Introduction
This document presents a discussion of the characteristics for consideration
during the validation of the analytical procedures included as part of registration
applications submitted within the EC, Japan and USA. This document does not
necessarily seek to cover the testing that may be required for registration in, or
export to, other areas of the world. Furthermore, this text presentation serves as
a collection of terms, and their definitions, and is not intended to provide
direction on how to accomplish validation. These terms and definitions are meant
to bridge the differences that often exist between various compendia and
regulators of the EC, Japan and USA.
The objective of validation of an analytical procedure is to demonstrate that it is
suitable for its intended purpose. A tabular summation of the characteristics
applicable to identification, control of impurities and assay procedures is
included. Other analytical procedures may be considered in future additions to
this document.
Types of Analytical Procedures to be Validated
The discussion of the validation of analytical procedures is directed to the four
most common types of analytical procedures:
- Identification tests;
- Quantitative tests for impurities' content.
- Limit tests for the control of impurities,
- Quantitative tests of the active moiety in samples of drug substance or drug
product or other selected component(s) in the drug product.
Although there are many other analytical procedures, such as dissolution testing
for drug products or particle size determination for drug substance, these have
not been addressed in the initial text on validation of analytical procedures.
Validation of these additional analytical procedures is equally important to those
listed herein and may be addressed in subsequent documents.
A brief description of the types of tests considered in this document is provided
below.
- Identification tests are intended to ensure the identity of an analyte in a
sample. This is normally achieved by comparison of a property of the sample
(e.g., spectrum, chromatographic behavior, chemical reactivity, etc) to that of
a reference standard.
- Testing for impurities can be either a quantitative test or a limit test for the
impurity in a sample. Either test is intended to accurately reflect the purity
characteristics of the sample. Different validation characteristics are required
for a quantitative test than for a limit test.
- Assay procedures are intended to measure the analyte present in a given
sample. In the context of this document, the assay represents a quantitative
measurement of the major component(s) in the drug substance. For the drug
product, similar validation characteristics also apply when assaying for the
active or other selected component(s). The same validation characteristics
may also apply to assays associated with other analytical procedures (e.g.,
dissolution).
The objective of the analytical procedure should be clearly understood since this
will govern the validation characteristics which need to be evaluated. Typical
validation characteristics which should be considered are listed below:
- Accuracy
- Precision
- Repeatability
- Intermediate
- Precision
- Specificity
- Detection Limit
- Quantitation Limit
- Linearity Range
Each of these validation characteristics is defined in the attached Glossary. The
table lists those validation characteristics regarded as the most important for the
validation of different types of analytical procedures. This list should be
considered typical for the analytical procedures cited but occasional exceptions
should be dealt with on a case-by-case basis. It should be noted that robustness is
not listed in the table but should be considered at an appropriate stage in the
development of the analytical procedure.
Furthermore revalidation may be necessary in the following circumstances:
- changes in the synthesis of the drug substance.
- changes in the composition of the finished product.
- changes in the analytical procedure.
- signifies that this characteristic is not normally evaluated
+ signifies that this characteristic is normally evaluated
- In cases where reproducibility has been performed, intermediate precision is not needed
- Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s)
- May be needed in some cases
ANALYTICAL PROCEDURE
The analytical procedure refers to the way of performing the analysis. It should
describe in detail the steps necessary to perform each analytical test. This may
include but is not limited to: the sample, the reference standard and the reagents
preparations, use of the apparatus, generation of the calibration curve, use of the
formulae for the calculation, etc.
SPECIFICITY
Specificity is the ability to assess unequivocally the analyte in the presence of
components which may be expected to be present. Typically these might include
impurities, degradants, matrix, etc.
Lack of specificity of an individual analytical procedure may be compensated by other
supporting analytical procedure(s).
This definition has the following implications:
Identification: To ensure the identity of an analyte.
Purity Tests: To ensure that all the analytical procedures performed allow an
accurate statement of the content of impurities of an analyte, i.e.
related substances test, heavy metals, residual solvents content, etc.
Assay (content or potency):
To provide an exact result which allows an accurate statement on the
content or potency of the analyte in a sample.
ACCURACY
The accuracy of an analytical procedure expresses the closeness of agreement between
the value which is accepted either as a conventional true value or an accepted
reference value and the value found.
PRECISION
The precision of an analytical procedure expresses the closeness of agreement (degree
of scatter) between a series of measurements obtained from multiple sampling of the
same homogeneous sample under the prescribed conditions. Precision may be
considered at three levels: repeatability, intermediate precision and reproducibility.
Precision should be investigated using homogeneous, authentic samples. However, if
it is not possible to obtain a homogeneous sample it may be investigated using
artificially prepared samples or a sample solution.
The precision of an analytical procedure is usually expressed as the variance,
standard deviation or coefficient of variation of a series of measurements.
- Repeatability
Repeatability expresses the precision under the same operating conditions over a
short interval of time. Repeatability is also termed intra-assay precision .
- Intermediate precision
Intermediate precision expresses within-laboratories variations: different days,
different analysts, different equipment, etc.
- Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies,
usually applied to standardization of methodology).
- DETECTION LIMIT
The detection limit of an individual analytical procedure is the lowest amount of
analyte in a sample which can be detected but not necessarily quantitated as an exact
value.
- QUANTITATION LIMIT
The quantitation limit of an individual analytical procedure is the lowest amount of
analyte in a sample which can be quantitatively determined with suitable precision
and accuracy. The quantitation limit is a parameter of quantitative assays for low
levels of compounds in sample matrices, and is used particularly for the
determination of impurities and/or degradation products.
- LINEARITY
The linearity of an analytical procedure is its ability (within a given range) to obtain
test results which are directly proportional to the concentration (amount) of analyte
in the sample.
- RANGE
The range of an analytical procedure is the interval between the upper and lower
concentration (amounts) of analyte in the sample (including these concentrations) for
which it has been demonstrated that the analytical procedure has a suitable level of
precision, accuracy and linearity.
- ROBUSTNESS
The robustness of an analytical procedure is a measure of its capacity to remain
unaffected by small, but deliberate variations in method parameters and provides an
indication of its reliability during normal usage.
