Stamp:

/ MINISTRY OF HEALTHCARE OF THE RUSSIA

ЛП-006288-230620
Approved/
MINISTRY OF HEALTHCARE OF THE RUSSIAN FEDERATION

Registration certificate No.

Registration date " _______ " _____________ 20 ____.

Limited Liability Company "PROMOMED RUS"

(PROMOMED RUS LTD), Russia

129090, Moscow, Prospekt Mira 13, bldg. 1, office 13

NORMATIVE DOCUMENT
_______________________ (number)

AREPLIVIR
trade name of the medicinal product

Favipiravir
International nonproprietary name or generic name

film-coated tablets, 200 mg

drug presentation, strength

MANUFACTURER
Biokhimik JSC, Russia

PACKER (PRIMARY PACKAGE)

Biokhimik JSC, Russia

WRAPPER (SECONDARY/TERTIARY PACKAGING)

Biokhimik JSC, Russia

RELEASE QUALITY CONTROL

Biokhimik JSC, Russia
 ND# _________________________ p. 2
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
Specification
AREPLIVIR
film-coated tablets, 200 mg
Biokhimik JSC, Russia

Characteristic Method Specification

Description Visual Round, double-convex, film-coated
tablets of light yellow colour.
In the cross section, the core is white to
almost white.
Identification SPh RF, HPLC The retention time of the principal peak
in the chromatogram of the test solution
must correspond to the retention time of
the principal peak in the chromatogram
of the favipiravir reference standard
solution.
Uniformity of mass SPh RF According to specifications
Dissolution SPh RF At least 75 % (Q) in 45 min
Product related impurities SPh RF, HPLC Any unspecified impurity - no more than
0.2 %
Total impurities - no more than 1.0 %
Microbiological purity SPh RF Category 3 A
Dosage uniformity SPh RF, method 2 With n = 10 AV ≤ L1, L1=15.0;
With n = 30 AV ≤ L1 and all values of xi
satisfy inequality [M- xi] ≤ 0.01 ∙ L2 • M
Assay SPh RF, HPLC From 180.0 to 220.0 mg
Package 10 tablets per blister package of polyvinyl chloride film with
lidding of printed lacquered aluminum foil or polyvinyl
chloride/polyvinylidene chloride film with lidding of printed
lacquered aluminum foil.
40 or 100 tablets per high density polyethylene jar sealed with
tamper-evident polypropylene lid. Free space in the jar is filled
with hygroscopic medical cotton.
Each jar or 4 blisters, together with package leaflet, are placed
in outer carton.
Labeling In accordance with ND
Storage Store in secondary package at a temperature below 25 °C
Expiry period 2 years
 ND# _________________________ p. 3
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
Formula per tablet

Active ingredient:
Favipiravir 200.0 mg
(Biokhimik JSC, Russia)
Excipients:
Povidone (K-30) (ЕР, USP) 15.0 mg
Colloidal silicon dioxide (ЕР, USP) 8.0 mg
Low substituted hydroxypropyl cellulose (ЕР, USP) 60.0 mg
Microcrystalline cellulose (type 101) (ЕР, USP) 135.0 mg
Crospovidone (ЕР, USP) 14.0 mg
Stearic acid (ЕР) 3.0 mg
Tablet core weight 435.0 mg
Film coating:
Opadray® pre-finished film coating 03F220114 yellow 18.0 mg
(Inhouse normative document)
[Hypromellose 62.5 %
Titanium dioxide 30.09 %
Macrogol 4000 (polyethylene glycol 4000) 6.25 %
Yellow ferric oxide Е172] 1.16%
Weight of film-coated tablet 453.0 mg

Description
Round, double-convex, film-coated tablets of light yellow colour. In the cross section, the core
is white to almost white. Appearance of tablets must meet the requirements of SPh RF, GM
1.4.1.0015.15 Tablets.

Identification
The test is to be carried out by HPLC (SPh RF, GM.1.2.1.2.0005.15 "High performance liquid
chromatography") simultaneously with assay test. The retention time of the principal peak in the
chromatogram of the test solution must correspond to the retention time of the principal peak in
the chromatogram of the favipiravir reference standard (RS) solution.
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/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
Uniformity of mass
According to requirements of SPh RF, GM.1.4.2.0009.15 "Mass uniformity of dosage forms".

Dissolution
At least 75% (Q) of the declared amount of favipiravir should pass into the solution after 45
minutes.
Determination is to be carried out by UV spectrophotometry (SPh RF, GM.1.2.1.1.0003.15
"Spectrophotometry in ultraviolet and visible areas") in accordance with the requirements of SPh
RF, GM.1.4.2.0014.15 "Dissolution for solid dosage forms," using a paddle-type mixer. The
dissolution medium is hydrochloric acid solution 0.1 M; dissolution medium volume is 900 ml,
rotation speed - 50 rpm, dissolution time - 45 min, dissolution medium temperature - (37 ± 0.5) °
С.
Favipiravir reference standard solution. Add about 22.0 mg (exact weight) of favipiravir
(company standard) in a 100 ml measuring flask, add 70 ml of water, sonicate until dissolved,
cool, make up to the mark with the same solvent and mix.
Add 1 ml of solution into a volumetric flask of 25 ml, make up the solution volume to the mark
with 0.1 M hydrochloric acid solution and stir.
Use only freshly prepared solution.
Test solution. For the test, put 1 tablet into flask. After 45 minutes, take 10 ml of the solution,
filter through a Millipore filter with a pore diameter of 0.45 μm, discarding the first portions of the
filtrate.
Add 1 ml of filtrate into 25 ml volumetric flask, make up the solution volume to the mark with
0.1 M hydrochloric acid solution and stir.
Use only freshly prepared solution.
Method and calculations. Measure the optical density of test solution on spectrophotometer in
maximum absorption at wavelength 320 nm in cuvette with layer thickness 10 mm.
Measure the optical density of favipiravir RS solution in parallel.
For comparison use 0.1 M hydrochloric acid solution.
The percentage (X) of favipiravir converted to solution is calculated by the formula:

𝐴𝐴1 ∙ 𝑎𝑎0 ∙ 900 ∙ 1 ∙ 25 ∙ 𝑃𝑃 𝐴𝐴1 ∙ 𝑎𝑎0 ∙ 9 ∙ 𝑃𝑃

𝑋𝑋 = =
𝐴𝐴0 ∙ 100 ∙ 1 ∙ 25 ∙ 𝐿𝐿 𝐴𝐴0 ∙ 𝐿𝐿

where A 1 - optical density of test solution;

 ND# _________________________ p. 5
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
A 0 - optical density of favipiravir RS solution;
a 0 - aliquot of favipiravir RS, in milligrams;
L - content of favipiravir in one tablet according to specification, in milligrams;
P — percentage content of favipiravir in RS.
Product related impurities
The limit for single unidentified impurity in the product is 0.2%, the limit for total impurities
is 1.0%.
The analytical determination must be carried out by HPLC (SPh RF, GM.1.2.1.2.0005.15
"High performance liquid chromatography").
Mobile phase A. Add 1.4 g of potassium dihydrophosphate in a 1000 ml measuring flask,
dissolve in 950 ml of water, adjust pH to (4.00 ± 0.05) potentiometrically using concentrated
phosphoric acid, make up the solution volume to the mark with water and stir. Filter the resulting
solution through a Millipore filter with a pore size of 0.45 μm and degass using any convenient
method.
Mobile phase B: Acetonitrile.
Solvent. Add mobile phase A and a mobile phase B (40:60) in 1000 ml beaker and stir.
Test solution. Take 10 tablets, determine their average weight, rub to powder. Add about 226.5
mg (exact weight) of the powder in a 100 ml measuring flask, add 70 ml of solvent, sonicate for
20 minutes, cool, make up the solution volume to the mark with the same solvent, stir and filter
through a Millipore membrane filter with a pore diameter of 0.45 μm, discarding the first portions
of the filtrate.
Placebo solution. Add about 126.5 mg of placebo components in appropriate proportions in a
100 ml measuring flask, add 70 ml of solvent, sonicate for 20 minutes, cool, make up the solution
volume to the mark with the same solvent, stir and filter through a Millipore membrane filter with
a pore diameter of 0.45 μm, discarding the first portions of the filtrate.
Comparison solution. Add approximately 10.0 mg (accurately weighed) of favipiravir RS
(company standard) in a 100 ml volumetric flask, dissolve in 70 ml of solvent, make up the solution
volume to the mark with the same solvent and stir.
Add 5 ml of solution into a 50 ml volumetric flask, make up the solution volume to the mark
with solvent and stir.
Sensitivity check solution. Add 2.5 ml of the comparison solution in a 10 ml measuring flask,
make up the solution volume to the mark with solvent and stir.
Resolution check solution. Add 10 mg (exact weight) of favipiravir RS (company standard) in
a 10 ml measuring flask, add 100 μl of concentrated sulfuric acid and 100 μl of concentrated nitric
 ND# _________________________ p. 6
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
acid, shake for 10 seconds, add 9 ml of solvent and shake until completely dissolved. Make up the
solution volume to the mark with solvent and stir.
Use solutions immediately after preparation.
Typical chromatogram of the resolution check solution

Chromatographic conditions:
- instrument - high pressure liquid chromatograph equipped with a UV detector;
- column - stainless steel column Kromasil С18 250x4.6 mm, particle size 5 μm or
similar, meeting the requirements of the test "Checking the suitability of the
chromatographic system";
- wavelength - 210 nm;
- flow rate - 1.0 ml/min;
- column temperature - 30 °C;
- injection volume - 10 μl;
- run time - 55 min;
- gradient mode according to the program:

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v)

0 95 5
10 95 5
20 90 10
35 65 35
45 65 35
46 95 5
55 95 5
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Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
The analysis results shall be considered reliable, where the requirements of the system
suitability test are fulfilled.
System suitability test. Inject 10 μl of sensitivity check solution into equilibrated
chromatographic system, resolution check solution and comparison solution, record at least six
chromatograms for comparison solution.
The chromatographic system is considered suitable if the following conditions are fulfilled:
- the relative standard deviation of the favipiravir peak area on the comparison solution
chromatograms at repeated injections should not exceed 5.0%;
- the efficiency of chromatographic column calculated by the favipiravir peak on the
chromatogram of the comparison solution should be at least 1000 theoretical plates;
- asymmetry factor calculated for favipiravir peak on chromatogram of comparison solution
should not exceed 2.0;
- the resolution calculated between the favipiravir peak and the decomposition product peak
(relative retention time of about 1.25) on the chromatogram of the resolution check solution should
be not less than 2.0;
- signal-to-noise ratio calculated by the favipiravir peak on chromatogram of the sensitivity
check solution should be not less than 10.
Method and calculations. Inject 10 μl of solvent, placebo solution and test solution into
balanced chromatographic system and record chromatograms.
Calculate the percentage of any single impurity (Xi) by the formula:

𝑆𝑆𝑖𝑖 ∙ 𝑎𝑎0 ∙ 100 ∙ 1 ∙ 𝐺𝐺 ∙ 𝑃𝑃 ∙ 100 𝑆𝑆𝑖𝑖 ∙ 𝑎𝑎0 ∙ 𝐺𝐺 ∙ 𝑃𝑃

𝑋𝑋𝑖𝑖 = =
𝑆𝑆0 ∙ 𝑎𝑎 ∙ 100 ∙ 50 ∙ 100 ∙ 𝐿𝐿 𝑆𝑆0 ∙ 𝑎𝑎 ∙ 𝐿𝐿 ∙ 50

where:
S i - peak area of any single impurity in the test solution chromatogram;
S 0 - mean peak area of favipiravir on comparison solution chromatograms;
a 0 - weighed portion of favipiravir RS comparison solution, in milligrams;
a - weighed portion of test sample, in milligrams;
L - content of favipiravir in one tablet according to specification, in milligrams;
G - average tablet weight, in milligrams;
P - percentage content of favipiravir in RS.
When calculating the content of related impurities, the following peaks are not taken into
account: solvent peaks, placebo solution peaks, peaks with area less than the favipiravir peak area
 ND# _________________________ p. 8
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/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
on the chromatogram of the sensitivity check solution (less than 0.05%).
Sum of impurities is determined by summation of individual impurities.
Microbiological purity
The medicinal product must comply with the requirements of SPh RF, GM.1.2.4.0002.18
"Microbiological purity," category 3A.
Dosage uniformity
At n=10 AV≤L1 (L1=15.0). At n=30 AV≤L1 and all values х i satisfy the inequality |М-
х i |≤0.01∙L2∙М (L2=25.0).
Analytical determination is to be carried out in accordance with the requirements of SPh RF,
GM.1.4.2.0008.18 "Dosage uniformity". Method 2.
Assay
The content of favipiravir in one tablet should be from 180.0 to 220.0 mg, based on the average
weight of the tablet.
Analytical determination is to be carried out by HPLC (SPh RF, GM.1.2.1.2.0005.15 "High
performance liquid chromatography").
Buffer solution. Add 1.4 g of potassium dihydrophosphate in a 1000 ml measuring flask,
dissolve in 950 ml of water, adjust pH to (4.00 ± 0.05) potentiometrically using concentrated
phosphoric acid, make up the solution volume to the mark with water and stir. Filter the resulting
solution through a Millipore filter with a pore size of 0.45 μm and degass using any convenient
method.
Mobile phase. Add buffer solution and acetonitrile (90:10) in a 1000 ml beaker and stir.
Solvent. Add buffer solution and acetonitrile (40:60) in a 1000 ml beaker and stir.
Test solution. Take 20 tablets, determine their average weight, rub to powder. Add about 226.5
mg (exact weight) of the powder in a 100 ml measuring flask, add 70 ml of solvent, sonicate for
20 minutes, cool, make up the solution volume to the mark with the same solvent, stir and filter
through a Millipore membrane filter with a pore diameter of 0.45 μm, discarding the first portions
of the filtrate.
5 ml of the solution obtained are placed into a volumetric flask of 50 ml, the solution volume
is diluted to the mark with solvent and stir.
Favipiravir reference standard solution. Add approximately 25.0 mg (accurately weighed) of
favipiravir RS (company standard) in a 50 ml volumetric flask, dissolve in 40 ml of solvent, make
up the solution volume to the mark with the same solvent and stir.
5 ml of the solution obtained are placed into a volumetric flask of 25 ml, the solution volume
is diluted to the mark with solvent and stir.
 ND# _________________________ p. 9
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/
Chromatographic conditions:
- instrument - high pressure liquid chromatograph equipped with a UV detector;
- column - stainless steel column Kromasil С18 250x4.6 mm, particle size 5 μm or similar,
meeting the requirements of the test "Checking the suitability of the chromatographic system";
- wavelength - 210 nm;
- flow rate - 1.0 ml/min;
- column temperature - 30 °C;
- injection volume - 1 μl;
The analysis results shall be considered reliable, where the requirements of the system
suitability test are fulfilled.
System suitability test. Inject 10 μl of favipiravir RS into balanced chromatographic system
and record at least five chromatograms.
The chromatographic system is considered suitable if the following conditions are fulfilled:
- The chromatographic column efficiency calculated from the favipiravir peak must be at
least 1000 theoretical plates;
- asymmetry factor calculated for favipiravir peak should not exceed 2.0;
- the relative standard deviation of the favipiravir peak area at repeated injections should
not exceed 2.0%.
Method and calculations. Successively inject 10 μl of test solution into balanced
chromatographic system and record at least three chromatograms.
The content of favipiravir (C5H4FN3O2) in one tablet (X), in milligrams, is calculated by the
formula:

𝑆𝑆1 ∙ 𝑎𝑎0 ∙ 100 ∙ 50 ∙ 5 ∙ 𝐺𝐺 ∙ 𝑃𝑃 𝑆𝑆1 ∙ 𝑎𝑎0 ∙ 𝐺𝐺 ∙ 𝑃𝑃

𝑋𝑋 = =
𝑆𝑆0 ∙ 𝑎𝑎1 ∙ 5 ∙ 50 ∙ 25 ∙ 100 𝑆𝑆0 ∙ 𝑎𝑎1 ∙ 25

where S 1 - mean value of the favipiravir peak area calculated from chromatograms of test solution;
S 0 - mean value of the favipiravir peak area calculated from chromatograms of favipiravir RS
solution;
а 0 - weighted portion of favipiravir RS, in milligrams;
aa 1 - weighted portion of tablet powder, in milligrams;
G - average tablet weight, in milligrams;
P - percentage content of favipiravir in the favipiravir RS.
 ND# _________________________ p. 10
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/

Package
10 tablets per blister package of polyvinyl chloride film as per GOST 25250-88 and printed
lacquered aluminum foil as per GOST 745-2014 or polyvinyl chloride/polyvinylidene chloride
film (Bilcare Research GmbH, Germany) and lacquered aluminum foil as per GOST 745-2014.
40 or 100 tablets per high density polyethylene jar according to manufacturer's specification
(Nolato, Sweden) sealed with tamper-evident polypropylene lid according to manufacturer's
specification (Nolato, Sweden). Free space in the jar is filled with hygroscopic medical cotton as
per GOST 5556-81.
The jar is labeled with a label made of offset paper according to TU 5431-083- 00279404-2003
or corporate standard STO GOZNAK 09.0001-2016 or a self-adhesive label according to TU
5457-002-34911995-97.
Each jar or 4 blister packs, together with package inserts, are placed in a pack made of
cardboard for consumer packaging according to GOST 7933-89 or imitation chromo cardboard of
waste paper according to TU5453-010-04766354-2006 or other material of similar quality.
The transportation containers shall conform to GOST 17768-90.

Labeling
1) Primary packaging
Blisters are marked with the following information: trade name of the product, international
non-proprietary name, dosage form, strength, batch number, shelf life, PROMOMED®.
The label on a jar indicate trade name of the product, international non-proprietary name,
dosage form, strength, number of tablets, batch number, shelf life, "Manufactured by JSC
BIOKHIMIK, PROMOMED®.
2) Secondary packaging
The package indicates trade name of the product, international non-proprietary name, dosage
form, strength, name and content of the active ingredient in one tablet, number of tablets in the
package, prescription status, storage conditions, "Keep out of reach of children," "Method of
administration: see package insert", registration number, batch number, shelf life, bar code,
"Manufactured by JSC BIOKHIMIK," brief production address (country, city), PROMOMED®."
In addition, cardboard may be marked with identification information to enable tracing of the
product movement from the manufacturer to the end user.
 ND# _________________________ p. 11
Stamp:
/ MINISTRY OF HEALTHCARE OF THE RUSSIA
ЛП-006283+230620
Approved/

Storage
Store in secondary package at a temperature below 25 °C.

Expiry period
2 years.

Note
1. Reagents and titrated solutions mentioned in
this normative document are described in the
corresponding sections of the State Pharmacopoeia
of the Russian Federation.
2. The company guarantees free supply of
reference standards necessary for quality control of
the medicinal product.

Deputy Head of Department for

Registration and Regulatory Affairs
PROMOMED RUS LTD T. V. Lyutova