Validation Of Analytical Methods - Ikev
VALIDATIONOFANALYTICAL METHODSINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS1
GERT BEUVINGINTERNATIONAL PHARMACEUTICAL OPERATIONSINTERNATIONAL QUALITY SYSTEMSTASKS:- Internal auditing- Auditing of suppliers and contract manufacturers- Preparing for and guiding of external inspections- Review of and advice on procedures & validationsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS2
GeneralValidationFDA-guidelines:Validation is establishing documented evidence which provides ahigh degree of assurance that a specific process will consistentlyproduce a product meeting its pre-determined specifications andquality attributesEU-guidelinesAction of proving, in accordance with GMP-principles that anyprocedure, process, equipment, material, activity or system actuallyleads to the expected resultsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS3
GeneralConclusion:- Need for pre-determined operational & performance userrequirements (URS) of process or system- Provide evidence of meeting pre-defined operational &perfomance requirements- Provide evidence on consistency of meeting theserequirementsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS4
GeneralMore specific:“Methods validation is the process ofdemonstrating that analytical procedures aresuitable for their intended use”(ICH Topic Q2B, March 1995)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS5
GeneralWhy validation?1. GMP-legislation2. Good economics3. Good science practicesINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS6
Validation guidelinesGuidelines1. ICH Q2AText on validation of analytical procedures: Definitions andterminology (March 1995)2. ICH Q2BValidation of analytical procedures: Methodology (June 1997)3. FDA(Draft) Guidance for Industry: Analytical procedures and methodsvalidation4. PharmacopoeiasUSP and European PharmacopoeiaINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS7
What methods to be validated?GuidelinesDefined for:- identification- quantitative tests for content of impurities- limit tests for control of impurities- quantitative tests for active moiety in drug substances and drugproductsReferred to:- dissolution testing- particle size determination (drug substance)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS8
GuidelinesWhen should methods be validated?Development and tox:No validation requiredPhase 1No validation data requiredPhase 2For both drug substance and drug product supporting validation dataon analytical methods should be available on requestINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS9
GuidelinesWhen should methods be validated?Phase 3 (Pivotal studies):Appropriate validation information should be provided.Assay validation should cover accuracy, precision, specificity(including stress testing), quantitation & detection limits, linearityand range (where appropriate)Degradation should be identified, qualified and quantifiedNDA submissionFull validation reports of relevant methods must be includedINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS10
What aspects to cover?GuidelinesSpecificity:Definition:Ability to assess unequivocally the analyte in the presence of ofcomponents which may be expected to be present (impurities,degradants, matrix)Aspects:- Identification- Purity tests- Assay (Content/potency)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS11
GuidelinesLinearity:Definition:Ability (within a specified range) to obtain test results which aredirectly proportional to the concentration of analyte in the sampleAspects:- Test across the range (at least 5 concentrations)- Evaluate linearity by visual inspection of the plot and by statisticaltechniques- Calculate corr. coefficient, y-intercept, slope and res. sum ofsquaresINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS12
GuidelinesRange:Definition:Interval between upper and lower concentration of the analyte in thesample for which it has been demonstrated that the procedure has asuitable level of precision, accuracy and linearityAspects:- Defined from linearity study- Depends on the application of the method (assay, dissolution test,content uniformity)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS13
GuidelinesAccuracyDefinition:Expresses the closeness of agreement between the value which isaccepted either as a conventional true value or an acceptedreference value and the value found.Methods:Drug substance- use of reference standard with known purity- comparison with independent, well-characterised procedure- may be inferred once precision, linearity and specificity areestablishedINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS14
GuidelinesAccuracyDrug product- spiking of placebo mixture- addition of analyte to ‘active’ material- comparison of results obtained with independent, well-characterisedprocedure- may be inferred once precision, linearity and specificity areestablishedImpurities- spiking of product samples- use of independent, well-characterised procedureINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS15
GuidelinesAccuracyRecommended data- Assessed by 9 determinations over a minimum of 3 concentrationlevels covering the specified range- To be reported as percent recoveryINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS16
GuidelinesPrecisionDefinitionCloseness of agreement (‘scatter’) between a series ofmeasurements obtained from multiple sampling of the samehomogeneous sample.Aspects- Repeatability- Intermediate precision- ReproducibiltyINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS17
GuidelinesPrecision - RepeatabilityDefinitionPrecision under the same operating conditions over a short interval oftime.Method- 9 determinations covering the specified range- or: 6 determinations at 100% of the test concentrationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS18
GuidelinesPrecision - Intermediate precisionDefinitionExpresses within laboratory variations.Method- Depends on circumstances of usage of the methods- Should include variations in days, analists, columnsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS19
GuidelinesPrecision - ReproducibilityDefinitionPrecision between laboratoriesMethod- Dependent on usage of method- Should include interlaboratory studyINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS20
GuidelinesDetection limitDefinitionLowest amount of an analyte in a sample which can be detected butnot necessarily quantitated.Method- Based on visual evaluation- Based on signal-to-noise ratio (3:1)- Based on st.dev. (SD) of response and slope (DL 3.3xSD/S)- Report results and method of choiceINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS21
GuidelinesQuantitation limitDefinitionLowest amount of an analyte in a sample which can be quantitativelydetermined with a suitable precision and accuracyMethod- Based on visual evaluation- Based on signal-to-noise ratio (10:1)- Based on st.dev. (SD) of response and slope (DL 10xSD/S)- Report results and method of choiceINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS22
GuidelinesRobustnessDefinitionMeasure of the capacity of a method to remain unaffected by smallvariations in method parameters.Aspects- To be considered during development- To be used for establishment of system suitability criteria- Include testing of stability of solutions- To be tested by introducing small variations in method parametersINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS23
GuidelinesSystem Suitability TestDefinitionSet of parameters and criteria thereoff to ensure the system isworking properly.Aspects- Dependent on type of test- For chromatographic methods: tailing factor, rel. retention times,resolution factor, rel. st. deviation, number of theoretical plates- To be checked before start of run and to be verified afterwards- Described in PharmacopoeiasINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS24
Recommended Validation characteristics of various Types of TestsType of on-repeatabilityPrecisionIntermediate precisionSpecificityDetection limitQuantitation LimitLinearityRangeRobustnessTesting for ive Limits- - - - - INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS25
Analytical method IONAL QUALITYQUALITY SYSTEMSSYSTEMS26
ImplementationImplementation of Guidelines- Standard protocols- Set up as procedures- Mutual agreement on tests- Mutual agreement on criteria- Mutual agreement on documentation MUTUAL DEVELOPMENT PROCEDURES (MDP)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS27
ImplementationMDP 6-01“Validation of the assay method of active compoundsby HPLC, capillary electrophoresis or gaschromatography in drug products”INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS28
ImplementationMDP 6-01 - SelectivityTests- Inject solutions of standard, product, impurities, knowndegradation products, excipients;- Inject solutions of degraded/stressed products and placebo- 2 hours art. daylight (70-90 klux)- 1 week at 75 C/amb. humidity and 75 C/100% RH- 24 hrs 3% H2O2, 1 mol/L HCl, 1 mol/L NaOH- Demonstrate separation- Demonstrate peak purityINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS29
ImplementationMDP 6-01 - SelectivityCriteria- Separation between relevant peaks of at least Rs 2.0- Peak of analyte should be pureDocumentation- Chromatograms of all solutions- retention times- peak purity results- data of contents of active substance and degradation productsin stress samplesINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS30
ImplementationMDP 6-01 - LinearityTests- Inject solutions of 25%, 50%, 75%, 100%, 125% and 150% ofexpected concentration in duplicate;- Calculate by statistical techniques the order of function (first orsecond), significance of intercept and correlation coefficient- In case of second order and/or significant deviation ofintercept from zero: determine the degree of linearity in therange of 70-130%.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS31
ImplementationMDP 6-01 - LinearityCriteria- Use of one reference concentration is acceptable when:- regression line is linear (lack of fit test)- true zero is within 95% conf. interval of calculated interceptor in case of second order curve:- if experimental rel. response at 70% and 130% does notdeviate by more than 1% from the calculated values- Linear when corr. coefficient 0.9990INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS32
ImplementationMDP 6-01 - LinearityDocumentation- Plots of peak height and peak areas- Statistical results (equations, significance of intercept, lack-offit test, rel. responses, corr. coefficient)- Plots of peak area and peak heights residualsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS33
ImplementationMDP 6-01 - AccuracyTest- Prepare placebo sample- Prepare spiked placebo samples: 3 replicates over 3concentration levels (e.g. 70%, 100%, 130% of theoreticalstrength)- Carry out the method- Calculate mean percent recoveries and rel. standard deviation(RSD) from both peak area and peak height responses.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS34
ImplementationMDP 6-01 - AccuracyCriteria- The average result of the mean for each level should be 98.0 102.0%- Range for response of placebo within -1% and 1%- RSD of pooled results should be 2%Documentation- Details on sample preparations- Individual results (peak areas and peak heights)- Calculated % recovery and pooled RSDINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS35
ImplementationMDP 6-01 - Repeatability of systemTest- Inject in six-fold one of the 100% solutions from the accuracyexperiment- Calculate RSD for both peak height and peak areaCriterionRSD 1.5%DocumentationResults and statistical calculationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS36
ImplementationMDP 6-01 - Repeatability of methodTest- Analyse within one day by one operator with one column 6times a homogeneous sample of the product- Calculate the RSD for results of both peak height and peakareaCriterionRSD 2%DocumentationResults and statistical calculationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS37
ImplementationMDP 6-01 - Intermediate precisionTest- Same as for repeatability of the method but by at least 2analists, more days, different labs, different (batches of)columns- Calculate the RSD on overall resultsCriterionRSD 2.5%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS38
ImplementationMDP 6-01 - Intermediate precisionDocumentation- Description of preparation of homogeneous sample- Description of experimental conditions- Results and statistical evaluationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS39
ImplementationMDP 6-01 - Detection and quantitation limitDetermination not necessaryOnly applicable for impurities and degradation productsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS40
ImplementationMDP 6-01 - RangeNo specific test:Normally a range of 70-130% is acceptable, unless a widerrange is required based upon the nature of the dosage form(e.g. metered dose inhalers)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS41
ImplementationMDP 6-01 - Robustness (1)Test on stability of solutions- Prepare 2 sample and 2 reference standard solutions- Store in refrigerator and at room temperature- Analyse at zero time and after at least 24 and 72 hoursstorage- Calculate differences between samplesCriterionStorage period is defined by period with no more than 1%difference between room temperature and refrigeratorINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS42
ImplementationMDP 6-01 - RobustnessDocumentation- Individual results- Calculations, difference between room and refrigeratorsamplesINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS43
MDP 6-01 - Robustness (2)ImplementationTest on variations- Vary relevant analytical parameters e.g.- composition and/or pH of mobile phase- column temperature- different column (other batch or brand/supplier)- stability of chromatographic systemCriteria- Chromatographic results meet system suitability criteria- Typically plate count should not decrease by more than 50%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS44
ImplementationMDP 6-01 - Robustness (2)Documentation- Relevant chromatograms- Calculations and results of system suitability parametersUse results from method development experiments!!INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS45
ImplementationMDP 6-01 - System Suitability TestingTest- Collect all data from previous experiments with regard to- number of theoretical plates- tailing factor- relative retention- resolution factor- precision of the system- Include information on minimum resolution between analyteand most-difficult-to-resolve impurity/degradation productINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS46
ImplementationMDP 6-01 - System Suitability TestingCriteria- Criteria dependent on development and validation results.- Evaluate and optimise defined criteria when more experienceis gained with the method.Documentation- Summary of data on individual parameters- Calculations and relevant chromatogramsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS47
ImplementationMDP 6-04“Validation of the determination of an impurity in adrug product by HPLC, capillary electrophoresis orgas chromatography”INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS48
ImplementationMDP 6-04 - SelectivityTests and documentationSame as for determination of active substance.Criteria- Assay of impurity should not be influenced by any other peakoriginating from other components in the sample solution.Resolution factor between 2 peaks should be at least 1.5.Resolution between active substance and impurity should be 2.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS49
ImplementationMDP 6-04 - LinearityTests- Inject solutions of 10%, 50%, 100%, 150%, and 200% ofexpected concentration in duplicate (concentration based uponregistered limit; if not defined then 1%);- Calculate by statistical techniques the order of function (first orsecond), significance of intercept and correlation coefficient- In case of second order and/or significant deviation ofintercept from zero: determine the deviation in the relativeresponse of the 10% and 200% points.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS50
ImplementationMDP 6-04 - LinearityCriteria- Use of one reference concentration is acceptable when:- regression line is linear (lack of fit test)- true zero is within 95% conf. interval of calculated interceptor in case of second order curve:- if deviation of the rel. response of 10% point isd less than20% and of the 200% point is less than 5%values- Linear when corr. coefficient 0.995INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS51
ImplementationMDP 6-04 - LinearityDocumentation (same as for DS)- Plots of peak height and peak areas- Statistical results (equations, significance of intercept, lack-offit test, rel. responses, corr. coefficient)- Plots of peak area and peak heights residualsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS52
ImplementationMDP 6-04 - RangeNo specific test:Normally a range of 10-200% is acceptable. In most cases100% is 1% relative to the drug substance.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS53
ImplementationMDP 6-04 - AccuracyTest- Prepare placebo sample- Prepare spiked placebo samples: 3 replicates over 3concentration levels (e.g. 2 x QL, 100% and 200% of 1% of thedrug substance concentration)- Perform analysis- Calculate mean percent recoveries and rel. standard deviation(RSD) from both peak area and peak height responses.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS54
ImplementationMDP 6-04 - AccuracyCriteria- The average result of the mean for 100% and 200% levelshould be 90-110% and for 2xQL 70-130%- RSD of 100 and 200%: 5% and 2xQL level: 15%Documentation- Details on sample preparations- Individual results (peak areas and peak heights)- Calculated % recovery and pooled RSDINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS55
ImplementationMDP 6-04 - Repeatability of systemTest- Inject in six-fold one of each of the strengths of the referencesolutions from the accuracy experiment- Calculate RSD for both peak height and peak areaCriterionRSD (2xQL) 15%; RSD (100% and 200%) 5%DocumentationResults and statistical calculationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS56
ImplementationMDP 6-04 - Repeatability of methodTest- Inject in six-fold one of each of the strengths of the samplesused in the accuracy experiment- Calculate the RSD for results of both peak height and peakareaCriteriaRSD (2xQL) 15%; RSD (100% and 200%) 5%DocumentationResults and statistical calculationINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS57
ImplementationMDP 6-04 - Intermediate precisionTest and documentationSame as for assay but tested on spiked samples at 1% levelCriterionRSD 10%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS58
ImplementationMDP 6-04 - Detection and quantitation limitTest- Determine peak-to-peak distance of baseline at the position ofthe analyte in a blank sample. Calculate noise as 0.5 times thisdistance- Calculate the detection limit as 3 times noise and quantitationlimit as 10 times noise- Verify the calculated DL and QL by injecting at least onesolution with a concentration at or near the DL and QL.INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS59
ImplementationMDP 6-04 - Detection and quantitation limitCriterionThe Quantitation Limit is, by preference, less than 0.1% relativeto the drug substance.Documentation- Chromatograms used for calculations- Chromatogram of sample at a concentration near DL and QLINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS60
ImplementationMDP 6-04 - Robustness (1)Test and documentation on stability of solutionsSame as for assayCriterionStorage period is defined by period with no more than 5%difference between samples stored at room temperature and inthe refrigeratorINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS61
ImplementationMDP 6-04 - Robustness (2)Test, Criteria and Documentation on variationsSame as for assayINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS62
ImplementationMDP 6-04 - System Suitability TestingTest, Criteria and DocumentationSame as for AssayINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS63
Implementation - ExampleImplementation - A practical exampleLivial capsules 1.25 mgProduct is developed for post-menopausal complaints and alsoprevents osteoporosesAn analytical method was developed to determine drugsubstance and main degradation products simultaneouslyINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS64
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS65
Implementation - ExampleAnalytical procedureExtraction:Sonification and mixing with ethanol (conc. OD 14: 0.156 mg/ml)HPLC:- column: Nova-pak 18, 150x3.9 mm, dp 4 mcm- mobile phase: Tetrahydrofuran water (28 72)- column temperature: 40 C- Detection: UV 210 (OD 14) UV 240 (degradation products)INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS66
Implementation - ExampleAnalytical procedure - SpecificityResults of stress-testingConditionContentOD 14100%Pur. factorOD 140.9985ContentOM 08 0.1ContentOM 060.1ContentOM 380.2Totalothersnd2 hrs art. daylight80.3 %0.9985 0.10.30.20.31 wk 75 C/amb. RH83.6%0.99932.12.010.90.11 wk 75 C/100% RH4.6%-1.53.812.3nd2 hrs 1M HClndndnd 0.1900.72 hrs 1M NaOHndnd0.40.153.41.22 hrs 3% H2O291.4%0.9981 0.10.20.2 0.1Non stressedINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS67
Implementation- ExampleLegend1. Org OD 14 RT: 14.4 min2. Org 30205 RT 15.8 min3. OM 38 RT: 7.3 min4. OM 08 RT: 3.5 min5. OM 06 RT: 5.1 min6. OH 45 RT: 33.6 minINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS68
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS69
Implementation - ExampleAnalytical procedure - LinearityOD 14Concentrations of 1, 25, 50, 75, 100, 125 and 150% of 0.15 mg/mLDegradation productsConcentrations of 0.1, 0.5, 1.0, 1.5, 2.0, and 2.5% with respect toconcentration of OD 14 (0.15 mg/mL)Solutions prepared and injected in duplicate.Results evaluated for peak heights and peak areasINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS70
Implementation - ExampleAnalytical procedure - LinearitySummary of Results for OD 14CurveAreaLinear, 1 orderCorr.coefficient0.9999HeightLinear, 1st order0.99970.410.62CriteriaLinear 0.9990 0.05 NATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS71
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS72
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS73
Implementation - ExampleAnalytical procedure - AccuracySummary of Results for OD erion for mean recovery: 98-102%Criterion RSD: 2.0%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS74
Implementation - ExampleAnalytical procedure - AccuracySummary of Results for OM rionCriterionCriterionfor mean recovery at 0.1% : 70-130%for mean recovery at 1.0 and 2.0% : 90-110%RSD at 0.1% : 15%RSD at 1.0 and 2.0%: 5.0%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS75
Implementation - ExampleAnalytical procedure - RepeatabilityOD 14:Calculated from pooled standard deviation of the accuracy results coveringthe range from 70 to 130%Peak area: RSD 1.15%Peak height: RSD 1.06 %Criterion: 2.0%Degradation products:Calculated from accuracy results per concentration levelINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS76
Implementation - ExampleAnalytical procedure - Intermediate PrecisionScheme for testing of intermediate precision of OD 141Number mnc1AnalystPeak Area: RSD 1.71%Peak Height: RSD 1.65%Criterion: RSD 2.5%INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS77
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS78
Implementation- ExampleINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS79
Implementation - ExampleAnalytical procedure - System Suitability TestingCriteria obtained from validation dataRetention time (tR) of OD 14 (min)Number of theoretical plates (N)Tailing Factor (T)Rel. St. deviation (RSD) of reference solutionRatio of mean response factors of standards12.0 tR 16.0N 30000.9 T 2.0RSD 1.5%0.985 Q 1.015INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS80
Analytical ProductionLabINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS81
Implementation - TransferMDP 6-02“Analytical Method Transfer Procedure”INTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS82
MDP 6-02Implementation - Transfer- Select labs- Prepare protocol including:- detailed description of analytical method- samples to be tested- items to be checked: assay, precision (reproducibilty &intermediate precision), SST values- calculation formulas- way of reporting- Carry out analyses and report results- Perform statistical analysis on results and report on conclusionsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS83
Transfer - ExampleImplementation - TransferTest:OD 14 and degradation products in 1.25 mg tabletsLabs involved:Organon, Oss (NL)Organon, Swords (IRL)Tested on:Non-stressed and stressed (1 month 60 C/Amb. RH) tabletsINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS84
Implementation - TransferTransfer - ExampleTest schedule and criteria for transferAHPLCa pp ara tu sIHPLCc olu m nc11N um be r ofa na ly se s323AIIc233BIc1DayA na ly s tTo ta l: 9 re s ults for e a ch ty p e of s a m pleC rite ria for m e th od tra ns ferM eth od re pe a ta b ility 2.0 %D e grad a tio nprod uc ts 5%Inte rm ed ia te pre c isio n 2.5 % 10 % 3.0 %N o s ta t. s ign if.diffe re nc e or 2 % 15 %A s s ayR e prod uc ib ilityM ax . differe nc e of m e a nbe tw ee n lab sINTERNATIONALINTERNATIONAL QUALITYQUALITY SYSTEMSSYSTEMS85
THANK YOU FOR YOUR ATIONAL QUALITYQUALITY SYSTEMSSYSTEMS86
Validation guidelines 1. ICH Q2A Text on validation of analytical procedures: Definitions and terminology (March 1995) 2. ICH Q2B Validation of analytical procedures: Methodology (June 1997) 3. FDA (Draft) Guidance for Industry: Analytical procedures and methods validation 4. Pharmacopoeias USP and European Pharmacopoeia Guidelines
Keywords: analytical validation, pharmaceutical analysis, analytical method INTRODUCTION Analytical methods play an essential role in the adequate fulfillment of product quality attributes. However, the proper quality can only be reached if the analytical method undergoes an appropriate validation pr
contents of the tool box" used for validation. The methods and techniques listed in the report are grouped as - review - models - analysis - dynamic methods - methods regarding formality - development methods The validation methods have to be combined together in a validation plan. The plan shall list requirements and validation methods.
contents of the tool box" used for validation. The methods and techniques listed in the report are grouped as - review - models - analysis - dynamic methods - methods regarding formality - development methods The validation methods have to be combined together in a validation plan. The plan shall list requirements and validation methods.
Analytical Method Development and Validation of Bendamustine in Bulk Using RP-HPLC J Pharm Res Analytical Method Development and Validation of Bendamustine in Bulk Using RP-HPLC . Table 3: Variables in HPLC.-Hplc Method Validation is a key process for effective quality assurance. "Validation" is established documented .
The protocol on the validation study should include the follow-ing points in the validation study: 1) the purpose and scope of the analytical method, 2) the type of analytical method and validation characteristics, 3) acceptance criteria for each validation character-istics. Consideration on the following points will be useful to pre-
Cleaning validation Process validation Analytical method validation Computer system validation Similarly, the activity of qualifying systems and . Keywords: Process validation, validation protocol, pharmaceutical process control. Nitish Maini*, Saroj Jain, Satish ABSTRACTABSTRACT Sardana Hindu College of Pharmacy, J. Adv. Pharm. Edu. & Res.
Non-pharmacopoeial methods 141 5. Method validation 142 6. Method verification 143 7. Method transfer 8.144 Revalidation 145 9. Characteristics of analytical procedures 146 147 1. PRINCIPLE 148 149 1.1 This appendix presents some information on the characteristics that should be considered 150 during validation of analytical methods. Approaches .
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