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PHARM 462
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European and International regulatory bodies andtheir guidelines on different aspects of QA
Body
F ul l name Guidance on
Eurachem F ocus for Analytical Chemistry in Europe M ethod vali dation
CI TAC Cooperation of I nternational Traceabil ity inAnalytical Chemistry
Prof iciency testingQuali ty Assur ance
EA European Cooperation for Accreditation Accreditation
CEN European Committee for Normalization StandardizationI UPAC I nternational Uni on of Pure & Appli ed Chem. M ethod vali dation
I SO I nternational Standardization Organisation Standardisation
AOAC
ILAC
Association of Off icial A nalytical Chemists
I nternational L aboratory Accreditation Cooperat.
I nternal qual. ControlProf iciency testing
Accreditation
F DA US F ood and Dr ug Admini stration M ethod vali dation
USP Uni ted States Phar macopoeia M ethod vali dation
I CH I nternational Conf erence on H armonization M ethod vali dation
2 2009
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M ethod Validation
Validation of analytical procedures is the process of determining the
su i t ab i l i t y o f a g iven me thodo logy fo r p rov id ing u se fu l
analytical data.
J. Guerra, Pharm. Tech. M arch 1986
Validation is the formal and systematic proof that a method compiles
w i t h t h e r e q u i r e m e n t s f o r t e s t i n g a p r o d u c t w h e nobserving a defined procedures.
G. Maldener, Chromatographia, Ju ly 1989
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Method validation is the process of demonstrating that analytical
procedures are suitable for their intended use and that they supportthe identity, strength, quality, purity and potency of the
drug substances and drug products
Method validation is primarily concerned with:
identification of the sources of potential errors
quantification of the potential errors in the method
An method validation describes in mathematical and quantifiable
t e r m s t h e p e r f o r m a n c e c h a r a c t e r i s t i c s o f a n a s s a y
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Examples of M ethods That Requi re
Validation Documentation
Chromatographic Methods - HPLC, GC, TLC, GC/MS, etc.
Pharmaceutical Analysis - In support of CMC.
Bioanalytical Analysis - In support of PK/PD/Clinical Studies.
Spectrophotometric Methods UV/VIS, IR, NIR, AA, NMR,
XRD,MS
Capillary Electrophoresis Methods - Zone, Isoelectric Focusing
Particle Size Analysis Methods - Laser, Microscopic, Sieving, SEC, etc.
Automated Analytical Methods - Robots, Automated Analysis.
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Considerations Prior toM ethod Validation
Suitability of Instrument
Status of Qualification and Calibration
Suitability of MaterialsStatus of Reference Standards, Reagents, Placebo Lots
Suitability of Analyst
Status of Training and Qualification Records
Suitability of Documentation
Written analytical procedure and proper approved protocol
with pre-established acceptance criteria
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Validation Step Define the application, purpose and scope of the method.
Analytes? Concentration? Sample matrices?
Develop a analytical method.
Develop a validation protocol.
Qualification of instrument. Qualify/train operator
Qualification of material.
Perform pre-validation experiments.
Adjust method parameters and/or acceptance criteria if necessary. Perform full validation experiments.
Develop SOP for executing the method in routine analysis.
Document validation experiments and results in the validation report.
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Purpose of M ethod Validation
Identification of Sources and Quantitation of Potential errors
Determination if Method is Acceptable for Intended Use
Establish Proof that a Method Can be Used for Decision Making
Satisfy FDA Requirements
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What is not Analytical M ethod Validation?
Calibration
The Process of Performing Tests on Individual System
Components to Ensure Proper function
For example) HPLC Detector calibration
Wavelength Accuracy/ Linear Range/ Noise Level/ Drift
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System Suitability
Test to verify the proper functioning of the operating system,
i.e., the electronics, the equipment, the specimens and the
analytical operations.Minimum Resolution of 3.0 between the analyte peak and
internal standard peaks
Relative Standard Deviation of replicate standard injections
of not more than 2.0%
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11
System Suitability
Sample
Validation
Methodnalyst
Calibration
Pump
Detector
Injector
Data System
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M ethod L ife Cycle
12
Validation
Development Optimization
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Verif ication vs. Validation
Compendial vs. Non-compendial Methods
Compendial methods-Verification
Non-compendial methods-Validation requirement
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Compendial Analytical Pr ocedur es
The Analytical procedures in the USP 25/NF 20 are legally recognized under
section 501(b) of the Federal Food, Drug and Cosmetic Act as the regulatory
analytical procedures for the compendial items. The suitability of these
procedures must be verified under actual conditions of use. When using USP
25/NF 20 analytical procedures, the guidance recommends that information be
p r o v i d e d f o r t h e f o l l o w i n g
characteristics: Specificity of the procedure
Stability of the sample solution
Intermediate precision 142009
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Published Validation Guidelines
1978 Current Good Manufacturing Practices (cGMPs)1987 FDA Validation Guideline
1989 Supplement 9 to USP XXI
1994 CDER Reviewer Guidance:
Validation of Chromatographic Method
1995 ICH Validation Definitions:
Q2A, Text on Validation of Analytical procedures
1997 ICH Validation Methodology:
Q2B, Validation of Analytical Procedures: Methodology
1999 Supplement 10 to USP 23 : Validation of Compendial Methods
1999 CDER Bioanalytical Method Validation for Human Studies
2000 CDER Draft Analytical Procedures and Method Validation 152009
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Regulatory and ComplianceRequirements Review
Validation of an analytical method is the
process by which it is established, by
laboratory studies, that the performancecharacteristics of the method meet the
requirements for the intended analytical
applications
16
USP 23 GeneralInformation
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T h e a c c u r a c y, s e n s i t i v i t y, s p e c i f i c i t y, a n d
reproducibility of test methods employed by the firm
shall be established and documented. Such validation
and documentat ion may be accomplished in
a c c o r d a n c e w i t h 2 1 1 . 1 9 4 ( a ) ( 2 ) .
17
21 CFR PART 211 - CURRENT GOOD MANUFACTURINGPRACTICE FOR FINISHED PHARMACEUTICALS
Subpart I-Laboratory Controls
211.165 Testing and release for distribution (e)
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The objective of validation of an analytical
procedure is to demonstrate that it is suitablefor its intended purpose
18
ICH Guideline forIndustryQ2A, Text on
Validation ofAnalytical ProceduresMarch 1995
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In practice, it is usually possible to design the experimental
work such that the appropriate validation characteristicscan be considered simultaneously to provide a sound,overall knowledge of the capabilities of the analyticalprocedure, for instance: Specificity, Linearity, Range,
Accuracy, andPrecision.
19
ICH Guideline for IndustryQ2B, Validation of AnalyticalProcedures: Methodology
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Today s Validation Requirements
20
ICH/USP
GMPs
(legal) FDA
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I CH /USP Validation Requirements &Parameters
Specificity
Linearity
Range
Accuracy
Precision
Repeatability
Intermediate Precision
Reproducibility
Limit of Detection
Limit of Quantitation21
ICH
Specificity
Linearity and RangeAccuracy
Precision
Limit of Detection
Limit of QuantitationRuggedness
Robustness
USP
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USP Data Elements RequiredF or Assay Validation
22
AnalyticalPerformance
Parameter
AssayCategory 1
Assay Category 2Assay
Category 3Quantitative Limit Tests
Accuracy Yes Yes * *
Precision Yes Yes No Yes
Specificity Yes Yes Yes *
LOD No No Yes *
LOQ No Yes No *
Linearity Yes Yes No *
Range Yes Yes * *
Ruggedness Yes Yes Yes Yes
* May be required, depending on the nature of the specific test.2009
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USP Categories
Category 1: Quantitation of major components or
active ingredients
Category 2: Determination of impurities or
degradation products
Category 3: Determination of performancecharacteristics
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I CH Validation Character istics vs.Type of Analytical Procedure
24
Type ofAnalyticalProcedure
IdentificationImpurity testing
AssayQuantitative Limit Tests
Accuracy No Yes No Yes
Precision
Repeatability No Yes No Yes
Interm. Prec. No Yes No Yes
Specificity Yes Yes Yes Yes
LOD No No Yes No
LOQ No Yes No No
Linearity No Yes No Yes
Range No Yes No Yes2009
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Specificity/Selectivity Ability of an analytical method to measure the analyte free from
interference due to other components .
Selectivity describes the ability of an analytical method to differentiate
various substances in a sample
Original term used in USP
Also Preferred by IUPAC and AOAC
Also used to characterize chromatographic columns
Degree of Bias (Used in USP)
The difference in assay results between the two groups
- the sample containing added impurities, degradation products, related chemical
compounds, placebo ingredients
- the sample without added substances
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Specif ici ty: I mpur ities Assay
Chromatographic Methods
Demonstrate Resolution
Impurities/Degradants Available
Spike with impurities/degradants
Show resolution and a lack of interference
Impurities/Degradants Not Available
Stress SamplesFor assay, Stressed and Unstressed Samples should becompared.
For impurity test, impurity profiles should be compared.
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F orced Degradation Studies
Temperature (50-60 )
Humidity (70-80%)
Acid Hydrolysis (0.1 N HCl)
Base Hydrolysis (0.1 N NaOH)
Oxidation (3-30%)
Light (UV/Vis/Fl)
Intent is to create 10 to 30 % Degradation
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Linearity
Ability of an assay to
elicit a direct and
proportional response
to changes in analyte
concentration.
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L inearity Should be Evaluated
By Visual Inspection of plot of signals vs. analyte
concentration
By Appropriate statistical methodsLinear Regression (y = mx + b)
Correlation Coefficient, y-intercept (b), slope (m)
Acceptance criteria: Linear regression r 2 > 0.95
Requires a minimum of 5 concentration levels
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Range
Acceptable range having linearity, accuracy, precision.For Drug Substance & Drug product Assay
80 to 120% of test Concentration
For Content Uniformity Assay
70 to 130% of test Concentration
For Dissolution Test Method
+/- 20% over entire Specification Range
For Impurity Assays
From Reporting Level to 120% of Impurity Specification for Impurity
Assays
From Reporting Level to 120% of Assay Specification for Impurity/Assay
Methods302009
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Accuracy
Closeness of the test
results obtained by the
method to the true value.
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Accuracy Should be established across specified range of
analytical procedure.
Should be assessed using a minimum of 3 concentrationlevels, each in triplicate (total of 9 determinations)
Should be reported as:
Percent recovery of known amount added orThe difference between the mean assay result and the accepted
value
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Accuracy Data Set (1 of 3)
33
AmountAdded (mg)
AmountFound (mg)
PercentRecovery
0.0 0.0 ---
50.2 50.4 100.5
79.6 80.1 100.6
99.9 100.7 100.8
120.2 119.8 99.7
150.4 149.7 99.5
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Precision
The closeness of agreement (degree of
scatter) between a series of
measurements obtained from
multiple samplings of the same
homogeneous sample.
Should be investigated using
homogeneous, authentic samples.
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Precision Considered at 3 L evels
Repeatability
Intermediate Precision
Reproducibility
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Repeatabil i ty
Express the precision
under the same
operating conditions
over a short interval of
time.
Also referred to as
Intra-assay precision
36
Should be assessed
using minimum of 9
determinations(3 concentrations/ 3
replicates) r
Minimum of 6determinations at the
100 level.
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I ntermediate Precision
37
Express within-laboratory
variations.
Expressed in terms of
standard deviation,
relative standard deviation
(coefficient of variation)
and confidence interval.
Depends on the
circumstances under which
the procedure is intended
to be used.
Studies should include
varying days, analysts,
equipment, etc.
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Repeatabil i ty & I ntermediate Precision
Day 1 Day 2100.6 99.5
100.8 99.9
100.1 98.9
100.3 99.2
100.5 99.7
100.4 99.6
38
GrandMean = 100.0RSD = 0.59
Mean = 100.5RSD = 0.24 Mean = 99.5RSD = 0.36
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Reproducibil i ty
Definition: Ability reproduce data
within the predefined precision
Determination: SD, RSD and
confidence interval
Repeatability test at two different
labs.
Note: Data not required for BLA/NDA
Lab 1 Lab 2 Lab 3
Day1 Day2 Day1 Day2Day1 Day2
Man1
Man2
Man1
Man 2 Man1
Man2
3Prep
3Prep
3Prep
3Prep
3Prep
3Prep
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Detection L imit (LOD)/Quantitation L imit (L OQ)
LOD
Lowest amount of analyte in a
sample that can be detected
but not necessarily
quantitated.
Estimated by Signal to Noise
Ratio of 3:1.
40
LOQ
Lowest amount of analyte
in a sample that can be
quantified with suitable
accuracy and precision.
Estimated by Signal to
Noise Ratio of 10:1.
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1. Based in Visual Evaluations
- Used for non-instrumental methods
2. Based on Signal-to Noise-Ratio
- 3:1 for Detection Limit
- 10:1 for Quantitation Limit
3. Based on Standard Deviation of the Response and
the Slope
41
LOD and LOQ Estimated by
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S = slope of calibration curve
s = standard deviation of blank readings or
standard deviation of regression line
Validated by assaying samples at DL or QL
42
DL =3.3s
QL =10s
S S
LOD and LOQ Estimated by
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43
Ybl
LOD LOQ
Statistical estimate of LOD & LOQ
LOD = 3.3 Sbl / b LOQ = 10 Sbl / b
Y = b X + a
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Definition: Capacity to remain unaffected by small but deliberate
variations in method parameters
Determination: Comparison results under differing conditions
with precision under normal conditionsExamples of typical variations in LC
Influence of variations of pH in a mobile phase
Influence of variations in mobile phase composition
Different columns (different lots and/or suppliers)
Temperature
Flow rate
44
Robustness
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Ruggedness
Degree of reproducibility of test results
under a variety of conditions
Different Laboratories
Different Analysts
Different Instruments
Different Reagents
Different Days
Etc.
Expressed as %RSD
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I CH /USP System Suitabili ty
ICH
Definition: evaluation of equipment, electronic,analytical operations and samples as a whole
Determination: repeatability, tailing factor (T), capacity
factor (k ), resolution (R), and theoretical Plates (N)
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USP 23
System Suitability Requirements
47
Parameters Recommendations
K In general k 2.0
RR > 2, between the peak of interest and theclosest potential interferent (degradant,internal STD, impurity, excipient, etc ..)
T T 2 N In general N > 2000
Repeatability RSD 2.0 (n 5)
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Re-validation
When Method parameters have been changed The scope of the method has been changed
Synthetic methods have been changed Impurity profile has been changed
What Preferably everything. Exceptions should be
scientifically justified
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H ow do we Know the expectations ofthe F DA?
FDA Form 483FDA Warning Letters
Personal Experiences
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483 ObservationsThere was inadequate method validation specificity
data to demonstrate that each method was capable ofdistinguishing 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 identifies themajor degradation products
was not included for each product.502009
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F DA Waning Letter
On addition to the example of modifying both compendialmethods and customer supplied methods, we also observedthe use of unvalidated in-house methods as well as
u n v a l i d a t e dmodifications to in-house methods.
A statement indicating that the method has not beenvalidated in the particular formulation was included in thecertificate of analysis for use of this statement does nota b s o l v e f r o m 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)
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F DA Systems Based I nspection: L aboratory System
52
MethodValidation
13
Training/Qual.
4Stability Program
21
InadequateRecords
27
Controls. General35
Feb July 2002: 212 Inspections (US)
* Reference: Albinus D Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 presentation.
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ICH Update:
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A Unique Approach
International Conference on Harmonisation(ICH) was created in 1990
Agreement between the EU, Japan and theUSA to harmonize different regional requirements for registration of pharmaceuticaldrug productsUnique because joint effort by regulators andassociated pharmaceutical industry tradeassociations
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ICH Objectives
Identification and elimination of the need to duplicatestudies to meet different regulatory requirementsMore efficient use of resources in the R&D process,as a consequenceQuicker access for patients to safe and effective newmedicines
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Working Groups
SAFETY EFFICACY
QUALITY MULTIDISCIPLINARY
STEERING COMMITTEEEndorses topics, guidelines and monitors progress
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Related Site
www.fda.gov
www.fda.gov/cder/
www.waters.com
www.usp.org
www.ich.org
www.aoac.org
www.pharmweb.net
http://www.fda.gov/http://www.fda.gov/cder/http://www.waters.com/http://www.usp.org/http://www.ich.org/http://www.aoac.org/http://www.pharmweb.net/http://www.pharmweb.net/http://www.aoac.org/http://www.ich.org/http://www.usp.org/http://www.waters.com/http://www.fda.gov/cder/http://www.fda.gov/