1. International Conference on
Harmonization

2. Validation of Analytical Procedure
Q2(R1)

3. Part 1
Text on Validation of Analytical
Procedures.

4. objective
To demonstrate that the analytical
procedure is suitable for its intended
use.

5. Types of analytical
procedures to be validated
1.
2.
3.
4.
Identification tests
Quantitative tests for impurities
content
Limit tests for the control of impurities
Quantitative tests of the active in
samples of drug substance or drug
product or the selected components
in the drug product

6. .
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

7. .
• Specificity
• Detection limit
• Quantitation limit
• Linearity
• Range
• robustness
This should be typical for analytical
procedures but occasional exceptions
should be dealt with on a case-by-case
basis.

8. Furthermore revalidation for:
• Changes in the synthesis of the drug
substance
• Changes in the composition of the
finished product
• Changes in the analytical procedure

9. glossary
Analytical procedure:
it is the way of performing the analysis
And should be described in detail the
steps necessary to perform each test
for sample, reference standard and
reagents preparations , use of
apparatus , generation of calibration
curve ,etc.

10. specificity
The ability to assess unequivocally the
analyte in the presence of components
Which may be expected to be present.
Like: impurities , degradants , matrix .
• To ensure the identity of an analyte
• As a purity test
• Assay (content or potency)

11. accuracy
Closeness of agreement between the
value which is accepted and the value
found.

12. precision
Closeness of agreement between a
series of measurements obtained from
multiple sampling of the same
homogeneouse sample under the
prescribed conditions.

13. Detection limit
It is the lowest amount of analyte in a
sample which can be detected but not
necessarily quantitated as an exact
value

14. Quantitation limit
It is the lowest amount of analyte in a
sample which can be quantitatively
determined with suitable precision and
accuracy.
It is used for the determination of
impurities and/or degradation
products

15. linearity
it is the procedure's ability to obtain
test results which are directly
proportional to the concentration of
analyte in the sample

16. range
It is the interval between the upper
and lower concentration of analyte in
the sample for which it has been
demonstrated that the analytical
procedure has a suitable level of
precision , accuracy and linearity

17. robustness
It is a measure of procedures capacity
to remain unaffected by small , but
deliberate variations in method
parameters and provides an indication
of its reliability during normal usage.

18. Part 2
Validation of Analytical Procedures:
Methodology

19. specificity
An investigation of specificity should be
conducted during the validation of
identification test , the determination
of impurities and the assay.
1. Identification
Suitable identification tests should be
able to discriminate compounds of
closely related structures which are
likely to be present.

20. .
2. Assay and impurity tests
For chromatographic procedure ,
representative chromatograms should
be used to demonstrate specificity and
individual components should be
appropriately labelled.
To provide evidence that there is no
interference from other components

21. .2.1.impurities are available
This can be done by spiking pure
substance with appropriate levels of
impurities or/and excipients and
demonstrate that the assay results is
unaffected by the presence of these
materials by comparison with the assay
result obtained on unspiked samples.

22. 2.2. impurities are not available
In this case specificity may be
demonstrated by comparing the test
results of samples containing impurities
to a second well-characterized
.procedure , like pharmacopoeial
method.
This should include samples stored
under relevant stress conditions, like
light , heat , humidity, acid/base
hydrolysis and oxidation

23. linearity
Should be evaluated by visual
inspection of a plot of signals as a
function of analyte concentration. If
there is a linear relationship , test
results should be evaluated by
appropriate statistical method.
For thee stablishment of linearity , a
minimum of 5 concentrations is
recommended.

24. range
The specified range is normally derived from
linearity studies and depends on the intended
application of the procedure
Some of the minimum specified ranges that
should be considered are :
• For assay of a drug substance or drug
product ;80%-120% of test concentration
• For content uniformity;70%-130% of test
concentration
• For dissolution testing ; +/-20% over the
specified range

25. accuracy
1.Assay for drug substance and drug
product : there are several methods of
determining accuracy.
2.Impurities (quantitation) :
Accuracy should be assessed n samples
spiked with known amount of impurities
3.Recommended data :
Accuracy should be assessed using a
minimum of 9 determinations over a
minimum of 3 concentration levels covering
the specified range

26. precision
1.Repeatability : using a min. of 9
determination covering the specified range
for the procedure , or min. of 6
determination at 100% of the test
concentration
2.reproducibility: is assessed by means of
an inter-lab trial and reproducibility should
be considered in case of the
standardization of an analytical procedure

27. Detection limit
1. Based on visual evaluation:
Visual evaluation may be used for noninstrumental methods. The detection limit
is by analyzing a sample with a known
concentration with minimum level in
which can be detected
2. Based on the standard deviation of the
response and the slope:
DL=3.3 * std deviation of response/slope
of the calibration curve

28. Quantitation limit
1. Based on visual evaluation:
For non-instrumental methods and
determined by analysis of samples with
known concentrations of analyte and
minimum level at which the analyte can
be quantified with acceptable accuracy
and precision
2.Based on signal-to-noise approach:
It is performed by comparing measured
signals from samples with known low
concentration that the analyte can be
quantified ; signal –to-noise ratio is 10:1.

29. robustness
One consequence of the evaluation of
robustness should be that a series of
system suitability parameters is
established to ensure that the validity
of the analytical procedure is
maintained whenever used.
For example : different columns and
,flowrate.

30. Thank you
Noushin Javidvand
2013