Page 344 - Chiral Separation Techniques

13.5 Guidelines from the International Conference on Harmonization 337

13.5.4 Analytical Validation

There are two ICH guidelines on analytical validation. The first provides a glossary
of terms and the second addresses methodology. The first guideline, ICH Topic Q2A
Validation of analytical procedures: Definitions and terminology, reached Step 4 in
October 1994. It sought only to present a collection of terms and definitions and not
to provide direction on how to accomplish validation. The guideline was intended to
bridge the differences which could exist between the various compendia and regula-
tors in the three regions of the ICH. In the EU, the guideline was approved by the
CPMP in November 1994 (CPMP/III/5626/93) and came into operation in June
1995. As mentioned above, the FDA incorporated the ICH definitions of analytical
terms into its guidance on validation of chromatographic methods in November
1994.
The guideline states that the objective of validation is to demonstrate that an ana-
lytical method is fit for its purpose and summarizes the characteristics required of
tests for identification, control of impurities and assay procedures (Table 13-2). As
such, it applies to chiral drug substances as to any other active ingredients. Require-
ments for other analytical procedures may be added in due course.

Table 13-2. Characteristics of analytical procedures requiring validation (indicated by a tick).

Control of impurities
Identity Assay
Quantification Limit test
Accuracy and precision
Specificity
Limit of detection ( )
Limit of quantitation
Linearity and range

Assays may be applied to the active moiety in the drug substance or drug product
or to other selected components of the product. They are used for content/potency
determinations and for measurement of dissolution. Precision includes repeatability
(intra-assay precision) and intermediate precision (within laboratory) except the lat-
ter is not required where reproducibility (inter-laboratory) has been performed. If
there is lack of specificity in one analytical procedure, compensation by other sup-
porting methods is allowed. The characteristics listed in Table 13-2 are considered
typical, but allowance is made for dealing with exceptions on a case-by-case basis.
Robustness is not listed, but should be considered at an appropriate stage in devel-
opment. Revalidation of analytical procedures is required following changes in the
synthesis of a drug substance, composition of the finished product or in the analyti-
cal procedure.
The second guideline, ICH Topic Q2B, Validation of analytical procedures:
Methodology, reached Step 4 in November 1996, was approved by the CPMP in
Europe in December 1996 (CPMP/ICH/281/95) and came into operation in June
1997. It is complementary to the first guideline and provides some guidance and rec-