ANTI-ALLERGIC AFLUTICASONE NASAL

SPRAY

Prepared &Presented by :K. MondalM. Pharma

Fluticasone propionateFluticasone propionate, is a synthetic

corticosteroid drug

Fluticasone propionate, a medium-potency synthetic corticosteroid, is used topically to relieve inflammatory and pruritic symptoms

of dermatoses, intranasally to manage symptoms of allergic and non-allergic rhinitis,

and orally for the treatment of asthma.

Some taxonomy and property as follows:

Chemical Formula C25H31F3O5S Molecular Weight 500.57 Classes Steroids and Steroid Derivatives Half life 10 hours State White to off-white crystalline solid powder Melting point 272-273o C water solubility 0.51 mg/L (insoluble) Soluble in Ethanol pH 7.5 - 9.5 Protein binding 91% Volume of distribution 2.3 to 16.7 L/kg Clearance 1093 mL/min   Categories Anti-inflammatory Agents Adrenergic Agents Dermatologic Agents Bronchodilator Agents Anti-Allergic Agents

CLINICAL PHARMACOLOGYMechanism of Action

PharmacokineticsAbsorptionDistribution Metabolism EliminationPharmacodynamics

PLAN OF WORK Fluticasone Nasal Spray, 50 mcg is an aqueous suspension of microfine fluticasone propionate for topical administration to the nasal mucosa by means of a metering, atomizing spray pump.

PRODUCT DETAILSProduct Name Fluticasone Nasal Spray BP (50 mcg per Actuation)

Generic Name Fluticasone Propionet Nasal Spray BP (50 mcg per Actuation)

Shelf Life 24 Months(Proposed)Half life 10 hoursPrimary Pack 15 g SuspensionStorage   Store at temperature between 15⁰ -

30⁰ C. Do not freeze. Protect from light.Label Claim Each spray delivers:

Fluticasone Propionate BP 50 mcg Composition: Fluticasone Propionate

BP…………………..…..0.05%w/w Benzalkonium chloride BP (as preservative)...

….0.05%w/w Excipients……………………………………….q.s

Item no. Ingredient Quantity/Batch in Kg

Grade Function

1. Fluticasone Propionate*(Micronized)

0.020 BPActive

2. Dextrose anhydrous 3.000 USP

Tonicity agent

3. MCC and CMC Sodium(Avicel RC591)

0.50 BPSuspending agent

4. Polysorbate 80(Super refined Tween 80)

0.015 BP

Surfactant

5. Benzalkonium Chloride 0.020 BP

Preservative

6. Disodium Edetate 0.002 BP

pH Stabilizer

7. Water for injection qs to 100% BP

Vehicle

8. Sodium hydroxide# 0.01 BP

For pH adjustment

Ingredients list

Sr. No.

Equipment Name

1. Jacketed Manufacturing vessel 50 liter(for cooling WFI)

2. Jacketed Manufacturing vessel 10 liter(for preparation of Dextrose solution)

3. Manufacturing vessel with homogenizer 40 liter(for preparation of polymer suspension phase)

4. SS container 10,2/5, 1 liter

5. Cartridge Filter Assembly with 0.2 micron filter

8. Conical Sieve 200#

9. Sieve 40#

10. Remi Stirrer

11. Float tank 150 liter with stirrer (for storage and holding final suspension)filter

12. Air Jet Cleaning Machine

13. Automatic Four Head Filling Machine

14. Automatic Four Head Crimping Machine

15. Leak Test Apparatus

16. Remi Homogenizer

Equipment details:

Manufacturing process:Preparation of dextrose solution.

Preparation of polymer suspension phase.

Preparation of drug suspension phase.

Mixing of drug suspension phase and polymer suspension phase.

Preparation of Benzalkonium chloride solution.

Mixing of Benzalkonium chloride solution and polymer drug suspension phase.

Preparation of Disodium edetate solution.

Mixing of Disodium edetate solution and polymer drug suspension phase.

PH measurement.

Final weight and adjustment and mixing.

Filtration.

Addition In- House Test1. pH 5.0 to 7.0

2. Osmolality 250-350 mOsm

3. Viscosity in cPs By Brookfield viscometer 30 to 130 cPs

4. Minimum fill (Net content) Mean NLT 15.0gOut of 10 containers

5. Weight per ml Between 0.950 to 1.050

6. No. of delivery per container NLT 120 dose.

7. Shot weight(pump delivery) Individual : 85.0-115.0 mgMean : 90.0-110.0 mg

8. Particle size by Microscopy 90% particle below 10µm and 100.0% particle below 30µm.

9. Preservative contentContent of Benzalkonium chloride

80.0% to 120.0 amount of LC

11. Particulate Matter No black particle Should be present.

CRITICAL PROCESS PARAMETERS:-Process / Parameters Limit Environment conditions Relative HumidityTemperature :

Below 55%Between 21-25°C

Preparation of DextroseSolution:Mixing timeFrequency of agitator Temperature of filtered Dextrose solution

:Record the timeRecord the frequency30oC – 50oC

Preparation of polymer suspension phase:Avicel RC591addition timeRPMTemperature of Dextrose solution

:

20-30 minutes

2000-2800 RPM

30oC – 50oC

Preparation of Drug suspension Phase:Mixing time

Mixing RPM: 30 minutes

500-1500 RPM

Process / Parameters Limit

Mixing of drug suspension and polymer suspension phase: Mixing time

Mixing RPM

:5-15 minutes

2000-2800 RPM

Preparation of Benzalkonium chloride Solution:Mixing timeMixing RPMTemperature of solution

:Record the timeRecord the RPMRecord the Temperature

Mixing of Benzalkonium chloride solution and polymer phase:RPMMixing time

:1500-2800 RPM

2-5 minutes

Preparation of Disodium edetate solution phase:RPMMixing time

: Record the RPMRecord the time

Mixing of Disodium edetate solution and Polymer suspension phase:RPMMixing time

: 1500-2800 RPM 15-30 minutes

Final mixing before filtration:RPMMixing time

: 1500-2800 RPM 15-30 minutes

pH of suspension : 6.00-7.00

Final mixing after filtration:RPMMixing time

: 200-300 RPM20-30 minutes

Filling:Fill WeightLeak TestNo. of Spray per vial

:

Limit : 15.0 g – 15.6 gThere should not be any leakageNLT 120 sprays

Stage Sampling Location & Quantity Test

Manufacturig stage(Before filtration from 40 litre manufacturing vessel)

10 ml sample each from top, middle and bottom after 15, 22 and 30 minutes.

Assay 95.0 to 115.0 % Preservative Content 80.0 to 120.0 %

200 ml Composite Sample (of top, middle and bottom) after 15, 22 and 30 minutes.

Assay 95.0 to 115.0 % Preservative content 80.0 to 120.0 %

pH 5.00 to 7.00

Osmolality 250 – 350 mOsm

Weight per ml 0.950 to 1.050 g/mlViscosity in cPs 30 to 130 cPs

Manufacturig Stage (After filtration from Float Tank)

10 ml sample each from top, middle and bottom after 15, 22 and 30 minutes.

Description -White to off white translucent thick suspension free from lumps.

200 ml Composite Sample (of top, middle and bottom) after 15, 22 and 30 minutes.

As per SFG specification

SAMPELING

PROCEDURE

 DISCUSSION

The samples of all the three batches should be subjected for stability.

A protocol and report should be documented. Any Incidents/Deviations from the protocol related to manufacturing process & packing process, equipments used, sampling, in-process controls and analytical methods should be authorized and documented in the batch manufacturing and packing record as well as the validation report.

Referances:

U.S. Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER) May 1999 

Revision Bulletin Official February 1, 2011

FDA, (CBER), Validation of Procedures for Processing of Human Tissues Intended for Transplantation, guidance for industry, May 2002.

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