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VALIDATION OF ANALYTICAL VALIDATION OF ANALYTICAL METHODSMETHODS
Validation
FDA-guidelines: Validation is establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes
EU-guidelines: Action of proving, in accordance with GMP-principles that any procedure, process, equipment, material, activity or system actually leads to the expected results
ICH
“Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use”
Why validation?
1. GMP-legislation 2. Good economics3. Good science practices
The Purpose Of Analytical Method Validation
Identification of Sources and Identification of Sources and QuantitationQuantitation of potential of potential errorserrors
Determination if Method is Acceptable for Intended UseDetermination if Method is Acceptable for Intended Use
Establish Proof that a Method Can be Used for Decision Establish Proof that a Method Can be Used for Decision MakingMaking
Satisfy FDA RequirementsSatisfy FDA Requirements
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 Guidance for Industry: Analytical procedures and methods validation 4. Pharmacopoeias USP and European Pharmacopoeia
Method Validation Strategy
1. Develop a validation protocol or operating procedure for the validation2. Define the application, purpose and scope of the method3. Define the performance parameters and acceptance criteria4. Define validation experiments5. Verify relevant performance characteristics of equipment6. Qualify materials, e.g. standards and reagents7. Perform pre-validation experiments8. Adjust method parameters or/and acceptance criteria if necessary9. Perform full internal (and external) validation experiments10. Develop SOPs for executing the method in the routine11. Define criteria for revalidation12. Define type and frequency of system suitability tests and/oranalytical quality control (AQC) checks for the routine13. Document validation experiments and results in the validation report
What methods to be validated?
Defined for: identification quantitative tests for content of impuritieslimit tests for control of impurities quantitative tests for active moiety in drug substances and drug products
Referred to: -dissolution testing
Validation SOPValidation SOP
What is it?
- It is your laboratory’s documented
procedure/philosophy that describes:
What methods require validation
Who is responsible for performing validation
How much validation will be done for different methods
How the validation process will be documented
Validation SOPValidation SOPContent
- Purpose
This document describes the procedures for validating analytical methods in the XYZ Pharmaceutical Company
- Scope
This document applies to all analytical methods used for releaseand stability testing
- Responsibilities
State who will
- Prepare the validation protocol/guideline
- Review and approve the protocol
- Prepare the validation report
- Review and approve the validation report
- DefinitionsDefine any unique of ambiguous terms used within your company
- Compendial, selectivity/specificity, evaluation criteria, etc.
- Validation of non-compendial methodsNoncompendial methods will be evaluated according to the current ICH/FDA guidelines
- Validation of compendial methodsCompendial methods used for their intended compendial material will be tested for sepcificity, intermediate precision,and sample solution stability.Compendial methods used for non-compendial materials will be validated according to the current ICH and FDA guidelines
-- Revalidation of methodsRevalidation of methods
state your process for state your process for
-- Updating validation for older productsUpdating validation for older products
-- Revalidating when changes in synthesis, formulation, or analyticRevalidating when changes in synthesis, formulation, or analytical al
procedure occurprocedure occur
-- Validation reportsValidation reports
state who is responsible for writing, reviewing, approving, state who is responsible for writing, reviewing, approving,
and archivingand archiving
Validation ProtocolValidation Protocol
It is a description of…– How specific validation studies will be performed for a given
type of method
– How results will be evaluated for acceptability
It is an opportunity to document your customer’s needs, and their acceptance of your plan
Validation ProtocolValidation Protocol
Example content:
– Linearity-standard solutions will be prepared and
analyzed at 5 levels over the range of 80 to 120%
of the target concentration. This will be
performed in triplicate.
– Repeatability precision-a homogeneous
sample will be analyzed 6 times.
Validation SpecificationValidation Specification
How good to my validation results need to be?
– Agree on the acceptance criteria (specifications) before
beginning the validation.
– Acceptance criteria should be based on
- The intended use of the method
- Sufficient experience with the method
Validation SpecificationValidation Specification
Examples
– Linearity-standard curves will have correlation
coefficients ≥ 0.99 and y-intercept values less than 2%
of the target level response.
– Repeatability precision-the test results will have a RSD
≤ 2%.
Considerations Prior to Considerations Prior to Method ValidationMethod Validation
Suitability of Instrument Suitability of Instrument
Status of Qualification and Calibration Status of Qualification and Calibration
Suitability of Materials Suitability of Materials
Status of Reference Standards, Reagents, Placebo Lots Status of Reference Standards, Reagents, Placebo Lots
Suitability of Analyst Suitability of Analyst
Status of Training and Qualification Records Status of Training and Qualification Records
Suitability of Documentation Suitability of Documentation
Written analytical procedure and proper approved protocol with pWritten analytical procedure and proper approved protocol with prere--
established acceptance criteriaestablished acceptance criteria
Reference StandardsReference Standards
ICH states that “Well characterized reference
materials, with documented purity, should be
used throughout the validation study.”
Method validation parametersMethod validation parameters
SpecificitySpecificity
PrecisionPrecision–– RepeatabilityRepeatability–– Intermediate PrecisionIntermediate Precision
LinearityLinearity
RangeRange
AccuracyAccuracy
Limit of Detection (LOD)Limit of Detection (LOD)
Limit of Limit of QuantitationQuantitation (LOQ)(LOQ)
RobustnessRobustness
Specificity
Definition:Ability to assess unequivocally the analyte in the presence of components which may be expected to be present (impurities, degradants, matrix).Aspects:-Identification-Purity tests-Assay (Content/potency)
Specificity: Identification Identification
Should be able to discriminate between compounds Should be able to discriminate between compounds closely related in structure.closely related in structure.
Confirmed by obtaining negative results for samples with Confirmed by obtaining negative results for samples with spiked related compounds and positive results for spiked related compounds and positive results for samples with samples with analyteanalyte..
Choice of potential interfering substances should be Choice of potential interfering substances should be based on sensible scientific judgment considering based on sensible scientific judgment considering substances that could likely occur.substances that could likely occur.
Specificity: Impurities/AssaySpecificity: Impurities/Assay
Chromatographic MethodsChromatographic Methods–– Demonstrate Resolution of critical pairDemonstrate Resolution of critical pair
NonNon--specific method use other supporting analytical procedures e.g. specific method use other supporting analytical procedures e.g. titration+TLCtitration+TLC
Impurities/Impurities/DegradantsDegradants Available Available –– Spike with impurities/Spike with impurities/degradantsdegradants and/or and/or excipientsexcipients
–– For assay, compare with For assay, compare with unspikedunspiked samplessamples
–– For impurity test, impurities are separated individually and froFor impurity test, impurities are separated individually and from sample matrixm sample matrix
Impurities/Impurities/DegradantsDegradants NotNot AvailableAvailable–– Stress SamplesStress Samples
–– For assay, Stressed and Unstressed Samples should be compared.For assay, Stressed and Unstressed Samples should be compared.
–– For impurity test, impurity profiles should be compared.For impurity test, impurity profiles should be compared.
–– Demonstrate peak purity (HPLCDemonstrate peak purity (HPLC--DAD, mass)DAD, mass)
Stress conditionsStress conditions
Heat Heat High Temperature (50 to 60 High Temperature (50 to 60 ooCC))
Humidity Humidity HumidityHumidity (70 to 80%)(70 to 80%)
Acid Hydrolysis Acid Hydrolysis (0.1 N (0.1 N HClHCl))
Base Hydrolysis Base Hydrolysis (0.1 (0.1 NaOHNaOH))
Oxidation (Oxidation (3 to 30% H3 to 30% H22OO22))
LightLight
Intent is to create 10 to 30 % Degradation
LinearityDefinition:Ability (within a specified range) to obtain test results which are directly proportional to the concentration of analyte in the sample
Aspects:– Test across the range (at least 5 concentrations)– Evaluate linearity by– visual inspection of the plot and by– statistical techniques
Calculate corr. coefficient, y-intercept, slope and residualsResponse factor
Range
Definition: Interval between upper and lower concentration of the analyte in the sample for which it has been demonstrated that the procedure has a suitable level of precision, accuracy and linearity Aspects:– Defined from linearity study– Depends on the application of the method
assay (80-120 %)content uniformity (70-130%)dissolution test(± 20 % over the specified range)Impurity from specs to 120 % of the specs
AccuracyDefinition: Expresses the closeness of agreement between the value found and the true value.Methods: Drug substance – use of reference standard with known purity– comparison with independent, well-characterized procedure – may be inferred once precision, linearity and specificity are
establishedMethods: Drug product– Analysis of synthetic mixture– comparison with independent, well-characterized procedure– Standard addition method
Methods: Drug product– Spiking– comparison with independent, well-characterized procedure
Accuracy
Recommended data – Assessed by 9 determinations over a minimum of 3
concentration levels covering the specified range – To be reported as percent recovery or difference
between mean and true value with confidence interval
Precision
Definition – Closeness of agreement (‘scatter’) between a series
of measurements obtained from multiple sampling of the same homogeneous sample.
Aspects – Repeatability – Intermediate precision – Reproducibility
PrecisionPrecisionRepeatabilityRepeatability–– Precision under the same conditions over a short interval of timPrecision under the same conditions over a short interval of time.e.–– MethodMethod
9 determinations covering the specified range 9 determinations covering the specified range or: 6 determinations at 100% of the test concentrationor: 6 determinations at 100% of the test concentration
Intermediate precision– Expresses within laboratory variations. – Method
Should include variations in days, analysts, columns
Reproducibility– Precision between laboratories – Method
-Dependent on usage of method -Should include interlaboratory study
Recommended dataRecommended data–– SD, RSD and confidence intervalSD, RSD and confidence interval
Detection limit
Lowest amount of an analyte in a sample which can be detected but not necessarily quantitated.Method
1. Based on visual evaluation2. Based on signal-to-noise ratio (3:1)3. Based on st.dev. (SD) of response and slope
(DL=3.3xSD/S)Recommended dataRecommended data–– DL and relevant chromatograms for 1&2DL and relevant chromatograms for 1&2–– For 3, Estimated DL is validated by analysis of For 3, Estimated DL is validated by analysis of
samples at the DLsamples at the DL
Quantitation limit
Lowest amount of an analyte in a sample which can be quantitatively determined with a suitable precision and accuracy Method– Based on visual evaluation– Based on signal-to-noise ratio (10:1)– Based on st.dev. (SD) of response and slope
(DL=10xSD/S)Recommended dataRecommended data–– QL and relevant chromatograms for 1&2QL and relevant chromatograms for 1&2–– For 3, Estimated QL is validated by analysis of For 3, Estimated QL is validated by analysis of
samples at the DLsamples at the DL
Signal-to Noise-Ratio
Robustness
Measure of the capacity of a method to remain unaffected by small variations in method parameters.– Aspects
To be considered during developmentTo be used for establishment of system suitability criteriaInclude testing of stability of solutionsTo be tested by introducing small variations in method parameters
System Suitability Test
ICHICH
–– Definition: evaluation of Definition: evaluation of
equipment, electronic, equipment, electronic,
analytical operations and analytical operations and
samples as a wholesamples as a whole
–– Determination: repeatability, Determination: repeatability,
tailing factor (T), capacity tailing factor (T), capacity
factor (kfactor (k’’), resolution (R), ), resolution (R),
and theoretical Plates (N)and theoretical Plates (N)
T T ≤≤ 22TT
RSD RSD ≤≤ 2.0% (n 2.0% (n ≥≥ 5)5)RepeatabilityRepeatability
In general N > 2000In general N > 2000NN
R > 2, between the peak of R > 2, between the peak of interest and the closest interest and the closest potential interferent potential interferent ((degradantdegradant, internal STD, , internal STD, impurity, excipient, etcimpurity, excipient, etc……..)..)
RR
In general kIn general k’’ ≥≥ 2.02.0KK’’
RecommendationsRecommendationsParametersParameters
USP 23 <621>USP 23 <621>–– System Suitability RequirementsSystem Suitability Requirements
Recommended Validation characteristics of various Types of Tests
*YesYesYesYesRuggedness
***YesYesRange**NoYesYesLinearity**NoYesNoLOQ**YesNoNoLOD
Yes*YesYesYesSpecificity*YesNoYesYesPrecision***YesYesAccuracy
Assay Assay Category Category
IVIV
Assay Assay Category Category
IIIIII
Assay Assay Category IICategory IILimit testLimit test
Assay Assay Category IICategory II
QuantitativeQuantitative
Assay Assay Category ICategory I
AnalyticalAnalyticalPerformancePerformance
ParameterParameter
483 Observations483 Observations
There was no inadequate method validation specificity data to demonstrate that each method was capable of distinguishing the active ingredient from its impurities and degradation products.Specificity studies did not include the minimum stress conditions of acid and base hydrolysis, oxidation, thermal degradation and photolysis, degradation schematic for the active ingredient that ident i f ies the major degradat ion products
was not included for each product.
483 Observations483 Observations
Stress studies conducted as part of method validation do not target a minimum amount of degradation. … a standard period of two hours as commonly used for stress studies with no
justification…Spreadsheets used to calculate linearity, percent recovery, and final assay results for the cleaning validation of …were not validated and the data transcribed from chromatographs to the s p r e a d s h e e t s w e r e n o t c h e c k e d f o r a c c u r a c y .
FDA Waning LetterFDA Waning Letter
On addition to the example of modifying both compendialmethods and customer supplied methods, we also observed the use of unvalidated in-house methods as well as unvalidated
modifications to in-house methods.A statement indicating that the method has not been validated in the particular formulation was included in the certificate ofanalysis for…use of this statement does not absolve…from u s i n g v a l i d , a c c u r a t e , a n d
reproducible methods. (June 2000)
FDA Warning LetterFDA Warning Letter
Change control procedures in the laboratory failed to document test method changes to assure accurate, reliable, and reproducible results. The test method did not state whether a helix was to be used during dissolution testing. A … was reportedly used during method development, validation and daily method runs, but there is no documentation of a … being
used in any of the documents.
There is no assurance that qualification or maintenance of the laboratory equipment can consistently produce valid and accurate analytical results in that numerous examples of test data were invalidated due to instrument malfunction.
(December 2000)
FDA Warning LetterFDA Warning Letter
Attempts to corroborate data in the validation report with suppoAttempts to corroborate data in the validation report with supporting rting
raw data in the laboratory were difficult and frustrating for thraw data in the laboratory were difficult and frustrating for the FDA e FDA
p e r s o n n e l c o n d u c t i n g t h e i n s p e c t i o n .p e r s o n n e l c o n d u c t i n g t h e i n s p e c t i o n .
OOS accuracy results reported by analyst 3 were never submitted OOS accuracy results reported by analyst 3 were never submitted in in
the final report. Repeat analysis performed in a different systethe final report. Repeat analysis performed in a different system m
p a s s e d s p e c i f i c a t i o n s a n d t h e s e r e s u l t s w e r e p a s s e d s p e c i f i c a t i o n s a n d t h e s e r e s u l t s w e r e
submitted in the report.submitted in the report.
Raw data and calculations were not checked by a second responsiRaw data and calculations were not checked by a second responsible ble
individuals required by your procedures. Inaccurate calculationsindividuals required by your procedures. Inaccurate calculations were were
n o t e d i n t h e r e p o r t . ( N o v e m b e r 1 9 9 7 ) n o t e d i n t h e r e p o r t . ( N o v e m b e r 1 9 9 7 )
FDA Warning LetterFDA Warning Letter
The process validation samples were assays using an HPLC method that had not been validated. The method validation used for bothproducts … did not include a protocol that included specification and acceptance criteria. … The method validation was not reviewed and approved until during the current inspection. Lots of both products were released for distribution prior to completion of the method v a l i d a t i o n . ( A u g u s t 2 0 0 1 )
Method validation for the product Sennosides is inadequate in that the data does not assess all variables, such as different mobile phase concentrations and analytes, to demonstrate that the method can s u s t a i n v a r i a n c e . ( N o v e m b e r 2 0 0 1 )
Recent 483s and warning lettersRecent 483s and warning letters
HPLC SST did not include limits for HPLC SST did not include limits for RsRs, T, N., T, N.Limits of Limits of quantitationquantitation and detection not and detection not established for individual bulk drug impurities.established for individual bulk drug impurities.Impurity peaks in HPLC assay not identifiedImpurity peaks in HPLC assay not identifiedSample dilution not recordedSample dilution not recorded
Validation of the assay method of active compounds
by HPLC
Selectivity
Tests – Inject solutions of standard, product, impurities,
known degradation 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% RH24 hrs 3% H2O2, 1 mol/L HCl, 1 mol/L NaOH
– Demonstrate separation – Demonstrate peak purity
Selectivity
Criteria – Separation between relevant peaks of at least Rs > 2.0 – Peak of analyte should be pure
Documentation – Chromatograms of all solutions – retention times – peak purity results – data of contents of active substance and degradation products in
stress samples
Linearity
Tests – Inject solutions of 25%, 50%, 75%, 100%, 125% and 150% of
expected 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 the range of 70-130%.
Linearity
Criteria 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 intercept
or in case of second order curve:-if experimental rel. response at 70% and 130% does not deviate by more than 1% from the calculated values
– -Linear when corr. coefficient > 0.9990
Linearity
Documentation Plots of peak height and peak areas
Statistical results (equations, significance of intercept,, response factor, corr. coefficient)
Plots of peak area and peak heights residuals
Accuracy
Test Prepare placebo sample Prepare spiked placebo samples: 3 replicates over 3 concentration levels (e.g. 70%, 100%, 130% of theoretical strength)Carry out the method Calculate mean percent recoveries and rel. standard deviation (RSD) from both peak area and peak height responses.
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 RSD
Repeatability of system
Test Inject in six-fold one of the 100% solutions from the accuracy experiment Calculate RSD for both peak height and peak area
Criterion RSD < 1.5%
Documentation Results and statistical calculation
Repeatability of method Test
Test– Analyze within one day by one operator with one column 6
– times a homogeneous sample of the product -Calculate the RSD for results of both peak height and peak area
Criterion – RSD < 2%
Documentation – Results and statistical calculation
Intermediate precision
Test -Same as for repeatability of the method but by at least 2 analysts, more days, different labs, different (batches of) columns -Calculate the RSD on overall results
Criterion RSD < 2.5%
Intermediate precision
Documentation– Description of preparation of homogeneous sample– Description of experimental conditions – Results and statistical evaluation
Detection and quantitation limit
Determination not necessary Only applicable for impurities and degradation products
Range
No specific test:Normally a range of 70-130% is acceptable, unless
a wider range is required based upon the nature of the dosage form (e.g. metered dose inhalers)
Robustness
Test on stability of solutions– Prepare 2 sample and 2 reference standard solutions -Store in
refrigerator and at room temperature – Analyze at zero time and after at least 24 and 72 hours storage -
Calculate differences between samples
Criterion– Storage period is defined by period with no more than 1%
difference between room temperature and refrigerator
Documentation–– Individual results Individual results –– Calculations, difference between room and refrigerator samplesCalculations, difference between room and refrigerator samples
Robustness (2) Test on variations– Vary relevant analytical parameters e.g.
composition and/or pH of mobile phasecolumn temperature different column (other batch or brand/supplier) stability of chromatographic system
Criteria– Chromatographic results meet system suitability criteria – Typically plate count should not decrease by more than 50%
DocumentationRelevant chromatogramsCalculations and results of system suitability parameters
System Suitability Testing Test
– 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 analyte and most-difficult-to-resolve impurity/degradation product
System Suitability Testing
Criteria – Criteria dependent on development and validation
results. – Evaluate and optimise defined criteria when more
experience is gained with the method. Documentation-Summary of data on individual parameters-Calculations and relevant chromatograms
Validation Of The Determination Of An Impurity In A Drug Product By HPLC
Selectivity
Tests and documentation – Same as for determination of active substance.
Criteria – -Assay of impurity should not be influenced by any other peak
originating 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.
Linearity
Tests – Inject solutions of 10%, 50%, 100%, 150%, and 200% of
expected concentration in duplicate (concentration based upon registered limit; if not defined then 1%);
– Calculate by statistical techniques the order of function (first or second), significance of intercept and correlation coefficient
– In case of second order and/or significant deviation of intercept from zero: determine the deviation in the relative response of the 10% and 200% points.
Linearity
Criteria – 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 intercept
– or in case of second order curve:
if deviation of the rel. response of 10% point isd less than 20% and of the 200% point is less than 5%values-Linear when corr. coefficient > 0.995
Linearity
Documentation (same as for DS) – Plots of peak height and peak areas
– Statistical results (equations, significance of intercept, lack-of-fit test, rel. responses, corr. coefficient)
– -Plots of peak area and peak heights residuals
Range
No specific test:Normally a range of 10-200% is acceptable. In most cases 100% is 1% relative to the drug substance.
Accuracy
Test – Prepare placebo sample– Prepare spiked placebo samples: 3 replicates over 3
concentration levels (e.g. 2 x QL, 100% and 200% of 1% of the drug substance concentration)
– Perform analysis – Calculate mean percent recoveries and rel. standard
deviation (RSD) from both peak area and peak height responses.
Accuracy
Criteria -The average result of the mean for 100% and 200% level should
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 RSD
Repeatability of system
Test – Inject in six-fold one of each of the strengths of the reference
solutions from the accuracy experiment – Calculate RSD for both peak height and peak area
Criterion – RSD (2xQL) < 15%; RSD (100% and 200%) < 5%
Documentation – Results and statistical calculation
Repeatability of method
Test – -Inject in six-fold one of each of the strengths of the samples
used in the accuracy experiment – -Calculate the RSD for results of both peak height and peak area
Criteria – RSD (2xQL) < 15%;– RSD (100% and 200%) < 5%
Documentation– Results and statistical calculation
Intermediate precision
Test and documentation– Same as for assay but tested on spiked samples at
1% level
Criterion RSD < 10%
Detection and quantitation limit
Test – Determine peak-to-peak distance of baseline at the
position of the analyte in a blank sample. Calculate noise as 0.5 times this distance
– Calculate the detection limit as 3 times noise and quantitation limit as 10 times noise
– Verify the calculated DL and QL by injecting at least one solution with a concentration at or near the DL and QL.
Detection and quantitation limit
Criterion – The Quantitation Limit is, by preference, less than
0.1% relative to the drug substance. Documentation– Chromatograms used for calculations -Chromatogram of sample
at a concentration near DL and QL
Robustness (1)
Test and documentation on stability of solutions– Same as for assay
Criterion– Storage period is defined by period with no more
than 5% difference between samples stored at room temperature and in the refrigerator
Robustness
Test, Criteria and Documentation on variations – Same as for assay
System Suitability Testing
Test, Criteria and Documentation – Same as for Assay
“Analytical Method Transfer Procedure”
Select labs- Prepare protocol including:– detailed description of analytical method– samples to be tested– items to be checked: assay, precision (reproducibility & intermediate
precision), SST values– calculation formulas– way of reporting
- Carry out analyses and report results- Perform statistical analysis on results and report on conclusions
c1 I B 33
c2 II A 32
c1 I A 31
HPLC column HPLC apparatus
Analyst Number of analyses
Day
Test schedule and criteria for transfer
No stat. No stat. signifsignif. . difference or < 2%difference or < 2%
Max. difference of meanbetween labs
< 15%< 3.0%< 3.0%Reproducibility< 10%< 2.5%< 2.5%Intermediate precision< 5%< 2.0%< 2.0%Method repeatability
DegradationDegradationproductsproducts
AssayAssayCriteria for method transfer
Specificity
<0.1 0.20.2<0.1 0.998191.40%2 hrs 3% H2O2
1.253.40.10.4ndnd2 hrs 1M NaOH
0.790<0.1 ndndnd2 hrs 1M HCl
nd12.33.81.5-4.60%1 wk 75°C/100% RH
0.110.922.10.999383.60%1 wk 75°C/amb. RH
0.30.20.3<0.1 0.998580.30%2 hrs art. daylight
nd0.20.1<0.1 0.9985100%Non stressed
Total Contentothers
Content OM 38
ContentOM 06
Pur. factor OM 08
ContentOD 14
Condition
Results of stress-testing
Validation Report
ContentsContents–– TitleTitle–– SummarySummary–– Validation dataValidation data–– DiscussionDiscussion–– Conclusion Conclusion
Validation Report
Summary– Simple statement about the results of the validation
study. – Example, “The method for the assay of product XYZ
by HPLC was found to be accurate, precise, selective, linear and stability indicating.”
Validation Report
Analytical Validation Data– Analytical data should be presented in tabular and
graphical form.– Copies of raw data (chromatograms and notebook
pages)– Analytical results for each validation parameter, plus
all calculations used. Be sure to include all graphs, curves and).
Validation Report
Discussion– Describe the outcome of the validation in
detail. – Problems encountered and rationale for
accepting or rejecting the validation. – Repeated experiments. – Deviations from acceptance criteria must be
explained. – Restrictions.
conclusions
8585
References References ICH Q2A
ICH Q2B
21 Code of Federal Registrations Part 210 and 211
Michael E. Swatrz and Ira S. Krull, Analytical method development and validation. Marcel Dekker, Inc. New York, 1997.
USP 23 <1225>
http://www.waters.com