Verification of Compendial Methods

Verification of
Compendial Methods
..

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Scopes :
Overview
- Asean Analytical Validation Guidelines
Verification of Compendial Methods
- EDQM
- AOAC
- USP
- ACTD
- BDN ?
2
From ASEAN Analytical Validation Guidelines
Type of Analytical
Identification Testing for Impurities Assay
Procedure
Performance -dissolution
Quantitative Limit test
Characteristic -content/potency
Accuracy - + - +
Precision
Repeatability - + - +
Interm.Precision - + - +
Specificity + + + +
LOD - - + -
LOQ - + - -
Linearity - + - +
Range - + - +
3
Specificity:
The ability to measure accurately and specificity the

analyte in the presence of components that may be
expected to be present in the matrix
The degree of interference :

- Active ingredients
- Excipients
- Impurities
- Degradation Products
- etc
4
Specificity:
Identification Tests
- Demonstrate ability to select between compounds of
closely related structure
- confirm positive and negative results
Assay
- Demonstrate that the results are unaffected by spiked
impurities or excipients
Impurities
- Spike the drug product/substance with impurities and
demonstrate appropriate accuracy and precision
5
Specificity:
Impurities are available

- Demonstrate that the assay is unaffected by the
present of spiked material (impurities and/or excipients)
Impurities are not available
- Compare test results to a second well-characterized
procedure
- For assay : compare the two result
- For Impurity Tests : compare purity profiles
- Peak Purity Test (e.g. PDA, MS)
6
Linearity:
The ability of the method to elicit test results that
are directly proportational to concentration within a
given range
Range:
Interval between upper and lower levels of analyte
demonstrated by the method
Precision and accuracy expressed in the same units
as the test results
7
Evaluation of Linearity
- Established across the range of the method
- Dilutions
- Separate weighings
- Evaluate by appropriate statistical methods
(e.g.regression)
- include correlation coefficient, y-intercept,
slope, plot
- Minimum 5 concentrations
8
Determination of appropriate range
Minimum specified range :

- assay : 80-120%
- Impurity test : from QL to 120% spec
- Content unformity : 70-130% test conc
- Dissolution testing : +/- 20% over specified range
9
Precision:
The measure of the degree of agreement among

test results when the method is applied repeatedly
to multiple samplings of a homogeneous sample
Expressed as %RSD for a statiscally significant
number of samples
10
Precision:
should be performed at 3 levels
- Repeatability
- Intermediate Precision
- Reproducibility
11
Precision:
Repeatability
- Same operating conditions, short time interval
- Min of 9 determinations covering specified range of
procedure (3 levels, 3 reps each)
- Min of 6 determinations at 100% test conc
Intermediate Precision
- Within-lab variations
- Different days, analysts, equipment
Reproducibility
- Precision between labs
- Collaborative studies
12
Accuracy:
The closeness of test results to the true value

obtained by the method
- established across the range
13
Accuracy:
Drug Substance
- Analysis of reference material
- Compare results to a second, well-characterized method
Drug Product
- Analysis of synthetic mixtures spiked with known
quantities of components
- Compare results to a second, well-characterized method
Determined concurrently with precision, linearlity and
specificity
14
Accuracy:
Impurities (Quantitation)
- Analysis of sample (Drug substances/Drug product)
spiked with known amounts of impurities
Recommended Data
- Min of 9 determinations over a min of 3 conc levels
covering the specified range (e.g. 3 conc/3 replicates
each)
- Report as % recovery of known, added amount, or
difference between the mean and true value, with
confidence intervals
15
Detection Limit (LOD):
Lowest concentration of analyte in a sample that

can be detected (not necessarily quantitated)
Limit test : above or below a certain level
Expressed as concentration (%, ppb)
Almost necessary not determine actual detection limit
16
Detection Limit (LOD):
Visual (Non-instrumental methods)

Signal to noise ratio (3:1 or 2:1 generally accepted)
Detection limit may be based on the standard
deviation of the response and slope:
DL = (3.3)STD/S
STD = standard deviation of the response
S = slope of the calibration curve
17
Quantitation Limit (LOQ):
Lowest concentration of analyte in a sample that

can be determined with acceptable precision and
accuracy under stated operational conditions
Expressed as concentration of analyte
- accuracy
- precision
18
Quantitation Limit (LOQ):
Visual (Non-instrumental methods)
Signal to noise ratio (10:1 is typical)
Quantitation limit may be based on the standard
deviation of the response and slope:
QL = (10)STD/S
STD = standard deviation of the response
S = slope of the calibration curve
Both DL and QL are validated by analyzing a suitable
number of samples. Method should be documented.
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Verification of Compendial Methods
EDQM
AOAC
USP
ACTD
20
From EDQM :
1. Transfer of a Method
A verification of suitability under conditions of use
(=method transfer check) has to be done
1.1 Pharmacopoeial (compendial) method
1.1.1 Active substance
- Identification:
no formal validation required
- Testing for Impurities:
- Assay:
21
From EDQM :
1.1 Pharmacopoeial (compendial) method
1.1.2 Medicinal product
- Identification:
- no formal validation required
- Testing for Impurities:
- specificity: no interference from excipients
- reporting threshold (at least the quant. limit)
- Assay:
- specificity
- accuracy: mainly recovery, min 1 det.
- precision (repeatability): around the target test
conc. (min 2 independent det.)
- linearity at three measuring points in the range
around the target value.
22
From AOAC :
How to meet ISO 17025 requirements for
Method Verification
Activities needed for method verification are

a subset of those for validation.
23
From AOAC :
Performance Characteristics Included in a Validation
Analyte at Analyte at Analyte at Analyte at

Performance Identifica-
low conc low conc high conc high conc Quanlitative 6
Characteristic tion 1
quantitative 2 Limit test 3 quantitative 4 Limit test 5
Accuracy No Yes No Yes Yes No
Precision No Yes No Yes Yes No
Specificity Yes Yes Yes Yes Yes Yes
LOD No Yes Yes Yes/No No No
LOQ No Yes No Yes/No No No
Ruggedness No Yes No Yes No No

Linearity/
No Yes No Yes No No
Range
24
From AOAC :
Method Verification
Category1 :
Confirmation of identity A method that
ensures a material is what it purports to be or
confirms the detection of the target analyte
25
Category1 : Identification
Performance
Verification Verification Activities
Characteristic
Specificity No If the labs samples are NA
identical to those in the
standard method and if and
differences in
instrumentation do not
impact specificity
Yes if the labs sample
Same as those required
differ from those in the
for validation
standard method
Yes if differences between The activity need only
instruments could affect deal with the unique
specificity aspects of the labs
samples or
instrumentation 26
From AOAC :
Method Verification
Category2 :
Analyte at Low Concentration, Quantitative
27
Category2:Analyte at Low Concentration, Quantitative
Performance
Characteristic
1. Accuracy Yes If the concentration range for which
the method is validated is narrow (<1
order of magnitude), analyze one
reference material/standard/spike at
one concentration level. Otherwise,
demonstrate accuracy at each
concentration level (low, middle, high)
by anlyzing one reference
material/standard/spike at each level.
28
Performance
Characteristic
2. Precision Yes Perform the repeatability test once. If
the method covers a concentration
range>1 order of magnitude, then the
repeatability test must include low,
middle and high concentrations.
29
Performance
Characteristic
3. Specificity No/Yes
4. LOD Yes Run a sample close to LOD
5. LOQ Yes Run a sample close to LOQ
30
From AOAC :
Method Verification
Category3 :
Analyte is present above or below a
specified, low concentration (Limit Test)
31
Category3 : Limit Test
Performance
Characteristic
2. LOD Yes Run a sample close to LOD
3. LOQ Yes Run a sample close to LOQ
32
From AOAC :
Method Verification
Category4 :
Quantifying an analyte at high concentration
33
Category4 : Assay
Performance
Characteristic
1. Accuracy Yes If the concentration range for which
the method is validated is narrow
(<1 order of magnitude), analyze
one reference material/standard/
spike at one concentration level.
Otherwise, demonstrate accuracy at
each concentration level (low,
middle, high) by anlyzing one
reference material/standard/spike at
each level.
34
Category4 : Assay
Performance
Characteristic
2. Precision Yes Perform the repeatability test once.
If the method covers a
concentration range>1 order of
magnitude, then the repeatability
test must include low, middle and
high concentrations.
35
From USP :
Verification of Compendial
Procedures <1226>
36
USP: Validation of Compendial Procedures <1225>
Category II
Performance Category I (Impurities) Category III Category IV
Characteristic (Assay) (dissolution) (Identification)
Accuracy + + - - -
Precision + + - + -
Specificity + + + - +
LOD - - + - -
LOQ - + - - -
Linearity + + - - -
Range + + - - -
37
Verification of Compendial Procedures<1226>
Verification of Compendial Procedures. The purpose
of this new general information chapter is to provide
guidelines for verifying the suitability of a
compendial procedure under actual conditions of
use, as stated in 21 CFR 211.194(a)(2). Because it is not
necessary for users of compendial procedures to
perform a complete validation, but rather, to confirm that
the procedure works for their drug substance, excipient,
or dosage form, verification can be accomplished by
assessing a subset of validation characteristics. This
new chapter is considered an extension of the general
information chapter Validation of Compendial Methods
<1225>, and both chapters use similar terminology.
Interested parties are encouraged to submit comments
by July 15, 2005. 38
Verification of Compendial Procedures<1226>
verifying the suitability of a

compendial procedure under
actual conditions of use
But No Guidelines
39
Data Elements for Verification of Drug Substances and Excipients*
Category Category II Category III Category IV

Technique
(assay) (impurities) (dissolution) (identification)
Precision
Specificity
HPLC/GC Precision Specificity - Specificity
LOD
LOQ
Spectro
Precision Specificity
photometric/ Precision - Specificity
LOQ LOD
colorimetric
-
Titrimetric Precision Precision - -
Specificity Specificity
TLC - - Specificity
LOQ LOD
Gel Electro Specificity Specificity

- - Specificity
Phoresis LOQ LOD
* Not official 40
Data Elements for Verification of Dosage Forms
Category I Category II Category III Category IV
Technique
(assay) (impurities) (dissolution) (identification)
Precision
Precision
HPLC/GC Specificity Precision Specificity
Linearity LOD
LOQ
Range
Spectro Precision
Precision Specificity
photometric/ Linearity Precision Specificity
LOQ LOD
colorimetric Range
Precision
-
Titrimetric Linearity Precision - -
Range
TLC - - Specificity
LOQ LOD
Gel Electro Specificity Specificity
- - Specificity
phoresis LOQ LOD
* Not official 41
Category I: Analytical procedures for quantitation of
major components of drug substances or active
ingredients (including preservatives) in finished dosage
forms.
Category II: Analytical procedures for determination of
impurities in drug substances or degradation compounds
in finished pharmaceutical products. These procedures
include quantitative assays and limit tests.
Category III: Analytical procedures for determination
of performance characteristics (e.g., dissolution, drug
release).
Category IV: Identification procedures.
42
From ACTD
P5 : Control of Finished Product
5.3 Validation of Analytical Procedure
Verification of compendial method applicability -
Accuracy
Precision
43
Comparison : Assay
USP EDQM AOAC
Specificity Specificity Specificity
Precision Precision Precision
Linearity Linearity -
Range - -
- Accuracy Accuracy
44
Recommendation (BDN):
For Assay:
- Specificity
- Precision at 100 % (6 det.)
- Accuracy at 100% (3 det.)
- Linearity (5 points)
45
Comparison : Impurity (Quantitative)
USP EDQM AOAC
Precision - Precision
LOQ LOQ LOQ, LOD
- - Accuracy
46
For Impurity (Quantitative) :

- Specificity
- LOQ
- Precision (6 det.)
- Accuracy (3 det.)
47
Comparison : Impurity (Limit tests)
USP EDQM AOAC
LOD LOQ (LOD?) LOQ, LOD
48
For Impurity (Limit tests) :

- Specificity
- LOD
49
Comparison : Identification
USP EDQM AOAC

No formal
Specificity validation Specificity
required
50
Verification documentation :
The verification exercise must be planned, approved, and
documented and a final report kept on file to demonstrate the
lab can perform the method adequately.
Verification documentation should be created that:
Described the procedure to be verified
Details the analytical performance characteristics to
be evaluated
Established acceptance criteria used to determine
that the procedure perform suitably
Justifies deviations from reference method
51
Thank You
for
Your Attention
52

Verification of Compendial Methods

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Verification of Compendial Methods

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Verification of

The ability to measure accurately and specificity the

The degree of interference :

Impurities are available

Minimum specified range :

The measure of the degree of agreement among

The closeness of test results to the true value

Lowest concentration of analyte in a sample that

Visual (Non-instrumental methods)

Lowest concentration of analyte in a sample that

Activities needed for method verification are

Analyte at Analyte at Analyte at Analyte at

Accuracy No Yes No Yes Yes No

Precision No Yes No Yes Yes No

Specificity Yes Yes Yes Yes Yes Yes

LOD No Yes Yes Yes/No No No

LOQ No Yes No Yes/No No No

Ruggedness No Yes No Yes No No

4. LOD Yes Run a sample close to LOD

5. LOQ Yes Run a sample close to LOQ

2. LOD Yes Run a sample close to LOD

3. LOQ Yes Run a sample close to LOQ

verifying the suitability of a

Category Category II Category III Category IV

Gel Electro Specificity Specificity

Verification of compendial method applicability -

USP EDQM AOAC

Specificity Specificity Specificity

Precision Precision Precision

- Precision at 100 % (6 det.)

- Accuracy at 100% (3 det.)

USP EDQM AOAC

Specificity Specificity Specificity

LOQ LOQ LOQ, LOD

For Impurity (Quantitative) :

USP EDQM AOAC

Specificity Specificity Specificity

LOD LOQ (LOD?) LOQ, LOD

For Impurity (Limit tests) :

USP EDQM AOAC

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