Seminor on Scale Up Techniques In The Production Of Sterile Products And Ophthalmic Products DEPARTMENT OF PHAEMACEUTICS

INTRODUCTION PILOT PTANT: It is defined as a part of pharmaceutical industry where a lab scale formula is transformed into a product by the development of procedure for manufacturing. It is defined as a part of pharmaceutical industry where a lab scale formula is transformed into a product by the development of procedure for manufacturing. R & D Production R & D Production SCALE UP: It is defined as the art of designing of prototype using the data obtained from the pilot plant. It is defined as the art of designing of prototype using the data obtained from the pilot plant.

Importance of Pilot Plant: Examination of formulae. Review of range of relevant processing equipments. The specification of the raw materials. Production rates. The physical space required. Appropriate records and reports to support GMP.

SCALE UP OF PARENTRAL PRODUCTS para: outside enteron: intestine (i.e. beside the intestine) These are the preparations which are given other than oral routes. Injections: These are  Sterile,  Pyrogen free preparations intended to be administered parenterally (outside alimentary tract).

Scale-up for parenterals

Formulation aspects  Solvent: solvent used for parenteral production is water for injection. solvent used for parenteral production is water for injection. WFI is prepared by distillation or reverse osmosis. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving WFI is prepared by distillation or reverse osmosis. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving Water miscible vehicles: Water miscible vehicles: Ethyl alcohol, PEG, PG Ethyl alcohol, PEG, PG Non aqueous vehicles: Fixed oils Fixed oils

Solubilizing agents used in sterile products include: 1. co-solvents: glycerine, ethanol, sorbitol, etc. 2. Surface active agents: polysorbate 80, polysorbate 20, lecithin. 3. Complexing agents: cyclodextrins etc They act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical, conductance capabilities of the solvent and thus increase the solubility. They act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical, conductance capabilities of the solvent and thus increase the solubility.  Solubilizers: They are used to enhance and maintain the aqueous solubility of poorly water-soluble drugs. They are used to enhance and maintain the aqueous solubility of poorly water-soluble drugs.

 Antimicrobial agents: Added for fungistatic or bacteriostat action or concentration Added for fungistatic or bacteriostat action or concentration Used to prevent the multiplication of micro-organisms Used to prevent the multiplication of micro-organisms Ex.. Ex.. Benzyl alcoholBenzyl alcohol Benzethonium chlorideBenzethonium chloride Methyl parabenMethyl paraben  Preservatives: Multidose containers must have preservatives unless prohibited by monograph. Multidose containers must have preservatives unless prohibited by monograph. Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses. Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses.

 Buffers: They are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum or optimal solubility of the drug in solution. They are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum or optimal solubility of the drug in solution. Exampies:Acetic acid, benzoic acid, citric acid, lactic acid Exampies:Acetic acid, benzoic acid, citric acid, lactic acid  Antioxidants: Antioxidants function by reacting prefentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction. Examples: phenol ( %), m-cresol ( %) etc. Antioxidants function by reacting prefentially with molecular oxygen and minimizing or terminating the free radical auto-oxidation reaction. Examples: phenol ( %), m-cresol ( %) etc.  Chelating agents: Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation. They form a complex which gets dissolved in the solvents. They form a complex which gets dissolved in the solvents.  Examples: Disodium edetate, Disodium calcium edetate Disodium edetate, Disodium calcium edetate

 Stabilizers: As parenterals are available in solution form they are most prone to unstabilize As parenterals are available in solution form they are most prone to unstabilize Used to stabilize the formulation Used to stabilize the formulation Maintain stable Maintain stable  Examples: Creatinine, Glycerin Creatinine, Glycerin  Tonicity- adjusting agents: Used to reduce the pain of injection. Used to reduce the pain of injection. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Buffers may acts as tonicity contributor as well as stabilizers for the pH. Isotonicity depends on permeability of a living semipermaeable membrane Isotonicity depends on permeability of a living semipermaeable membrane Hypotonic : swelling of cells (enlargement)Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction)Hypertonic: shrinking of cells (reduction)  Example: Glycerin,Lactose, Mannitol Glycerin,Lactose, Mannitol

Instrumentation  Mixer  Homogenizer  Filteration assembly  Filling machinery

Mixer/Homogenizer

Bottling/Filling machinery

Sterilization and Depyrogenation  Steam sterilization  Dry-heat sterilization and depyrogenation  Gas and vapour sterilization  Radiation sterilization  Sterilization by filteration

LAY OUT OF PARENTERAL MANUFACTURING AREA

 Clean- up area: Non aseptic area Non aseptic area Free from dust,fibres & micro-organisms Free from dust,fibres & micro-organisms Constructed in such a way that should withstand moisture, steam & detergent Constructed in such a way that should withstand moisture, steam & detergent Ceiling & walls are coated with material to prevent accumulation of dust & micro-organisms Ceiling & walls are coated with material to prevent accumulation of dust & micro-organisms Exhaust fans are fitted to remove heat & humidity Exhaust fans are fitted to remove heat & humidity The area should be kept clean so that to avoid contamination to aseptic area The area should be kept clean so that to avoid contamination to aseptic area The containers & closures are washed & dried in this area. The containers & closures are washed & dried in this area.

 Preparation area: The ingredients are mixed & preparation is prepared for filling The ingredients are mixed & preparation is prepared for filling Not essential that the area is aseptic Not essential that the area is aseptic Strict precaution is taken to prevent contamination from outside Strict precaution is taken to prevent contamination from outside Cabinets & counters: SS Cabinets & counters: SS Ceiling & walls : sealed & painted Ceiling & walls : sealed & painted  Aseptic area: Filtration & filling into final containers & sealing is done Filtration & filling into final containers & sealing is done The entry of outside person is strictly prohibited The entry of outside person is strictly prohibited To maintain sterility, special trained persons are only allowed to enter & work To maintain sterility, special trained persons are only allowed to enter & work Person who worked should wear sterile cloths Person who worked should wear sterile cloths Should be subjected for physical examination to ensure the fitness Should be subjected for physical examination to ensure the fitness Minimum movement should be there in this area Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment

 Cabinets & counters: SS Mechanical equipments : SS Mechanical equipments : SS AIR: AIR: Free from fibres, dust & micro organismsFree from fibres, dust & micro organisms HEPA filters are used which removes particles upto 0.3 micronHEPA filters are used which removes particles upto 0.3 micron Fitted in laminar air flow system, in which air is free from dust & micro organisms flows with uniform velocityFitted in laminar air flow system, in which air is free from dust & micro organisms flows with uniform velocity Air supplied is under positive pressure which prevents particulate contamination from sweepingAir supplied is under positive pressure which prevents particulate contamination from sweeping UV lamps are fitted to maintain sterilityUV lamps are fitted to maintain sterility

 Quarantine area: After filling, sealing & sterilization the products or batch is kept in this area After filling, sealing & sterilization the products or batch is kept in this area The random samples are chosen and given for analysis to QC dept. The random samples are chosen and given for analysis to QC dept. The batch is send to packing after issuing satisfactory reports of analysis from QC The batch is send to packing after issuing satisfactory reports of analysis from QC If any problem is observed in above analysis the decision is to be taken for reprocessing or others.. If any problem is observed in above analysis the decision is to be taken for reprocessing or others..

 Finishing and packaging area: After proper label, the product is given for packing After proper label, the product is given for packing Packing is done to protect the product from external environment Packing is done to protect the product from external environment The ideal Packing is that which protects the product during transportation, storage, shipping & handling. The ideal Packing is that which protects the product during transportation, storage, shipping & handling. The labeled container should be packed in cardboard or plastic containers The labeled container should be packed in cardboard or plastic containers Ampoules should be packed in partitioned boxes. Ampoules should be packed in partitioned boxes.

Opthalmic Solutions Ophthalmic preparations are sterile product that are intended to be applied to the eyelids or placed in the space between eyelids or placed in the space between the eye lids and the eyeball

Ideal property 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 DISADVANTAGES convenience - rapid corneal elimination. - loss of drug by drainage. - No sustained action 2) Suspensions- ADVANTAGES DISADVANTAGES - patient compliance loss of both solution - slow dissolution & suspended solid.

FORMULATION (1) Vehicles: There are two types of vehicles which are:  Aqueous vehicles:- e.g. Water is used as vehicle because water is tolerated well by the body  Non-aqueous vehicles:- e.g. Oils and Alcohols, such as, fixed oils, almond oil, ethyl alcohol, propylene glycol.

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. They are added to provide protection from Oxidation. e.g Sodium metabisulphite - Sodium thiosulphate - Thiourea. - ascorbic acid. e.g Sodium metabisulphite - Sodium thiosulphate - Thiourea. - ascorbic acid.  Wetting agents. e.g. Polysorbate 20 Polysorbate 80 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. Commonly used tonicity adjusting agents are Nacl, Kcl, buffer salts, dextrose,glycerin, propylene glycol and mannitol.  Preservatives. - Benzalkonium chloride - Benzalkonium chloride - Phenylmercuric acetate - Phenylmercuric acetate - Phenylemercuric nitrate - Phenylemercuric nitrate

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

Manufacturing considerations Manufacturing considerations  Manufacturing Environment: The environment should be sterile and particle-free through: - The environment should be sterile and particle-free through: - Laminar-flow should be used throughout the manufacturing area. 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, smooth and non- affected by surface cleaners or disinfectants.

 MANUFACTURING OPERATION 1) AREA REQUIREMENT 1) AREA REQUIREMENT Minimum of 10 m 2 → for ancillary area. Minimum of 10 m 2 → for ancillary area. Minimum of 25 m 2 → for basic installation. Minimum of 25 m 2 → for basic installation. Manufacturing & filling shall be carried out in air – conditioned areas under aseptic condition. 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. The rooms shall be further dehumidified as considered necessary if preparation containing antibiotics are manufactured.

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

 PACKAGING  Plastic containers → ease of use. → little breakage. → little breakage. → less spoilage. → 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 color coding are given by the FDA.

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

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

Documentation: Documentation: 1. Master formula records. 2. Batch formula records. 3. Equipment & containers records. 4. Filtration & filling records. 5. Batch Packaging & Labeling Records.

 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 pharmacopoeia, vol – 1.  Controlled drug delivery by Roop K.Khar & S.P.Vyas, Page No.( ,399,403)  Modern pharmaceutics edited by Gilbert S. Banker.  Pharmaceutical dosage forms parenteral medications volume 2 edited by Kenneth E. Avis, Leon Lachman.  Pharmaceutical dosage forms Disperse systems volume2 