Protocol for Validation of
Test Method for Assay of
Location: Analytical Laboratory
Number of pages: 16
(Inclusive of covering pages)
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TABLE OF CONTENTS
Page No.
1. Introduction .................................................................................................................... 4
2. Purpose ......................................................................................................................... 4
3. Scope ............................................................................................................................ 4
4. Responsibility ................................................................................................................. 4
5. Design of the study ........................................................................................................ 5
5.1 Sample details ........................................................................................................ 5
5.1.1 Active drug substance ...................................................................................... 5
5.1.2 Finished Products............................................................................................. 5
5.1.3 Excipients ......................................................................................................... 5
5.2 Method of Analysis.................................................................................................. 5
5.2.1 Chromatographic condition ............................................................................... 5
5.2.2 Reagents .......................................................................................................... 6
5.2.3 Buffer Solution .................................................................................................. 6
5.2.4 Mobile phase .................................................................................................... 6
5.2.5 Standard preparation ........................................................................................ 6
5.2.6 Sample preparation .......................................................................................... 6
5.2.7 Calculation ....................................................................................................... 7
5.3 Validation parameters ............................................................................................. 7
6. Validation ....................................................................................................................... 8
6.1 Specificity ............................................................................................................... 8
6.2 Precision ................................................................................................................. 9
6.2.1 Repeatability of standard solution – System precision ...................................... 9
6.2.2 Reproducibility sample solution – Method precision ....................................... 10
6.3 Linearity and Range .............................................................................................. 10
6.4 Accuracy ............................................................................................................... 12
6.5 Intermediate precision ........................................................................................... 14
7. Acceptance Criteria...................................................................................................... 14
8. References .................................................................................................................. 16
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APPROVAL PAGE
This protocol after review and approval by listed signatories is certified for execution. The
approval is a joint responsibility of the listed functional areas
Name Department Signature and Date
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1. Introduction
Drug substanceis an active pharmaceutical ingredient categorised as ACE inhibitor
indicated in treatment of hypertension. The amount of Drug substancein drug
substance is estimated by quantitative methods – HPLC.
The suitability range of method would be evaluated as range between 20 % of the
lowest strength (i.e. Drug substancetablets 2.5 mg) to 160% of the highest strength
(i.e. Drug substancetablets 20.0 mg)
2. Purpose
Establishing documented evidence, which provides a high degree of assurance that
the analytical method for assay of Drug substancedrug substance detailed in this
protocol shall consistently analyse the Drug substancecontent quantitatively in tablets.
3. Scope
This validation protocol is applicable to quantitative analytical method - Assay, which is
used for the estimation of Drug substancecontent in tablets, in support of regulatory
requirements.
Being compendial method, evaluation of only key parameters i.e., Specificity,
Precision, Linearity and Range, Accuracy and Intermediate precision shall be
performed during method validation.
4. Responsibility
PERSON ROLE & RESPONSIBILITY
Analyst It is a responsibility of the Analyst to perform the work in
accordance with this protocol, and to record all results in a
laboratory notebook
Analyst It is a responsibility of the Analyst in Coordinating for protocol
preparation and documentation of results
Sr. Analyst It is a responsibility of the Sr. Analyst to keep continuous check
on the work being done for adherence to the protocol and ensure
proper documentation of the data
Head It is a responsibility of the Head of Quality to review and
authorize this protocol and the work
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5. Design of the study
5.1 Sample details
5.1.1 Active drug substance
The batch number and other relevant details of the Drug substancedrug substance
used shall be specified in the validation report.
5.1.2 Finished Products
The batch number and other relevant details of the Drug substancetablets 2.5 mg, 5
mg, 10 mg and 20 mg used shall be specified in the validation report.
5.1.3 Excipients
The details of the excipients used in the manufacturing of the Drug substancetablets
are presented below.
Drug substancetablets USP 2.5 mg Drug substancetablets USP 10 mg
i. Drug substanceUSP i. Drug substanceUSP
ii. Anhydrous lactose NF ii. Anhydrous lactose NF
iii. Ferric Oxide NF Yellow shade iii. Ferric oxide NF Orange shade
iv. Zinc stearate USP iv. Zinc stearate USP
Drug substancetablets USP 5 mg Drug substancetablets USP 20 mg
i. Drug substanceUSP i. Drug substanceUSP
ii. Anhydrous lactose NF ii. Anhydrous lactose NF
iii. Zinc stearate USP iii. Ferric oxide NF Yellow shade
iv. Ferric oxide NF Orange shade
v. Zinc stearate USP
Batch Numbers of the excipients used in the experiments shall be included in the
validation report
5.2 Method of Analysis
5.2.1 Chromatographic condition
Instrument : HPLC Alliance/Agilent 1100 series or equivalent
Wave Length : 215 nm
Column : Lichrosorb RP-8, 5m, 4.6 x 250 mm or equivalent
Column temperature : 500C
Injection volume : 50 l
Flow rate : 2.0 ml/min
Run time : 30 minutes
Details of the HPLC system used in experiments shall be included in the validation
report.
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5.2.2 Reagents
1. Monobasic Sodium Phosphate (NaH2PO4 H2O) AR grade or equivalent
2. Phosphoric acid, concentrated, AR grade
3. Acetonitrile, HPLC grade.
4. Water, purified
5.2.3 Buffer Solution
Dissolve 1.38 g of Monobasic Sodium Phosphate in 1000 ml water, adjust pH to 2.2
0.05 with Phosphoric acid
5.2.4 Mobile phase
Mix buffer solution and Acetonitrile in the ratio of 75:25.
Batch Numbers (applicable) of the chemicals used in the study shall be included in the
validation report.
5.2.5 Standard preparation (in duplicate)
(For all strengths)
Enalaprilat stock solution:
Weigh accurately about 10 mg of Enalaprilat WS and transfer into a 25 ml volumetric
flask. Dissolve and dilute to volume with water. Mix well. (Conc. 0.4 mg/ml).
Standard solution preparation:
Weigh accurately about 20 mg of Drug substanceWS and transfer into a 100 ml
volumetric flask. Transfer 0.5 ml of Enalaprilat stock solution into the flask, and add
about 50 ml of buffer solution, sonicate 2 minutes or until dissolve. Dilute to volume
with buffer solution, and mix well. (Conc. 0.2 mg/ml of Drug substanceand 0.002 mg/ml
for Enalaprilat).
5.2.6 Sample preparation
For 2.5 mg tablet
Transfer 20 tablets into a 250 ml volumetric flask and add about 150 ml of buffer
solution. Sonicate for 15 minutes and shake by mechanical means for 30 minutes.
Dilute to volume with buffer solution, shake well and sonicate for 15 minutes. Mix and
filter through 0.45 membrane filter.
For 5 mg tablet
Transfer 10 tablets into a 250 ml volumetric flask and add about 150 ml of buffer
solution. Sonicate for 15 minutes and shake by mechanical means for 30 minutes.
Dilute to volume with buffer solution, shake well and sonicate for 15 minutes.
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For 10 mg tablet
Transfer 10 tablets into a 500 ml volumetric flask and add about 300 ml of buffer
solution. Sonicate for 15 minutes and shake by mechanical means for 30 minutes.
Dilute to volume with buffer solution, shake well and sonicate for 15 minutes. Mix and
filter through 0.45 membrane filter.
For 20 mg tablet
Transfer 10 tablets into a 1000 ml volumetric flask and add about 500 ml of Buffer
Solution. Sonicate for 15 minutes and shake by mechanical means for 30 minutes.
Dilute to volume with buffer solution, shake well and sonicate for 15 minutes. Mix and
filter through 0.45 membrane filter.
5.2.7 Calculation
Asample Ws V %p 100
% Enalapril Maleate
Astd 100 N 100 LC
Where,
Asample = Peak Area of Drug substancein sample preparation
Astd = Peak Area of Drug substancein standard preparation
Ws = Weight of Drug substanceWS
V = Volume diluted to (ml)
N = Number of tablets
%p = Percentage potency of Drug substanceWS
LC = Label claim (mg)
5.3 Validation parameters
The method validation involves establishing of the following parameters:
1. Specificity
2. Precision
i. Repeatability of standard solution – System precision
ii. Reproducibility of sample solution – Method precision
iii. Intermediate precision
3. Linearity and Range
4. Accuracy
Note: System suitability shall be evaluated, before proceeding to the next validation
parameter
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6. Validation
6.1 Specificity
Specificity is the ability to assess unequivocally the analyte in the presence of
components, which may be expected to be present.
Specificity shall be evaluated as interference against:
1. Diluent (pH 2.2 buffer)
2. Tablet placebo (for respective strengths)
Standard preparation
Prepare as directed in section 5.2.5
Blank/Diluent
Buffer solution as per section 5.2.3
Enalapril diketopiperazine solution
Carefully place about 20 mg of Drug substanceWS in a 100-mL beaker to form a
mound on the bottom of the beaker. Place the beaker on a hot plate at about one-half
the maximum hot plate temperature setting. Heat for about 5 to 10 minutes until the
solid is melted. Immediately remove the beaker from the hot plate, and allow to cool.
[NOTE—Avoid overheating to prevent heat-induced degradation, which would give rise
to a brown colour.]
To the cooled residue in the beaker add 50 ml of Acetonitrile, and sonicate for a few
minutes to dissolve. The solution typically contains, in each ml, between 0.2 mg and
0.4 mg of Enalapril diketopiperazine
System suitability preparation
Transfer 0.5 ml of Enalapril Diketopiperazine solution (prepared as directed above) to
a 25 ml volumetric flask, dilute with standard solution to volume, and mix well.
Placebo preparations
A solution of the placebo shall be prepared in the same manner as the sample
preparation described in the method of analysis section, filtered and injected into the
chromatograph.
For 2.5 mg tablet
Weigh accurately 1750 mg of respective tablet placebo, into a 250 ml volumetric flask.
And add about 150 ml of buffer solution. Sonicate for 15 minutes and shake by
mechanical means for 30 minutes. Dilute to volume with buffer solution, shake well
and sonicate for 15 minutes. Mix and filter through 0.45 membrane filter.
For 5 mg tablet
Weigh accurately 1750 mg of respective tablet placebo, into a 250 ml volumetric flask.
And add about 150 ml of buffer solution. Sonicate for 15 minutes and shake by
mechanical means for 30 minutes. Dilute to volume with buffer solution, shake well
and sonicate for 15 minutes. Mix and filter through 0.45 membrane filter.
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For 10 mg tablet
Weigh accurately 1700 mg of respective tablet placebo, into a 500 ml volumetric flask.
And add about 300 ml of buffer solution. Sonicate for 15 minutes and shake by
mechanical means for 30 minutes. Dilute to volume with buffer solution, shake well
and sonicate for 15 minutes. Mix and filter through 0.45 membrane filter.
For 20 mg tablet
Weigh accurately 1600 mg of respective tablet placebo, into a 1000 ml volumetric
flask. And add about 500 ml of buffer solution. Sonicate for 15 minutes and shake by
mechanical means for 30 minutes. Dilute to volume with buffer solution, shake well
and sonicate for 15 minutes. Mix and filter through 0.45 membrane filter.
Procedure
1. Inject 50l of each solution as indicated in the table below:
Solution No. of Injections
Blank/diluent 1
System suitability preparation 1
Standard 1 6
Standard 2 (check standard) 2
Respective placebo preparations 2 each
2. Evaluate the chromatograms for any interference at the RT of major peak.
6.2 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, reproducibility and intermediate precision.
6.2.1 Repeatability of standard solution – System precision
Standard preparation (in duplicate)
Prepare as directed in section 5.2.5
1. Perform six replicate injections of the above standard solution 1 and duplicate
injection of standard 2.
2. Calculate the mean and relative standard deviation (%RSD) of six replicate
injections of standard 1.
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6.2.2 Reproducibility sample solution – Method precision
Standard preparation
Prepare as directed in section 5.2.5
System suitability preparation
Prepare as directed in section 6.1
Sample preparations
Prepare as directed in section 5.2.6
Prepare six preparations each at 100% of nominal working concentration.
Blank
Buffer solution
Procedure
1. Inject 50l of each solution as indicated in the table below:
Solution No. of Injections
Blank/diluent 1
System suitability preparation 1
Standard 1 6
Standard 2 (check standard) 2
2.5 mg sample 6 preparations 2 each
5 mg sample 6 preparations 2 each
10 mg sample 6 preparations 2 each
20 mg sample 6 preparations 2 each
2. Determine the average, standard deviation and relative standard deviation of six
replicate injections of standard 1.
3. Calculate the amount of Drug substancein each strength individually (Refer
section 5.2.7)
4. Calculate the mean, standard deviation and relative standard deviation of the
assay results at each level.
6.3 Linearity and Range
The linearity of an analytical procedure is its ability (within a given range) to obtain test
results which are directly proportional to the concentration of analyte in the sample.
The range is derived from the linearity studies.
Linearity solutions will be prepared by quantitative dilutions of the stock solution of
Drug substanceworking standard to obtain solutions in the range 20% to 160% of the
working concentration. Linearity shall be established over a minimum of 7 points.
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Standard solution
Weigh accurately about 100 mg of Drug substanceinto a 100 ml volumetric flask.
Approximately add 75 ml of diluent, sonicate 2 minutes or until dissolve and dilute up
to the mark with diluent and mix. This is standard solution (S1) containing 1000 ppm of
Enalapril Maleate.
Linearity solutions
Prepare Linearity dilutions as indicated below
1. Linearity level-1 solution (20%): L1
Dilute 2.0 ml of standard solution (S1) to 50.0 ml with diluent (40 ppm)
2. Linearity level-2 solution (40%): L2
Dilute 4.0 ml of standard solution (S1) to 50.0 ml with diluent (80 ppm)
3. Linearity level-3 solution (80%): L3
Dilute 8.0 ml of standard solution (S1) to 50.0 ml with diluent (160 ppm)
4. Linearity level-4 solution (100%): L4
Dilute 10.0 ml of standard solution (S1) to 50.0 ml with diluent (200 ppm)
5. Linearity level-5 solution (120%): L5
Dilute 6.0 ml of standard solution (S1) to 25.0 ml with diluent (240 ppm)
6. Linearity level-6 solution (140%): L6
Dilute 7.0 ml of standard solution (S1) to 25.0 ml with diluent (280 ppm)
7. Linearity level-7 solution (160%): L7
Dilute 8.0 ml of standard solution (S1) to 25.0 ml with diluent (320 ppm)
Blank
Buffer solution
Procedure
1. Inject 50 μl of diluent into the HPLC system
2. Inject 50 μl of Linearity level-1 (L1) solution six times
3. Inject 50 μl Linearity level solutions L2, L3, L4, L5, L6, in duplicate, into the HPLC
system
4. Inject 50 μl of Linearity level-7 (L7) solution six times into the HPLC system
5. A graph of mean peak area v/s concentration (ppm) shall be plotted and the
equation of regression line shall be determined. The slope, intercept and
correlation coefficient of the regression line shall be reported
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6.4 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 found value.
Standard preparation
Prepare as directed in section 5.2.5.
Blank solution
Buffer solution
Standard solutions for Accuracy study
Three preparations for Level 1 (0%), Level 2 (50%) and Level 4 (150%)
Six preparation for level 3 (100%)
For 2.5 mg tablets
1. Accuracy level-1 solution (0%): A1
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, sonicate for 15 minutes and shake by mechanical means for 30 minutes and
dilute up to the mark with diluent.
2. Accuracy level-2 solution (50%): A2
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 25 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 100 ppm)
3. Accuracy level-3 solution (100%): A3
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 50 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 200 ppm)
4. Accuracy level-4 solution (150%): A4
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 75 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 300 ppm)
For 5 mg tablets
1. Accuracy level-1 solution (0%): A1
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask sonicate for 15 minutes and shake by mechanical means for 30 minutes and
dilute up to the mark with diluent
2. Accuracy level-2 solution (50%): A2
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 25 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 100 ppm)
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3. Accuracy level-3 solution (100%): A3
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 50 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 200 ppm)
4. Accuracy level-4 solution (150%): A4
Weigh accurately about 1750 mg of placebo and transfer to a 250 ml volumetric
flask, introduce accurately weighed (about 75 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 300 ppm)
For 10 mg tablets
1. Accuracy level-1 solution (0%): A1
Weigh accurately about 1700 mg of placebo and transfer to a 500 ml volumetric
flask sonicate for 15 minutes and shake by mechanical means for 30 minutes and
dilute up to the mark with diluent
2. Accuracy level-2 solution (50%): A2
Weigh accurately about 1700 mg of placebo and transfer to a 500 ml volumetric
flask, introduce accurately weighed (about 50 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 100 ppm)
3. Accuracy level-3 solution (100%): A3
Weigh accurately about 1700 mg of placebo and transfer to a 500 ml volumetric
flask, introduce accurately weighed (about 100 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 200 ppm)
4. Accuracy level-4 solution (150%): A4
Weigh accurately about 1700 mg of placebo and transfer to a 500 ml volumetric
flask, introduce accurately weighed (about 150 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 300 ppm)
For 20 mg tablets
1. Accuracy level-2 solution (0%): A1
Weigh accurately about 1600 mg of placebo and transfer to a 1000 ml volumetric
flask sonicate for 15 minutes and shake by mechanical means for 30 minutes and
dilute up to the mark with diluent
2. Accuracy level-2 solution (50%): A2
Weigh accurately about 1600 mg of placebo and transfer to a 1000 ml volumetric
flask, introduce accurately weighed (about 100 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 100 ppm)
3. Accuracy level-3 solution (100%): A3
Weigh accurately about 1600 mg of placebo and transfer to a 1000 ml volumetric
flask, introduce accurately weighed (about 200 mg) quantity of Drug substanceto the
same volumetric flask, dilute up to the mark with diluent ( 200 ppm)
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4. Accuracy level-4 solution (150%): A4
Weigh accurately about 1600 mg of placebo and transfer to a 1000 ml volumetric
flask, introduce accurately weighed (about 300 mg) quantity of Drug substanceto the
same volumetric flask sonicate for 15 minutes and shake by mechanical means for
30 minutes and dilute up to the mark with diluent ( 300 ppm)
Procedure
1. Inject 50 μl of diluent into the HPLC system.
2. Inject 50 μl of standard solution into the HPLC system
3. Inject 50 μl of accuracy solution A1, A2, A3 and A4 of each strength individually,
into the HPLC system
Calculation
1. Calculate the content of Drug substancein the sample (Refer section 5.4.7)
2. Calculate the percentage recovery as follows
Amount found in mg
% Recovery 100
Actual amount added in mg
6.5 Intermediate precision
The intermediate precision of an analytical procedure is a measure of its capacity to
remain unaffected by change in instrument and analyst.
The mean, standard deviation and relative standard deviation of the assay results of
each strength shall be calculated.
A different analyst shall perform the following parameters on a different day on a
different instrument using a different column of same make
1. Repeatability of standard solutions (Refer section 6.2.1)
2. Reproducibility of Drug substancesample solutions (Refer section 6.2.2)
7. Acceptance Criteria
No. General acceptance criteria
1. Signature of personnel employed in validation activity shall be documented.
2. All checklists shall be completely signed with archive proof ink, documented and approved.
3. Deviations shall be investigated and corrective action taken shall be documented.
4. Test results shall be recorded in the laboratory notebook. Complementary data sheets and/or
test results are to be referenced and placed in an appendix to show actual results.
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Specific acceptance criteria
No. Parameter Experiment Acceptance criteria
5. Specificity Diluent There should not be interference at the retention
time of Drug substanceas in standard run
Placebo
6. Precision System suitability The relative retention times are about 0.2 for
maleic acid, 0.3 for Enalaprilat, 1.0 for Enalapril,
and 2.5 for Enalapril diketopiperazine.
The column efficiency is not less than 1000
theoretical plates for Enalaprilat, not less than
300 theoretical plates for Enalapril, and not less
than 2500 theoretical plates for Enalapril
diketopiperazine.
The tailing factor for Enalapril is not more than
2.0.
The resolution, R, between maleic acid and
enalaprilat is not less than 2.0, between
Enalaprilat and Enalapril is not less than 2.0,
and between Enalapril and Enalapril
diketopiperazine is not less than 2.0
Repeatability of The RSD of the six replicate injections of
standard solution – standard 1 is not more than 2.0%
System precision
Repeatability of The Assay of individual samples shall be within
sample solution – the specified limits
Method precision RSD for mean assay value shall be not more
than 2.0%
Intermediate Precision The % RSD of the six replicate injections of
standard 1 is not more than 2.0%
The assay of individual samples shall be within
the specified limits
The cumulative RSD of the results for
reproducibility & Intermediate Precision should
not be more than 2.0% and the ratio of the two
mean results should be between 0.98 and 1.02
at all levels and for all the strengths
7. Linearity Correlation coefficient Should not be less than 0.998
Slope Record Results
Intercept Record Results
8. Range 20 to 160% Record Results
9. Accuracy Percentage recovery Individual percentage recovery should be
(External standard between 97.0% to 103.0%
method) Mean recoveries should be between 98.0% to
102.0%
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8. References
1. USP 28 – NF 23 <1225> VALIDATION OF COMPENDIAL METHODS.
2. ICH Harmonised Guideline (Q2A): Text on Validation of Analytical Procedures
3. ICH Harmonised Guideline (Q2B): Validation of Analytical Procedures: Methodology
History
Document No: : ARI/02/PRT/19/A Supersedes: None
Nature of Change : Not applicable
Reason for Change : Not applicable
THIS IS THE END OF THE DOCUMENT
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