectionGradients, temperaturesOptimization QbD Software Optimize GradientProfilespH conditionsFlow rates, temperatures32
Step # 2: OptimizationFusion AE QbD SoftwareOptimization of flow rate, gradient slope, pH, column temperatureVariable ParametersStudy RangePump Flow rate (mL/min)Intermediate hold time (min)Final % Strong Solvent (Gradient 1)*Oven Temperature ( C)0.550, 0.600,0.6503.00 Intermediate Hold Time 7.0030.0 Final % Strong Solvent 35.033.0, 36.0, 39.0Constant ParametersConstant ValueColumn TypeWavelengthStrong Solvent typepHInjection VolumeEquilibration TimeInitial Hold TimeGradient 1 Time*Gradient 2 Time*Final Hold TimeFinal Hold % OrganicInitial % Strong Solvent3.0X100 mm,1.8 µm ZORBAX RRHD Eclipse Plus Phenyl-Hexyl245 nm 4 nm (ref off)Acetonitrile7.01µl2.50 minGradient 1: 5%B-(30-35)%B1.00 minGradient 2: (30-35)%B-90%B5.17 min9.28 min2.00 min90.0 %B5.0% B33
Step # 2: OptimizationResults: peak purity and separation after optimization 99.8% '''' ''''' 'Set by User ------ ---------- 10.510.5510.610.6510.710Purity foreOptimization1599.8 % purity2.510.2min10.007mAU10.543998Set by imization12.51517.520min34
QbD Based Method Development WorkflowOverall workflow whichconsists of four main stepsnamely Step #1: Screening Step #2: Optimization Step #3: d Column ChemistrypH conditionsOrganic SolventSelectionGradients, temperaturesOptimization QbD Software Optimize GradientProfilespH conditionsFlow rates, temperaturesDesign of Experiments QbD Software Multivariate studyRobust regionDesign Space35
Step #3 : Design of ExperimentsResults: Design SpaceCritical MethodParameters (CMPs)ProvenAcceptableRange (PARs)Column: Agilent ZORBAXRRHD Eclipse Plus C83.0X50 mm, 1.8 µmCritical MethodAttributes(CMAs)No. of peaks ( 40)API resolution( 1.5)Peak purity ( 98%)Peak tailing ( 1.5)Strong solvent: Methanol% Strong solvent:90.5% 1.5%Aqueous solvent pH: 7.7 0.1Gradient range: 5% to90.5%Oven Temperature:45 CGradient time: 15 minFlow rate: 0.6 mL/minWavelength: 292 nmCMAs to create a Design Space The Design Space is a region in which changes to method parameters will notsignificantly affect the results.36
QbD Based Method Development WorkflowScreeningOverall workflow whichconsists of four main stepsnamelyAgilentMethodScoutingWizard Optimization Step #1: Screening Step #2: Optimization Step #3: Robustnessstudy Step #4: Method Transfer& VerificationColumn ChemistrypH conditionsOrganic SolventSelectionGradients, temperaturesQbD Software Optimize GradientProfilespH conditionsFlow rates, temperaturesDesign of ExperimentsQbD Software Multivariate studyRobust regionDesign SpaceMethod Transfer &VerificationISETQbD Software Agilent Method TranslatorISETQbD OptimizationVerification37
Step # 4: Method Transfer & VerificationFrom UHPLC to erTarget SystemEmulation byISETRobustness studyby QbD softwareTarget SystemsinQA/QC labVerification38
Robustness Study After TransferModeling a HPLC design space on an emulated 1260 systemHPLC design space parametersCritical MethodParameters (CMPs)ProvenAcceptableRange(PARs)Column: AgilentZORBAX Eclipse PlusC8 4.6X150 mm, 3.5µmHPLC design space with new CMACritical MethodAttributes(CMAs)No. of peaks ( 40)API resolution( 4)Peak purity ( 98%)Peak tailing ( 1.3)Strong solvent:Methanol% Strong solvent:87.5.% 1.5%Aqueous solvent pH:7.7 0.1Gradient range: 5%to 87.5%Oven Temperature:37 CGradient time: 45 minFlow rate: 1.4mL/minWavelength: 292 nm39
Proof Of Robustness After TransferConditions applied from center point and the four corner points of the Design SpaceCritical Method Attributes remain within the 500TmAU350250150500DmAU350250150500CAPI Rs 4 and API tailing 1.2 for allruns% B max: 86 %; pH: 0304050min% B max: 89 %; pH: 7.610% B max: 87.5 %; pH: 7.710% B max: 89 %; pH: 7.810% B max: 86 %; pH: 7.81040
Verification Of The Final Method with the Target SystemResults: 1260 Infinity data compared to 1290 Infinity data in emulation modemAU24.115Final gradient1260 target system40030023.347200API Rs 4.1API tailing 3.15mAU4001024.0910201290 emulated as 1260304050304050min300100API Rs 4.2API tailing 1.223.34420001020minCritical Method Attributes are within the defined limits41
Agilent Application NoteTitle: QbD Based Method Development on anAgilent 1290 Infinity UHPLC system Combinedwith a Seamless Method Transfer to HPLCUsing Intelligent System Emulation TechnologyType: Application NotePublication Number: 5991-5701ENPages: 8Target segments: Pharmaceutical QA/QCLanguage: EnglishAuthor: Vinayak A.K.LitStation Availability: May 5, 2015, CPOD42June 8, 2015
Conclusion Due to shorter runtimes when using sub-2-micron columns the efficiencyof the method development process has been increasedExperimentsSub-2-µm columns(time in hours)Conventional columns(time in hours)ScreeningOptimization*Total2028*48472067 ISET can be used to emulate seamless different target systems QbD software has been applied to optimize the chromatographicconditions maximizing the resolution, purity and peak symmetry A multivariate study is used to create a design spacecompensating any unforeseen variables yet delivering consistent results*An extra HPLC optimization time is added after the method transfer to conventional particle sizes to optimize CMAs.43
POLLING44June 8, 2015
THANK YOUConfidentiality Label45June 8, 2015
QbD terminology in Method DevelopmentAppendixAnalytical QbD TerminologyQbD process terminologyAnalytical QbDterminologyExamplesAnalytical Target Profile(ATP)Accurate quantitation of APIwithout interferences fromdegradantsQuality Target ProductProfile (QTPP)Quality Target Method Profile(QTMP)pKa, Log P, SolubilityCritical Process Parameters(CPP)Critical Method Parameters(CMP)Flow rate,Temperature, pHCritical Quality Attributes(CQA)Critical Method Attributes(CMA)Resolution, PeakTailing, Peak CapacityControl StrategypH 0.1; Wavelength 2 nm
Appendix: Agilent Application NotesMethod Transfer by ISET Fast screening of mobile and stationary phases with the Agilent 1290 Infinity LCand seamless method transfer to an Agilent 1200 Series LC using ISETAgilent Application Note 5991-0989EN Developing faster methods for generic drugs within USP 621 allowed limitsAgilent Application Note 5991-0278EN Effective use of pharmacopeia guidelines to reduce cost ofchromatographic analysisAgilent Application Note 5991-1053EN Developing faster methods for generic drugs within EP 2.2.46E allowed limitsAgilent Application Note 5991-0394EN47
Appendix : Agilent Application NotesQbD based Method Development Quality-by-Design Approach to Stability Indicating MethodDevelopment for Linagliptin Drug Product–Agilent Application Note 5991-3834EN Automated QbD Based Method Development and Validation ofOxidative Degraded Atorvastatin–Agilent Application Note 5991-4944EN Development of an UHPLC Method for Azithromycin Tablets UsingChromSword Auto Software–Agilent Application Note 5991-5428EN QbD Based Method Development on an Agilent 1290 Infinity UHPLCsystem Combined with a Seamless Method Transfer to HPLC UsingIntelligent System Emulation Technology- Agilent Application Note 5991-5701EN48
A practical approach of method development under QbD principles - Screening - Optimization - Robustness study, Design of Experiments - Transfer & Verification . Agilent Solutions for QbD Method Development ISET Intelligent System Emulation Technology RA Remote Advisor Harmonized Qualification ACE Method Development System & Method Scouting SW . Agilent Method Development Systems 15 1352 .
and validate high-performance liquid chromatography (HPLC) methods to meet the FDA's expectation for protein analysis and quality control of antibodies. Using the systematic approach of quality by design (QbD) experiments ensures a more efficient and robust process for method development and approval. However, QbD setup can be time-consuming.
HPLC method development by QbD approach HPLC method development by Analytical QbD was as follows. Selection of quality target product profile The QTPP plays an important role for identifying the variables that affect the QTPP parameters. The retention time, theoretical plates, and peak asymmetry were iden-tified as QTPP for proposed HPLC method .
Quality assurance and GMP. 2. Total Quality Management (TQM)-Definition, elements, and philosophies. 3. ICH Guidelines- Purpose, participants, process of harmonization, Brief overview of QSEM, with special emphasis on Q-series guidelines, ICH stability testing guidelines. 4. Quality By Design (QbD)-Definition, overview, elements of QbD program .
1 2 Qualityby Design Metrics Framework This Quality by Design (QbD) Metrics Framework1 helps key stakeholders in clinical research organizations to identify measures that quantify2 the outcomes of QbD implementation and guide continuous improvement efforts. Selection of metrics should consider organizational context.
DOE and QbD Design Of Experiments is an essential component in QbD. It leads to detailed verification of how product and process definition affect key quality characteristics. It establishes a basis for defining the design space. Experiments enable us
process control, based on sound science and . The QbD approach promotes a holistic understanding of the product, its integrated delivery system and the manufacturing process. As a first step in initiating QbD . bioburden, and endotoxin levels are within acceptable limits. The most common methods for
FDA Reflections on Joint Regulators/Industry QbD Workshop January 29, 2014 London, UK Christine M. V. Moore, Ph.D. Acti
with representatives from the Anatomy sector. These relate to the consent provisions of the Human Tissue Act 2004 (HT Act), governance and quality systems, traceability and premises. 3. The Standards reinforce the HT Act’s intention that: a) consent is paramount in relation to activities involving the removal, storage and use of human tissue; b) bodies of the deceased and organs and tissue .
