10 MATERIALS & METHODS - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/12278/10/10_chapter...

Ph.D. (Pharmaceutical Sciences) Thesis

Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) 8 of 124

2. MATERIALS & METHODS

2.1 Preparation of Non-Infringement opinion

2.1.1 Selection of a product to work on.

Product marketing team , International Export team, experts and Buyers provided the

name of Product which was required for export and marketing there according to the

demand of the drug product in prevalent disease condition and profitability in that

geographical area.

Preparation of non infringing strategy: Flow Chart

Prior art search

Evaluation of patent identified as relevant

Ideas against claims, strategies, objectives, and resources

Patented and develop product concepts

proposed plan for a proper strategy

Analysis of profit

(Costs, Market, & Competition, etc)

Technical and commercial product development

Implementation of Proposed product

Commercialization

2.1.2 Compilation of all the details of oral capsule formulation comprising

Tianeptine sodium.

• Search for innovator’s formulation

The capsule formulation was not available in public domain search.

• Designing of the formulation

A formulation was designed after thoroughly studying the various factors of

compatibility study and various literature studies supported by laboratory


Shri Jagdish Prasad Jhabarmal Tibrewala University, Jhunjhunu, (Raj) Page 19 of 124

experimentation work. The strengths of inactive ingredients were calculated on the

behalf of usual ranges of inactive ingredients prescribed in the text books and

formularies.

2.1.3 Retrieve detail information related to patents existing in each of these

countries for Tianeptine sodium Capsules

2.1.3.1 Formulation of a search strategy

A search strategy was formulated after understanding the client’s proposed product,

process and technology thoroughly. Key search terms were decided for doing searches

on available electronic databases like www.uspto.gov, www.espacenet.com,

www.patentoffice.nic.in etc.

2.1.3.2 Determine Key Search Areas

Key search areas were determined viz. product patents, process patents, formulation

patents, polymorph patents indication and method of use patents.

2.1.3.3 Perform searches

Searches were conducted on available electronic databases with each of the

predetermined key terms and results of the search were downloaded. The searching

for patents available in these countries was performed on electronic databases

available for these countries.

2.1.4 Patent Search Strategy

It was done to save time & it allowed us to search information at different places & to

find a larger amount of relevant information

2.1.4.1 Basis of the search strategy

The search strategy was formulated after understanding the client’s proposed product,

process and technology thoroughly.

Following key conclusions were drawn after carefully examining the proposed

project:

•••• The client wanted to manufacture and sell a pharmaceutical formulation in the

countries viz. US, U.K and Russia.

•••• The proposed formulation was Capsule and comprised of Tianeptine

sodium.



•••• The proposed process of manufacturing was conventional wet granulation

method.

•••• The product is indicated for the treatment of depression.

2.1.4.2 Available Electronic Databases

There are many electronic databases available on internet. Some of the most reliable

electronic databases useful for the proposed project were:

Orange Book: Approved Drug Products with Therapeutic Equivalence

Evaluations

United States Patent and Trade Mark Office (USPTO)

European Patent Office (EPO): Espacenet Patent search

The World Intellectual Property Organization (WIPO)

2.1.4.3 Key search Areas

Key search areas were identified to find out relevant patents.

�� Patents on Compositions/formulations comprising of Tianeptine

�� Product, Process and Polymorph patents of API

�� Patent search with Assignee Names for patents on Process/ Technology

for making the formulation i.e. Capsules

2.1.4.4 Search terms for patent searching

Following search terms were used to perform searching on the selected databases:

I) For patents on tablet formulation comprising of Tianeptine

II) For patents of Active Pharmaceutical Ingredients (APIs)

For product/ process patents

Patent number search for any prior art patent cited in the downloaded relevant patents

and/or Manual search in Merck Index and/or

For polymorph patents

Tianeptine AND Polymorph AND Crystal AND Hydrate AND Solvate AND

Amorphous

For patent search with assignee names

(For process/ technology for making the formulation i.e. Capsules)

“Teva Pharma” AND Capsules AND Dosage form



2.1.5 Prepararation of a detailed Non-infringement opinion for all these

countries with respect to patents existing in each of these countries for

Tianeptine sodium Capsules.

2.1.5.1 Identification of relevant patents

Out of the all downloaded patents, the relevant patents were identified.

2.1.5.2 Infringement analysis

For each of the identified relevant patents infringement analysis was done by

following the step procedure viz.

Claim Construction and Claim Comparison.

2.1.5.3 Conclusion

Based on the results of infringement analysis conclusions were drawn.

2.1.6 Designing of a Formulation Consisting Of Tianeptine

Description of the Proposed Formulation

Proposed Formulation

Following formulation was designed. This formulation is proposed to be sold in US,

U.K. and Russia

Dosage Form: Capsule

Route of Administration: Oral

Table 1: Formula of the Proposed Formulation

B. Size: 10,000 Capsules

Table 2.1 Batch formula of BRUTINE (Tianeptine sodium Capsules 12.5 mg) for

10000 Capsules.

Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)

Quantity per Capsules (mg)

Function

A: Granules Preparation Tianeptine sodium BP * 0.1313 * 0.1313 12.5 Active Microcrystalline cellulose (PH 102)

BP 0.5167 0.5167 51.0 Diluent

Microcrystalline cellulose Plain

BP 0.1000 0.1000 10.0 Diluent

Starch BP 0.1000 0.1000 10.0 Diluent

Magnesium stearate BP 0.0100 0.0100 1.0 Lubricant



Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function

Colloidal anhydrous silica BP 0.0070 0.0070 0.7 Glidant

Purified Talc BP 0.0100 0.0100 1.0 Glidant Croscarmellose sodium BP 0.0150 0.0150 1.5 Disintegrant

Sodium starch glycolate BP 0.0150 0.0150 1.5 Disintegrant Crospovidone BP 0.0150 0.0150 1.5 Disintegrant

B: Capsules shell: Empty Hard gelatin capsule shells Light green-Light green; Size 5

IHS 10200nos 10200nos 1 no Protective shell

* Overages of Tianeptine sodium- 5%

Average weight of Capsule is 120.5 mg

Note: The quantities of inactive ingredients mentioned in the formula are based on

the ranges of inactive ingredients prescribed in text books. These were

required to be optimized experimentally to get the final formula.

Indications

The product is indicated for the treatment of depression

Capsule Manufacturing Process

Capsule was prepared by the conventional wet granulation for granulation

compounding method. Major steps involved in the manufacturing process were

depicted here.

Dry Mixing of Tianeptine with microcrystalline cellulose

Granulation of mixture with water in a high shear granulator

Wet mass was screened,dried and milled

Milled granules were blended with Crospovidone and Magnesium Stearate to produce

the compression mix & add the other Excipients

Granules were compressed at size



Granules were filled in the capsules

Note: The above mentioned process is based on typical wet granulation

manufacturing processes prescribed in text books. This process was required

to be optimized experimentally.



2.2 Preparation of Dossier in EU-CTD format for BRUTINE (Tianeptine Sodium

Capsules 12.5 mg) for U.K.

The Common Technical Document (CTD) is provides five modules. (Notice to

Applicants, Volume 2B, 2006)

• Requirement for module 1




2.2.1 MODULE 1 Administrative Information and prescribing information

Refer to “EU CTD MODULE 1” inAnnexure 1

2.2.2 MODULE 2 Common Technical Document Summaries

Refer to “3.RESULT & DISCUSSION” & “4.SUMMARY AND

CONCLUSION”

2.2.3 MODULE – 3 QUALITY

2.2.3.1 Table of contents of Module 3

Refer to “Comprehensive Table of Contents” in Annexure 1.

2.2.3.2 DRUG SUBSTANCE

Refer to “DMF (Open Part)” in Annexure 2.

2.2.3.3 DRUG PRODUCT

2.2.3.3.1 Description and Composition of the Drug Product

Nomenclature

INN : Tianeptine Sodium

USAN: Tianeptine Sodium

Molecular formula : C21H24ClN2NaO4S

CAS:—66981–73–5

ATC code: N06AX14



Chemical Name: 7 - [ ( 3 – Chloro – 6, 11 – dihydro – 6 – methyldibenzo [c, f] [1, 2]

thiazepin – 11 – yl) - amino] heptanoic acid S, S - dioxide

Chemical Structure:

Molecular Weight: 458.9

Tianeptine is a tricyclic antidepressant. Available in market as a racemate & its more

active form is l-isomer. The primary metabolites have the same basic structure; There

are -2 & 4 -carbons respectively on side chain.

Table 2.2 Product Information of Tianeptine sodium Capsules 12.5 mg

Product Name BRUTINE (Tianeptine sodium Capsules 12.5 mg) Product Code R/018

Description Light green-Light green Hard gelatin Capsules, Size 5.

Label Claim Each Capsules contains : Tianeptine Sodium BP 12.5 mg

Average Wt 120.5 mg Dosages form Hard Gelatin Capsules

Shelf Life 24 Months Storage Condition Store at temperature not exceeding 250 C, Keep in dry place

away from light. Standard Batch Size 100000 Capsules Batch No. BC1210007

B. Size: 1,00,000 Capsules


100000 capsules

Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function


BP 5.167 5.167 51.0 Diluent


BP 1.000 1.000 10.0 Diluent




Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function




Sodium starch glycolate BP 0.150 0.150 1.5 Disintegrant Crospovidone BP 0.150 0.150 1.5 Disintegrant B: Capsules shell: Empty Hard gelatin capsule shells Light green-Light green; Size 5

IHS 102000 nos

102000 nos

1 no Protective shell


* Overages = 5%

Primary Packing Components

• Printed Aluminium foil

• PVC

Secondary Packing Components: Carton

Tertiary Packing Components

The cartons are to be packed in a corrugated fiberboard box depending on the type of

packing details. All the cartons were poly-laminated in a group of 10 cartons, which

protects the cartons from humidity and other damages

2.2.3.3.2 Pharmaceutical Development

2.2.3.3.2.1 Components of the Drug Product

a) Drug Substance

Specifications of Drug Substance

Material Name Tianeptine sodium BP

Table 2.4 Specification of Tianeptine sodium BP

Test parameters Specification Reference

Appearance White to yellowish powder Very hygroscopic powder

B.P.

Solubility Freely soluble in water and methanol

B.P.

Identification Reaction positive B.P.

Related substance Individual impurity: Not more than 0.1%

B.P.



Total impurities: Not more than 0.4%

B.P.

Methanol Not more than 0.3% B.P.

Dichloromethane Not more than 0.06% B.P.

Ethyl acetate Not more than 0.5% B.P.

Water Not more than 5.0% B.P.

Assay (on anhydrous basis) 99%-101.0% B.P.

Testing procedure: Tianeptine sodium BP

Identification

A. Infrared absorption spectrophotometry.

Comparison: Comparision European Pharmacopoeial reference spectrum of

Tianeptine Sodium B.P sodium.

B. It gives reaction (a) of sodium.

Assay

0.165 g dissolved in 50 ml of anhydrous acetic acid R. titrated with 0.1 M perchloric

acid, End-point were determined by potentiometric titration.

1 ml of 0.1 M perchloric acid is ≡ to 22.95 mg of C21H24ClN2NaO4S.

b) Excipients

Table 2.5 Function of Excipients

Excipients Specification Function

Microcrystalline cellulose (PH 102) BP Diluent

Microcrystalline cellulose Plain BP Diluent

Maize Stach BP Diluent

Magnesium stearate BP Lubricant

Colloidal anhydrous silica BP Glidant

Purified Talc BP Glidant Croscarmellose sodium BP Disintegrant

Sodium starch glycolate BP Disintegrant Crospovidone BP Disintegrant

Capsules shell: Empty Hard gelatin capsule shells Light green/Light green; Size 5

IHS Protective shell



2.2.3.3.2.2 Drug Product

2.2.3.3.2.2.1 Formulation Development

FORMULATION DEVELOPMENT

A). Scope: This development report is applicable to development of Tianeptine

sodium Capsules 12.5 mg using the facility of Brawn Laboratories Ltd., located at

Faridabad, India.

B). Systematic Approach: A Systematic approach to Tianeptine sodium Capsules

12.5 mg was designed and product development activities were sub divided into

literature search, formulation development and process development. The various

studies carried out during these phases were given below.

C). Literature Search: Preliminary activities in a drug product development project

started with a literature review & prior art search in reference books on the

pharmaceutical and analytical parameters.

Reference books, the current United State Pharmacopoeia, British pharmacopoeia,

European Pharmacopoeia, Physician’s Desk Reference, World intellectual property

Organization, Martindale: The complete drug reference and Merck Index were

reviewed on physical and chemical parameters on the active ingredient and its

formulations.

An extensive online internet searching relating to drug substance and the drug product

was done.

Field of the Research: The present research is related to development of a novel

pharmaceutical formulation - Tianeptine sodium Capsules 12.5 mg

D). Background of the Research

i) Drug Information: Tianeptine (Stablon, Coaxil, Tatinol ) (Tianeptine, 2011) is a

drug product useful for treating major depressive cases like (mild, moderate, or

severe). It is structurally similar to tricyclic antidepressants, but having different

pharmacological properties. Actions were also found on the NMDA and AMPA

receptors.

Recently, Tianeptine was approved in France, there it is marketed & is manufactured

by Laboratoires Servier SA; & is also marketed by a other EU countries under brand



name of ‘Coaxil’ also in Latin America & Asia as "Tatinol" &“Stablon" and but it is

not available in US or UK.

E) Active Sourcing, Evaluation & Purchasing

• Sourcing for Active Raw Material: We selected International Suppliers US,

EU, Asian

• Potential Suppliers List: Request samples and COA and Specifications.

We Selected & evaluated at least two suppliers source.

1. Vivan Life sciences, Thane, Mumbai (India)

2. Shanghai soyoung Biotech Inc.

Refer to “COA’S” in Annexure 2

F) Active Testing

Tianeptine

i) Drug information (Active ingredient Tianeptine Sodium)

Physicochemical properties

Chemical structure

Chemical name: [ 3 – chloro – 6 - methyl - 5,5 – dioxo - 6,11-dihydro - (c, f)-

dibenzo - (thiazepine) - 11 - yl) amino] -7 heptanoic acid, sodium salt.

Molecular formula: C21H24ClN2NaO4S

Molecular weight: 458.9

Appearance: White or yellowish powder, very hygroscopic.

Solubility: Freely soluble in water, methylene chloride & methanol.

ii) Testing of Active Substance sample:

Chemical testing by the R&D lab as per Pharmacopoeia method (as per Ph Eur & BP)

&/ Inhouse.

Protocol: BP 2011 was followed for the analysis.



iii) Stability Summary and Conclusions

Substance : Tianeptine Sodium B.P

Proposed expiry : 24 months

Storage : Store < 25°C, Protect from light and moisture.

Stability studies :Accelerated stability study at 40°C & Long term stability study

at 250C are carried out and stability data are attached.

iv) Packing Condition

Tianeptine Sodium B.P is packaged in a light resistant cardboard container Package

10 kg/drum, or according to customers.

For detail refer to “DMF (Open Part)” in Annexure 2 .

G) Excipients

Evaluation of formulation with suitable excipients:

Excipient compatibility tested using DSC method and stability assessment was done.

Table 2.5 Function of Excipients

Excipients Specification Function

Microcrystalline cellulose (PH 102) BP Diluent

Microcrystalline cellulose Plain BP Diluent

Maize Stach BP Diluent

Magnesium stearate BP Lubricant

Colloidal anhydrous silica BP Glidant

Purified Talc BP Glidant Croscarmellose sodium BP Disintegrant

Sodium starch glycolate BP Disintegrant Crospovidone BP Disintegrant

Capsules shell: Empty Hard gelatin capsule shells Light green/Light green; Size 5

IHS Protective shell

All excipients were compatible with each other & with API

H). Container Closure System





• PVC

Secondary Packing Components

1. Carton


The cartons were packed in a corrugated fiberboard box depending on the type of

packing details. All the cartons are poly-laminated in a group of 10 cartons, by which

cartons were protected from humidity and other damages.

I) R & D BATCHES:

Optimization of Product (Tianeptine sodium Capsule 12.5 mg)

Table 2.6 Composition of Tianeptine sodium Capsule 12.5 mg formulations

S. No

Ingredients F1 F2 F3 F4 F5 F6 F7 F8

1 Tianeptine sodium 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5

A : Excipients

2 Starch 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0

3 Magnesium stearate 0.4 0.5 0.5 0.7 0.9 1.0 1.4 1.7

4 Colloidal anhydrous silica 0.5 0.4 0.5 0.5 0.6 0.6 0.7 1.0

5 Purified Talc 0.5 0.6 0.8 0.9 1.0 1.2 1.5 1.8

6 Croscarmellose sodium 0.3 0.5 0.8 1.2 1.4 1.5 1.8 2.0

7 Sodium starch glycolate 2.0 2.4 0.8 1.3 1.2 1.6 1.9 1.2

8 Crospovidone 0.2 0.7 0.9 1.2 1.5 1.6 1.9 2.0

9


1 no 1 1 1 1 1 1 1

Batches F4, F5, & F6 were selected for further study & optimized for the further

study because these provide better dissolution profile.

Development of the formulation here was mainly based on the type of Excipients in

different combinations were used so as to get desire in vitro drug release from

Capsule. Tianeptine sodium is water soluble drug, and dose taken is 12.5 mg. So, in

the present study attempts were made to get capsule with desire drug release profile of

the capsule.



Manufacture of capsule As described in the methodology chapter the, Granules

prepared by wet granulation method by mixing the ingredients.

J) SCALE-UP BATCHES:

In scale-up 3 batches were selected & prepared out of which one Batch was found to

provide appropriate & better results, which was selected for the proposed formulation

as Pilot Scale Batch.

i) Formula of the Proposed Formulation

B. Size: 10,000 Capsules


10,000 Capsules

Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function


BP 0.5167 0.5167 51.0 Diluent


BP 0.1000 0.1000 10.0 Diluent

Maize Starch BP 0.1000 0.1000 10.0 Diluent





IHS 10200nos 10200nos 1 no Protective shell

Average weight of a Capsule is 120.5 mg

Overages = 5%



ii) Manufacturing Process and process Controls

PROCESS FLOW DIAGRAM

FLOW CHART OF MANUFACTURING

Manufacturing process

a) Weighing and Checking

Weights were checked for the raw materials as per the formulation sheet (i.e. page

No.3) The AR No. of all the materials was also checked as per the issuance sheet.

b) Sieving:

Tianeptine Sodium was sieved through #80 and others through # 60 sieve fitted to a

Vibrosifter and collected in separate Intermediate Process Containers

c) Granulation:

Granulation was done with the help of Purified water with the following Raw material

in quantities as mentioned herewith.

Approved Raw Material & Excipients

Sifting

Blending

Capsule Polishing/Dedusting

Final Packing

Transfer to Finished Goods

Store

Dispatch

Capsule Filling

Granulation



Ingredients Standard Quantity(Kg)

Specification

Tianeptine sodium * 0.1313 BP Microcrystalline cellulose (PH 102) 0.5167 BP Microcrystalline cellulose Plain 0.1000 BP

Maize starch 0.1000 BP

Magnesium stearate 0.0100 BP

Colloidal anhydrous silica 0.0070 BP

Purified Talc 0.0100 BP Croscarmellose sodium 0.0150 BP

Sodium starch glycolate 0.0150 BP Crospovidone 0.0150 BP

d) Blending (Lubrication):

All the sieved materials were sifted in Double cone Blender and blended for 30

minutes at 10 RPM. Unloaded the granules in double polythene lined drums and

closed tightly. Labeled the drums appropriately and recorded all the details including

Product Name, Batch No., Batch size, Mfg. Date. Request slip was sent to QA

department to draw the sample for bulk analysis done by QC department.

• Ensured that temperature and humidity in the Capsule filling area is 25°C± 2°C, &

RH: NMT 45 %± 5% respectively.

• Undue storage of granules Avoided. Granules were taken up immediately for

filling into Capsule shells.

e) In-Process Checking

In process parameters at regular intervals were monitored and recorded in the

following formats. Q.A. / Q.C. for to do in-process checks as per the norms set by

them.

• Send the sample of blend to QC for Assay.

• Attached the requisition slip and QC In-process results slip received from QC.

• After blend was released from QC, bulk was filled into capsules as per

specification.

• Storage Condition :Store below 25 º C , Protect from light

TEST LIMIT Description Off white granular Powder Assay : Tianeptine sodium BP 98.0 to 102.0%



Moisture content NMT 2 % f) Quality Assurance / Quality Control Approval

After getting Quality Approval, the Blend was transfered to Capsule Filling dept. and

the product was filled as per specifications and instructions

g) Filling

• Ensured that temperature and humidity in the filling area was 25°C± 2°C, NMT

45%± 5% respectively.



• The Capsule Filling Machine was set as per respective SOP.

• In process parameters at regular intervals were monitored and recorded in the


them.

• The filling parameters were adjusted as per the standards given below:-

Table 2.7 Capsule Filling parameters as per the standards

Parameters Standards Appearance Light green / Light green hard gelatin

capsule size ‘5’, containing off white granular powder.

Standard Fill Weight of Capsule 93mg + 2 % Weight of Filled Capsule 120.5 mg + 2 % Weight of 20 Capsules 2.41 g Individual Weight Variation + 10 % Disintegration Time NMT 20 minutes Locking Length of Filled Capsule 10 ± 0.2 mm

h) In-Process Checking Frequency



them

Weight of 20 Capsules Every 30 minutes Fill Variation Every 120 minutes Disintegration time Every 120 minutes Locking Length of Filled Capsule Every 120 minutes

i) Rejection



The Rejection/Recovery of the Blend/Capsules were collected, recorded, labeled

appropriately and destroyed as per respective SOP

j) Quality Assurance / Quality Control Approval

Request slip to Q.A. Department was sent to draw the sample for finished product

analysis to be done by QC Dept.

After getting Quality Approval, Capsules were transfered the to packing dept. and

packed the product as per current packaging specifications and instructions

k) Packaging:

Batch Issuance Slip from Manufacturing to Packing

Table 2.8 Requisition of Packing Material

Item code

Items UOM Standard quantity

PRIMARY PACKING COMPONENTS

B.P

.F76

9

Aluminum Blister foil Size 185mm

Kg 4.500

B.P

.01

8

PVC Film Size 188 mm clear

Kg 19.250

SECONDARY PACKING COMPONENTS

B.P

.AA

26 Printed cartons Tianeptine

sodium Capsules 10 x 10 Nos

1000

B.P

.J0

11

Corrugated Box G-50

Nos

10.00

B.P

.T7

6

Literature Tianeptine sodium Capsules

Nos

1000

B.P

.K10

Plastic film 500 mm (20“) Kg 2.500

l) Batch Details Instructions and Certification

• Transfer the batch IPCs to the packing cubicle and check if the number of

containers received for the batch.

• Load the IPC in machine hopper in serial order

• Load the Printed foil on winding shaft of the Blister Packing machine



• Perform the Leak test on the samples drawn during machine setting as per the

relevant SOP. Start the machine only after the Blister passes the leak test and

record the observation.

• Set the sealing heater temperature. Monitor it initially and there after every 60

minutes by Production Department and after every 120 minutes by QA

Department. Record the observations in the In – Process Sheet.

iii) Testing Procedure:

• Average weight:

20 Capsules were randomly selected & then average weight was calculated by

following equation:

Average Wt. = Wt. of 20 Capsules --------------------------- 20

Average weight of Capsules = 120.5 mg ±10%

• Uniformity of weight:

20 Capsules were weighed and then average weight of 20 capsules was calculated.

Then 20 Capsules were weighed individually. The Capsules having highest weight

and the Capsules having lowest weight in the above 20 Capsules were find out by:.

Calculate the maximum & minimum deviation as follows:

(WH -A) x 100 Maximum deviation (+ve) = ———————— A (A - WL) x 100 Minimum deviation (-ve) = ———————— A Where-

A: Average weight of Capsules

WH: Highest weight of Capsules

WL: Lowest weight of Capsules

Limits: ±10%



• Moisture content (In process Control Test for Granules)

Moisture content of the granules was determinated with infrared dryer (Sartorius MA

100), by evaporation of bound and unbound moisture. Approximately 4 g of granules

was tested immediately on the manufacturing floor.Mass change was determined and

water content was expressed as percentage of the total mass. Sample was heated until

105 0C. Measurement was terminated when weigh loss in percent is less than 0.1 % in

50 seconds.

Moisture content: (S1 – S2) X 100

S1= Initial sample; S2 = Sample after heating

Limit: NMT 2%

• Disintegration time:

Placed 1 Capsule each in 6 tubes of the basket with a disc. The apparatus was

operated using the medium as specified in Pharmacopoeia, the apparatus was

maintained at 37 ± 2 °C, as the immersion fluid. At the end of the mentioned time, the

basket was lifted and observed the capsules. All of the capsules were disintegrated

completely.

Limits: NMT 30 minutes.

• Dissolution:

Medium:- 0.1 N Hcl ; 900 mL.

Apparatus:- 2: 50 rotation per minute

Time:- 45 minutes.

Procedure— Apparatus II was used. The medium 900 ml of 0.1M hydrochloric acid

was used and the paddle was rotated at 50 revolutions per minute. A sample of 10 ml

was withdrawn from the medium and filtered. The absorbance of the filtered sample

was measured, diluted if necessary with 0.1M Hcl, at the maximum at 220 nm, using

0.1M hydrochloric acid in the reference cell, and compared with that of a standard

solution in 0.1M hydrochloric acid having a known concentration of Tianeptine

sodium equivalent to about 10 to 20 µg of C21H24ClN2NaO4S per ml. The total

content of Tianeptine sodium in the medium was calculated.



• Analytical Procedure:

Method of Analysis

Details of Tianeptine on HPLC

1. Column:- C18

2. Mobile Phase: - Mobile phase consist of acetonitrile: 50 mM potassium

dihydrogen phosphate, pH 3.5 (33:67, v/v/).

3. Flow rate: - It having pump at a flow rate of -1ml/min.

4. λmax: - Operating at -214 nm.

Standard stock solutions

Standard stock solutions of 100 µg/mL was prepared in mobile phase by dissolving

the pure drug in it.

Preparation of the calibration curves

Aliquots were prepared by serial dilution method sufficient to produce 50-300 ng/mL.

Each solution was injected one by one and chromatogram was recorded at 214 nm.

The peak area of drug was noted and calibration curve was plotted as peak area

against concentration of drug.

Analysis of capsule formulation

The contents of twenty capsules were mixed and weighed accurately. Powder

equivalent to specification transferred into a 100 mL volumetric flask, dissolved in

water and sonicated for 5 min., the volume was made up with water, shaken well for 5

min. and then filtered, further absorbance value was noted in triplicate at 214 nm

against reagent blank.

Instrumental Conditions:

Instrument: UV-VIS Spectrophotometer (Shimadzu make Model-1800)

Wavelength: 214 nm

Procedure

The absorbance of the test solution was measured by using the UV-VIS

Spectrophotometer at the maximum at 214 nm and record the spectra was recorded.

Calculation:

The content was calculated taking 562 as the value of A (1%, 1 cm) at the maximum

at 214 nm.

Test Abs 1000 100 50 potency = ---------- x --------x ----------x---------- x------------ x 100

562 100 Test wt 10 100



• Microbiological Attributes

Standard Operating Procedure is applicable for Microbial limit test in microbiology

laboratory in Quality Control department at Brawn Laboratories Limited, Faridabad.

1.

MICROBIAL CONTAMINATION: TOTAL BACTERIAL COUNTS TOTAL FUNGAL COUNTS OTHER MICROORGANISM:

NMT 1000 CFU/G NMT 100 CFU/G ABSENT

Refer to “SOP- Microbial Limit Test” in Annexure 2.

• Stability study:

The objective of the study on BRUTINE (Tianeptine sodium Capsules 12.5 mg) was

to find out the stability profile of capsules stored under accelerated stability study

conditions. The Capsules were put in an inverted position so that there was a contact

with the inner container.

The batches kept under stability study were provided in the following table:

Table 2.9 Batches used under stability study during F & D

Dosage Batch No. Manufacturing Scale Total Batch Size

API Batch No.Date Site

12.5mg/ Capsule

BC121 0001

02/12/2010 Faridabad Pilot scale 10000 Capsules

BP/BPA_ 001/D/10/021

12.5mg/ Capsule

BC121 0002


BP/BPA_ 001/D/10/012

12.5mg/ Capsule

BC121 0003


BP/BPA_ 001/D/10/014

Finally the Commercial or Production scale batch was prepared after the better

results obtained during course of Testing & Stability study performed.

• Summary: The report shows the stability data on BRUTINE (Tianeptine sodium

Capsules 12.5 mg) Samples were stored for 6 months in the primary container closure

system.

Any storage-related changes occurring in the finished product were checked by means

of control tests specified in stability study. The test was designed on basis of stability

profile of Tianeptine sodium BP for the certain specific requirements of Capsules.

Chemical stability does not affected by Storage of Capsules under accelerated



conditions for 6 months. There was not found any significant change in content value

of BRUTINE (Tianeptine sodium Capsules 12.5 mg) compared to its initial value.

Conclusion: The stability data demonstrated that all lots of the product BRUTINE

(Tianeptine sodium Capsules 12.5 mg) remained within specifications at all times

during the accelerated stability conditions at 40 °C ± 2 °C, 75% ± 5 % Relative

humidity. Based on the above, we concluded that the product BRUTINE (Tianeptine

sodium Capsules 12.5 mg) was stable for 6 months.

The method used to conduct the stability studies was taken as ICH guidance

document Q1A-(R2). The above study was performed at Brawn Laboratories Limited

under the supervision of our analyst manager.

iv) Batch formula – Production; Batch no. BC1210007

Size: 1, 00,000 Capsules


100000 capsules

Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function


BP 5.167 5.167 51.0 Diluent


BP 1.000 1.000 10.0 Diluent

Maize Starch BP 1.000 1.000 10.0 Diluent




Sodium starch glycolate BP 0.150 0.150 1.5 Disintegrant Crospovidone BP 0.150 0.150 1.5 Disintegrant


IHS 102000 nos

102000 nos



* Overages = 5%



Overages 5 %, Overages taken due to waste of raw materials that occured during

manufacturing of finished products

v) Critical parameters:

Table 2.10 Critical Parameters & Acceptance criteria

STAGE PARAMETER ACCEPTANCE CRITERIA Blending Assay 98.0 to 102.0%

Moisture Content NMT 5 % Capsule Filling Average fill 93 mg ± 2%

Fill Variation ± 10 % Disintegration time NMT 20 minutes Length 5 ±0.2 mm Chemical Analysis As per Finished Product Specification Microbial Analysis Total bacteria count –(NMT 1000 cfu/gram).

Total fungal count –(NMT100 cfu/gram) Hold Time Study Blend Assay 98.0 to 102.0%

Moisture Content NMT 5 % Microbial Analysis Total bacteria count –(NMT 1000 cfu/gram).

Total fungal count –(NMT100 cfu/gram) Capsule Filling Average fill 93 mg ± 2%

Fill Variation ± 10 % Disintegration time NMT 20 minutes Length 5 ±0.2 mm Chemical Analysis As per Finished Product Specification Microbial Analysis Total bacteria count –(NMT 1000 cfu/gram).

Total fungal count –(NMT100 cfu/gram) Blister Packing Leak Test None of the strips shall fail in the leak test

Acceptance Criteria

i) All the tests performed during the process should qualify the specifications.

ii) Any deviation from the acceptance criteria of the specific check point shall be

Reported and decision should be taken for the acceptance, rejection, change in the

Formulation /process



vi) Batches used for Validation

Table 2.11 Batches used for validation during F & D

1 Batch No Batch Size Mfg Date Exp Date BC1210005 100000 Capsules 06/12/2010 05/11/2012


3 Batch No Batch Size Mfg Date Exp Date BT1210007 100000 Capsules 11/12/2010 10/11/2012

vii) Batch Analyses: Refer to “3.2.1.1 Batch Analyses” in 3. RESULT &

DISCUSSION

viii) Dissolution Profile Comparison by using Model Independent Approach Using a Similarity Factor

a) Samples details:

Sample: BRUTINE (Tianeptine sodium Capsules 12.5 mg)

Manufactured By: BRAWN LABORATORIES LTD

Batch No. : Batch no. BC1210007

Manufacturing Date: 12/2010

Expiry Date: 11/ 2012

Description: Light green-Light green Hard gelatin Capsules, Size ‘5’.Containing off

white granular powder.

Average Weight: 120.5 mg

b) Samples Details of Innovator’s Product:

Sample: STABLON (Tianeptine sodium Tablets 12.5 mg)

Manufactured By: Les Laboratories Servier, (France)

Batch No. : LSC0502

Manufacturing Date: 11/2010

Expiry Date: 10/ 2012

Description: Sugar coated Tablets.

Average Weight: 180 mg

Chemicals: Hydrochloric Acid

Reagent: 0.1 N hydrochloric acid



c) Dissolution test procedure:

Equipments: Tablet Dissolution Test Apparatus - USP 24 (Model No. TDT-06P,

Electrolab, India);

Instrument: Shimazdzu UV-1601

Medium: 0.1 N Hcl; 900 mL.

Apparatus 2: 50 rpm

Time: 45 minutes.

Procedure— Apparatus II was used. The medium 900 ml of 0.1M hydrochloric acid

was used and the paddle was rotated at 50 revolutions per minute. A sample of 10 ml

was withdrawn from the medium and filtered. The absorbance of the filtered sample

was measured, diluted if necessary with 0.1M hydrochloric acid, at the maximum at

220 nm, using 0.1M hydrochloric acid in the reference cell, and compared with that of

a standard solution in 0.1M hydrochloric acid having a known concentration of

Tianeptine sodium equivalent to about 10 to 20 µg of C21H24ClN2NaO4S per ml. The

total content of Tianeptine sodium in the medium was calculated.

d) Comparitive Dissolution Profile of BRUTINE and STABLON

Figure: 2.1 Comparative Dissolution Profiles of BRUTINE and STABLON

e) Result

Dissolution profile of BRUTINE was compared with STABLON & Factor F2 was

found to be 71%. On this basis BRUTINE was bioequivalent with STABLON.



This also provided recommendations for dissolution tests to help ensured continuous

drug product quality in each & every steps and performance after some post approval

manufacturing changes.

2.2.3.3.2.2.2 Overages

Refer to section “2.2.3.3.2 2.1 Formulation Development”

2.2.3.3.2.2.3 Physiochemical and Biological Properties


2.2.3.3.2.3 Manufacturing Process Development


2.2.3.3.2.4 Container Closure System

Refer to section “2.2.3.3.7 Container Closure System”

2.2.3.3.2.5 Microbiological Attributes

Standard Operating Procedure is applicable for Microbial limit test in microbiology

laboratory in Quality Control department at Brawn Laboratories Limited, Faridabad.

1.

MICROBIAL CONTAMINATION: TOTAL BACTERIAL COUNTS TOTAL FUNGAL COUNTS OTHER MICROORGANISM:

NMT 1000 CFU/G NMT 100 CFU/G ABSENT

Refer to “SOP- Procedure for Microbial Limit Test” in Annexure 2.

2.2.3.3.2.6 Compatibility

Not applicable

2.2.3.3.3 Manufacture

2.2.3.3.3.1 Manufacturer

Brawn Laboratories Ltd.

13, N.I.T. Industrial Area, Faridabad-121 001, (Haryana), India

Telephone: +91-11-29815331, 29815264, Fax: 91-11-29810424

Email: [email protected]; Website: www.brawnlabs.com



2.2.3.3.3.2 Batch Formula

Table 2.2 Product Information of Tianeptine sodium Capsules 12.5 mg

Product Name BRUTINE (Tianeptine sodium Capsules 12.5 mg) Product Code R/018

Description Light green-Light green Hard gelatin Capsules, Size 5.

Label Claim Each Capsules contains : Tianeptine Sodium BP 12.5 mg

Average Wt 120.5 mg Dosages form Hard Gelatin Capsules

Shelf Life 24 Months Storage Condition Store at temperature not exceeding 250 C, Keep in dry place

away from light. Standard Batch Size 100000 Capsules Batch No. BC1210007

B. Size: 1,00,000 Capsules


100000 capsules

Ingredients Spec

Standard Quantity

(Kg)

Quantity required

(Kg)


Function


BP 5.167 5.167 51.0 Diluent


BP 1.000 1.000 10.0 Diluent






IHS 102000 nos

102000 nos


Average weight of Capsule is 120.5 mg * Overages = 5%



2.2.3.3.3.3 Description of Manufacturing Process and process Controls

Process Flow Diagram

Flow Chart of Manufacturing

Approved Raw Material & Excipients

Sifting

Blending

Capsule Polishing/Dedusting

Final Packing

Transfer to Finished Goods

Store

Dispatch

Capsule Filling

Granulation



Manufacturing Process

A General Instructions / Precautions

• Ensure area and equipment cleanliness before starting the manufacturing

operations.

• Check and ensure that all manufacturing equipments and other required

accessories are clean and ready for use.

• Check calibration of respective equipment / machine before use

• Wear Gloves and Nose mask during all manufacturing process.

• Counter check the weights of all ingredients before using in the batch.

• Get line clearance from QA for manufacturing.

• AHU system should be kept ON throughout the manufacturing process.

• Temperature should be kept at 250C ± 20 C and Relative Humidity should be

kept at 45% ± 5% RH. Check and maintain record of humidity and

temperature at least twice in a shift.

• Ensure that only QC approved Purified Water is being used for manufacturing

purpose. Record AR No.

• During the preparation of this product, no other product processing should be

done in the same area.

• Whatever sifting or filtration through SS mesh is involved, check the mesh

integrity before and after use.

• All critical aspects during manufacturing like temperature, duration of mixing,

weight etc. must be checked and recorded by the supervisor.

• Supervisor to ensure completion of all in-process records during various stages

of manufacturing operations till completion of the batch.

• Release from QA should be taken for all in-process tests mentioned in batch

manufacturing record.

• No over writing is allowed in the Batch Manufacturing Record. If the initial

data is wrongly entered, cancel the data by single stroke across and initial.

Record reasons for change as foot- note on the same page.

• All the details whatever is necessary should be recorded in Batch

Manufacturing Record and Batch Packaging Record.

• Send a Test Request Form to QC after manufacturing is completed.



• Check all polyethylene bag before and after material loading for black

particles.

Manufacturing Equipments:

Table 2.12 Manufacturing Equipments used during Capsule manufacturing

Sr. no. EQUIPMENT NAME 1. Weighing balance 220 g capacity

2. Weighing balance 20 Kg capacity

3. Double Cone Blender 200 Liters

4. Multi mill 5. Double cone Blender

6. Oscillating Granulator

7. Intermediate process containers / drums (IPC)

8. Capsule Filling Machine Ancher

9. Capsule Polishing Machine

10. Capsule Sorter 11. Strip/Blister Packing Machine 12. Packing Conveyor Belt 13. Air Displacement Unit

Manufacturing process:

a) Weighing and Checking

Weights were checked for the raw materials as per the formulation sheet (i.e. page

No.3) The AR No. of all the materials was also checked as per the issuance sheet.

b) Sieving:

Tianeptine Sodium was sieved through #80 and others through # 60 sieve fitted to a

Vibrosifter and collected in separate Intermediate Process Containers

c) Granulation:

Granulation was done with the help of Purified water with the following Raw material

in quantities as mentioned herewith.



Table 2.13 Standard quantities of Raw materials used during Granulation

Ingredients Spec Standard Quantity (Kg)

Tianeptine sodium BP * 1.313 Microcrystalline cellulose (PH 102) BP 5.167 Microcrystalline cellulose Plain BP 1.000

Maize starch BP 1.000

Magnesium stearate BP 0.100

Colloidal anhydrous silica BP 0.070

Purified Talc BP 0.100 Croscarmellose sodium BP 0.150

Sodium starch glycolate BP 0.150 Crospovidone BP 0.150

d) Blending (Lubrication):

All the sieved materials were sifted in Double cone Blender and blended for 30

minutes at 10 RPM. Unloaded the granules in double polythene lined drums and

closed tightly. Labeled the drums appropriately and recorded all the details including

Product Name, Batch No., Batch size, Mfg. Date. Request slip was sent to QA

department to draw the sample for bulk analysis done by QC department.

• Ensured that temperature and humidity in the Capsule filling area is 25°C± 2°C,

NMT 45 %± 5% respectively.



e) In-Process Checking



them.

• Send the sample of blend to QC for Assay.

• Attached the requisition slip and QC In-process results slip received from QC.

• After blend was released from QC, bulk was filled into capsules as per

specification.




TEST LIMIT Description Off white granular Powder Assay : Tianeptine sodium BP 98.0 to 102.0%

Moisture content NMT 2 %

f) Quality Assurance / Quality Control Approval

After getting Quality Approval, the Blend was transfered to Capsule Filling dept. and

the product was filled as per specifications and instructions

g) Filling

• Ensured that temperature and humidity in the filling area was 25°C± 2°C, NMT

45%± 5% respectively.



• The Capsule Filling Machine was set as per respective SOP.

• In process parameters at regular intervals were monitored and recorded in the


them.

• The filling parameters were adjusted as per the standards given below:-

Table 2.7 Capsule Filling parameters as per the standards

Parameters Standards Appearance Light green / Light green hard gelatin

capsule size ‘5’, containing off white granular powder.

Standard Fill Weight of Capsule 93mg + 2 % Weight of Filled Capsule 120.5 mg + 2 % Weight of 20 Capsules 2.41 g Individual Weight Variation + 10 % Disintegration Time NMT 20 minutes Locking Length of Filled Capsule 10 ± 0.2 mm

h) In-Process Checking Frequency



them



Weight of 20 Capsules Every 30 minutes Fill Variation Every 120 minutes Disintegration time Every 120 minutes Locking Length of Filled Capsule Every 120 minutes

i) Rejection

The Rejection/Recovery of the Blend/Capsules were collected, recorded, labeled

appropriately and destroyed as per respective SOP

j) Quality Assurance / Quality Control Approval

Request slip to Q.A. Department was sent to draw the sample for finished product

analysis to be done by QC Dept.

After getting Quality Approval, Capsules were transfered the to packing dept. and

packed the product as per current packaging specifications and instructions

k) Packaging:

Batch Issuance Slip from Manufacturing to Packing

Table 2.8 Requisition of Packing Material

Item code

Items UOM Standard quantity

PRIMARY PACKING COMPONENTS

B.P

.F7

69 Aluminum Blister foil

Size 185mm

Kg 4.500

B.P

.018

PVC Film Size 188 mm clear

Kg 19.250

SECONDARY PACKING COMPONENTS

B.P

.A

A2

6

Printed cartons Tianeptine sodium Capsules 10 x 10

Nos

1000

B.P

.J0

11

Corrugated Box G-50

Nos

10.00

B.P

.T

76 Literature Tianeptine sodium

Capsules

Nos

1000

B.P

.K

10

Plastic film 500 mm (20“) Kg

2.500



l) Batch Details Instructions and Certification

• Transfer the batch IPCs to the packing cubicle and check if the number of

containers received for the batch.

• Load the IPC in machine hopper in serial order

• Load the Printed foil on winding shaft of the Blister Packing machine

• Perform the Leak test on the samples drawn during machine setting as per the

relevant SOP. Start the machine only after the Blister passes the leak test and

record the observation.

• Set the sealing heater temperature. Monitor it initially and there after every 60

minutes by Production Department and after every 120 minutes by QA

Department. Record the observations in the In – Process Sheet.

Line Setting

• Set the packing line

• After setting all the parameters check and certify the line setup

• Checker should check individual Strip/Blister

• Pack 10 Capsules in each blister

• Pack Such 10 Blisters in a Carton

• Insert a Literature in each carton

• Pack such 100 cartons in corrugated box

• Wrap the Shipper with plastic film 500 mm

• Seal the shipper using BOPP tape

• Label the shipper using sticker label. Number each shipper serially on center of

the corrugated box.

• In case any excess packing material is required to complete the batch, get the

same on Additional Material Requisition form.

Transfer of finished products to quarantine finished goods store: After

completion of terminal inspection and getting Quality Assurance approval on the

Finished Goods, the entire quantity of Finished Products was transferred to the

quarantine finished goods store by Transfer Note.



2.2.3.3.3.4 Control of critical steps and intermediates

Table 2.10 Critical Parameters & Acceptance criteria

Stage Parameter Acceptance criteria Blending Assay 98.0 to 102.0%

Moisture Content NMT 5 % Capsule Filling Average fill 93 mg ± 2%

Fill Variation ± 10 % Disintegration time NMT 20 minutes Length 5 ±0.2 mm Chemical Analysis As per Finished Product Specification Microbial Analysis Total bacteria count (NMT 1000 cfu/gm)

Total fungal count (NMT100 cfu/gm) Hold Time Study Blend Assay 98.0 to 102.0%

Moisture Content NMT 5 % Microbial Analysis Total bacteria count (NMT 1000 cfu/gm)

Total fungal count (NMT100 cfu/gm) Capsule Filling Average fill 93 mg ± 2%

Fill Variation ± 10 % Disintegration time NMT 20 minutes Length 5 ±0.2 mm Chemical Analysis As per Finished Product Specification Microbial Analysis Total bacteria count (NMT 1000 cfu/gm)

Total fungal count (NMT100 cfu/gm) Blister Packing Leak Test None of the strips shall fail in the leak test

Acceptance Criteria

i) All the tests performed during the process should qualify the specifications.

ii) Any deviation from the acceptance criteria of the specific check point shall be reported and

decision should be taken for the acceptance, rejection, change in the formulation /process.

2.2.3.3.3.5 Process Validation and/or Evaluation

a) Objective:

To validate the manufacturing process of “Tianeptine Sodium Capsule 12.5 mg”as

per the Batch Manufacturing Record to establish documentary evidence that the

process will consistently producing the product meeting its in-process & finished

product specifications by examining three consecutive production batches



b) Scope:

Retrospective validation was carried out for 3 consecutive production batches for

“Tianeptine Sodium Capsule 12.5 mg”; critical steps were monitored and validated.

The objective of this process validation report for “Tianeptine Sodium Capsule 12.5

mg” was to establish documented evidence that the process was capable of

consistently producing a product of predetermined specifications and quality

attributes.

c) Batches Used for Validation

Table 2.14 Batches used for validation

1 Batch No Batch Size Mfg Date Exp Date

BC1210008 100000 Capsules 05/12/20010 05/11/2012


BC1210009 100000 Capsules 17/12/20010 17/11/2012


BT1210010 100000 Capsules 22/12/20010 22/11/2012

d) In-Process Checking

• The sample of blend was sent to QC for Assay.

• The requisition slip was attached and QC In-process results slip received from

QC.

• After release of blend from QC, the bulk was filled into capsules as per

specification.


TEST LIMIT Description Off white granular Powder Assay : Tianeptine sodium BP

98.0 to 102.0%

Moisture content NMT 2 %

e) In-Process Checking Frequency


following formats. Q.A. / Q.C. for In-process checks as per the norms set by them.

Weight of 20 Capsules Every 30 minutes Fill Variation Every 120 minutes Disintegration time Every 120 minutes



Locking Length of Filled Capsule Every 120 minutes

f) Sampling plan:

Sampling Locations for Double Cone Blender

After completion of mixing for the defined period of time, the samples were collected

from different locations.

� Top left (T7-1)

� Top right (T7-2)

� Middle left (M7-1)

� Middle right (M7-2)

� Bottom left (B7-1)

� Bottom right (B7-2)

20 g (10 g from left + 10 g from right) sample was collected from each sampling point

perform the same activity with the time interval of 5, 10, 15 minutes. (T7, T8, T9).

g) Validation Sampling Plan

Table 2.15 Sampling Plan Validation

Unit Operation

Sampling point Sample quantity

Sample code

Controlled parameter

Measured response

Acceptance criteria

Blending Sample was drawn from 9 locations of the blender interval of 15,25,30 min

20 g each from each sampling location

L-1 M-2 R-1 L-2 M-2 R-2 L-3 M-3 R-3

• RPM of the blender • Blending time

• Assay • Identify • Moisture

content

Assay-98.0 to 102.0% Water NMT 5 %

IPC Sample 40 g composite sample from Top, middle, bottom layers after unloading the material into intermediate process containers.

40 g S1 --- • Assay • Moisture content

Assay-98.0 to 102.0% Water-

NMT 5%

Blend Hold Time Study

20 g (2×20) g (for chemical and microbial limit tests) composite sample

40 gm (20 gms for chemical analysis and,20 gm for microbial limit tests)

S2-A, S2-B --- • Assay • Moisture Content • Microbial tests

Assay-98.0 to 102.0% Water- NMT 5%



Capsule Filling

-------- 20 Capsules after every 2 hours, 20 Capsules after every 30 minutes,

-------- Vacuum , Air, Speed, Height of Powder in Hopper

Average fill Fill Variation • DT

• Avg fill 93mg±10%

• Fill Variation 10%

DT: NMT 20 min

80 capsules composite sample for Finished Product Analysis.

S3 --------- Chemical Analysis Microbial Analysis

Assay-98.0 to 102.0% Water- NMT 5%

Filled capsules

Hold Time Study

-------- 80 Caps(50 Caps) for chemical analysis + 30 Caps for microbial limit tests)

S4 -------

• Assay • Moisture Content

• DT • Microbial Tests

Assay-98.0 to 102.0% Water- NMT 5% DT: NMT 20 min

Blister packi ng

Strips were withdrawn after every 2 hrs intervals for leak testing (no of strips that are taken for leak testing shall represent each cavity of the sealing rollers).

---

S-6

• Sealing/ roller temperature

• Leak test None of the strips were failed in the leak test

h) Tabulation of the Test Results for following batches:

Table 2.14 Batches used for validation



3 Batch No Batch Size Mfg Date Exp Date BT1210010 100000 Capsules 22/12/2010 22/11/2012

i) Evaluation of Data, and Where Applicable, including Statistical Process

Control Analysis:

Refer to “4.3.2 Manufacture” in Chapter 3.RESULT & DISCUSSION.



j) Batch Analyses

Table 2.16 Batch Analyses for BRUTINE (Tianeptine sodium Capsules 12.5 mg)

Test BC1210008 BC1210009 BC1210010 Limits

Description

Light green-Light green Hard gelatin

Capsules, Size ‘5’.Containing

off white granular powder.







Light green-Light green Hard gelatin Capsules,

Size ‘5’.Containing


Identification Positive Positive Positive Positive for

Tianeptine sodium

Average fill Weight

93.6 mg 93.8 mg 93.4 mg 93.5 mg ±5.0 %

Uniformity of Weight

120.7 mg± 10.00 %

120.5 mg ± 10.00 %

120.8 mg ± 10.00 %

± 10.00 % of the average weight

Dissolution 35-42 minutes

28- 35minutes 32-37 minutes

NLT 75.00 % of the labelled amount of Tianeptine sodium dissolved in 45 min.

Assay: Each Capsule contains- Tianeptine sodium BP 12.5 mg

99.93% 99.21% 99.44% Claim 12.5 mg 95.00-105.00

%

k) Results

Statement was made for in this report on acceptability of manufacturing process meet

the objective of protocol.

2.2.3.3.4 Control of Excipients

2.2.3.3.4.1 Specifications

The excipients Microcrystalline Cellulose BP, Purified Talc BP, Magnesium Stearate

BP, Maize Starch BP, Sodium Starch Glycolate BP, Colloidal Anhydrous Silica BP,



Croscarmellose Sodium BP, Crospovidone BP and Purified Water BP were procured

as official specifications.

Protocol (For all compendial Excipients): British Pharmacopoeia 2011

Hard Gelatin was obtained as In-house specifications.

HARD GELATIN CAPSULES

PROTOCOL: In-house

Table 2.17 Specification for Hard Gelatin Capsule Shells

Sr. No. Tests Specification 1 Description Light green/ Light green, Empty Hard Gelatin, Size

“5” Capsules. 2. Odour Shell should not develop any foreign odour. 3 Identification A precipitate should produce. 4 Average Weight 27.5 mg ± 10% w/w. 5 Dimension Outside Diameter of Cap

Outside Diameter of Body Length of Cap Length of Body Joined Length

4.57 – 4.69 mm 4.26 – 4.38 mm 5.68 – 6.68 mm 9.82 – 10.22 mm 11.67 – 12.17 mm

6 Disintegration time Not more than 15 minutes. 7 Loss on drying Between 12.5% to 16.0 % determined on 1.0 gm

sample 8 Microbial

Contamination Total microbial count: Not more than 1000 CFU per gm. 1.0 gm is free from Escherichia coli and Salmonellae. spp.

2.2.3.3.4.2 Analytical Procedures

Hard Gelatin Capsules shell

Description: Light green/ Light green, Empty Hard Gelatin, Size “5” Capsules.

Odour: Shell was not develop any foreign odour.

Identification: One capsule shell was boiled with 20 ml of water, allowed to cool and

centrifuged. To 5 ml of the supernatant liquid, 1 ml of picric acid solution was added

and to another 5 ml, 1 ml of tannic acid solution was added; a precipitate was

produced in each case.



Average weight:

100 capsule shells were weighed and the average weight was determined of a capsule.

The average weight was within +/-10% of the target weight.

Disintegration time:

The capsule shells were complying with the disintegration test for tablets and

capsules, using the discs. The capsules were disintegrated within 15 minutes.

Loss on drying:

Loss on drying was determined by drying of 1.0 g of capsule shells in an oven at 105o

for 4 hours / constant weight. Value lies between 12.5 and 16.0%,

Microbial Contamination:

Total microbial count: Not more than 1000 CFU per gm.

1.0 gm is free from Escherichia coli and Salmonellae. spp.

2.2.3.3.4.3 Validation of Analytical Procedures

As all the Excipients were present in the official monograph i.e. B.P. and EP, So there

was no requirement for the analytical method validation.

2.2.3.3.4.4 Justification of Specifications

As all the Excipients were present in the official monograph i.e. B.P. and EP, so there

was no requirement for the Justification of Specifications.

2.2.3.3.4.5 Excipients of Human or Animal Origin

Gelatin was used in Capsule shell manufacturing was BSE free and was conferred by

a BSE risk free certificate from the Capsule shell manufacturer. Find attachment in

Annexure 1 as “Certificates”

2.2.3.3.4.6 Novel Excipients

Not Applicable



2.2.3.3.5 Control of Drug Product

2.2.3.3.5.1 Specification

Table 2.18 Specification for BRUTINE (Tianeptine sodium Capsules 12.5 mg)

Product Name: BRUTINE (Tianeptine sodium Capsules 12.5 mg) Mfg Date: 12/2012

Batch No: BC1212007 Exp Date: 11/2014

Quantity: 40 Capsules Date of Analysis: 05/12/2012

Test Specification Result

Description

Light green-Light green Hard

gelatin Capsules, Size

‘5’.Containing off white granular

powder.

Light green-Light green

Hard gelatin Capsules,

Size ‘5’.Containing off

white granular powder.

Identification Positive with Test A and B Positive

Average fill Weight 93.5 mg ±5.0 % 93.6 mg

Uniformity of Weight ± 10.00 % of the average weight 120.7 mg± 10.00 %

Ethyl acetate(ppm) NMT 5000 112

Individual impurity: Not more than 0.2 % 0.081%

Total Impurities NMT 1.0 % 0.24%

Dissolution

NLT 75.00 % of the labelled

amount of Tianeptine sodium

dissolved in 45 min.

30-40 minutes

Assay:

Each Capsule contains:

Tianeptine sodium BP

12.5 mg

Claim 12.5 mg

95.00-105.00 %

99.93%

Specification of Tianeptine sodium Capsules 12.5 mg was In-house & the test &

methods were validated as per the analytical method validation, stability study & other

testing as dissolution.



2.2.3.3.5.2 Analytical Procedures

Method of Analysis


5. Column:- C18

6. Mobile Phase: - Mobile phase consist of acetonitrile: 50 mM potassium


7. Flow rate: - It having pump at a flow rate of -1ml/min.

8. λmax: - Operating at -214 nm.


Standard stock solutions of 100 µg/mL was prepared in mobile phase by dissolving








The contents of 20 capsules were mixed and weight accurately. Powder equivalent to

specification transferred into a 100 mL volumetric flask, dissolved in water and

sonicated for 5 min., the volume was made up with water, shaken well for 5 min. and

then filtered, further absorbance value was noted in triplicate at 214 nm against

reagent blank.



Wavelength: 214 nm

Procedure


Spectrophotometer at the maximum at 214 nm and record the spectra was recorded.

Calculation: The content was calculated taking 562 as the value of A (1%, 1 cm) at

the maximum at 214 nm.


562 100 Test wt 10 100



2.2.3.3.5.3 Validation of Analytical Procedures

By: UV-visible double beam spectrophotometer

Refer to Annexure 2 “Chromatograms & Testing Procedure” By: HPLC:

(a) Objective:

This report is intended to perform the experiments and established the validity of the

titled method for its intended use for the determination of assay content of Tianeptine

sodium capsules 12.5 mg.

The assay method was developed and verified for its intended purpose.

(b) Scope:

This method validation report is applicable to the determination of the assay of

Tianeptine sodium capsules 12.5 mg.

(c) Responsibility

a. Quality Control :

i. To prepare the method validation report

ii. To evaluate the results against the acceptance criteria

iii. To review the report for its compliance

b. Quality Assurance

i. To approve the method validation report.

(d) Instrument used

i. UV-VIS Spectrophotometer

ii. Ultra sonic bath

iii. Analytical Balance

iv. HPLC

(e) Reagent Used

i. Ethyl Acetate

ii. 0.5 M Sulphuric Acid

iii. Tianeptine WS



(f) Method of Analysis


9. Column:- C18

10. Mobile Phase: - The Mobile phase consist of acetonitrile: 50 mM Potassium


11. Flow rate: - It having pump at a flow rate of 1ml/minute.

12. λ max: - Operating at -214 nm.


A standard stock solution of 100 µg/mL was prepared in mobile phase by dissolving








The contents of 20 capsules were mixed and accurately weight the content of 20

Capsules. Powder equivalent to specification transferred into a 100 mL volumetric

flask, dissolved in water and sonicated for 5 min., the volume was made up with

water, shaken well for 5 min. and then filtered, further absorbance value was noted in

triplicate at 214 nm against reagent blank.



Wavelength: 214 nm

Procedure


Spectrophotometer at the maximum at 214 nm and the spectra was recorded.

Calculation:

The content was calculated taking 562 as the value of A (1%, 1 cm) at the maximum

at 214 nm.


562 100 Test wt 10 100



(g) Specificity

Acceptance Criteria:

No any interference observes at maximum 214nm from the diluents and

placebo maxima.

Procedure: Blank solution, placebo and test solution by using Tianeptine sodium

capsules were prepared as per method of analysis and taken the absorbance of the test

solution and calculated the measured the peak response of the major maxima.

(h) System Suitability


a) The tailing factor for Tianeptine Sodium peak is not more than 2.0.

b) The column efficiency determined from the Tianeptine Sodium peak is not less

than 2500 theoretical plates.

c) The % RSD for three replicates absorbance of test solution is not more than 2%.

Procedure: Blank solution and test solution (concentration: 1 mg/mL) were prepared

as per method of analysis and the maximum was observed at 214 nm and calculated

the % RSD for the three replicates absorbance of the test solution.

(i) Method precision


% RSD of the assay content from the six sample preparation should be not

more than 2.0%

• Procedure

The method passed the test for repeatability as determined by %RSD of the replicates

absorbance of the test solution at 100% test concentration.

(j) Accuracy


% Recovery should be between 95% and 105 % and % RSD of the 9

determination of the samples should be not more than 2.0%



Tianeptine API was spiked in our Capsule.

The result of accuracy given in tabulated below revealed that the method was found

accurate for all above purposes.

Table 2.19 % Recovery of Tianeptine at different sample concentration

Sr. No.

Sample Concentration

(in %) of the Target conc.

Sample ID % Recovery of Tianeptine

% Recovery

1

75%

Sample Preparation -1

100.9

Mean : 99.97% RSD : 0.789%

2 Sample Preparation -2

99.8


101.2

4

100%


99.9


98.9


100.4

7

125%


100.2


99.6


99.1

(k) Limit of detection & Limit of quantitation:

LOD (Limit of detection):

LOD is X + (3 x SD).

LOD (Limit of detection) value - 10 ng/mL

LOQ (Limit of quantitation)

LOQ is X + (10 x SD).

LOQ (Limit of quantitation) value - 45 ng/mL

Ruggedness: Ruggedness of an analytical method was checked by performance the

method used for precision on different days by different analyst with different

regent. The ruggedness data was found within the acceptance limit NMT 2.0%

RSD.



(l) Conclusion

The determination of assay content of Tianeptine in Tianeptine sodium capsules; was

verified by using the HPLC. On basis of the analytical data and results it was found

that method was specific, precise, Accurate and system suitability parameters

observed well within the pre-defined acceptance criteria.

Hence it was concluded that method for the determination of assay of Tianeptine in

Tianeptine sodium capsules was suitable for our intended purpose.

2.2.3.3.5.4 Batch Analyses

Refer to “3.4.3 Batch Analyses” in Chapter 3. RESULT & DISCUSSION.

2.2.3.3.5.5 Characterisation of Impurities

IMPURITIES A. Br - [CH2]6- CO- O -C2H5: ethyl 7 - bromoheptanoate,

B. R = H, R1 = [CH2]6- CO- O- C2H5 : ethyl 7- [[(11RS) -3- chloro- 6-methyl -6,11-dihydrodibenzo [c,f] [1,2] thiazepin-11-yl]amino] heptanoate S, S-dioxide, E. R = R1 = [CH2]6-C O2H: 7, 71- [[(11RS) -3- chloro- 6- methyl-6,11- dihydrodibenzo [c,f] [1,2] thiazepin – 11 - yl] imino] diheptanoic acid S, S-dioxide,

C. X = O: 3 -chloro -6-methyldibenzo [c,f] [1,2] thiazepin- 11 (6H)- one S,S-dioxide, D. X = N - [CH2]6-CO2H: 7- [[ (11RS)-3- chloro-6-methyldibenzo [c,f] [1,2]

thiazepin-11 (6H) -ylidene] amino] heptanoic acid S,S-dioxide.



2.2.3.3.5.6 Justification of Specification(s)

Table 2.20 Justification of Specification BRUTINE (Tianeptine sodium Capsules

12.5 mg)

Test Limits Result BC111004

Specification

Description

Light green-Light green Hard gelatin Capsules, Size ‘5’.Containing off white granular powder.

Light green-Light green Hard gelatin Capsules, Size ‘5’.Containing off white granular powder.

IHS

Identification Positive with Test A and B

Positive IHS

Average fill Weight

93.5 mg ±5.0 % 93.6 mg IHS

Uniformity of Weight

± 10.00 % of the average weight

120.7 mg± 10.00 % IHS

Ethyl acetate(ppm)

NMT 5000 108 IHS

Individual impurity:

Not more than 0.2% 0.080% IHS

Total Impurities NMT 1.0% 0.24% IHS

Dissolution

NLT 75.00 % of the labelled amount of Tianeptine sodium dissolved in 45 min.

30-35 minutes

IHS

ASSAY: Each Capsule contains- Tianeptine sodium BP 12.5 mg

Claim 12.5 mg 95.00-105.00 %

99.93% IHS

The testing Procedure was justified from data of analytical method validation and the

other methods like dissolution and other In-process results were justified from process

validation and Stability study upto the shelf life of Product.



2.2.3.3.6 Reference Standards or Materials

Given below was the detail of working standard used for analyzing the samples of

Capsules and API.

The IR spectra of the working standard was also attached.

Table 2.21 Reference standard/Materials

Name Batch no. Assay

Tianeptine Sodium BP BP/BPA_001/D/10/025 99.65% w/w

TEST STANDARD RESULT

Description White to yellowish powder, very

hygroscopic.

Off-white powder,

hygroscopic

Identification Should Be Complies Complies

Water NMT 5.0%W/W 0.55%

Assay NLT 99.00% and NMT 101.00

% W/W (O.A.B)

99.65% w/w

Refer to “Annexure 2” for Certificate of Analysis.

2.2.3.3.7 Container Closure System



• PVC

Secondary Packing Components

• Carton


The cartons were packed in a corrugated fiberboard box (depending on the type of

packing details). All the cartons were poly-laminated in a group of 10 cartons,by

which the cartons were protected from humidity and other damages.

The corrugated fiberboard boxes were made of export worthy material and were

sealed with a BOPP tape.

Transportation: Transported with precautions.

The cautions like - Not for loose handling



Protect from water

Avoid vigorous transportation

Care should be taken.

SPECIFICATION OF PACKING MATERIAL

PRESENTATION FORM:

10 x 10’ blister pack in a unit carton along with pack inserts; such cartons were

packed in a corrugated box sealed with cello tape and labeled.

PRIMARY PACKAGING MATERIAL:

Table 2.22 Specifications for Printed Aluminium foil

Sr. No. Tests Limits / Requirements 1. Description

i) Print color Printed aluminium blister foil with VMCH coating. As per artwork / standard.

2. Width 185.79mm 3. Thickness 0.024 mm 4. Total GSM 69.34GM/CM2 5. Aluminium GSM 66.53GM/CM2 6. 7. 8. 9. 10. 11.

VMCH GSM Ink Lifting Test Suitability Defects Supply Storage

2.81GM/CM2 Should passes the test 1. Winding of rolls not to be loose / telescopic. 2. Rolls should be free from wrinkles, creasing, / dents and collapsed / damaged core 3. Ink used for printing should be HR grade and withstand temp. up to 180°C, there should not be lifting or fading of ink during blister sealing Sample size of 5% rolls to be inspected at random for corroded or oxidized surface, improper coating, and improper winding and incorrect diameter of roll. Rolls wrapped in polythene film with brawn paper. Rolls should properly label with quantity, item name, and supplied by. Storage: Protect from light and moisture at a temperature < 30°C



Table 2.23 Specifications for Clear PVC Film

Sr. No. Tests Specification

1 Description A clear, smooth Poly Vinyl Chloride film

2 Width 188 ± 1 mm

3 Grammage 340 gm/m2 ±8 %

4 PVC Thickness 0.025 mm ± 0.02 %

5 Pin Holes Should be absent

6 Colour As per specification

7 Inner Dia Core 75 ± 1mm

Table 2.24 Specifications for Cartons (10x10’s)

Sr. No. Tests Specification 1. Description

i) Color ii) Shape iii) Material of Construction

As per artwork / standard. Rectangular, side opening, reverse tuck Printed / unprinted, duplex board.

2. Dimension: (Outer) i) Length ii) Breadth iii) Width

As per approved sample As per approved sample As per approved sample

3. Grammage 300g ± 10% of GSM (For duplex board carton)

4. 5. 6. 7.

Printed Matter Suitability Supply Storage

Sharp and elegant as per artwork The inks used for printing should be scuff-proof and rub resistant. Cartons should pass the test when checked on scuff-proof tester. Banded in bundles of 100 nos. and such 10 bundles wrapped in brown paper clearly marked with item name, quantity and supplied by. Storage: Protect from light and moisture at a temperature < 30°C.



Table 2.25 Specifications for BOPP Tape (Printed Self Adhesive Tape)

Sr. No. Tests Specification 1. Description

Transparent self-adhesive BOPP tape printed as per approved text and design in blue color.

2. Dimension: i) Width ii) Thickness of BOPP iii) Total Thickness

63 ± 1 mm 25-30 microns 50-55 microns

3. Grammage 50 g ± 10% 4. 5. 6. 7. 8.

Core Diameter Internal Adhesive Adhesion test Supply Storage

75 ± 1 mm Should be uniform, printed surface should pass tape test. Seal the flaps in length on corrugated fiber box the tape using a hand dispenser or manually. Ensure no wrinkles/air bubbles are formed while pasting and proper pressure should be applied. Leave the box for 10 minutes and try to separate the tape from the end. Tape should separate with fiber tearing. Supplied in rolls of 65 meters packed in a box and clearly marked with item name, quantity and supplied by. Storage: Protect from light and moisture at a temperature < 30°C.

Table 2.26 Specifications for Corrugated Box G -56

Sr. No. Tests Specification

1 Description A Brown Craft Paper Corrugated box G-56 with 5 ply.

2 Width

Length 480 mm ± 5mm

Width 348 mm ± 5mm

Height 347 mm ± 5mm

3 Grammage NLT 630 gm/m2

4 Bursting Strength N.L.T 8 kg/cm2

5 No of ply 5

6 Type of Fluting “B”

7 Joint Stapled/Pasted Should comply

8. Moisture content 7% to 10%.

9 Text Matter As per approved art work.

10 Printing and colour scheme As per approved art work.



2.2.3.3.8 Stability

2.2.3.3.8.1 Stability Summary and Conclusion

Refer to “4.3.6 Stability” in Chapter 4 SUMMARY AND CONCLUSION.



2.2.3.3.8.2 Post-approval Stability Protocol and Stability Commitment

Not applicable

2.2.3.3.8.3 Stability Data

Refer to “3.6 Stability” in Chapter 3 RESULT & DISC USSION.

2.2.3.4 APPENDICES

2.2.3.4.1 Facilities and Equipment

Attached

2.2.3.4.2 Adventitious Agents Safety Evaluation

Not applicable

2.2.3.4.3 Excipients

Not applicable

2.2.3.5 Module 3.2.R

Regional Information for EU

Process Validation Scheme for the Drug Product

Provided in “2.2.3.3.3.5 Process Validation and/or Evaluation”

Medical Device

Not applicable

• Certificate(s) of Suitability

ASMF – Information about Drug substance needed for open part is already provided

in Annexure 2 as “DMF (Open Part).

• Medicinal products containing or using in the manufacturing process materials

of animal and/or human origin.

BSE free certificate from manufacturer of Capsule sheel is provided and attached in

“Annexure 1”

Literature References: Refer to “5. REFERENCES”



2.2.4 Module 4: Nonclinical Study Reports (Public Assessment Report,

Flurbiprofen 2012)

The application was submitted as per Article 10.3 of Directive 2001/83/EC, as amended

No Nonclinical data provided with these types of applications and also not required for

the applications of this type.

Safety

No new data was submitted and not such data are required for this application.

The expected adverse events are listed in the SmPC and were relevant with the

already patented product.

Refer to “Disclaimer & Limitation”



2.2.5 Module 5 Clinical Study Reports (Public Assessment Report, Flurbiprofen

2012)

Not applicable

These applications were submitted as Hybrid applications as per the article 10(3) of

Directive 2001/83/EC).

No Clinical data had been supplied with these applications and no data are required for

the applications of this type.

No new bioequivalence / bioavailability study was submitted. Although, it was

referenced from a previous study conducted with same strength but with different

dosage form-Tablet (Stablon) of the product. This reference product was considered

appropriate for comparision as the proposed product is an oral Capsule.

Efficacy

No new data was submitted with this application.

Refer to “Disclaimer & Limitation”



2.3 Preparation of Dossier in CTD Format for BRUTINE (Tianeptine Sodium

Capsules 12.5 mg) for Russia.

Part 1: Administrative documents:

Application form: Refer to Annexure 1 “Application form Russia”

Find attached documents like Manufacturing License, CPP, WHO-GMP as

attachment “Annexure 1”

Other Part of Dossier is same as U.K dossier, Please refer “2.2 PREPARATION

OF DOSSIER IN EU-CTD FORMAT FOR BRUTINE (TIANEPTINE SODIUM

CAPSULES 12.5 MG) FOR U.K.”



2.4 Preparation of Dossier in CTD format for Tianeptine Sodium Capsules 12.5

mg for US.

MODULE 1 ADMINISTRATIVE INFORMATION

Refer to “Module 1 US” in Annexure 1

Other Part of Dossier is same as U.K dossier, Please refer “2.2 Preparation of

Dossier in EU-CTD format for BRUTINE (Tianeptine Sodium Capsules 12.5 mg)

for U.K.”

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