OPHTHALMIC PRODUCTS DEPT. OF PHARMACEUTICS,

CONTENTS: 1.INTRODUCTION. Definition. ideal properties of ophthalmic preparation. Types of ophthalmic dosage forms 2.MANUFACTURING OPERATION i . Area requirement. ii. Equipments as per schedule M. iii. Packaging. iv. Process flow chart. 3.FACTORS AFFECTING OPHTHALMIC STABILITY. 4. QUALITY CONTROL TESTS. 5. DOCUMENTATION. 6. REFERENCES

OPHTHALMICS PRODUCTS :   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.

Ideal properties for ophthalmic preparation.: Sterility. (Avoidance of pyrogens ) Preservation. Tissue compatibility. Suitable packaging. Must be isotonic with lacrymical fluids. should have P H approx 7.4. viscosity.  

Types of ophthalmic dosage forms.: 1) Solutions- ADVANTAGES -convenience DISADVANTAGES - rapid corneal elimination. - loss of drug by drainage. - No sustained action 2) Suspensions- - patient compliance - slow dissolution - loss of both solution & suspended solid.

3.EMULSIONS: Advantages: prolonged release Disadvantages: Patient non compliance. Blurred vision. 4. OINTMENTS: improved drug stability Disadvantage: poor patient compliance

5.GELS: 6.Erodible inserts: Advantages: -comfortable -less blurred vision than ointments. Disadvantage: -no rate control on diffusion. 6.Erodible inserts: -effective -need only to be introduced into eye, and not removed. -patient discomfort -occasional product.

7.Non-erodible inserts: Advantages: -prolonged delivery -controlled rate of release. Disadvantage: -tissue fibrosis -patient discomfort -irritation to eye.

FORMULATION 1. Vehicles: There are two types of vehicles which are: i. Aqueous vehicles:- e.g. Water is used as vehicle because water is tolerated well by the body ii. Non-aqueous vehicles:- e.g. Oils and Alcohols, such as, fixed oils, almond oil,, ethyl alcohol, propylele glycol. 2. Adjuvants: Thickening agents - methyl cellulose. - carboxy methyl cellulose. - polyvinyl alcohol. - polyethylene glycol. Buffers - Boric acid. - Sodium acid phosphate. - Sodium citrate.  

Anti-oxidants.: They are added to provide protection from Oxidation. e.g - Sodium metabisulphite - Sodium thiosulphate - Thiourea . - ascorbic acid. Wetting agents. e.g. Polysorbate 20 Polysorbate 80

Tonicity Adjusting Agents. Commonly used tonicity adjusting agents are Nacl , Kcl , buffer salts, dextrose,glycerin , propylene glycol and mannitol . Preservatives. - Benzalkonium chloride - Phenylmercuric acetate - Phenylemercuric nitrate

VARIOUS FACTORS AFFECTING STABILITY OF FORMULATIONS Temperature. pH. Excipients. Oxidation. Light. packaging.

Manufacturing considerations: Manufacturing Environment: The environment should be sterile and particle-free through: - Laminar-flow should be used throughout the manufacturing area. Relative humidity controlled to between 40 and 60%. Walls, ceilings and floors should be constructed of materials that are hard, non flaking, and non-affected by surface cleaners or disinfectants.  

Manufacturing Environment:

FLOW DIAGRAM SHOWING ARRANGEMENT OF DIFFERENT AREA RAW MATERIAL PREPARATION AREA CLEAN UP ASEPTIC AREA STERILIZATTION QUARANTINE AREA PACKAGING AREA STORAGE AREA

PROCESS FLOW CHART WFI INGREDIENTS VEHICLES ADDITIVES EQUIPMENTS CONTAINERS CLOSURES COMPOUNDING FILTRATION STERILIZATION WASHING ASEPTIC FILLING AND SEALING INSPECTION INPROCESS QC PACKAGING MATERIAL PACKAGING LABELLING FINISHED PRODUCTS STORAGE PRODUCT OUTPUT WFI PROCESS FLOW CHART

MANUFACTURING OPERATION 1) AREA REQUIREMENT Minimum of 10 m 2 → for ancillary area. Minimum of 25 m 2 → for basic installation. Areas must meet the requirements of class 1,00,000 space in all areas where open containers and closures are not exposed or filling and capping operations are not taking place. Manufacturing & filling shall be carried out in air –conditioned areas under aseptic condition (class 100). The rooms shall be further dehumidified as considered necessary if preparation containing antibiotics are manufactured .

Equipments as per schedule M.: For Ophthalmic solutions & suspensions 1) Jacketed kettle/stainless steel tanks(steam gases electrically heated). 2) Mixing & storage tanks of stainless steel/planetary mixer. 3) Sintered glass funnel. 4) Liquid filling equipments (semi automatic & automatic filling machine).  For Ophthalmic Ointments 1)Colloid mill/ointment mill. 2) Tube filling & crimping equipment(semi automatic & automatic filling machine). 3) Tube cleaning equipments (air jet type). 4) Tube washing & drying equipments.

EQUIPMETNS 1)Thermostatically controlled Hot air oven. (preferably double ended) 2) Autoclave. 3) Air conditioning & dehumidification arrangement. 4) Laminar air flow units. 6) Automatic vial washing machine. 7) Vial drying oven. 8) Distillation unit. 9) Packaging & labelling. 10) Inspection machine.

Multicolumn distillation unit: specially designed columns . (Principle inter stage heat exchange). stainless steal & Teflon. Spiral baffle system. ( centrifugal force)  

SS Tank with Stirrer Manufacturing vessel: -Available from 50 ltrs to 10,000 ltrs. -With SS steam jacketed & insulation with SS cladding. -Different type of stirrer (paddle/ anchor/propeller) available. -Electric heating also possible for small scale.  

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 -Tube holders are of spring loaded type to take care of any tube diameter variation. - Fill accuracy : + 98.8 %. -Useful in filling paste, lotion, cream, gums, etc. -Accurate tail cutting arrangement. Audio alarm. Output up to 50 - 55 Tubes/minute. Can fill from 3 Grams to 500 Grams. GMP model contact parts SS 304 / SS 316 (As per customer requirement). Power consumption 0.75 HP, 230 Volts / 415 Volts. - Overload c protection. memory to indicate the number of filled tubes.  

Vial filling machine : Suitable for 2 ml to 30 ml vials STEAM STERILIZER or AUTOCLAVE: Vial filling machine : Suitable for 2 ml to 30 ml vials - Output Speed up to 120 VPM

PACKAGING: Plastic containers → ease of use. → little breakage. → less spoilage. Large volume intraocular solutions of 250ml &500ml have been packaged in glass. Type 1 glass vials with appropriate stoppers are used for intraocular ophthalmic products administered by injection. Different ophthalmic cap colour coding are given by the FDA.

OPHTHALMIC CAP COLOR CODING : Colour Pharmaceutical class Yellow or blue Beta blockers Gray Non steroidal Pink Steroidal Brown Anti infective Orange Carbonic anhydrase inhibitors Turquoise Prostaglandins Red Mydriatics Green Mitotic color Pharmaceutical class Yellow or blue Beta blockers Gray Non steroidal pink steroidal brown Anti infective orange Carbonic anhydrase inhibitors red mydriatics green mitotic

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 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.

Evaluation of final product: Evaluation is the test of the finished ophthlmic products are free from of micro organism or not. Evaluation of the opthalmic products is done by following tests. 1. Sterility test 2. Clarity test 3. Leaker test 4. Metal particles in ophthalmic ointments

Sterility Test: Two basic methods for sterility testing. Direct inoculation method : Involves the direct introduction of product test samples in to culture media. Membrane filtration method: Involves filtering test samples through membrane filter, washing the filter with fluid to remove inhibitory property and transferring the membrane aseptically to appropriate culture media. Detection of contamination using two culture media - A. Soybean- Casein digest medium incubated at 20o to 250C B. Fluid thioglycollate medium incubate at 300 to 350C on 7 days

Clarity test: Ophthalmic solutions by definition contains no undissolved ingredients and are essentially free from foreign particles. Visual inspection- under a good light , baffled against reflection in to the eyes, and viewed against a black and white background, with the content set in motion with a swirling action . Instrumental method utilizing the principle of light scattering, light absorption and electrical resistance to obtain particle count and size distribution-destrution of product units- only for quality control testing. Instrumental method utilizing video image projection detects moving particles without destrution of product units- used for inline detection.

Leaker test: Select 10tubes of the Ointment with seals applied when specified. Thoroughly clean and dry the exterior surfaces of each tube with an absorbent cloth. Place the tubes in a horizontal position on a sheet of absorbent blotting paper in an oven maintained at a temperature of 600±30for 8hours. No significant leakage occurs during or at the completion of the test. If leakage is observed from one, but not more than one, of the tubes, repeat the test with 20 additional tubes of the Ointment. The requirement is met if no leakage is observed from the first 10 tubes tested, or if leakage is observed from not more than one of 30 tubes tested.  

Metal particles in ophthalmic ointments Extrude, as completely as practicable,the contents of 10 tubes individually into separate,clear,flat-bottom,60-mm Petri dishes that are free from scratches. Cover the dishes, and heat at 85 for 2 hours, increasing the temperature slightly if necessary to ensure that a fully fluid state is obtained. Taking precautions against disturbing the melted sample, allow each to cool to room temperature and to solidify. Remove the covers, and invert each Petri dish on the stage of a suitable microscope adjusted to furnish 30 times magnification and equipped with an eye-piece micrometer disk that has been calibrated at the magnification being used.

Examine the entire bottom of the Petri dish for metal particles. Count the number of metal particles that are 50µm or larger in any dimension The requirements are met if the total number of such particles in all 10tubes does not exceed 50, and if not more than 1tube is found to contain more than 8 such particles. If these results are not obtained, repeat the test on 20additional tubes: The requirements are met if the total number of metal particles that are 50µm or larger in any dimension does not exceed 150in all 30tubes tested, and if not more than 3 of the tubes are found to contain more than 8 such particles each.

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

Master formula records Name of the product________________________________________ Name and Weight of API ____________________________________ Name and Weight of Ingredients _______________________________ 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______________________________________

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 Sr no Ingredients Item code Standards ATR no Label claim Qty required Qty issued  

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 : Articles Date Time when Desired temp. Temp. Time when oven started attained oven switched off

REFERENCES: Remington-The science and practice of pharmacy 21 st edition volume I. Controlled drug delivery by N.K.Jain , Page No.(82,85,86,92,94-96). Indian pharmacopiea , 2007 . vol – 1. Controlled drug delivery by Roop K.Khar & S.P.Vyas , Page No.(384-397,399,403). Modern pharmaceutics edited by Gilbert S. Banker.

THANQ