FAVIPRAVIR TABLET 200mg

TABLE OF CONTENT

01 Objective

02 Product details

03 Pharmacokinetics
FAVIPRAVIR
TABLET 200mg 04 Drug Substance properties

05 Innovator details

06 Project Flow & Critical

Quality attributes
07 Formulation Aspects

08 Manufacturing Details

09 Comparative Dissolution

10 Clinical Trials
OBJECTIVES: a) To develop a stable robust generic product of Favipiravir Tablets 200mg.
b) Safety and Efficacy of test product should be in-line with reference
product and patient acceptability.
PRODUCT DETAILS

FAVIPRAVIR 200mg
 PRODUCT DETAILS

BRAND NAME AVIGAN TABLETS

NDA Applicant TOYAMA CHEMICAL CO., LTD.

Dosage forms Immediate Release Tablets

Strength 200 mg

Therapeutic indication Novel or re-emerging influenza virus

RLD / RS 200 mg

First Approval March 2014

Country of Origin Japan

 PHARMACOKINETICS

Absorption The bioavailability of Favipiravir is almost complete at 97.6%. Average Tmax is around 0.5 hrs.

Distribution The apparent volume of distribution of Favipiravir is 15 - 20 L. Plasma protein-bound of

Favipiravir is around 54%.

Favipiravir undergoes hydroxylation primarily by aldehyde oxidase. Major part of Favipiravir is

Metabolism
excreted through urine.

Elimination Elimination half-life of Favipiravir is estimated to range from 2 to 5.5 hours

DRUG SUBSTANCE PROPERTIES
 DRUG SUBSTANCE PROPERTIES

PROPERTY DESCRIPTION

Chemical Name & Structure 6-Fluoro-3-hydroxypyrazine-2-carboxamide.

M. Formula C5H4FN3O2

Sparingly soluble in acetonitrile and methanol, slightly soluble in water and ethanol .
Solubility
Water solubility: 8.7mg / mL
Log p 0.49

Pka 5.1

Melting point 187 ºC – 193ºC

Molecular Weight 157.1

Therapeutic Category Influenza Anti-viral Agent

INNOVATOR ASPECTS
 INNOVATOR DETAILS
Brand Name AVIGAN
Generic Name Favipiravir tablets
Dosage form Immediate release tablets
Manufactured by/ Marketed by Toyama Chemical Co., Ltd.
Pack type Press through pack / Blister pack
Pack Count 100 tablets (10 X10 blisters)

Storage Store at room temperature.

Pill available (Yes/No) Yes

Round, yellow, film coated tablets printed with “AVIGAN 200” on one side and
Description plain on other side.

Weight of Tablets (mg) 254.0 – 268.1mg

Thickness (mm) 4.27 – 4.35

Hardness (kP) 8.2 – 9.7

Disintegration 2 min 10 sec – 3 min 05 sec

 INNOVATOR PACK DETAILS

NAME STRENGTH TABLET COLOUR / SHAPE IMPRINTING PACK

Press though pack of 10

Favipravir 200mg Round , Yellow coloured Tablets AVIGAN 200
tablets

Reference Product: AVIGAN

Storage: Store at room temperature.

PROJECT FLOW & CRITICAL QUALITY ATTRIBUTES
PROJECT FLOW
 IDENTIFICATION OF QTPP
QTPP Element Target Justification
Dosage form Immediate - Release Tablet Pharmaceutical equivalence requirement: same dosage form
Pharmaceutical equivalence requirement: same route of
Route of administration  Oral
administration
Dosage strength 200 mg Pharmaceutical equivalence requirement: same strength
At least 24-month shelf-life at Equivalent to or better than RLD shelf-life
Stability
control room temperature
Bioequivalence requirement in order to ensure efficacy.
Pharmacokinetics Should be Bioequivalent to RLD.
Physical Attributes
Identification
Assay
  Uniformity of dosage
Drug product units Pharmaceutical equivalence requirement: Meeting the same or compendial or other applicable
quality Related substances (quality) standards (i.e., identity, assay, purity, and quality)
attributes Residual solvents
Dissolution
Water content
Microbial limits
Needed to achieve the target shelf-life and ensure tablet integrity
Container closure system Press through / Blister pack
during shipping.
Administration/concurrence with
Similar food effect as RLD Information is provided in the RLD labeling
labeling
 IDENTIFICATION OF CQA
Drug product
Is this a
Sr. No Quality Target Justification
CQA?
Attributes
Not directly linked to safety and efficacy however rough appearance impact
Same as reference standard
1.  Appearance Yes on quality of product . Therefore, they are critical. The target is set to ensure
patient acceptability.

Though identification is critical for safety and efficacy, this CQA can be
effectively controlled by the quality management system and will be
2. Identification Same as reference standard No monitored at drug product release. Formulation and process variables do not
impact identity. Therefore, this CQA will not be discussed during formulation
and process development.

Similar to Reference Dissolution of the tablet is critical for the efficacy and it depends on the
3.  Dissolution
Product
Yes
material attributes and process parameters.

4.  Content uniformity Needs to meet specification Yes Content uniformity is critical as it affects the efficacy of product.

Assay variability will affect the safety and efficacy. Process variables may
5.  Assay 95% -105% Yes affect the assay of the drug product. Thus, assay will be evaluated throughout
the product and process development.

Should not exceed the ICH They affect safety and efficacy. it is critical and formulation and process
6.  Related Substances
limits
Yes
variables are likely to impact this CQA.
FORMULATION ASPECTS
 COMPARATIVE QUALITATIVE COMPOSITION
REFERENCE vs. TEST PRODUCT
SL. NO. INGREDIENTS REFERENCE PRODUCT TEST PRODUCT
01 Low- substituted HPC √ √
02 Povidone √ √
03 Crospovidone √ √
04 Sodium steryl fumarate √ √
05 Colloidal silicon dioxide √ √
Opadry Film coating composition
06 Hypromellose √ √
07 Titanium Dioxide √ √
08 Talc √ √
09 Ferric oxide √ √
 MANUFACTURING PROCESS

SL. NO. Manufacturing Process REFERENCE PRODUCT TEST PRODUCT

(As per Literature)
01 Dispensing √ √

02 Sifting √ √

03 Dry mixing & wet Granulation √ √

04 Drying √ √

05 Sizing √ √

06 Blending & Lubrication √ √

07 Compression √ √

08 Film coating √ √
 MANUFACTURING FORMULA
S.No Ingredients mg/Tablet
Intra granular
1 Favipiravir 200
2 Low substituted HPC --
3 Colloidal silicon Dioxide --
4 Povidone K30 --
Binder solution
5 P. Water --
Extra granular
6 Crospovidone --
7 Colloidal silicon Dioxide --
Lubrication
8 Magnesium Stearate --
Core Tablet weight 255.0
Opadry yellow --
Coated tablet weight 262.5
MANUFACTURING PROCESS
 COMPARATIVE FINISHED PRODUCT PARAMETERS
REFERENCE vs. TEST PRODUCT

Parameters Reference Product Test Product

Round, yellow film coated Tablets printed

Round, yellow film coated Tablets printed with with “7”on one side and plain on other
Description
“AVIGEN 200”on one side and plain on other side. side.

Weight tablets (mg) 254.0 – 268.2mg 256.2 – 267.9 mg

Thickness (mm) 4.27 – 4.35 4.26 – 4.33

Hardness (kP) 8.2 – 9.7 8.9 – 10.2

Disintegration time (min) 2 min 10 sec – 3 min 05 sec 2 min 30 sec – 3 min 20 sec
 COMPARATIVE DISSOLUTION

900mL of pH 4.5 Acetate buffer, Paddle at 50

Media
RPM

Time point (min) RLD TEST PEODUCT

5 58 60

10 81 83

15 88 90

20 91 91

30 94 93

45 95 94

F2 Value 84.9
 FINISHED PRODUCT SPECIFICATION
S.No Tests Specification
Round, yellow film coated Tablets printed with “7”on one side and plain on other
1. Description
side.
Identification The retention time of the Favipiravir peak in sample chromatogram should
A) By HPLC correspond to that of the standard chromatogram obtained in the Assay.
2.  
B) By UV Spectrophotometer The Spectrum of Favipiravir peak of the sample solution should correspond to that
PDA detector. of standard solution.
3.   Water Content (by KF) Not more than 7.0 % w/w
Assay (By HPLC) Each tablet shall contain not less than 90.0 % w/w and not more than 110.0 % w/w
4.  
 % Labeled amount of labeled amount of the Favipiravir. (180.0 mg – 220.0 mg)
Dissolution (By HPLC)
Not less than 70% (Q) of the labeled amount of Favipiravir is dissolved in 45
5.  (Medium: pH 4.5 Acetate Buffer, Apparatus –Paddle, Volume-
minutes.
900 mL, RPM-50)
Dissolution (By HPLC)
Not less than 70% (Q) of the labeled amount of Favipiravir is dissolved in 45
6.  (Medium: pH 4.5 Acetate Buffer, Apparatus –Paddle, Volume-
minutes.
900 mL, RPM-50)
Related Substances (By HPLC)
7.  Any individual impurity Not more than 0.10% w/w
Total impurities Not more than 1.0% w/w
Uniformity of Dosage Units
The acceptance value is less than or equal to 15.0. (L1 Stage).
8.  (By weight variation)
The acceptance value is less than or equal to 25.0. (L2 Stage).
(Meets the requirements of USP general chapter <905>)
9 Residual solvent The product should meet the requirements of USP <467> option I.
The product should meet the requirements of ICH Q3D.
10 Elemental Impurities

Microbial Enumeration Test

a.Total Aerobic microbial (TAMC) Not more than 10 3
11
b.Total combine yeast (TYMC) Not more than 10 2
c.E. Coli Absent in 1g
FINISHED PRODUCT COA
 NOTE ON PRODUCT PERFORMANCE

 Qualitative composition of drug product is similar to reference product.

 Physical parameters of drug product is in-line with reference product.
 In-vitro dissolution profile of test product is in-line with reference product which indicates the
equivalency of test product with reference. Moreover assay value of test product is within the
specification limit of 90 – 110% which indicates the efficacy aspect of drug product.
 Impurity profile of drug product is well with in the ICH specification indicating safety of drug
Product.
 Physio-chemical parameters of drug product is meeting pre-defined specification and similar to RLD.
 Hence the patient acceptance is high.
 CLINICAL TRIALS

1. Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

ABSTRACT: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its caused coronavirus disease 2019 (COVID-
19) have been reported in China since December 2019. More than 16% of patients developed acute respiratory distress syndrome, and the fatality
ratio was about 1%–2%.

Herein, we examined the effects of Favipiravir (FPV) versus Lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19. Patients with laboratory-
confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2–14: 600 mg twice daily) plus interferon (IFN)-a by aerosol
inhalation (5 million U twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1–14: 400
mg/100 mg twice daily) plus IFN-a by aerosol inhalation (5 million U twice daily) were included in the control arm.

Changes in chest computed, tomography (CT), viral clearance, and drug safety were compared between the two groups. For the 35 patients
enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms.

A shorter viral clearance time was found for the FPV arm versus the control arm (median (interquartile range, IQR), 4 (2.5–9) d versus 11 (8–13) d,
P < 0.001). The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of
91.43% versus 62.22% (P = 0.004).

After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest imaging. Multivariable Cox
regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse events were found in the FPV arm
than in the control arm. In this open-label before-after controlled study, FPV showed better therapeutic responses on COVID-19 in terms of disease
progression and viral clearance. These preliminary clinical results provide useful information of treatments for SARS-CoV-2 infection

Reference: Cai Q, 2020, Experimental treatment with Favipravir for COVID-19: An Open Label control study, http://www.sciencedirect.compii>
 CLINICAL TRIAL DESIGN

The study was conducted in the Third People’s hospital of Shenzen

Forty six patients with Covid-19 were screened from Ninety one patients with Covid-19 were screened from
30th January to 14th February 2020 24th January to 30th February 2020

Excluded ( 21 ) Excluded (46 )

Age lower 16 & older than 85 years (5) Age lower 16 & older than 85 years (7)
Duration from Onset longer than 7 day (7 ) Duration from Onset longer than 7 day (19)
RNAs tested negative before treatment (3) RNAs tested negative before treatment (7)
Refused the informed consent (4) Refused the informed consent (5)
For Other exclusion criteria (2) For Other exclusion criteria (8)

FPV arm (N=35) Control arm (N=45)

FPV (Day 1= 1600mg twice daily ) LPV/RTV (Day 1-14: 400/100mg twice daily)
Days 2-14: 600mg twice daily

Followed up to 14 days after treatment Followed up to 14 days after treatment

35 patients from FPV arm & 5 Patients from Control arm were
Included in safety & efficacy analysis

Reference: Cai Q, 2020, Experimental treatment with Favipravir for COVID-19: An Open Label control study, http://www.sciencedirect.compii>
Conclusion: In this open-label comparative controlled study of patients with COVID-19, those treated with FPV appeared to have faster viral
clearance and better chest imaging change than patients treated with LPV/RTV.

The current study also found that early viral clearance contributed to the improvement of chest imaging on Day 14. This finding suggests that
improvement of the disease may depend on inhibition of the SARS-CoV-2, and that FPV controls the disease progression of COVID-19 by
inhibiting the SARS-CoV-2.

The study introduced the time of viral clearance, which can be used as a primary endpoint for trials on antiviral treatment, and might be a
useful surrogate outcome for designing protocols investigating COVID-19 related treatments as well

Reference: Cai Q, 2020, Experimental treatment with Favipravir for COVID-19: An Open Label control study, http://www.sciencedirect.compii>
 2. Favipiravir Vs Arbidol for COVID-19: A Randomized Clinical Trial

Methods
A prospective, randomized, controlled, open-label multi-centre trial involving adult patients with COVID-19 was conducted. Patients
were randomly assigned in a 1:1 ratio to receive conventional therapy plus Umifenovir (Arbidol) (200mg*3/day) or Favipiravir
(1600mg*2/first day followed by 600mg*2/day) for 10 days. The primary outcome was clinical recovery rate of Day 7. Latency to relief
for pyrexia and cough, the rate of auxiliary oxygen therapy (AOT) or non-invasive mechanical ventilation (NMV) were the secondary
outcomes. Safety data were collected for 17 days.

Results: 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive Favipiravir (116 assessed),
and 120 to receive Arbidol (120 assessed). Clinical recovery rate of Day 7 does not significantly differ between Favipiravir group
(71/116) and Arbidol group (62/120) (P=0.1396, difference of recovery rate: 0.0954; 95% CI: -0.0305 to 0.2213). Favipiravir led to
shorter latencies to relief for both pyrexia (difference: 1.70 days, P<0.0001) and cough (difference: 1.75 days, P<0.0001). No difference
was observed of AOT or NMV rate (both P>0.05). The most frequently observed Favipiravir-associated adverse event was raised serum
uric acid (16/116, OR: 5.52, P=0.0014).

Conclusions
Among patients with COVID-19, Favipiravir, compared to Arbidol, did not significantly improve the clinically recovery rate at Day 7.
Favipiravir significantly improved the latency to relief for pyrexia and cough. Adverse effects caused
Favipiravir are mild and manageable.

Reference: Chen C, 2020, Favipravir Vs Arbidol for COVID 19: A Randomized Clinical Trial, 14 th March, <http://doi.org/10.1101/2020.03.17.20037432>
 322 Participants were assessed for eligibility 82 were excluded
53 didn’t meet exclusion criteria
21 declined to participate
240 underwent randomization 8 had other reason

120 allocated to Arbidol

120 allocated to Favipravir

4 withdraw consent Favipravir 1 took the medicine Day 4

120 continued in Arbidol group 1 took the medicine Day 1
2 took the Medicine Day 5,
116 continued in Favipravir group (Complete recovery & discharge
from the Hospital)
4 took the Medicine Day 6
( Complete recovery & Discharge )
116 completed Favipravir treatment 112 completed Arbidol treatment

2 used Diclofenac sodium once

2 repeated use of Ibuprofen without
( Headache or Toothache )
Prescription (Fever)
1 repeated use of Celocoxib without
Prescription (Fever)
Analyzed for Primary endpoint

120 analyzed for Primary end-point

Clinical Trial Design

Reference: Chen C, 2020, Favipravir Vs Arbidol for COVID 19: A Randomized Clinical Trial, 14 th March, <http://doi.org/10.1101/2020.03.17.20037432>
 Results: 240 enrolled COVID-19 patients underwent randomization; 120 patients were assigned to receive Favipiravir (116 assessed), and 120 to receive
Arbidol (120 assessed). Clinical recovery rate of Day 7 does not significantly differ between Favipiravir group (71/116) and Arbidol group (62/120)
(P=0.1396, difference of recovery rate: 0.0954; 95% CI: -0.0305 to 0.2213). Favipiravir led to shorter latencies to relief for both pyrexia (difference: 1.70
days, P<0.0001) and cough (difference: 1.75 days, P<0.0001). No difference was observed of AOT or NMV rate (both P>0.05). The most frequently
observed Favipiravir-associated adverse event was raised serum uric acid (16/116, OR: 5.52, P=0.0014).
Conclusions
Among patients with COVID-19, Favipiravir, compared to Arbidol, did not significantly improve the clinically recovery rate at Day 7. Favipiravir significantly
improved the latency to relief for pyrexia and cough. Adverse effects caused
Favipiravir are mild and manageable.
Reference: Chen C, 2020, Favipravir Vs Arbidol for COVID 19: A Randomized Clinical Trial, 14 th March, <http://doi.org/10.1101/2020.03.17.20037432>
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