459

ASSIGNMENT OF VALIDATION PARAMETERS

9.4

ASSIGNMENT OF VALIDATION PARAMETERS

The type and degree of validation depends on the nature of the test. In particular, methods described in pharmacopeias may not have to be validated but
should be verified, if needed. Different test methods require different validation parameters. As development of the project progresses and as more analytical and product-specific information is acquired, the analytical methods
evolve and are gradually updated. The extent of validation increases and the
documentation is completed. Table 9-1 outlines the validation parameters that
are usually required for the early development stage, and Table 9-2 outlines
the validation parameters that are usually required for the full development
stage.
The proposed acceptance criteria in Table 9-3 should be included in the
validation protocol, especially for the full development stage.
There are numerous method validation examples in the literature [918].
Each company has their own approach and own set of acceptance criteria for
different analytical assays, but these approaches must be within the confines
of their line unit QA department and be in accordance with any regulatory
provisions. In the next section a description for each of the parameters to be
validated (figures of merit) are described in detail and examples are given
for each.

TABLE 9-1. Early Development

Type of Tests to Be Validated
Validation Parameters

Identity

Weight Percent/Assay/Content
Uniformity/Dissolution

Impurity Testing:
Quantitative Testa

Specificity
Linearity
Accuracy
Precision (repeatability)
Limit of detection
Limit of quantitation
Stability of the solutions

Yes
No
No
No
No
Nog
No

Yes
Yesb
Yesc
Yes
No
No
Yes

Yes
Yesb
Yesd
Yese
Yesf
Yesd
Yes

If impurities not available, with drug substance.

Four points may be adequate.
c
For drug product only (assay/CU/dissolution).
d
A spiking experiment carried out is adequate at this stage (only possible if impurity/impurities
are available).
e
At least triplicate analysis.
f
Not required, but recommended.
g
For the identity test of a 0-mg formulation (placebo), it may be necessary to document the
absence of drug substance, and an LOQ determination will then be required.
b

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METHOD VALIDATION

TABLE 9-2. Full Development

Type of Tests to Be Validated
Validation Parameters
Specificitya
Linearity
Accuracy
Precision (repeatability)
Precision (intermediate
precision)b
Precision (reproducibility)
Range
Limit of detection
Limit of quantitation
Stability of the solutions
Robustness

Identity

Weight Percent/Assay/Content
Uniformity/Dissolution

Impurity Testing:
Quantitative Test

Yes
No
No
No
No

Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes
Yes
Yes

No
No
No
Nod
No

Yes
No
No
Yes
Yes

Yes
Yese
Yes
Yes
Yes

Lack of specificity of one analytical procedure may be compensated for by other supporting
analytical procedures.
b
In cases where reproducibility has been performed, intermediate precision not needed.
c
In exceptional cases.
d
For the identity test of a 0-mg formulation (placebo) it may be necessary to document the absence
of drug substance and an LOQ determination will then be required.
e
Not required by ICH, but recommended.
f
May be required, depending on the nature of the test.

9.4.1

Accuracy

The test for accuracy is intended to demonstrate the closeness of agreement

between the value found and the value that is accepted either as a conventional true value or as an accepted reference value [19]. Therefore, accuracy
can be defined as the agreement between the result obtained with method
being validated and an accepted reference value. The accuracy can be inferred
from precision, linearity, and specificity. The results for the method being
validated can be compared to the results with those of a well-characterized,
independent method. These results may be compared to an alternate
reversed-phase HPLC method (phenyl versus C18 or separation run at different pH using the same column) using the same detection scheme. In some,
cases an orthogonal method is used to demonstrate accuracy. The methods
should differ with respect to separation mode and therefore provide orthogonal information concerning related substances and degradation products.
For example, one method would use reversed-phase (RP) separation mode on
a C18 column, and the second method would use a strong cation exchange
(SCX) column [20]. The orthogonal methods may show different selectivities
toward the degradation products, thereby demonstrating the orthogonal
nature of the two separation techniques. The accuracy would be demonstrated