3.2.S.4.-1

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CHLOROUINALDOL
3.2.5.4 Control of drug substance
3.2.S.4.1 Specification
CHARACTERISTICS AD MISS IB ILITY C RITE RIA METHODS OF

ANALYS$
1. Appearance:
A yellow to yellow brown Visuai
crystalline powder, faint
characteristic odour
2. Solubility: practically insoluble in water, DAC 2OO3
soluble in acetone and ether,
slightly soluble in ethanol96Yo
3. Identification:
A. IR spectrum IR absorption spectrum of
the Eur Ph. (2.2.24)
substance to be analyzed
corresponds to the IR spectrum of
the reference substance
B HPLC simultaneously with assay I
Eur. Ph. (2.2:29)

determination HPLC method
C Melting point 109 -1 140 C Eur. Ph. (2.2.t4),
caoillarv method
4. Appearance of solution The solution is clear and not more Eur. Ph. (2.2.1 and
intensely coloured than reference 2.2.2, method II)
solution BY3
5. Acidity or alkalinity Maximum DAC 2OO3
0,25 ml NaOH 0,01 mol/l or
0,25 ml HCl0,01 mol/l
6. Chlorides, ppm Max.500 Eur. Ph. (2.4.4.)
7. Loss ondryrng,o/o Max.0,2 Eur.Ph. (2.2.32.)
8. Sulfated ash,oh Max.0,1 Eur.Ph. (2.4.14.)
9. Related substances, o/o : HPLC
- 5 -chloro- 8 -hydroxyquinaldine Max.0,15 Eur.Ph. (2.2.29)
- any other impurity Max.0,10
- total Max. 1
10. Assay : chlorquinaldol,Vo; 98 - t02 Eur.Ph. (2.2.29)
- HPLC
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CIIARACTEKISTICS AD MISS I B ILITY CRITERIA METHODS OF
ANALYSIS
I 1. Microbiological Quality: Eur.Ph. (5.1.4)
- total aerobic microbial count
(rAMC) Max. 1000 CFU/g
- total combined yeasts/moulds
count (TYMC) Max. 100 CFU/g
-Escherichia coli Absence/g
I 2.Residual solvent, ppm:* Eur.Ph. (2.2.28)
- acetone Max.2000
* It was performed only on the 6 batches (3 pilot and 3 industrial), which was
conducted the
process validation. The results on the 6 batches are much lower than the limit of admissibility from
specification (2000 ppm), and ten times lower than the limit of 5000 ppm, fitted in European
Pharmacopoeia, and ICH Q3 guideline on "Residual Solvents". So we believe that this parameter is
not required to be included in the current product quality specification .
"l
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3.2.5.4.2 Analytical procedures
1. Appearance : yellow to yellow brown cristaline powder with faint characteristic odour.
2. Solubilify : practically insoluble in water, soluble in acetone and ether, slightly soluble in ethanol
96%.
-insoluble in water: weigh 1 mg of in a stoppered tube, add 10 ml of water, shake

substance
vigorously for 1 minute holding the temperature constant at 25,0 + 0.5 .C. Substance has not
dissolved.
-soluble in acetone: weigh 100 mg substance in a stoppered tube, add 3 ml of acetone, shake
vigorously for I minute holding the temperature constant at25,0 + 0.5 oc. Substance has dissolved.
-soluble in ether : weigh 100 mg substance in a stoppered tube, add 3 ml diethyl ether, shake
vigorously for 1 minute holding the temperature const ant at 25,0 + 0.5 oc. Substance has dissolved.
-slightly soluble in ethanol 96%o: weigh 10 mg substance in a stoppered tube add l0 ml of ethanol 96
o/0,
shake vigorously for 1 minute holding the temperature constantat25,0 x.0.5
"C. Substance has
dissolved.
3.Identification :
A. IR spectrum: IR absorption spectrum of the substance to be analyzed corresponds to the IR

spectrum of the reference substance.
B. HPLC Q.2.9), simultaneously with Assay determination. The retention time of the principal peak
from the chromatogram obtained with test solution coffespond with the retention time of the peak
due to chlorquinaldole in the chromato-gram obtained with reference solution.
C. Melting point: the melting point of Pure Chlorquinaldole is between 109 - I 14oC by capillary
method.
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Solution (S) : shake 0,75 g test substance with 25 ml carbon dioxide-free water R and boil for 2
minutes. Cool and filtrate. Dilute the filtrate with the same solvent to 30 ml.
4. Appearance of solution: dissolve 75 mg test substance in 15 ml ethanol 96% (with gently

heating). Cool resulted solution. The solution is clear (Eur. Ph. 2.2.I) and not more intensely
coloured than reference solution BY3 (Eur. Ph. 2.2.2., method II)
5. Acidity * alcalinity : to 10 ml solution (S) add 0,1 ml of cresol red solution (1) and 0,25 ml
sodium hydroxide 0,01 mol/l solution. The colour of solution turn to red.
To 10 ml solution (S) add 0,1 ml of methyl red solution (I) and 0,25 ml hydrochloric acid 0,01 mol/l
solution. The colour of solution turn to red.
6. Chlorides (2.4.4): maximum 500 ppm

Dilute 4 ml solution (S) with 15 ml water. The solution complies with the limit test for chlorides..
,;l
7. Loss on drying (Eur. Ph.2.2.32) : Maximum 0,2 oh, determined on 1,000 g by oven drying at 55
- 600C, for 4 hours.
8. Sulfated ash (Eur. Ph.2.4.14): Maximum 0,I o .
Ignite a suitable crucible at 600 + 500 C for 30 min, allow to cool in a desiccator over silica gel or
other suitable desiccant and weigh. Place the prescribed amount of the substance to be examinated in
the crucible and weigh. Moisten the substance to be examinated with a small amount of sulfuric acid
R (usually 1 ml) and heat gently at as low a temperature as practicable until the sample is thoroughly
charred. After cooling, moisten the residue with a small amount of sulfuric acid R (usually 1 ml),
heat gently until white fumes are no longer evolved and ignite at 600 t 500 C until the residue is
completly incinerated. Ensure that flames are not produced at any time during the procedure. Allow
the crucible to cool in a desiccator over silica gel or other suitable desiccant, weigh it again and
calculate the procentage of residue. If the amount of the residue so obtained exceeds the prescribed
limit, repeat the moitening with sulfuric acid R and ignition, as previously, for 30 min periods until 2
consecutive weighings do not differ by more than 0,5 mg or until the percentage of residue complies
rvith the prescribed limit.
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cHLoReurNALDoL I
9. Related substances (HPLC) (Eur. Ph.2.2.29) z
- Principle of the method :
Determination of related substances are made by high-performance liquid chromatography.

The method is based on the quantitative determination of chemically related impurities by high
performance liquid chromatography according to DAC monograph "Chlorquinaldol".
LaChrom Merck Hitachi liquid chromatograph is equipped with a UV detector and a column of
steel filled with octadecylsilyl silica gel.
- Reagents :
- water R;
- methanol HPLC grade;
- acetic acid, glacial R;
- Mobile phase : homogenized and filtered mixture of methanol:water: acetic acid, glacial, in
proportion (84,5: 15: 0,5), (V:V:V).
- Test solution : transfer 6,0 mg test substance (pure chlorquinaldol) with methanol td 100 ml
volumetric flask, shake for 15 minutes , dilute to volume with the same solvent, homogenize and
filter, throw the first 10 ml.
1 ml test solution contain 60 pg chlorquinaldole.

- Reference solution (1): transfer 10 mg chlorquinaldol RS and 40 mg cloxiquin R (5-chloro-8-
hydroxyquinaldine) accurately weighted, with methanol to an 100 ml volumetric flask. Shake until
dissolved and dilute to volume with the same solvent. Dilute 1 ml of this solution to 100 ml with the
same solvent.
1 ml reference solution (1) contain 1 pg chlorquinaldole RS and 4 pg cloxiquin R.

- Reference solution (2) : dilute I ml test solution to 100 ml volumetric flask with methanol. Dilute 5
ml of this solution to 50 ml volumetric flask with the same solvent.

1 ml reference solution (2) contains 0,06 pg chlorquinaldole.
- Chromatographic system :
a) High performance liquid crhomatograph LaChrom Merck Hitachi:
- detector : spectrophotometer UV;

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- sample automatic injection : 0-100 pl;
- PC; Printer
' b) Column : Purospher STAR RPl8 endcapped,250 x 4,6 mm,5 pm, or equivalent.
- Chromatographic conditions :
- Flow rate : 1,5 ml/min;

- Injection volume :20 pl;
- Detection ; at250 wrt
- Procedure :
Equilibrate the HPLC column with mobile phase ( base line is a straight line). Inject 20 pl
reference solution (1) and record the chromatogram.
The test is not valid unless : the resolution between peaks due to cloxiquine (retention time :
aprox. 3 min. ) and chlorquinaldole ( retention time: aprox 5 min) is minimum 4.0.
Inject 20 pl reference solution (2) and20 pl test solution and record the chromatograms. Run
time for test solution is twice retention time of chlorquinaldole.
t
- Results :
In the chromatogram recorded for test solution :
- known impurities, individually:
5-chloro-8-hydroxyquinaldine: not more than 1,5 times area of the main peak in the
chromatogram obtained with reference solution (2) (0,15%).
- unspecified unknown impurities, individual: area of any secondary peak is not more than area of
the main peak in the chromatogram obtained with reference solution(2) (0,1%).
- total (sum of impurities) : sum area of the secondary peaks is not more than 10 times area of the
main peak in the chromatogram obtained with reference solution (2) (I%)
- disregard limit : 0,2 times the area of the principal peak in the chromatogram obtained with
reference solution (2) (0,02%).
Calculation formula:
AscsH
5-chloro-8-hydroxyquinaldine, o/o: -------- --- x 0,15

0,4x1,5xAe
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Ai
Any other impurity, individual, o/o: ---------------- x 0,1
Ae
TAi
Total impurities,o/o: ---------------- x 1,0
10xAe
where:
Ascsu- peak area of 5-chloro-8-hydroxyquinaldine in the chromatogram obtained with test

solution
Ai * unknown impurity peak area in the chromatogram obtained with test solution
Ae - clorchinaldol peak area of the reference solution (2) |
XAi - sum of the areas of all impurity peaks in the chromatogram obtained with test solution
10. Assay : chlorquinaldol93- t02o
The method is based on the quantitative determination of chlorquinaldole by high performance

liquid chromatography. HPLC system LaChrom Merck is equipped with a UV detector and a steel
column with octadecylsilane end-capped..
- Reagents :
- water R;
- methanol HPLC grade;
- acetic acid, glacial R;
- mobile phase: homogenized and filtered mixture of methanol : water : glacial acetic acid, in
proportion (84,5: 15: 0,5), (V:V:V).
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- Test solution : transfer 6 mg test substance accurately weight, with methanol to 100 ml volumetric
flask, sonicate and dilute to volume with the same solvent. Dilute 5 ml of this solution with methanol
to 50 ml.
1 ml test solution contains 6 pg chloquinaldol
- Reference solution : transfer 6 mg chlorquinaldole R.S. accurately weight, with methanol to 100 ml
volumetric flask, sonicate for 15 minutes, cooled to room temperature and dilute to volume with the
same solvent. Dilute 5 ml of this solution with methanol to 50 ml.
1 ml standard solution contains 6 pg chloquinaldol R.S.
- Chromatographic system :
a) HPLC System LaChrom Merck Hitachi with:
- detector UV;
- sample automatic injection : 0-100 trrl;
- PC; Printer
' b) column : Purospher srAR RPl8 endcapped, 250 x 4,6 mm,5 pm, or equivalbnt.
- Chromatographic conditions z ,ll,l
- flow rate : 1,5 ml/min;

- Injection volume :20 trtJ;
- Detection : at250 nrn
- Procedure :
Equilibrate the HPLC column with mobile phase (base line is a straight line). Inject standard
solution. The test is not valid unless the relative standard deviation of the peak area for the
chlorquinaldole in the standard solution is not more than 2o/o after replicate injections. Inject about20
pl test solution into the chromatograph. Record the chromatogram and measure the response for the
principal peak.
- Interpretation ofresults :
ApxmexCe
Chlorquinaldole, Yo: x 100
Aexmpx 100
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where:
Ap - peak area of chlorquinaldole in the chromatogram obtained with test solution.

Ae - peak area of chlorquinaldole in the chromatogram obtained with standard solution
me - weight of chlorquinaldol RS for standard solution, in mg ;
mp - weight of the sample for test solution, in mg ;
Ce - chlorquinaldole RS concentration,%o.
1 1. Microbiological Quality:Eur.Ph.
Characteristics
Microbiological quality - according to European Pharmacopoeia 8 Chapter 5.1.4., for non-sterile
dosage form "Non-aqueous preparations for oral use"
Total aerobic microbial count (TAMC)/g Maximum 1000

Total combined yeasts/moulds count (TYMC)/g Maximum 100
Escherichia colilg Absent
The method of analysis

The method of verification of the microbiological quality of the product allows a quantitative and
qualitative evaluation of the micro-organisms which may develop under aerobic conditions. The
determination of total aerobic microbial count and of total combined yeasts/moulds count is made
by the plate-count method - inoculation directly into the depth of the culture media, described in the
European Pharmacopoeia 8. 2.6.12. "Microbiological examination of non-sterile products: microbial
enumeration tests" and chapter 2.6.13. "Microbiological examination of non-sterile products: test for
specified micro-organisms". The method described below enables the use of selective media for
highlighting of the specific pathogenic micro-organism (Escherichia coli).
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Materials and equipment

- Petri dishes, pipettes of various volumes, graduated cylinder, tubes, Erlenmeyer flasks, bottles
(sterile materials)
- growing media (prepared and kept in accordance with the instructions of the manufacturer)
- sterile solution of hydrochloric acid 1 M and sodium hydroxide lM, to adjust the pH
- solvents to diluting the sample
- balance to weigh the accuracy adequate, disposable gloves, pH paper
- incubators, thermostated water bath, laminar air flow hood
A. THB DETERMINATION OF THE TOTAL AEROBIC MICROBIAL COUNT

1. Buffer solutions and growing media
- Buffered sodium chloride-peptone solution pH 7.0
- Casein Soya bean digest agar
- Polysorbat 80,1o
Dissolve the buffered sodium chloride-peptone solution pH 7.0 in water, sterilise and cool;'Jccording
to the instructions of the manufacturer. Dissolve the Casein Soya bean digest agar in water and add
as a surfactant I o/o Polysorbat 80 (1 ml Polysorbat 80 to 100 ml of media); sterilise and cool,
according to the instructions of the manufacturer.
2. Preparation of the sample to be analyzed
10 g of the sample to be analyzed is aseptically bring in 90 ml of buffered sodium chloride-peptone
solution pH 7.0. The container with the sample shake circular 5-10 times for soaking, then place in
the water bath at maximum 45"C and leave until to suspension (20-30 minutes). If necessary adjust
the pH value to about 6 to 8 with sterile solution of hydrochloric acid I M or sterile solution of
sodium hydroxide lM. If necessary, the following dilutions (l:100, 1:1000) shall be prepared using
the same diluent.
3. Negative control
To verify testing conditions, a negative control is performed using the chosen diluent in place of
sample to be analyzed. There must be no growth of micro-organisms on plate with diluent.
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4. The recovery of the micro-organism in the presence of the product
4.1. For each micro-organism used (Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus
subtilis) shall be given separate tests. Only the micro-organisms of the stem of testing added are
counted.
4.2.Is used the plate-count method.

4.3. Are used Petri dishes 9-10 cm in diameter. For each sterile Petri dish add I ml of the sample
preparated as described in chapter 2 and 15-20 ml of Casein soya bean digest agar liquefied medium,
at not more than 45oC. For each micro-organism (Staphylococcus aureus, Pseudomonas aeruginosa,
Bacillus subtilis) prepare two Petri dishes. Incubate the plates so prepared at 30-35oC for 3 days.
Count the colonies which develop on each plate, calculate the arithmetic average of the number of
colonies read and calculate the number of colony-forming units of the inoculum.
4.4.Yeify the conformity of the counting method on the plate as follows: the number of each micro-
organism test should not be more than twice the amount of control in the absence of the product to be
analyzed (around 200).
5. Procedure for the control of the product. Direct seeding in the culture medium - indculation
in depth
5.1. Is used the plate-count method
5.2. Are used Petri dishes 9-10 cm in diameter. For each sterile Petri dish add aseptically I ml of the
sample preparated as described in chapter 2 and 15-20 ml of Casein soya bean digest agar liquefied
medium with a surfactant 1 % Polysorbat 80, at not more than 45oC. Cover the plate with the lid,
rotates the plate slightly to homogenise the dilution of the sample with the culture medium and leave
at room temperature until solidify. Prepare two Petri dishes for each dilution of the sample. Incubate
the plates so prepared at 30-35"C for 5 days. Select the plates of dilutions on which we can rcad a
rnaximum of 250 colonies. Count the colonies which develop on each plate, calculate the arithmetic
average of the number of colonies read and calculate the number of colony-forming units per gram.
6.Interpretation of the results

The total aerobic microbial count is considered to be equal to the arithmetic average of the number of
colonies read using Casein soya bean digest agar with surfactant 1 % Polysorbat 80, multiplied by
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the dilution (e.g.10, 100 or 1000). If colonies of fungi are detected on this medium, they are counted
as part of the total aerobic microbial count.
B. THE DETERMINATION OF THE TOTAL COMBINED YEASTS/MOULDS COUNT

1. Buffer solutions and growing media
-Buffered sodium chloride-peptone solution pH7.0
-Sabouraud - dextrose agar
-Polysorbat 80, I Yo
Dissolve the buffered sodium chloride-peptone solution pH 7.0 in water, sterilise and cool, according
to the instructions of the manufacturer. Dissolve the Sabouraud - dextrose agar in water and add as a
surfactant 1% Polysorbat 80 (1 ml Polysorbat 80 to 100 ml of media); sterilise and cool, according to
the instructions of the manufacturer.
2.Preparation of the sample to be analyzed
Proceed as described in chapter A.2
3. Negative control
To verify testing conditions, a negative control is performed using the chosen diluent inrplace of
sample tobe analyzed. There must be no growth of micro-organisms on plate with diluent.
product
4. The recovery of the micro-organism in the presence of the
4.1. For each micro-organism used (Candida Albicans, Aspergillus brasiliensis) shall be given
separate tests. Only the micro-organisms of the stem of testing added are counted.
4.2.Is used the plate-count method

4.3. Are used Petri dishes 9-10 cm in diameter. For each sterile Petri dish add I ml of the sample
preparated as described in paragraph 2 and 15-20 ml of Liquefied Sabouraud-dextrose agar, at not
more than 45"C. For each micro-organism (Candida Albicans, Aspergillus brasiliensis) prepare two
Petri dishes. Incubate the plates so prepared at20-25"C for 5 days. Count the colonies which develop
on each plate, calculate the arithmetic average of the number of colonies read and calculate the
number of colony-forming units of the inoculum.
4.4. Verify the conformity of the counting method on the plate as follows: the number of each micro-
organism test should not be more than twice the amount of control in the absence of the product to be
analyzed (around 200).
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5. Procedure for the control of the product. Direct seeding in the culture medium - inoculation
in depth
5.1. Is used the plate-count method
5.2. Are used Petri dishes 9-10 cm in diameter. For each sterile Petri dish add aseptically I ml of the
sample preparated as described in paragraph 2 artd 15-20 ml of Liquefied Sabouraud - dextrose agar
with a surfactant 1% Polysorbat 80, at not more than 45"C. Cover the plate with the lid, rotates the
plate slightly to homogenise the dilution of the sample with the culture medium and leave at room
temperature until solidify. Prepare two Petri dishes for each dilution of the sample. Incubate the
plates so prepared at 20-25oC for 5 days. Select the plates of dilutions on which we can read a
maximum of 50 yeast/moulds count. Count the colonies which develop on each plate, calculate the
arithmetic average of the number of colonies read and calculate the number of colony-forming units
per gram.
6.Interpretation of the results

The total combined yeasts/moulds count per gram is considered to be equal to the arithmetic average
of the number of colonies read found using Sabouraud - dextrose agar with surfactant 1% Polysorbat
80, multiplied by the dilution (e.g.10 or 100). If bacteria are detected on this media, they are[ounted
as part of the total combined yeasts mouldsl count read.
C. HIGHLIGHTING OF TIIE SPECIFIC PATHOGENIC MICRO-ORGANISM

The tests described allow the use of selective media for the highlighting of the specific pathogenic
micro-organism. (Escherichia coli).
C.1. ESCHERICHIA COLI
1. Growing media
-Casein Soya bean digest broth
-MacConkey broth
-MacConkey agar
-Polysorbat 80,I oA
Dissolve Casein Soya bean digest broth media in water and add as a surfactant l%;o Polysorbat 80 (l
ml Polysorbat 80 to 100 ml media), sterilise and cool, according to the instructions of the
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manufacturer. Dissolve the media MacConkey broth and MacConkey agar in water, sterilise and
cool, in accordance with the instructions of the manufacturers.
2. Negative control
To verify testing conditions, a negative control is performed using the chosen diluent in place of
sample to be analyzed. There must be no growth of micro-organisms on plate with diluent.
3. Sample and enriched culture preparation

Samples were prepared using a 1:10 dilution of not less than I g of the product to be examinated.
Use 10 ml of the solution prepared in accordance with paragraph A.2. (quantity corresponding to 1 g
of the product), put aseptically in 100 ml Casein Soya bean digest broth media, add as surfactant 1 %
Polysorbat 80 (1 ml Polysorbat 80 to 100 ml of media), homogenize and incubate at 30-35"C for 18-
24 hours.
4.Highlighting of Escherichia coli

Shake the container with the culture media seeded with the sample to be analyzed. Transfer 1 ml of
the solution of enriched culture in accordance with paragraph C.l.3. in 100 ml of MacConkey broth
media and incubate at 42-44oC for 24-48 hours. Transfer subculture into Petri dishes contaiging the
media MacConkey agffi and incubate at 30-35oC for 18-72 hours. The possible presence of
Escherichia coli is indicated by the appearance of red gram-negative colonies, not mucoide. The
presence of Escherichia coli is confirmed by the identification tests, such as the production of indole.
The product is suitable where there is no evidence of a colony or identification tests are negative.
D. SOLUTIONS AND GROWING MEDIA

In order to verify the microbiological quality in accordance with the European Pharmacopoeia 8 are
used the following solutions and growing media :
Buffered sodium chloride-peptone solution pH 7.0

Potassium dihydrogen phosphate 3.6 e
Disodium hydrogen phosphate dihydrate 7 .2 g, equivalent at 0.067 M phosphate
Sodium chloride 4? o
')" E
Peptone (meat or casein) 1,0 g
Purified water 1000 ml
Sterilise by heating in an autoclave at I2I"C for 15 minutes.
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Casein Soya bean digest broth
Pancreatic digest of casein 17.0 g
Papaic digest of soya beans 3.0 g

Sodium chloride 5.0 g
Dipotassium hydrogen phosphate )5o
-'" b
Glucose monohydrate )\o b

-'"

Adjust the pH so that after sterilizationto be 7.3 x.0.2 at25"C. Sterilise by heating in an autoclave at
l2l"C for 15 minutes.
Casein Soya bean digest agar

Pancreatic digest of casein 15.0 g
Papaic digest of soya beans 5.0 g

Sodium chloride 5.0 g
Agar 15'o g
,:'!
Adjust the pH so that after sterilization to be 7.3 + 0.2 at25oC. Sterilise by heating in an autoclave at
I2l"C for 15 minutes.
Sabouraud-dextrose agar
Peptone (mixture of meat and casein) 10,0 g
Dextrose 40.0 g
Agar 15.0 g
Adjust the pH so that after sterilization to be 5.6 * 0.2 at25oC. Sterilise by heating in an autoclave at
l2l'C for 15 minutes.
MacConkey broth
gelatin)
Pancreatic digest (of 20.0 g
Lactose monohydrate 10.0 g
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Dehydrated ox bile 5.0 g
Bromocresol purple 10 mg
Adjust the pH so that after sterilizationto be 7 .3 + 0.2 at25"C. Sterilise by heating in an autoclave at
\21"C for 15 minutes.
MacConkey agar
Pancreatic digest (of gelatin) 17.0 g
Peptone (meat or casein) 3,0 g
Lactose monohydrate 10,0 g
Sodium chloride 5,0 g
Bile salts 1,5 g
Agar 13,5 g
Neutral Red 30,0 mg

Crystal violet lmg ,,1
Adjust the pH so that after sterilization to be 7.1 + 0.2 at25"C. Boil for 1 minute under constant
shaking, then sterili ze by heating in the autoclave at l2I"C for 1 5 minutes.
12. Residual solvents (2.2.28): acetone maximum 2000 ppm
- Principle of the method:

The method consists in the separation and the determination of the volatile compounds by gas
chromatography using the headspace technique for the injection of the sample.
This technique is based on the analysis of the phase of vapors in balance with a solid or liquid.
Identification of the analyte is carried out on the retention time of the substance standard.
The analytical procedure reproduce the conditions given by the current European Pharmacopoeia for
the "System A" (method 2.4.24.).
- Materials and reagents:
- Acetone ;
- Dimethylformamide (DMF ) ;
- Volumetric flasks Class A ;
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- Pipettes Class A
- Headspace vials of 20 ml capacity ;
- PTFE septs ;
- Aluminum caps ;
- Staple .
- Chromatograph system :
Thermo Electron gas chromatograph - FOCUS GC equipped with :
- Flame ionization detector (FID );

- inj ector split/splitless ;
- TriPlus headspace device ;
- Soft Chrom - card for chromatographic data acquisition and processing ;
- Capillary column TR-Vl(cyanopropylphenyl polysiloxane) 30 m x 0.53 mm x 3.0 pm

(Maximum temperature 300 " C);
- Nitrogen generator (Carrier gas and make-up) and air - purity gases of 99 .9999 %;
- Hydrogen generator- purity of 99.9999 %; ':'l
- Sartorius analytical balance, LE225D-OCE model: 0.01 mg accuracy.

- Procedure
Preparation of the solutions :
- blanck solution; transfer I ml DMF into the headspace vial of 20 ml. Staple with septum and squib.
- stock standard solution: weigh accurately 500 mg acetone into a 100 ml volumetric flask. Dilute to
volume with DMF.
- standard solution (50 ppm): Dilute 1 ml of the stock standard solution to 100 ml volumetric flask
with DMF. Transfer 1 ml of this solution into the headspace vial of 20 ml. Staple with septum and
squib.
- test solution: Transfer 100 mg of the substance to be analyzed accurately weighed into the
headspace vial of 20 ml. Staple with septum and squib. Prepare 2test solutions.
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CHLOROUINALDOL
- Working conditions:
C h romato g r ap hic co nditions :

- Nitrogen flow make-up: speed 5 ml/min;
- injection mode: split (split ratio 1: 8)
- inj ector temperatura: 250" C;
- detector temperatura: 250" C
- column temperature:
5 "C/min 20 oC/min
50 "c 80 "c 220'C

5 min 20 min 20 min
Headspace conditions:
- the temperature for echilibrating sample: 90oC
- echilibrating time: 30 min

- the temperature of the transfer line: 100oC
,,1
- pressurizer time: 0.5 min
- Injection volume: 2 ml gas phase
- Procedure:
After the chromatographic system is equilibrated, respectively the baseline is a straight line, inject
the standard solution. The relative deviation standard on 6 successive injections for peak area of
acetone must be less than l5o/o.Inject the test solutions. Under the conditions described the retention
time for acetone is approximately 1 minutes and for DMF approximately 13 minutes.
- Interpretation ofresults :
The content of acetone, expressed in ppm is calculated with the following formula:
Apx Cex1000
Acetone (ppm)
Aexmp
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CHLOROUINALDOL
Where : - Ap - peak area of acetone in the chromatogram of the test solution;
- Ce - the concentration of acetone in the standard solution, ppm;
- Ae - the average amount of area of the peaks of acetone from the chromatograms of the
standard solution;
- mp - mass of sample taken in work, in mg;
-1000 - factors of transformation.
':tl
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CHLOROUINALDOL
3.2.5.4.3 Validation of analytical procedures
3.2.5.4.3.1 METHOD VALIDATION FOR THE IDENTIFICATION OF

PURE CHLORQUINALDOLE THROUGH HIGH PERFORMANCE LIQUID
CHROMATOGRAPHY
The identification of Pure Chlorquinaldole is performed through high perforrnance liquid

chromatography, simultaneous with "assay" parameter.
The method is classified as a category IV of analyical determination according to USP 35
indications in "Analytical methods validation" chapter <1225>-.*ldentihcation tests" .
Method description:
Principle of the method: ':,1
Identification of chlorquinaldole is made through high perfonnance liquid chromatography,

simultaneous with "assay" parameter. Elite Lachrome Merck Hitachi liquid chromatograph is
equipped with a UV detector and a steel column containing octadecylsilyl silica gel or equivalent.
Reagents:
- methanol R;
- purified water R;
- glacial acetic acid R;
- mobile phase: homogenized and filtreted mixure of methanol R: purified water R: glacial
acetic acid R (84.5:15:0.5) (V:V:V);
- sample solution:6 mg pure chlorquinaldole is transferred in a 100 ml volumetric flask, with

5 ml of methanol R and sonicate the sample for 15 minutes until complete dissolution, cool to room
temperature, fill to volume with methanol and homogenise. Dilute 5 ml from the resulting solution to
50 ml in a volumetric flask with methanol R and homogenize.
I ml sample solution contains 0.006 mg pure cholrquinaldole.
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Page 52
CHLOROUINALDOL
- standard solution:6 mg chlorquinaldole RS is transferred in a 100 ml volumetric flask, with
5 ml of methanol R and sonicate the sample for 15 minutes until complete dissolution, cool to room
temperature, fill to volume with methanol and homogenise. Dilute 5 ml from the resulting solution to
50 ml in a volumetric flask with methanol R and homogenize.
I mI standard solution contains 0.006 mg cholrquinaldole RS.
Chromatographyc system:
a) Hygh Performance liquid chromatograph Elite LaChrome Merck Hitachi equiped with:
- UV detector;
- Automatic sample injection system with an injection volume of 100p1;
- PC,
- printer.
b) Chromatographyc column: Purospher STAR RP 18 endacapped, 250 x 4.6 mm, 5 pm, or

equivalent.
Working conditions2 ,-l
- flowrate: 1.5 ml/min;
- injection volume: 20 pl;
- wavelength:250 nm;
Determination procedure:
After chromatographic system is balanced, respectively base line is straight, inject standard
solution until the relative standard deviation for successive injections is less than2.0Yo.
Interpretation of results:
The retention time of peak of chlorquinaldole in sample solution chromatogram coincides
with the peak of chlorquinaldole in standard solution chromatogram;
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CHLOROUINALDOL
S PEC I FICITY . S ELE CTIW TY
In order to verify the specificity of the method for identification of pure chlorquinaldole,
samples were prepared according to the analysis method and were recorded chromatograms for:
- dilution mixture: methanol R;

- standard solution:6.0 mg chlorquinaldole RS is transferred in a 100 ml volumetric flask,
with 5 ml of methanol R and sonicate the sample for 15 minutes until complete dissolution, cool to
room temperature, fill to volume with methanol and homogenise. Dilute 5 ml from the resulting
solution to 50 ml in a volumetric flask with methanol R and homogenize.
I mI standard solution contains 0.0060 mg cholrquinaldole RS.
- sample solution'.6.1 mg pure chlorquinaldole is transferred in a 100 ml volumetric flask,

with 5 ml of methanol R and sonicate the sample for 15 minutes until complete dissolution, cool to
room temperature, fill to volume with methanol and homogenise. Dilute 5 ml from the resulting
solution to 50 ml in a volumetric flask with methanol R and homogenize.
I ml sample solutioncontains 0.0061 mg pure cholrquinaldole. ':l
To the analysis of chromatograms obtainedfor specfficity parameter results:
- chromatogram obtained with dilution mixture shows no peaks;

- chromatograms obtained with standard solution shows a peak with retention time of 6.49
minutes corresponding to chlorquinaldole.
- chromatogram obtained with sample solution shows a peak with retention time of 6.52
minutes assigned to chlorquinaldole.
Conclusion:
From the above mentioned results that:
- the retention time of peak of chlorquinaldole in sample solution chromatogram coincides with the
peak of chlorquinaldole in standard solution chromatogram.
Therefore it can be appreciated that the analysis method is specific and selective for the
identif,rcation of the PURE CHLORQUINALDOLE.
Representative chromatograms are presented in Appendix.
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Code: ASMF-CQ
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Page 54
CHLORQUINALDOL
CONCLUSION: Method validation for the identification of PURE
CHLORQUINALDOL by high performance liquid chromatography corresponds in terms of
specificity, according to GMP-GLP.
CONFIDENTIAL
S.C. MEDUMAN S.A. Code: ASMF-Ce
ASMF - CTD format - Applicant's part Edition: I
Revision:0
qrrlpRQUrr{ALDOL Page 55
SISIIEM IIPLC DLITE UV-z (Offline)
Data Filc: DJEZChrom Elite\Enqerprise\projec s\CLORCHINALDOL\Data\Specificitarea\ad.dar

Method: D:\EzchromErirs\Enterprise\projecrs\cloncutNaroolwt"u.ira"r",=rr**'
sequence; DlEZchrom elite\Enterpri.se\Froj.o,rcr.oniiiii.{nlDol\sequence\specificitate.seq
Acquired: llJ?9/2A16 9:54:3t AM
Sample lD; ad
via,t no: 191 Injeuion Volume: 20 pl
Retention T[me
Name
t,l
L
UV RcsllJs
CONFIDENTIAL
S.C. MEDUMAN S.A. Code: ASMF-CQ
ASMF - CTD format - Applicant's part Edition: 1
Revision:0
PURE Date:02102/20t7
qHT=ORQUINALDOL Page 56
SIFTEI{ F,Le EI;IXE UY-7 {ofl ine}
Di*a,.Fjlc: D:\EZCkronElite\Enrerrrir$\hoj6qB\ef0RcglNAtDol\D$a\Specificiut{s\etato!.d4t
Msthod: D:\EZCluom Eh'te\Enterpriscwrojcgtstc,roncilxAlDol-\rvledrod\dozare-met
$ce',.Eoc.' D:tE2ChronElitelEnaprirc\proj*rrcmrcnrwer,nOtiG;*\S;;ti,n*.*
Acquircd: lldga0ld 10;101564n{ --'--a--*irvt--'rFrEe
Sanpl,c ID; ctalon
Vial no: 192 l4jection Volune 20 pI
L Ith.tilc{
UVftruti!
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,{,*T=*= ,nf =={S f"f*"" e"yal X' R
elbrrhtualdol I 6.49 i
Revision:0
qHIORQUTNALDOL Page 57
;i:\1:iT:3:ireTiejI?sril+ur:.i;+-
SISTEM HPLC ETITE Uv.? (Offtine)

Dah File: D:\EZChrom Erite\Enterprise\projecm\cLoRCHTNALDoL\Data\specificitatea\test.dat
Method: DlEZChrom?i")i"*i"t"w."j..ilaidiiiunielDolwerhod\tlozare.met
i:li',l,Ti 'n}trfri{rii3u""'ii'i,.G,'j..*iiiSi,trnuarool\sequence\Spe.iti"r,u,".,"q
Sample tD: resr
Vial no: jg3 Injcction Volunre: 20
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Retention Timo
Name
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UV Results
CONFIDENTIAL
Revision:0
PURB Date:0210212017
qql-,oRQUTNALDOL Page 58
3.2.5.4.3.2 METHOD
VALIDATION FOR THE DETERMINATION OF
CHEMICALLY RELATED SUBSTANCES FROM THE
ACTIVE
SUBSTANCE CLORQUINALDOL
BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
clorquinaldol chemically related substances determination

is carried out by high
performance liquid chromatography (HPLC).This
method fal into category II of analytical
determinations according to USP 35" validation of Analytical Methods,, chapter -1225,,
"Analytical Methods for determination of impurities
or degradation compounds in pharmaceuticals,,.
Method validation consist of checking specificity,
selectivity, stability of solutions used in
the analysis, accuracy, precision, robusteness, linearity,
limits of quantification and detection,
precision of quantification limit.
Method description :
The method is based on the quantitative determination
of chemically related impurities by
high performance liquid chromatography according
to DAC monograph ,'chlorquinaldol,,. '-,
Merck Hitachi chromaster liquid chromatograph is

equipped with a DAD detector and a steel
column containing a filler of octadecylsilyl silica
gel.
Reagents:
- Purified water R;
- Methanol R;
- Glacial acetic acid R;

- Mobile phase: homogenized and filtered mixture
of methanol: purified water: acetic acid
(84.5: 15: 0.5) (V: V: V);
- Reference solution (1): transfer 10 mg chlorquinaldol cRS and 40 mg cloxyquin R

(accurately weighted with methanol to
), an 100 ml volumetric flask. Shake until dissolved
and dilute
to volume with the same solvent. Dilute I ml
of this solution to 100 ml with the same solvent.
I ml reference solution (1) contain I pg chlorquinaldol
and 4 pg cloxyquin.
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qHLORQUTI\ALDOL Page 59
- Test solution: transfer 6.0 mg test substance

with methanol to r00 rnl volumetric flask
shake for 15 minutes , dilute to volume
with the same solvent, homogenize and filter
, throw the first
10 ml.
1 ml test solution contain 60 pg chlorquinaldol.

- Reference solution (2) : dilute I ml test solution to 100 ml volumetric flask with methanol.
Dilute 5 ml of this solution to 50 ml volumetric
flask with the same solvent.
1 ml reference sorution (2) contains
0,06 prg chlorquinaldol.
Chromatographic system :
a) High performance liquid crhomatograph
Lachrom Merck Hitachi:
- detector : spectrophotometer UV;
- sample automatic injection : 0_100 pl;

- PC; Printer
b) column : purospher srAR Rplg endcapped, 250 x 4.6 mm,5 pm, or equivalent.
Chromatographic conditions :
t
- Flow rate : 1.5 ml/min;

- Injection volume :20 tril;
- Detection : at250 nm
Procedure :
Equilibrate the HpLC column with mobile phase
( base line is a straight line). Inject 20 pl
reference solution (1) and record the chromatogram.
The test is not valid unless : the resolution

between peaks due to cloxyquine ( retention
time :
aprox. 3 min.) and chlorquinaldol (retention
time: aprox 5 min) is minimum 4.0.
Inject 20 pl reference solution (2) and,20 pl
test solution and record the chromatograms.
Run
time for test solution is twice retention time
of chlorquinaldor.
Results:
In the chromatogram recorded for test solution
:
- 5-chloro-8-hydroxyquinaldine: not more than 1,5 times area of the principal peak in
the
chromatogram obtained with reference solution
(2) (0.15%).
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qgl,oRQUTNALDOL Page 60
- any other impurity: area of any secondary

peak is not more than area of the principal
peak in
the chromatogram obtained with reference
solutio n (2) (0.1%).
- sum of impurities : sum area of the secondary peaks
is not more than l0 times area of the
principal peak in the chromatogram obtained
with reference solutio n (2) (l%)
- disregard limit : 0.2 times the area of
the principal peak in the chromatogram
obtained with
reference solution (2) (0.02%).
Calculation formula:
AscsH
5 -chl oro -8 -hydroxyqu inaldine, %o : ----------- x or15
0,4x1,5xAe
Ai
Any other impurity, individual, %- _-______________
x 0,1 ,,1
Ae
xAi
Total impurities, o/o: ---------------_ x 1,0
10xAe
where:
AscsH- peak area of 5-chloro-8-hydroxyquinaldine in the chromatogram

obtained with test
solution
Ai - unknown impurity peak areainthe chromatogram obtained with test solution
Ae - clorchinaldol peak area of the reference
solution (2)
xAi - sum of the areas of all impurity peaks in the
chromatogram obtained with test solution
CONFIDENTIAL
S.C. MEDUMAN S.A. Code: ASMF-Ce
Revision:0
CHLORQUINALDOL Page 61
S PE CIFICI TY _ SELE C TIW TY

In order to verify the specificity of the method for
determining the chemically related
substances of active substance CHLORQUINALDOL,
samples were prepared according to the
method of analysis and chromatograms were
recorded for:
- Mixture of dilute : methanol.
- Reference solution (l);

- Test solution;
- Reference solution (2);
Preparation solutions:
- Reference solution (1): transfer quantitatively
10.02 mg chlorquinaldol cRS and 40.0g
mg
cloxyquin R (2-chloro-8-hidroxiquinaldine R)
into a volumetric flask of 100 ml with methanol
R and
mix until solubilization and completed to volume
with the same solvent. I ml of this solution was
diluted to 100 ml with the same solvent.
,:,1
- Test solution: transfer quantitativ ely
6.02 mg analytes (chlorquinaldol) into
a volumetric
flask of 100 ml with methanol R. Shake for
15 minutes, and completed with the
same solvent to
volume, mix and filter throwing the first
10 ml of filtrate.
- Reference solution (2): 1 ml of test
solution is diluted to 100 ml in a volumetric
flask with
methanol R' 5 ml of this solution was diluted
to 50 ml in a volumetric flask with the
same solvent.
In order to verify the selectivity of method

for determining the chemically related substances
of active substance CHLORQUINALDOL, samples
were prepared according to the method
of
analysis and chromatograms were recorded
for:
- Test solution prepared in methanol, chromatographed
when prepared, and after being kept
at 80 o c for 4 hours and then exposed to
254nm uv light for 12 hours: transfer
quantitatively 6.05
mg analytes (chlorquinaldol) into a volumetric
flask of 100 ml with methanol R. Shake for
15
minutes' completed with the same solvent
to volume, mix and filter throwing the
first l0 ml filtered.
- witness hydrochloric acid solution: 1 ml of methanol
R is transferred into a 100 ml
volumetric flask and diluted to vorume with
hydrochloric acid 0.r mol / r.
CONFIDENTIAL
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CHLORQUINALDOL
- Test solution prepared in hydrochloric acid 0.1 mol
/ l, chromatographed when prepared,
and after being kept at 80 o c for 4 hours
and then exposed to 254nm uv light for
12 hours: transfer
quantitatively 6'03 mg analltes (chlorquinaldol)
into a volumetric flask of 100 ml with I ml of
methanol R, shake for 15 minutes, complete
to volume with hydrochloric acid 0.1 mol
ll. Mix and
filter throwing the first l0 ml of filtrate.
- witness sodium hydroxide solution: I ml of methanol R is transferred into a 100 ml

volumetric flask and diluted to volume with sodium
hydroxide 0.1 mol / l.
- Test solution prepared in sodium hydroxide 0.1
mol / l, chromatographed when prepared,
o
and after being kept at 80 c for 4 hours and
then exposed to 254nm UV light for 12
hours: transfer
quantitatively 6'04 mg analytes (chlorquinaldol)
into a volumetric flask of 100 ml with I ml of
methanol R' shake for 15 minutes, complete
to volume with sodium hydroxide 0.1 mol
/ L Mix and
filter throwing the first l0 ml of filtrate.
- witness hydrogen peroxide solution: I ml of methanol R is transferred into r,l

t,
a
100 ml
volumetric flask and diluted to volume with hydrogen
peroxide;
- Test solution prepared in hydrogen peroxide, chromatographed
when prepared, and after
being kept at 80 ' c for 4 hours and then
exposed to 254 nm Uv light for 12 hours:
transfer
quantitatively 6'02 mg analltes (chlorquinaldol)
into a volumetric flask of 100 ml with I ml
of
methanol R' shake for 15 minutes, complete
to volume with hydrogen peroxide. Mix and filter
throwing the first 10 ml of filtrate.
It proceeded first to the validation of chromatographic

system using the reference solution (1)
the method of determination of chemically
related substances.
It provides:
- In the chromatogram obtained with reference solution (l) two peaks appear,one about to
three minutes assigned to cloxyquin and one
to about five minutes assigned to chlorquinaldol.
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CHLORQUINALDOL
- The resolution of the two peaks least 4.
The analysis of chromatograms obtained the following

results:
- The chromatogram obtained with reference solution
(r) shows a peak with retention time of
3.21 minutes assigned to cloxyquin and a peak with retention
time 6.16 minutes, assigned to
chlorquinaldol. The resolution achieved between the two peaks
is 10.6;
Therefore it can be concluded that the chromatographic
system fulfills the conditions imposed
by the DAC, the monograph "chrorquinaldol" for system
validation.
- The chromatogram obtained with the mixture of

dilution (methanol) do not show peaks that
interfere with peaks of interest;
- The chromatogram obtained with test solution shows

the following:
Retention time, minutes Peak name
34234371
- The chromatogram obtained with reference solution

(1) shows a peak with retention time of
6.16 minutes, assigned to chlorquinaldol.
The chromatograms obtained for the selectivity parameter

shows the following:
- Test solution prepared in methanol:
Initial moment After exposure for 4 houiJat g0tlnd
4 hours to UV light at 254 nm
Retention Peak name Area Retention Peak name Area

time,min time,min
3.66 Unknown 1 148s

8939 3.66 Unknown
impurity impurity
4.64 Unknown 3048 4.62 Unknown 344t
impurity impurity
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qHIORQUTT{ALDOL Page 64
Chlorquinaldol
- The chromatogram obtained with hydrochloric

acid solution 0. r mol / l, do not show peaks,
which interfere with the peak of interest.
- Test solution
loric acid 0.1 mol / I :
Initial moment After exposure rorffi
Retention
Retention
time,min
time,min
Chlorquinaldol 29319967
318351s0
Unknown
impurity
- The chromatogram obtained with the sodium hydroxide

solution 0.1 mol/l do not show
peaks which interfere with peak of interest;
- The test solution prepared in sodium
hydroxide solution 0.1 mol/l has the following:
Initial moment Afterexposuref@
Retention
Retention
time,min
time,min
CONFIDENTIAL
Revision:0
PURB Date:02/0212017
Chlorquinaldol 29775163
28956524
Unknown
Unknoun
impurity
impurity
- The chromatogram obtained with hydrogen peroxide
solution do not show peaks which
interfere with peak of interest;
- The test solution prepared in hydrogen

peroxide has the folrowing:
Initial moment After exposure fo" I trourslt AOqC uod
Retention
time,min
Unknown
impurity
Unknown 677513103
impurity
Chlorquinaldol 29775163 Chlorquinaldol

Conclusions:
From those exposed to it follows that:
- From the study of the chromatograms

of degraded test solutions we notice:
o in the mixture of dilution the level of impurities increases;
. in acid medium the level of impurities increases;
o in a basic medium the level of impurities increases
;
r in strong oxidizing medium the revel of impurities
increases
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qIIT9RQUINALDOL Page 66
- The method of analysis allows the qualitative

and quantitative determination of the
related
chemical impurities.
As a result it can be said that the method

of analysis is specific and selective for the
determination
of the chemically related substances of active
substance cHLoReuINALDoL.
Chromatograms are shown in Annexes.
':'
CONFIDENTIAL
ASMF - CTD format - Applicant's part Edition:
I
Revision:0
STABILITY OF THE SOLUTIONS TISED IN THE ANALYSg

Stability of the solutions used shall be carried
out in order to determine the period of time
in
which they are stable and can be used in the
analysis. The study was carried out on
the reference
solution (2) used for the assessment of impurities.
- The reference solution (2) shall be prepared

according to the method of analysis as
follows:
transfer quantitatively 6'0 mg of the substance
to be examined (chlorquinaldol) into a volumetric
flask of 100 ml with methanol R.ishake for
15 minutes, and completed with the same
solvent to
volume, mix and filter throwing the firsr l0 =r-ort
mr of filtrat.. r *- l ii
tn'.il'*o'l iil.das=*-*.lin'lfic 3$ffi,.- ni!v'$,di!8"4+ir5pr#fia131-tF-.
I ml of reference solution (2) containing 0.06 pg chlorquinaldol.

Was prepared in this way three solutions:
Quantify, mg
Solutions areas is determined according to

the method of analysis.
The solutions are kept at room temperature (25 r o
2 C) and 5 o C for 24 hours and protected
from light in both cases' calculate the percentage
retrieval from the value obtained at initial
moment.
Admissibility criterion: percentage retrieval for chlorquinaldol
to be in the range of 99 -
l0l% (compared with freshly prepared).
The results are presented in the following
tables:
Initial moment :
Initial momenf Area (mAU) Area frn Af T\ Area (mAU)

1 2 3
31411
2
29775
31124
a 29960
31218 Jll06 )q\6)
.+
31333 3t272
Nr.determinqfi^-o l..\ 30388
4
4
Average 3t272 3 1262 29921
Standard deviation ( s) t26 113 351
Relative Standard
CONFIDENTIAL
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S.C. MEDUMAN S.A. ASMF - CTD format - Applicant's part Edition: 1
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Page 68
CHLORQUTNALDOL
Deviation (RSD% 0.40 0.36 t.l7
The average confidence interva
95% 31128-31415 31135-31390 29s23-303t9
study conducted at room temperature away from light(25.C +

2"C) and at 5oC away
from light:
2 hours Area (mAU) Area (mAU)

1 )
Room temperature away from Study conducted
at 5oC
light (25"C r2.C) away from light
1
31220 31297
2 30941 31182
1
30937 JIISO
+ 31145 3t192
Nr.determinations (n) 4 4
Average 3106r 31205
{g4qlard deviation ( s) t44 64
Relative Standard
Deviation (RSD%) 0.46 0"20
The average confidenc e interval 95%o 30898-31224 31133-3t277
16 hours Area (mAU) Aree lrnAfT\

I 2
Room temperature away from Study conducted at 5oC
light (25"C t2c) away from light
31130 31497
2 3r453 31126
J 3tt43 31331
31019 31375
CONFIDENTIAL
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PURE Date:02102120t7
cHLORQUTNALDOL Page 69
Nr.determinations (n
Standard deviation (
3t332
s
Relative Standard
Deviation (RSD%
The average confidenc e interval 95%o 30975-31397 3tts7-3t507
24 hours Area (mAII) Area (mAU)

t 2
Room temperature away from Study conducted
at 5oC
light (25"C+2C) away from light
1
J IJ53
t 3't o?o
31339
31387
J 3 t499 30943 :,1
4 3l?q6 3 1058
Nr.determinations (n) 4 4
Average ?1?17
Qfan.l^-J J^- 31r82
uwvtqttult I J, 2U/ 215
Relative Standard 0,66
Deviation (RSD%) 0,69
The average confidenc e interval 95yo

31082- 3t552 30938 - 3t426
-
compare areas of freshly prepared solutions
and the same solutions analyzed by specified
intervals and calculate the percentage retrieval
reported at initial moment.
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qHLORQUTNALDOL Page 70
Room Retrieval
Time analysis temperatureo percentage Retrieval percentage
protected reported at reported at initial
from light initial moment moment
16 hours
31332
31317
Conclusions:
- The reference solution (2) : Is 24 hours stable,
kept at room temperature away from light
and at 5oC
protected from light;
,,1
CONFIDENTIAL
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PageTl
CHLORQUINALDOL
ACCURACY
This parameter was checked by carrying out

such determinations:
a) three determinations for three concentration
levels (50yo, r00% and, r50yo), in relation to the
chlorquinaldol concentration in the reference solution
(2), corresponding to limit 0.1%o of impurities
(0.06 pg lml);
b) three determinations for three concentration levels (50yo,
100% and 150%o), in relation to the
chlorquinaldol concentration corresponding to limit
0.15%of impurities(0.O9 pg / ml);
Is calculated the percentage retrieval for chlorquinaldol.
Admissibility criterion
The percentage of retrievar should be in the
range of 99.0 -r0r.0%.
a) For concentration corresponding to the limit
of impurities of o.ryo, samples were prepared as
follows:
- Standard solution: transfer quantitativ ely 6.04 mg clorchinaldol cRS
into a volumetric
flask of 100 ml with methanol R. Shake for 15
minutes, complete to volume with the same
solvent
and mix' 1 ml of this solution was diluted
to 100 ml in a volumetric flask with methanol R.
5 ml of
this solution was diluted to 50 ml in a volumetric
flask with the same sorvent.
- Test 50%o: ttansfer quantitatively 3.0 mg
analltes (chlorquinaldol) into a volumetric
flask of
100 ml with methanol R' Shake for 15 minutes,
complete with the same solvent to volume,
mix and
filter throwing the first 10 ml of filftate.1 ml of this
solution was diluted to 100 ml in a volumetric
flask with methanol R' 5 ml of this solution
was diluted to 50 ml in a volumetric flask
with the same
solvent.
1 ml50%o test solution contain 0.03 pg
chlorquinaldol.
Prepare three such solutions:
Quantity,mg
- Test 100o/o: transfer quantitatively 6.0

mg analytes (chlorquinaldol) into a volumetric
flask
of 100 ml with methanol R. Shake for 15 minutes, complete
with the same solvent to volume, mix
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and filter throwing the first 10 ml of filtrate. 1 ml of this solution was diluted
to 100 ml in a
volumetric flask with methanol R. 5 ml of this
flask
with the same solvent.
1 ml 100% test solution contain 0.06 pg chlorquinaldol.
- Test l50o/o: transfer quantitatively 9.0 mg analytes

(chlorquinaldol) into a volumetric flask
of 100 ml with methanol R. Shake for 15 minutes, complete
with the same solvent to volume, mix
and filter throwing the first 10 ml of filtrate.
I ml of this solution was diluted to 100 ml in a
volumetric flask with methanol R. 5 ml of this
flask
I mI150%o test solution contain 0.09 pg clorchinaldol
Quantify, mg
The results were calculated with the following

values:
- Standard sorution: concentration: 0.0604 pg
/ mlchlorquinaldol;
area:30 299
table:
Sample Xa area Xr o/
/o
mg ml.t I inj.2 | inj.3 | average mg retrieval
50-1 1A .^ t < -^^, i average
3.00 tat9) r)UU4 t4914
r
1 4q67
2.98 99.s3
50-2 2.98 t4541 1488s 14961 | 147e6 2.9s 99.05 99.5
50-3 3.02 t5286 r 5100 15075 151s4 3.02 99.97
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100-t 6.06 30300 30373 30383 303s2 6.05 99.85
r00-2 6.07 30152 30530 30523 30402 6.06 99.82 99.9
100-3 6.05 30321 30456 30282 30353 6.0s 100.06
150-1 9.07 45559 45476 45543 4s526 9.08 100.12

t50-2 9.02 45tr1 44969 45508 45196 9.01 99.89 99.8
150-3 8.96 45249 44470 44379 44699 8.91 99.41
where: Xa - chlorquinaldol quantity of the anaryzed,sample

Xr- quantity of chlorquinaldol retrieved.
The percentage of retrieval for the 9 samples is gg.g%.
b) For concentration corresponding to the limit of impurities of 0.l5yo,

samples were prepared as
follows:
- standard solution: transfer quantitatively 9.02mg chlorquinaldol
CRS into,a volumetric
flask of 100 ml with methanol R. Shake for 15 minutes, complete
to volume with the sagig solvent
and mix' 1 ml of this solution was diluted to 100 ml in
a volumetric flask with methanol R. 5 ml of
this solution was diluted to 50 ml in a volumetric flask with
the same solvent.
-Test 50% : transfer quantitatively 4.5 mg analytes (chlorquinaldol)
into a volumetric flask
of 100 ml with methanol R. Shake for 15 minutes, complete with the
same solvent to volume, mix
and filter throwing the first 10 ml of filtrate. 1 ml of this
solution was diluted to 100 ml in a
volumetric flask with methanol R. 5 ml of this solution was
diluted to 50 ml in a volumetric flask
1 ml50% test solution contain 0.045 pg chlorquinaldol.
Quantity, mg
-Test 100% : transfer quantitatively 9.0 mg analytes (chlorquinaldol)

into a volumetric flask
of 100 ml with methanol R. Shake for 15 minutes, complete with the same
solvent to volume, mix
and filter throwing the first 10 ml of filtrate. I ml of this
solution was diluted to 100 ml in a
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volumetric flask with methanol R. 5 ml of

flask
I ml100%otest solution contain 0.09 pg chlorquinaldol.
three such solutions:

".:, Sample' -,,,'
----.-_* 1 ) 3
Quantity, mg , 9.10 9.24 9.18
-Test 150%o : transfer quantitatively 13.5

mg analyes (chlorquinaldol) into a volumetric
flask of 100 ml with methanot R. Strat<e for i5
minutJs, complete with the same solvent
mix and filter throwing the first 10 ml of filtrate. to volume,
volumetric flask with methanor R. 5 ml of this
I ml of this solution was diluted to 100 ml
in a
sorution was diluted to 50 ml in a volumetric
with the same solvent. flask
1 ml 150% test solution contain 0.135 pg chlorquinaldol.
Quantityo mg
The results were calculated with the following

values:
- standard solution: concentration: 0.0902
pg r mrchlorquinaldol;
area: 44 917
table:
Sample Xa area Xr o/
/o
mg mJ. I I inj.2 mt 3 I evoro.ro mg :etrieval average
50-1 3.00 14963 I rsooa 14934 r4967 2.98 99.53
50-2 2.98 t4541 14885 14961 r4796
50-3 2.9s 99.05 99.5
3.02 15286 l5lnn 15075 Ist54 3.02 99.97
100-t 6.06 30300 ?n?7? 30383 30352 6.05

t oo_2 I 6.07 I zosz 30s30 | 30s23 30402 6.06
99.85
99.82 99.9
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CHLORQUINALDOL
r00-3 6.0s 30321 304s6 30282 303s3 6.05 100.06
r50-1 9.07 45559 45476 45s43 45\)6 9.08 t00.12

t50-2 9.02 45111 44969 45508 45t96 9.01 99.89
150-3 6.96 45249 44470 99.8
44379 ++oyy u.yl 99.4'/
Where: Xa - chlorquinaldol quantity of the analyzedsample
Xr- quantity of chlorquinaldol retrieved.
The percentage of retrieval for the 9 samples is 9g.g%
Conclusions: we conclude that the admissibility criterion

is met for accuracy.
'':
'
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PRECISION
Precision parameter is measured in terms of
repeatability and reproducibility on two different
days.
Admissibility criterion:
Relative standard deviation for six successive injections
to be 2%o for chlorquinaldol peak
areas.
a) To assess repeatability is done each six injections

of a sample containing chlorquinaldol
r00% in relation to the concentration of reference
solutio n (2), tolimit the impurities of 0.l0yo.
The reference solution (2) was prepared according
to the method of analysis as follows:
transfer quantitatively 6.02 mg analytes (chlorquinaldol)
into a volumetric flask of 100 ml with
methanol R' Shake for 15 minutes, complete
with the same solvent to volume, mix and filter
throwing the first 10 ml of filtrate. 1 ml of this
flask
with methanol R' 5 ml of this solution was diluted
to 50 ml in a volumetric flask with the same
solvent.
Results - are measured by standard deviation (and) relative

repeatability standard deviation
(RSD%) and the confidence interval of the
95yo ata safety threshold.
To assess the reproducibility were taken into account results

in two different days, two
different analysts.
transfer quantitatively 6'02 mg analytes (chlorquinaldol)
into a volumetric flask of 100 ml with
throwing the first 10 ml of filtrate. I ml of
flask
with methanol R' 5 ml of this solution was diluted
to 50 ml in a volumetric flask with the same
solvent.
Reproducibility -
is assessed by calculating the standard deviation
of reproducibility (s), the
relative standard deviation of reproducibility (RSD%)
and the appreciation of the confidence
interval
of the 95Yo at a safety threshold.
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The results are presented in the following tables:
REPEATABILITY
30721
Standard deviation ( s
Relative Standard deviation ( RSD
The average confidenc e intewal gjTo
30667 - 3t516
REPRODUCIBILITY
Sample
Area
I 7 3136s 30251
2 8
a 306s9 30793
J q
30970 JU16 /
IU 31790 30779
31044
6ltz 30721
30886
30703
Average
. Standard deviation (iJ------ 435
1,41
The average confidence interval-gi%- 305:,L ::ln9
b) To assess repeatability - is done each six injections of a sample containing chlorquinaldol
100% in relation to the concentration conesponding
to the limit of impurities of 0.15%o(0.09 pg /
ml).
The solution is prepared according to the method of analysis as follows: transfer
quantitatively 9'02 mg analytes (chlorquinaldol)
appropriate limit of 0.15% impurities, into a
volumetric flask of 100 ml with methanol R. Shake
for 15 minutes , complete tu volume with the
same solvent, mix and filter throwing the first
10 ml of filtrate. I ml of this solution was
diluted to
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CHLORQUINALDOL
100 ml in a volumetric flask with methanol R. 5 ml of this solution was diluted to
50 ml in a
volumetric flask with the same solvent.
Results- are measured by standard deviation (and) relative repeatability
standard deviation
(RSD%) and the confidence interval of the 95vo ata safety threshold.
To assess the reproducibility were taken into account results in two different
days, two
different analysts.
The solution is prepared according to the method of analysis as follows: transfer

quantitatively 9.02 mg analytes (chlorquinaldol) appropriate limit
of 0.15% impurities, into a
volumetric flask of 100 ml with methanol R. Shake for 15 minutes
, complete tu volume with the
same solvent, mix and filter throwing the first 10 ml of filtrate.
I ml of this solution was diluted to
100 ml in a volumetric flask with methanol R. 5 ml of this solution was diluted to 50
ml in a
Reproducibility -
is assessed by calculating the standard deviation of reproducifitity (s),
the
relative standard deviation of reproducibility (RSD%) and the
appreciation of the confidencJinterval
of the 95%o at a safety threshold.
The results are presented in the following tables:
REPEATABILITY
43913
Standard deviation (s )
43574 - 442s1
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CHLORQUINALDOL
REPRODACIBILITY
Sample Area
I 7 4?'.7?R 45140
2 8
a
43770 45142
J 9 4?450. 45071
4 l0 4400,1 44806
5 11 4407q 45267
6 t2 4443s 4537s
Average 44523
Standarddeviation (s) oyu
) 1,55
The average confidence intewal 95 %
44089 - 449s7
conclusion -The conditions of admissibility requirements for precision parameter

can
therefore conclude that the method of determining chemically
rerated substances coneslonds in
terms of accuracy. The chromatograms are shown in
Annex.
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CHLORQUINALDOL
ROBASTNESS
Robustness parameter was checked by changing

deliberately mobile phase flow parameter.
Standard value Changing studied

Mobile phase flow
1.4 mllmin 1.6 ml/min
Admissibility criterion :
Results are measured by standard deviation (and)

relative repeatability standard deviation
(RSD%) and confidence interval of the mean glyothreshold
at a safety.
To assess robustness:
a) Is done each six injections of a sample containing chlorquinaldol
100% in relation to the
concentration of reference solutio n (2), to limit the
impurities of 0. l0%.
transfer quantitatively 6.02 mg analy'tes (chlorquinaldol)
into a volumetric flask of too.*t wittr
throwing the first 10 ml of filtrate. 1 ml of this
flask
with methanol R' 5 ml of this solution was diluted to
50 ml in a volumetric flask with the same
solvent.
1.4 mU min 1.5 mV min 1.6 ml/min

Sample
Retention Retension Retension
Area, time, Areao time, Area, time,
mAU min mAU min mAU min
35603 6.64 43738 6.16 32017 5.78
z 35078 6.64 43770 6.17 32222 5.79
J 35853 6.64 434s0 6.17 32166 s.79
3s696 6.64 44003 6.16 32228 s.79
J 35507 6.63 44079 6.17 3257s
() 5,79
35232 6.63 4443s 6.16 32104 5.80
flvsragg 3s49s 6.64 43913
qevlanon ( s ) 6.t7 322r9 5.79
rr..xrruilr'(r 29r 0.0052 339 0,0055 192 0,0063
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CHLORQUINALDOL
Relative standard deviation
The average confidence 3s024- 6.63-6.64 6.16-6.17 32027- 5.78-5.80

intewal 95 Yo 35786 32410
b) Is done each six injections of a sample containing chlorquinaldol

100% in relation to the
concentration conesponding to the limit of impurities
of 0.r5%o(0.09 pg i ml).
The solution is prepared according to the method of analysis
as follows: transfer
quantitatively 9.02 mg analytes (chlorquinaldol) appropriate
limit of 0.15% impurities, into a
volumetric flask of 100 ml with methanol R. shake for 15
minutes , complete tu volume with the
same solvent, mix and filter throwing the first 10 ml
of filtrate. I ml of this solution was diluted to
100 ml in a volumetric flask with methanol R. 5 ml
of this solution was diluted to 50 ml in a
1.4 mU min 1.5 mU min .6 mUmin

Sample Area, Area,
Retention Area,
mAU mAU Retention Retention
time, min mAU
time, min fime- rnin
I s2569 6.52 43738 6.08 46s02
2 53048 6.52 43770 ,7^
6.08 46429
-l 52636 6"52 43450
t 52950 6.52 44003
6.08 45791 ,t0
6.08 570
I
6
52107 6,52 44079 6.08
47198
46802 570.
52311 6,52 44435 6.08 46696 570
Average s2604 6.52 43913 6,09 46570 5,70
Standarddeviation(s) 361 000 339 0.00 468 000
Relative standard deviation 0.69 0.00 0.77 0.00 L01 0.00
(RSD)
2243 6.52-6.52 43574 6.08-6.08
The average confidence interva. 46102 .70-5.70
2964 +4251
9s% 47037
conclusions: The values obtained are within the limits imposed, leading to a robust system.
The chromatograms are shown in Annex.
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LINEARITY
This parameter has been verified by preparing solutions containing
different amounts of
chlorquinaldol the range of 10Yo - 150% in relation to the concentration
of chlorquinaldol of
reference solution (2),by injecting each solution and calculate
the correlation coefficient between the
concentration ofchlorquinaldol and value corresponding to the
respective peak area.
The correlation coefficient must be greater than 0.995;
The reference solution (2)was prepared according to the method of analysis as follows:
amount of active substance corresponding to each concentration, transfer quantitatively
into a
volumetric flask of 100 ml of methanol R. shake for 15 minutes,
complete with the same solvent to
volume, mix and filter throwing the first 10 ml of filtrate. 1
ml of this solution was diluted to 100 ml
in a volumetric flask with methanol R. 5 ml of this solution was diluted
to 50 ml in a volumetric
Concentration
Concentration, Yo Sample weight, mg
chlorquinaldol, Area, mAU
pelml
150 9.02 0.090 43627
120 7.23 0.072 36907
110 6.60 0.066 3314t
100 6.01 0.060 29729
90 5.42 0.054 26807
80 4.81 0.048 24556
70 4.20 0.042 20307
60 3.61 0.036 I 8390
50 3.01 0.030 14561
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CHLOROUINALDOL
corresponding solutions concentration levels between r0% and 30% is prepared by

successive dilutions so:
Concentration Chlorquinaldol Area, mAU

Solution volume, ml Flask volume,
:o/g concentration
:,':' r j
ml
pg/ml
30 3 ml of solution 100% l0 ml 0.018 9623
20 2 ml of solution 100% 10 ml 0.0r2 5645
10 1 ml of solution I00% 10 ml 0.006 3400
Linear regression line equation is:

y:492435x+ 31T.07
The conelation coeffrcient is:

R:0.9976
Method of analysis according to DAC monograph "Chlorquinaldol', provides: , l

- Unspecified unknown impurities, individual: not more than the area of the main peak in the
chromatogram obtained with reference solution (Z) (0.10%);
- Total: not more than 10 times the area of the main peak in the chromatogram obtained with
reference solution (2) (1.0%);
For an accurate assessment of the percentage of 5-chloro-8-hydroxyquinaldine (cloxyquin)

determine the relative response factor (RRT).
Solutions were prepared in the range of 50% - 150% (0.045 pg / ml - 0.135 pg / ml)
compared to the concentration of 0.09 pg I m| corresponding to the limit of 0.15%.
- Stock solution: transfer quantitatively 9. 01 mg cloxyquin CRS into a volumetric flask
of
100 ml with methanol R. Shake for 15 minutes, complete to volume
with the same solvent and mix.
1 ml of this solution was diluted to 100 ml in a volumetric flask with methanol R. Of this
solution
appropriate dilutions are made so:
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Concentration Solution Flask

o/
Cloxyquin Area rmAU
/o volumrml volumerml concentration,
pglml
ls0 1.5 l0 ml 0.1 35 29436
t20 1.2 I0 ml 0.108 22942
ll0 1.1 l0 ml 0.099 20941
100 1.0 10 ml 0,090 1 8959
90 0.9 l0 ml 0.081 t6977
80 0.8 l0 ml 0.072 15034
70 0.7 10 ml 0.063 12746
60 0.6 10 ml 0.054 I 1384
50 0.5 10 ml 0.04s 9852
y :219310x-617.03
The correlation coefficient is:

R:0.9971
Relative response factor: -- ---j]::1T:::: -:':.t"to

-------_____ :0.5
Slope chlorquinaldot 429435
Resulting the formula for calculating the 5-chloro-8-hydroxyquinaldine

(cloxyquin):
AscsH
- impurity 5-chloro-8-hydroxyquinaldine, %: _______ __x 0.15
0.4 x1.5 x A"
where: - AscsH : atea peak of 5-chloro-8-hydroxyquinaldine

from chromatogram of the test
solution;
- A.: area peak de chlorquinaldol in reference solution (2);
conclusion: the criteria for admissibility required

for parameter linearity. It can be concluded that
the analysis method is a linear method.
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CHLORQUINALDOL
LIMIT OF QAANTIFICATION AND DETECTION
The sensitivity of the method is evaluated by determining

the limit of quantification and detection
limit.
Criteria for admissibility:

- Limit of quantification signal / noise ratio must be
l0;
- Limit of detection signal / noise ratio must be 3;
- correlation coefficient of linear regression line to
be at least 0.9900.
Use chromatograms obtained in the parameter nlinearity,,.
Concentration, o/o
Chlorquinaldol
concentration, pglml
Trace the linear regression line (signal / noise ratio

depending on concentration):
y = 683.23x+2.7761
The correlation coefficient obtained is:
*: o.9gt7
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The limit of quantification. corresponding to a concentration

equal to the signal / noise ratio
of 10: I is:
LQ : 0.011 pg / ml
concentration limit of quantification determined is lower than

the concentration limit of
neglect (0.02% - 0.012 pg / ml) .
Limit quantification
Limit of detection: -- ---;---- ___:0.0036
J
Detection limit concentration determined is less than about
3 times the concentration limit of
neglect (0.02% - 0,012 pg / ml).
Conclusion, ..,
/'!
For any impurity limit of quantification is equal to the limit
of negleot.
Are met the conditions of admissibility imposed for parameter
detection and quantification limit, so
we can conclude that the method of determining chemically
related substances corresponds in terms
of limit of detection and quantification.
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CHLORQUINALDOL
PRECISION OF QAANTIFICATION LIMIT
It was prepared a chlorquinaldol solution by concentration of 0.011 pg / ml (concentration
determined to be LQ for this method) and the precision was determined by performing
six injections
of this solution.
RSD on peak area of chlorquinaldol should be a maximum 5Yo, and confidence interval
of the
mean at a95%o threshold safety.
The results are presented in the following table:
Sample Area ( mAU ) Ration

signaVnoise
I 5273 9.38
2 5268 10.23
J 5177 9.92
4 :'l
5364 10.68
5 5433 10.15
6 s495 9.60
Average 533s
Standard deviation(s) 118
Relative Standard deviation (RSD) 2.21
The average confidence intewal 95 %o
5217 -s4s3
conclusion: are met, the conditions of admissibility requirements for precision, so we

can
conclude that the method of determining chemically related substances
in the product corresponds
studied in terms of accuracy limit of quantification.
calculation formulas used in this protocol validation are:
T r';
Average value : X* : l'l'
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CHLORQUINALDOL
["fl,.*--'i=lt"
''1
Standard Deviation: r: I|"\'"'r:-1 I
IJ I
The relative standard deviation: RSD :5*3so

.Ene
confidence interval of the mean at a95o/o safety threshold: 4: ,u.m *+
vlr
Percentage Retrieval: retrieval : & * 10fr
*=n
Where:
x;: the individual results obtained in the n measurements performed
x.: the average of the n determinations
n: number of determinations made
A: true value
t: student criterion for (n-1) degrees of freedom and9l%oprobability
x.: is the quantity of active principle found, mg
xu: the quantity of active principle to be dosed, mg
To estimate the linear regression line, y: ax + b, using least squares.
Calculation formulas used are:
rr' \ 1
iL*!:--rnlJLlt--t'mj
slope: u :
1 L.}r;-;rni,l'
originally ordered: b : 3* - Hffryx
the correlationcoefficient: : ri,.i-""dt-1i-*hrt

fi = LIir
i-x mi! f i;"i -.r-ii :l :.: i
where:
x1: independent variable (solutions concentration)
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CHLORQUINALDOL
y; : dependent variables (areas)
xml Ym: averages
CONCLUSToN: Method validation for the determination

of related substances in pURE
CHLORQUTNALDOL active substance by high performance
liquid chromatography
corresponds in terms of specificity, stability of solutions
used in the analysiso accuracy,
precision, robustness of the method, linearity, Iimit of quantification
and detection, precision of
quantification limit, according to GMp-GLp.
.tl
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CHLORQUII{ALDOL
SPECIFICITY . SELECTIVITY
.it
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CHLORQUINALDOL
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CONFIDENTIAL
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CHLORQUII{ALDOL
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CHLORQUINALDOL
S SISl'IM I:IPLC tit,IT[ l)AD I (Orfline)

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Iltta {l:\ljZChr.om lilirc,!nrr.rpriseiprojccrs\C:t.Ol{Cl.llNAt,DOl,\Dara\Selccriviruea\ad.dat
Mcthutl. {t:,,1:Z,Chr.onr l:lircilinre rpriscr},..;..,.,t1i.ijlic:f f f NAl.l)OL\Mcrhodrlnrpurirati.met
::ffi||j: iiiii?1"ilffe\r:nt*rprisev'roie"i'rci-iiiii:rrrsarDOr.\sequerrce,.-sei.*ioi,o,*.,.,q
Sanrple l.l): ad
Vill l.r: r'! I tb;..,
,,,.tc(tiot) Vollntc: 20 p;
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CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 94
CHLORQUINALDOL
I lill*]'l;i!I IIPLC lil.rln DAI) 2 (Ot'fline)
Dau file; {l:i}jZ-Chn:rnr ItliteiIntcryrisei,Projecls\CLOI{CIIINALDOL\Dara\Selcctivira!ea!,test

ad i_dat
14stircd: |]:iliZChr$nr }, lire\Lhreryrise\l,rojecrs\CI,ORCIItNALDOI-\tvf ethod\tmpuritati.nrei
Sequence: c:iilzLlhronl illirc\nnrerprise\ProjecLs\ct,oRCIIlNAL,l)o1..\Sequencc\Selectivit*te..ieq
Acquired; 7,/-i ii20l.1 I l;01:{)il A}r,l
Saniple lI}: 1e5i ad i
Vi*t no: 64 lniection VolLrme: ?0 r.l
.
Relailtion Time
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Narne Flt # fi,1' Arclr 'l'alero Asvm K R
i.66 89i9 47 t9 2"1 0.0
4.61 :i048 57.54 .,{ 3.6 4.3
chrchi:xrkiol 6. t3 i2tili92l I 4 l9l .6 5. 1 .1.8
s.d0 tJ65l 5"11U .3 7.6 :1.9
Code: ASMF-CQ
Revision: 0
Page 95
CHLORQUINALDOL
$ S[$'I'S$1 IIPLL'tit,I'[n DAD 2 (Offliuc)
Data [ile: C:1DZCix.om nlite\Enrerprisc\projects\C[,OltC]{lNAl..lJOL,,Data\,selectivitarea,irest

llethoJ: {l:iDZ("hr.nr Erile\[nrerprise',projecrs',cLoRoHrNnr-ool,*{;oc\r*purilaii.,ner ad idal
fir:qlencc;
Ar:q*ireel; i;ilf;lii]:i.i]i1{?rerprise\pr(iectscr.oRcHrNAr.DOr.rs"i,,"n.",s"r..rivira;.seq
Salirpi* lllr rest ad f
Viiii no: ?8 Injecrion Vrrlume : l0 i; I
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i f{ame
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Nam* t?kit R'r Arca 'I'alcre
l 3.(i6 It485
K g
3-52i 2. {) ,0
? 4.6? 344 I 4017 ''
dorchinirl<lol l 3.6 .(;
6.11 I l90ti88 4082
d "5. i 4 5
8.60 1464,1 _{ 167
7.6 5 i
",,-l t
lri,3F?-
I
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 96
CHLORQUINALDOL
I StSl'l;l.t ilp{,c rl,tr'Ii DAD 2 {Ofilinc)
Dam {":ile: (l:illzt.;hmn] rilire'rInterprise\projccrs\ct.oRCr'ilNAr,l)ol\Dataiserecriviratea\].rcr

illeth*d: .riat
{):',iiZChrom tilil{:\Erleryrise\Projecrs\Ct.ORClilNALDOl.\Merhod,,lmpuritari.ner
Scqueuce: c:"'1.izch*rm Elire\rrnterprise\r)rojecrs\cr,oRCl{rNAt,DoL\sequence\Sereetivirate.rcq
Acquir*d: 7l: t,'l0l'1 I I : l9:411 ANI
$nnplc ID: l.tfi
Vigi nr: 6: lnicction Volume:20 u j.
': l0
' R*tenti$n Time
.' Nanre
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N$me Pk#
Code: ASMF-CQ
Revision: 0
Page 97
CHLOROUINALDOL
!) st$T'!:11{ HPLC t,rt,I t'l: DAD 2 (Offlinc)
I^)ar; Pi1., {i;\l:zchi"dm Lilire'rlinrery:rise\pro_iects\ct.oRCl-ilNAt,DoL\Data\Selecliviuiea\tcsr

HCI i.dar
jl{rrlho<i: (:\li7-chroin riritc\Dnterprise\projecrs\,cLoRCl.ilNAI.DollMefiod\rrnPurilari.Jner
$equrnce: ciHZChr'nr nlire\n'rer prise\t ro-iecrs\cr,oRcr!{TNALDOL\sequen".is.r**,l,,iiui..r.,r
r\rcliriri:d: ll.1 i:'?014 I t:52:56 AM
Saitpi* ID; test HCI i
Viai no; {;7 lliection \rolume: 20 u.j.
j RGlertion Tise
Name !
6,1
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?5{i nn l{esults
Nanrc RT Area l'alcrc K R
4.6.5 203-i _.275
clorqhina ldol
t.? {.}.0
6.12 293 I 9967 l3 0l 5.1 4.1
8.61 I t-503 qi 0:l
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CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 98
CHLOROUINALDOL
r
:
I SISTIlll,t :{PLC [LIl'f] DAt] 2 (Ollline)

llura l:ile: {l:\[zchlom r'ilire',|')nrerprist'iprtiectsi(]l.,oRC].ilNAI-Dor.,\r)araiserecrivirarea..resi
H(.1 {:dal
:\;teilii.,d: ti:\l'13chr'nr l:litcrr")rrerp'ise\,Pro.iectsroLoRCFilNAr,DoL\Merhod.\rmpuNra.[i.mi]r
S*qui:lr:e: C:r.l"l7,chrom lr.rire\L)rrerprisc\pro"iec,*\cir..oncHINAt,Dor.,\seque'cg\Serecriviiarr.r*c
Acquirrd: It''l r'2ill4 ?: i 4:0? Irlr4
Sar:rpl* II) rest I.lCi i
Vial no: 8ft lnjection Volunre:20 p-i
1ll
Ral*nt;$n 'Iifie
Narrs
a8
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!\'*ml Pk# R't' Arca nltrc K t{
4.09 7395 3403 r.0 j1 ,l 0.0
4.89 12404 23 3.5 l ,9
0.8 :.3
*lorrhi*aldul 6.12 I 183_5 I 50 Ji li t.J 5 .I _t,u
8.58 r2367 4224 1.1 .6 5.2
,1 r
t,rjr:
I
Code: ASMF-CQ
Revision:0
Page 99
CHLOROUINALDOL
1f si$T'nsl ItrllLC lILITlt $AD 2 (Olllinc)
I],:t;r lrilt; cr:'rl'iz{lhn]lr Illire\llnterprise\pro.lects\ct..oRClIlNALDoL\Data\,seleciivirarca\Na()}{.dar

&'lethod; c:"fl2{""hrom }ilire\r."rnrer}rise\plojecrs\ol.,oRC}ilNALDOI-\M{ithod\rmpur.itali.mer
$rqu*nct: ll:illZChrcil l:ilire\[inrcrprise\Pro.iects\CLORClIlNAl.,DOl.,iSequcncoiSehsliyl;lig.5eq
Ar:q*ircCr ?r':l 1l:(i l4 I 2:09:i-l l,iV{
Siirxple lD: Na{)ll
Y r3J ir(]l 6li Injection Volunre: 20 irl
t0
: Rele.alrOrr Trnte
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:
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Code: ASMF-CQ
Revision: 0
Page 100
CHLOROUINALDOL
9 SlsTllill l{rLC ILITI DAD 2 (Offline)
i--lalrr f ile: {l:rE?Chronr lr:lit(.itjilterprrse\,proje cts\Ct,OItC)l lNALDOl,,,Data\Selc:ctiv

ilurea\resr }la( }11
i.dat
[.]:t]n{: (,':iDLl-'i:*:nr filii:ul'['rerprise'rrrnrjccts\Ct,oRCHINALDor..\Merhod\rmpurir;rii.met
Sequ*nce: ciile'\Enreryrise\'projecrs\cr..oRCHrNAr-Dor..\Sc'qu*rco\se
Acrluired:
!i{ii!ifom
?''il/:0ld l2:42:49
recri;,i1are_seq
f,tv,t
$ar4:ie l1): ldsr Naoll i
\:'1*l ttol 7A lnicctiol Vohult:2{} uj
,.--. . 1C
Ri.leniics Time
Nane
i
j
3.1
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i6
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Xame Pk# R't' Arca 'llcre
I 6865 335 l
s
2 1 0.0
slorclri*r !dol 6.1] 29?75 I 63 28?6 5 $.8
l l{.5ti 707i 3;186 ,6 4.6
Code: ASMF-CQ
Revision:0
Page 101
CHLORQUINALDOL
I $l$Tf,ill Ill'LU fiiJTti DAD 2 (Ofilinc)
l-)3td Irile: c:t'EZChr.* I'lilc\[nreryrise\t ru.iects\cl.oRCI.ilNAt,DOL\Datnrselectivirarcal,tcst

t'.rtrar
Naoll
il'l*ili*d: C:iEZlllrrunr i:lite\[interprise\]rrojecrs\CLORClllNAl..DOL\Method\lmpuririti.r)et
ScuLri:rri*: c:\lizc:la'om Elire\fir,terpris*\rrrojccrs\cr,oRClilNALDOr.,\Sequenceiserectiviratd.seq
Acquilerj: Itll"?*14l:47:f,] 1,M
San:rpl* l[) test Na0l.l i'
Vial lo: Sl Inlectirrrr Volumc: J0 ;r.i
loi
xelcnilon llme
Narae
w {-:
l
li
liil
rl
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llAl)-cHr
150 nm Rcsulrs
$i*nrc Pk# t{I Ar(lil 'fale rc
R
t !t 67,15 :t 3?5
el*refuinaltlal ?.7 0.0
6.t? 2ll9-s(r5l,l l99l :-l 7.0
8.ri I 9 t10 5140 7.6 5.2
tt*y*"
i
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 102
CHLOROUINALDOL
9 StSTfi,M ilPLC: Itl,n:Ill DAD 2 (Olflinc)
Data I'ih: (l;itzchtonr Iilitel,Enierprise\Prqiects\cLoRClllNALDoL\Data\Selecrir,iriliea\,ti2o2.d.,r

$'lathod: C';it-lzchR)m lilite\Enteryrise\l'r.riects\CLORCI{INAt,DOL\Melhod,,trnpurir:rii.mer
$*qi.t*tcel c:ihZChronr lllire\tsnlerprise\projeclsCLoRCl.llNAl..DoL,rsequence\Selecrir,itare.seq
Acquired: ?11 1i2014 2:.5i:51 f,jrl
SB|lqte lD: l.t:{}2
Vial n*: ?4 lqii:ctioll Volurne : l0 i:.i
; Rstentjqn Timb
Ntrnt
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l
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:
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& (, 2 I 10
W
D"{t)-cill
35{} nm lLrsults
Name llk # 'Ilalerc
Code: ASMF-CQ
S.C. MBDUMAN S.A. ASMF - CTD format - Applicant's Part Edition: 1
Revision:0
Page 103
CHLOROUINALDOL
9 SI$11'$$I llPt,C *:Lilt: t):trD I (Olflinc)

Datii f ils; f:\fizchrom EliterLnrerpr-isc'rl,ro.iectsicl,,oRClllNAl-DoL\Dala\Selectivilnreatesr I{2ol
i.da1
Me th*d: {):\t?(lh'rrnl lllile\Enleryrise\prqecrs\L'LOI{cIrtNAI..DOL,\Merhotr\rmpurit*ri.mtr
Srxll*rtcr: {.1;l},ilclirr'r Elire\[nterprise\projects\ct,oRCt{INALDoL\sequcnce\Sele*rviralr.seq
Acquired: 7 l -x 1 120 I 4 i t29 :0{r l}\4
S*mpl+ lll test ll:{}2 i
\tial **: ]6 lnj,ictiot Volume: 20 r:l
t*
i xete*{dn Tim*
Name i i
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;r..amc Pk# R'I] Arca 'falere
rrhinrltkrl
i 832 l 4609 |.2 4.3 0.0
rlo {r.1 6 265251(t9 281 I 1.5 5.2 2.j
'# I
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 104
CHLOROUINALDOL
$ SIli'l'UM IIPLC nl,lll'li DAI) 2 (Offline)

llalil l;'i)e : crlJ:lzcirronr lilire\llnterprise'Jrrojects\cLORCIIINALDOL\Data\Selccrivir.rlea\1est ll202
1.dai:
&{*tixxi: C::E?Chrour l.ilire\Enteqrrisr'rProjec*rOl..ORClllN,,\LDOL.Meth$d\lmpurix0ri.mcl
ilequerce: {;:i.[.i7{]hrurrr ElileiErlerprise\l,roiecrs\CL.ORCl.jlNAl,DOL.',suqucnce\Selectivitare.seq
,4rquir'*<1: ll,'l /?{} 1,1. 3 :5,r :48 pM
Sxrqrle 11.):
Vial rl: $6 Inidction Volurre; 20 ,"i.1
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ketentron lime
Narne
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clor*liinrkldl
,,i1 I
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t
Code: ASMF-CQ
Revision:0
Page 105
CHLOROUII{ALDOL
STABILITY OF SOLUTIONS
*l
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
PTIRE Date:0210212017
Page 106
CHLOROUINALDOL
9 SlSTEllll {ll'l C il,llll; DAD 2 (Olllinc)
lau iiil*i l:\lVCirorri lililtrtnterprise\Pro.ltcts:Cl,Ol{Cl llNAlDot,\Data\Siabilitctc$ohdic I
1t-Kep?.dai
!lriliild: (;:!l;ichrom L-liro\linicrprise\t'xrjeds{Il0RcIIINAt,DOL\Merhod'\lmp.me!
Srilurnc*: il:rL:ZCluonr tiliie!llnte|prise\Projgcts\Cl,ORCl{lNALDOL\Sequence\Stahililaie.seq
8i i i20 14 4:l.i:2li PM
"\r<1uir*d:
$rnpie ll.l: "rlirriil I
'10
Virl nl: i i lljeeiirn VoLLnne: 20 i:l
ilt
A*ei,lgn lim.,
flatil
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clorc)rnnkbl
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 107
CHLORQUINALDOL
I $lSTnl{ }IFLC liLI'I'tr: DAD 2 (Olllinc)

l)*ta Iril$: Ci'\lif(lrhrol11 lilire\'[:nterprise\ll.o-iectsiCI,ORCI.llNAI-DOL\D.rra\Srabilirate\rohrtic I
'{'il- Fl.epl}.dat
ivlerhod: C:\HZChrom lllite\[:interprise\l,rojects\Cl,Ol{CI.llNAL..l)Ot.iMethod\lnrlr.mct
Sequt:rtc: ("1:\}jzc]rrorrr lllite'rllnrerprise"l'rojecrs',cLORcFllNAl,l)ol,\sequence\Stabilitate.seq
S,cquire<!: 8i l,r:01.{ 4:.15:0d PIvl
Sarrple lI): solutie 1 l'{}
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to -i-- -.--r 10
i l1*tentico Time I
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Re.rnllll
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clorrhinaldrll 563 ri 5.2 0.0
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 108
CHLOROUINALDOL
9 SIS'I'H}I I1PLC $LII'tr DAI) 2 (Ofninc)

Ijata Fild: {.':\liZChronr L:li1e\[interyrise\Projccts'rCll.,Oli.ClllNAl,DOL,\Dara\Slabilitalo\solrlie I
'l'{}-I{.ep^$.drt
i!'lrthsd: {l:\.tr;lChronl Elite\llntcrprise\Pr(}iects\CI..ORCHINAI-DOL\N,Icthod\liltp.me1
Serluenr:c; Cr\EZClrrorn ljlile\Irntcrprise\Projects\CLORCIIINALDOL,\Scquenc:e!,slabilitats.serl
.i,c<1uirrd: 8i li20 1.4 4:.J1::i() PM
$;nlplo ID: solutie I l-0
\jili rxr: I I lnjerction Volume: 20 $i-
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flslenlian Tifiq
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I
6
3
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3${i nnr
It*sull,f
Nrtn:r RT' Area 'falerc Asvrn K R
*loxqhinal<l<:l 6.16 :t t.i.3.3 5589 1.2 5.: 0.0
CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 109
CHLOROUINALDOL
tl $trli'lli:l{ $II}I*{: $:Ll'f.[: l],lll X {(ffflit**}

l.Iil** i'il*:
.1.fi-R*$iL{1fl.r
{-:r',t:y-{.;lxr{rr$ Lil:ite-rl:r}lfrrFs*!*tl}r'rii{rtn1{:,1*$R{:* X!:i\{! ,l}t}{..rl}rdfil,,Si$hi tiris{rli*el$1,is ?
fu{ s:il1{:r.1 ,i,.1:iLX{.lkr*ia L:lirdl.h.$lsr:Frir*,prqJe{rs'.,'t:1.{-Ut{] lll:!41.{}d"}L''|\,lrihod)lilrt}^rir*t

$uq*r.sr*sr {-::'.lriI*hrnn* lil!ittiJint,iu'prisr:,tr]rrrjrer*'tl,{-}l$.iltrllfi,,\l.lX}t.iSr'rlrrrarrc.St;!brti(,iir.x<{l
$.+r;*ll*rl: s:;:;,1{} I 4 î :{r'*; }1: rjl{
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CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 110
CHLOROUINALDOL
s hils'rti&I IItlI"tl litit'l: illnll I {{-}#Iiqf}

1.1;rl* Yi,.r:; l;.r':l::Xilg1r{rilr li.lil+r'lrlltltr?rixsrl\t}jrr:tlilfi"{.}R{it ll }dr1l.,RX.)t"'.1.}rt;t1}t.rt\i lrli** }(}}u:vr l
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Mttlriui: {i:: r f1il{:leil$r !iiile!l ttt*l'i}r isr" ['r aac{lsif l.ORCf ll,\r\ t.t X]3!.1j!irlhf}d'11lH pJrut
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CONFIDENTIAL
Code: ASMF-CQ
Revision:0
Page 111
CHLOROUINALDOL
$ tils'rilH l{t,l,{: ,r,l-|.'I'b: lr.rl} I {$ffliutJ

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3.2.S.4.-1

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Code: ASMF-CQ

S.C. MEDUMAN S.A. ASMF - CTD format - Applicant's Part Edition: 1

3.2.5.4 Control of drug substance

CHARACTERISTICS AD MISS IB ILITY C RITE RIA METHODS OF

Eur. Ph. (2.2:29)

3.2.5.4.2 Analytical procedures

-insoluble in water: weigh 1 mg of in a stoppered tube, add 10 ml of water, shake

A. IR spectrum: IR absorption spectrum of the substance to be analyzed corresponds to the IR

4. Appearance of solution: dissolve 75 mg test substance in 15 ml ethanol 96% (with gently

solution. The colour of solution turn to red.

6. Chlorides (2.4.4): maximum 500 ppm

8. Sulfated ash (Eur. Ph.2.4.14): Maximum 0,I o .

9. Related substances (HPLC) (Eur. Ph.2.2.29) z

- Principle of the method :

Determination of related substances are made by high-performance liquid chromatography.

1 ml test solution contain 60 pg chlorquinaldole.

1 ml reference solution (1) contain 1 pg chlorquinaldole RS and 4 pg cloxiquin R.

ml of this solution to 50 ml volumetric flask with the same solvent.

a) High performance liquid crhomatograph LaChrom Merck Hitachi:

- detector : spectrophotometer UV;

- Flow rate : 1,5 ml/min;

- known impurities, individually:

5-chloro-8-hydroxyquinaldine, o/o: -------- --- x 0,15

Ascsu- peak area of 5-chloro-8-hydroxyquinaldine in the chromatogram obtained with test

10. Assay : chlorquinaldol93- t02o

The method is based on the quantitative determination of chlorquinaldole by high performance

a) HPLC System LaChrom Merck Hitachi with:

- flow rate : 1,5 ml/min;

- Detection : at250 nrn

Ap - peak area of chlorquinaldole in the chromatogram obtained with test solution.

mp - weight of the sample for test solution, in mg ;

Total aerobic microbial count (TAMC)/g Maximum 1000

The method of analysis

Materials and equipment

A. THB DETERMINATION OF THE TOTAL AEROBIC MICROBIAL COUNT

4.2.Is used the plate-count method.

6.Interpretation of the results

as part of the total aerobic microbial count.

B. THE DETERMINATION OF THE TOTAL COMBINED YEASTS/MOULDS COUNT

4.2.Is used the plate-count method

6.Interpretation of the results

C. HIGHLIGHTING OF TIIE SPECIFIC PATHOGENIC MICRO-ORGANISM

3. Sample and enriched culture preparation

4.Highlighting of Escherichia coli

D. SOLUTIONS AND GROWING MEDIA

Buffered sodium chloride-peptone solution pH 7.0

Papaic digest of soya beans 3.0 g

Glucose monohydrate )\o b

Purified water 1000 ml

Casein Soya bean digest agar

Papaic digest of soya beans 5.0 g

Purified water 1000 ml

Purified water 1000 ml

Peptone (meat or casein) 3,0 g

Lactose monohydrate 10,0 g

Sodium chloride 5,0 g

Bile salts 1,5 g

Neutral Red 30,0 mg

Purified water 1000 ml

12. Residual solvents (2.2.28): acetone maximum 2000 ppm

- Principle of the method:

- Volumetric flasks Class A ;

Thermo Electron gas chromatograph - FOCUS GC equipped with :

- Flame ionization detector (FID );