Ophthalmic drug delivery system

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SEMINAR ON OPHTHALMIC DOSAGE FORM : 

SEMINAR ON OPHTHALMIC DOSAGE FORM Presented By:- MUKESH SHARMA M.PHARMA

CONTENTS …. : 

CONTENTS …. 1. INTRODUCTION 1 Definition 2 Types of ophthalmic dosage forms 2. MANUFACTURING CONSIDERATION 1 Environment 2 Personnel requirements 3 Equipments 4 Raw material 5 PAT (process analytical technology) 3. MANUFACTURING OPERATION 1 Area requirement 2 Equipments as per schedule M 3 Process flow chart 4 Simpler flow diagram showing arrangement of different area 5 Manufacturing operation of ophthalmic preparations 6 Packaging 4. Ophthalmic preparation characteristics 5. Quality control tests 6. Documentation 7. References

1. INTRODUCTION : 

1. INTRODUCTION 1. DEFINITION: “ophthalmic preparation are sterile Product that are intended to be applied to the eyelids or placed in the space between the eyelids and the eyeball. Ophthalmic preparation are similar to parenteral dosage forms in their requirement for: 1.Sterility 2.Tonicity (osmotic pressure) 3.Preservation 4.Tissue compatibility 5.Particulate matter 6.Avoidance of pyrogens (not as critical as other parenteral products) 7.Suitable packaging

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TYPES/CLASSES OF OPHTHALMIC DOSAGE FORMS :

2. Manufacturing considerations in design of ophthalmic production facility: : 

2. Manufacturing considerations in design of ophthalmic production facility: Because the official compendia require all topically administered ophthalmic medication to be sterile, the manufacturer of such medication must consider all the current concepts in the manufacture of sterile pharmaceuticals in designing a manufacturing procedure for sterile ophthalmic pharmaceutical products. The manufacture of sterile ophthalmic pharmaceutical products requires special attention to: 1. Environment 2. Personnel Requirements 3. Equipments 4. Raw Material 5. PAT (Process Analytical Technology)

1 ENVIRONMENT: : 

1 ENVIRONMENT: Current U.S. std. for GMP provide for the use of specially designed environmentally controlled areas for the manufacturing of sterile large & small volume injections for terminal sterilization.

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Note : Grade A and B correspond to with class 100 Grade C correspond to with class 10000 Grade D correspond to with class 100000 (Class 100 : NMT 100 particles /ft3 of air of diameter of 0.5 µm or larger)

a)Walls, ceiling & floors Constructed of material →hard ,non flaking , smooth & unaffected by surface cleaning agents & disinfectants. For that epoxy or vinyl ceiling coat for finishing avoids holes on surface.b)All lights & windows Should be flush mounted in walls & ceilings for ease of cleaning & disinfectionc)U.V. lamps May be provided in recessed , flush mounted fixtures to maintain surface disinfection.(difficult to validate)d)Separate entrance For both personnel & equipments (specially designed air locks maintained at negative pressure relative to aseptic manufacturing area & at positive pressure relative to non-environmentally controlled area. : 

a)Walls, ceiling & floors Constructed of material →hard ,non flaking , smooth & unaffected by surface cleaning agents & disinfectants. For that epoxy or vinyl ceiling coat for finishing avoids holes on surface.b)All lights & windows Should be flush mounted in walls & ceilings for ease of cleaning & disinfectionc)U.V. lamps May be provided in recessed , flush mounted fixtures to maintain surface disinfection.(difficult to validate)d)Separate entrance For both personnel & equipments (specially designed air locks maintained at negative pressure relative to aseptic manufacturing area & at positive pressure relative to non-environmentally controlled area.

2 PERSONNEL REQUIREMENTS : 

2 PERSONNEL REQUIREMENTS No. of workers should kept to a minimum. Training of personal Personal hygiene:- All employees should be in good health, Subjected to Physical examination, Understood their responsibilities to report own illness like cold, a sore throat, or other infection.

3 EQUIPMENTS : : 

3 EQUIPMENTS : All tanks , valves , pipings →best available grade of corrosion-resistant stainless steel.(S.S. type 304 or 316) is preferable. All the product contact surface should be finished either mechanically or by electro polishing to provide a surface as free as possible from scratches or defects. For the equipment that will reside in aseptic filling areas such as filling & capping machine, care should be taken in their design to yield equipment as free as possible from particle generating mechanisms.

4 RAW MATERIAL : : 

4 RAW MATERIAL : Highest quality In most sterile dosage form largest proportion is of “water” which is main source of contamination. For the preparation intended for parenteral administration ,U.S.P. xxii requires the use of → WFI → SWFI → BWFI All of above are produced by distillation or reverse osmosis & kept in circulation at relatively high temperature up to 800c, or alternatively its disposal at every 24 hrs, in all S.S. equipment of highest attainable , corrosion resistant quality

5 PAT (PROCESS ANALYTICAL TECHNOLOGY) : 

5 PAT (PROCESS ANALYTICAL TECHNOLOGY) The product manufacturing & quality control is governed by the c GMP regulation. For better output ,PAT is to be followed. “System for designing ,analyzing & controlling manufacturing through timely measurements (during process) of critical quality & performance attribute of raw & in process material & process with a goal of ensuring final product quality. ”

3. Manufacturing operation : 

3. Manufacturing operation A. AREA REQUIREMENT Minimum of 10 m2 → for ancillary area Minimum of 25 m2 → for basic installation Manufacturing & filling shall be carried out in air –conditioned areas under aseptic condition The rooms shall be further dehumidified as considered necessary if preparation containing antibiotics are manufactured.

B. LIST OF EQUIPMETNS AS PER SCHEDULE M : 

B. LIST OF EQUIPMETNS AS PER SCHEDULE M For Ophthalmic solutions & suspensions Jacketed kettle/stainless steel tanks(steam gases electrically heated) Mixing & storage tanks of stainless steel/planetary mixer Sintered glass funnel , Seitz filter or filter candle(preferably cartridge & membrane filter) Liquid filling equipments (semi automatic & automatic filling machine) For Ophthalmic Ointments Colloid mill/ointment mill Tube filling & crimping equipment(semi automatic & automatic filling machine) Tube cleaning equipments (air jet type) Tube washing & drying equipments

EQUIPMETNS : 

EQUIPMETNS Thermostatically controlled Hot air oven. (preferably double ended) Autoclave (preferably ventilator autoclave) Air conditioning & dehumidification arrangement Laminar air flow units. Automatic vial washing machine Vial drying oven Distillation unit Packaging & labeling Inspection machine

Multicolumn distillation unit : 

Multicolumn distillation unit It consist of specially designed columns which make optimum use of the principles of inter stage heat exchange (Multi effect distillation method) to produce pure pyrogen free sterile distilled water for injectables as per IP/BP specification.

Mixing & Storage Tanks : 

Mixing & Storage Tanks

SS Tank with Stirrer / Manufacturing vessel : 

SS Tank with Stirrer / Manufacturing vessel With SS steam jacketed & insulation with SS cladding. Different type of stirrer (paddle/ anchor/propeller) available. Electric heating also possible for small scale.

Jacketed kettle / SS Tank (steam, gas or electrically heated) : 

Jacketed kettle / SS Tank (steam, gas or electrically heated)

Triple roller mill : 

Triple roller mill It’s used for grinding ointment, pastes, paints, etc. Side scrappers moves up and down with compression spring and knob to secure appropriate working pressure

ROTARY TUBE FILLING MACHINE : 

ROTARY TUBE FILLING MACHINE Rotary tube filling & closing (crimping) machine with coding device. Speed :- 30 to 80 TPM Another TWIN HEAD machine also available in market.

Vial filling machine : 

Vial filling machine . Suitable for 2 ml to 30 ml vials Output Speed up to 120 VPM

Fully Automatic Labeling Machine SBSL-120F : 

Fully Automatic Labeling Machine SBSL-120F Fully Automatic, User Friendly, Sticker (Self-Adhesive) Labeling Machine Model SBSL-120F, Suitable to apply accurate Labels on Double Side (Front & Back) of Flat/Oval/Square shaped products .

Manual Vial & Bottle Inspection machine : 

Manual Vial & Bottle Inspection machine

Automatic Packaging Conveyor : 

Automatic Packaging Conveyor Conveyor belt is used as a PVC coated canvas belt / endless rubberised belt. The Reduction Gear Box provides jerk less & noiseless performance for long time.

STEAM STERILIZER or AUTOCLAVE : 

STEAM STERILIZER or AUTOCLAVE used for sterilizing • Solutions in glass containers like ampoules, vials, glass bottles etc.

C. PROCESS FLOW CHART : 

C. PROCESS FLOW CHART

D. FLOW DIAGRAM SHOWING ARRANGEMENT OF DIFFERENT AREA : 

D. FLOW DIAGRAM SHOWING ARRANGEMENT OF DIFFERENT AREA OPHTHALMIC– MANUFACTURING PLANT LAYOUT

E. MANUFACTURING OPERATION OF OPHTHALMIC PREPARATIONS : 

E. MANUFACTURING OPERATION OF OPHTHALMIC PREPARATIONS Divided in to two separate areas:- 1. Ophthalmic preparation in glass container. 2. Ophthalmic preparation in plastic container.

1. OPHTHALMIC PREPARATIONS IN GLASS CONTAINER : 

1. OPHTHALMIC PREPARATIONS IN GLASS CONTAINER

2. OPHTHALMIC PREPARATIONS IN PLASTIC CONTAINER : 

2. OPHTHALMIC PREPARATIONS IN PLASTIC CONTAINER FORM-FILL-SEAL TECHNOLOGY OR BLOW-FILL-SEAL TECHNOLOGY SIMPLE FILL-SEAL TECHNOLOGY Form-Fill-Seal units are specially built automated machines in which through one continuous operation, container's are formed from thermoplastic granules, filled and then sealed . Fill-seal units are machines in which containers are molded (preformed) in separate clean rooms by non continuous operation then filling & sealing is carried out.

FORM-FILL-SEAL OR BLOW-FILL-SEAL MACHINE : 

FORM-FILL-SEAL OR BLOW-FILL-SEAL MACHINE

PACKAGING : 

PACKAGING Plastic containers → ease of use → little breakage → less spoilage Large volume intraocular solutions of 250ml &500ml have been packaged in glass, but even this parenteral type products are beginning to be packaged in specially fabricated polyethylene/polypropylene containers or flexible bags. Type 1 glass vials with appropriate stoppers are used for intraocular ophthalmic products administered by injection. Different ophthalmic cap color coding are given by the cooperative efforts of FDA , the ophthalmic industry & academy of ophthalmology .

OPHTHALMIC CAP COLOR CODING : 

OPHTHALMIC CAP COLOR CODING

4. Ophthalmic preparation characteristics : 

4. Ophthalmic preparation characteristics 1) Clarity: Ophthalmic solutions by definition contain no undissolved ingredients & are essentially free from foreign particles. But solution containing viscosity imparting polymers diminish clarity. In these situation it may be important to define both the visual clarity of the product & monitor its stability. The E.P. describes visual clarity & recommended standards that can be used for clarity specifications.

2) Stability: : 

2) Stability: The stability of a drug in an ophthalmic product depends on a number of factors including the chemical nature of the drug substance, product pH, method of preparation (particularly temperature exposure), solution additives, &type of packaging. Pharmaceutical manufacturers conduct comprehensive stability programs to assure the assigned expiration dating for each product. The stability of the preservative is also monitored by chemical means or by actual challenge of the preservative efficacy with appropriate test organisms.

3) Sterility: : 

3) Sterility: The important property of ophthalmic formulations is that they must be sterile. The USP-22 listed five methods of achieving sterility. a) Steam sterilization at 1210c b) Dry heat sterilization c) Gas sterilization d) Sterilization using ionizing radiation e) Sterilization by filtration The method chosen is often depends on resistance of the active ingredient & the resultant product to heat & to the type of packaging(i.e. container) used.

4) pH adjustment & buffers: : 

4) pH adjustment & buffers: The adjustment of ophthalmic solution pH by the appropriate choice of a buffer is one of the most important considerations. Ideally, ophthalmic preparations should be formulated at a pH equivalent to the tear fluid value of 7.4 5) Tonicity: Tonicity refers to the osmotic pressure exerted by salts in aqueous solution. An ophthalmic solution is isotonic with another solution when the magnitudes of the colligative properties of the solutions are equal.

5. QUALITY CONTROL SPECIFICATION : 

5. QUALITY CONTROL SPECIFICATION 1) Raw material 2) packing material - Description - Compatibility - Moisture content - Stability - Assay of ingredient - Purity 3) In process Product a) Mixing b) Filling - Assay - weight variation - Grittiness - content uniformity - Viscosity - Density - pH

4) Product Specification : 

4) Product Specification a) Microbial specification - limit for total microbial count - Absence of specific microorganism as per pharmacopoeia b) Chemical specification - pH - Content uniformity - Chemical potency c) Physical specification - clarity - Particle size - Density - Viscosity

Compendial requirements for semi-solid product : 

Compendial requirements for semi-solid product Semi-solid product must meet USP tests for, 1) Microbial content 2) Minimum fill 3) Packing 4) Storage 5) Labeling Ophthalmic ointment must meet to the, - USP sterility tests - Test for metal particles USP directs the ophthalmic ointment must be packed in collapsible tube with narrow tip.

6. Documentation : 

6. Documentation Master formula records Batch formula records Equipment & containers records Filtration & filling records Batch Packaging & Labeling Records IPQC records

1. Master formula records : 

1. Master formula records Name of the product________________________________________ Name and Weight of API ____________________________________ Name and Weight of Ingredient _______________________________ Description of equipment ____________________________________ Statement of theoretical yield_________________________________ Process and packaging procedure_____________________________ A description of container____________________________________ closure and packaging material _______________________________ In process control during processing ___________________________ In process control during packaging____________________________ Precaution to be taken______________________________________

Environmental controlProduct_______________________________ lot no.__________________________Room________________________________ date exposed_____________________Media____________________ : 

Environmental controlProduct_______________________________ lot no.__________________________Room________________________________ date exposed_____________________Media____________________

2. Batch Manufacturing Records : 

2. Batch Manufacturing Records Name of the company:-_______________________________________ Address:-___________________________________________________ Name of the product _________________________________________ Active pharmaceutical ingredient ______________________________ M F R No. __________________________________________________ Batch No._____________________ Batch size ____________________ Mfg. date _____________________Date of expiry_________________ Requisition slip

3. Equipment & containers records : 

3. Equipment & containers records Description of containers _______________________________________ Q/C report of container ________________________________________ Date ________________________ Equipment used__________________ Cleaning agent used ___________________________________________ Cycle of washing: _____________________________________________ Sign. Of officer_______________________________________________ If sterilized by dry heat or autoclave:

4. Filtration & filling records : 

4. Filtration & filling records Equipments used for filtration ___________________________________ Date__________________________ Time_________________________ Result of test or analysis of solution_______________________________ Equipment used for filling_______________________________________ Date________________________________________________________ Sign. Of officer_______________________________________________

5.Batch Packaging & Labeling Records : 

5.Batch Packaging & Labeling Records Product name_______________________ Batch no _______________________ Strength___________________________ batch size ______________________ Category___________________________ mfg date _______________________ MFG no____________________________ exp date _______________________ Batch Packaging & Labeling Records Description of packaging______________________________________________ Pre-coding of labels & printed packaging materials, examined & verified by _______________________________________________ No. of pre-coded ____________________________________________________ (ii). Printed packaging material received __________________________________ Result of bulk finished products ________________________________________ Sign. Of officer _____________________________________________________ Reconciliation of labeling and packaging material Quantity of material received___________________________________________ Quantity of material destroyed__________________________________________ Quantity of material used _____________________________________________ Quantity of material returned___________________________________________ Date of release____________________ quantity release____________________ Signature of supervisor _______________

6. IPQC records : 

6. IPQC records 1. Visual inspection: Description ________________________________________________________ Total no of filled, sealed & sterilized containers rejected __________________ Nature of defects ____________________________________________________ Name of worker who examined: (i). ________________________________________________ (ii). _______________________________________________ (ii). _______________________________________________

FDA APPROVED DRUGS FOR OPHTHALMOLOGY : 

FDA APPROVED DRUGS FOR OPHTHALMOLOGY * Restasis (Cyclosporine Ophthalmic emulsion): In treatment of low tear production. * Lumigan(Bimatoplast Ophthalmic Solution): For the reduction of intra ocular pressure in open-angle glaucoma. * Travatan(Travoplast Ophthalmic Solution) * Betaxon: For lowering intraocular pressure. * Quixin: For bacterial conjuctivitis. * Rescula: (Iso propyl) Ophthalmic Solution. In treatment of open-angle glaucoma. * Alamast: Potassium Ophthalmic Solution. * ZADITOR:For the prevention of itching of eye. * Alrex: For the treatment of allegic conjuctivitis. * Cosopit: For the treatment of glaucoma.

7. REFERENCES : 

7. REFERENCES Remington-The science and practice of pharmacy 21st edition volume I 1.Controlled drug delivery by N.K.Jain, Page No.(82,85,86,92,94-96) 2. Controlled drug delivery by Roop K.Khar & S.P.Vyas, Page No.(384-397,399,403) Modern pharmaceutics edited by Gilbert S. Banker volume 72 Pharmaceutical dosage forms parenteral medications volume 2 edited by Kenneth E. Avis, Leon Lachman Pharmaceutical dosage forms Disperse systems volume2 http:// www.optisgroup.com/TechnologyEyegate.htm www. Pharmamachine.com

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