Pilot Plant Scale-up Techniques for Injectables/parenterals

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Pilot Plant Scale-up Techniques of Injectables :

Pilot Plant Scale-up Techniques of Injectables Manmohan M.Pharm. (1 st year) Pharmaceutics. 1

CONTENTS :

CONTENTS INTRODUCTION. SCALE-UP FOR PARENTERALS. PRODUCTION AREA. FORMULATION. EQUIPMENTS USED. PROCESS OF MANUFACTURING. STABILITY AND QUALITY CONTROL. 2

INTRODUCTION:

INTRODUCTION In the pilot plant, a formulae is transformed into a viable product by the development of a reliable and practical method of manufacturing. So pilot plant is the intermediate plant between the laboratory scale and the production plant. 3

Why to build up a pilot-plant???:

Why to build up a pilot-plant??? To evaluate the effect on the process of a large scale of operation and to collect other data so that a good design of a larger unit may be made with a high probability of commercial success. To find and examine all products or waste which may not be seen in laboratory scale. By the use of pilot plant, it is possible to minimize the wastes, hence better yield of prescribed dosage form. 4

INJECTABLES:

INJECTABLES The majority of the parenteral solutions requiring a variety of equipments for liquid mixing, filteration, transfer and related activities. Most of the equipments are composed of stainless steel, with glass lined vessels employed for preparation of formulations sensitive to iron and other metal ions. The vessels can be equipped with external jackets for heating and/or cooling and various types of agitators, depending upon the mixing requirements. 5

LAYOUT OF THE PILOT PLANT:

LAYOUT OF THE PILOT PLANT 6 S T O C K R O O M

WORKING AREA OF A PARENTERAL PILOT PLANT:

WORKING AREA OF A PARENTERAL PILOT PLANT Incoming goods are stored in special areas for Quarantine, Released and Rejected status. A cold room is available for storage of temperature-sensitive products. Entrance into the warehouse and production areas is restricted to personnel. 7

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The route for final products is separated from the incoming goods. storage of final products is done in designated areas in the warehouse. Sampling and weighing of the raw material is performed in a dedicated sampling area and a central weighing suite, respectively. 8

PRODUCTION AREA:

PRODUCTION AREA 9

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10 First the materials are passed through class 100,000 i.e. grade D environment for presterilization. Transfer of materials are carried out in air-locks to avoid cross contamination The preparation areas are supplied with HEPA filters. There should be more than 20 air changes per hour The preparation place is Class 100 area.

PRODUCTION AREA:

PRODUCTION AREA 11

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HEPA FILTER:

HEPA FILTER 14

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HEPA filters, by definition, remove at least 99.97% of Airborne particles 0.3 micrometers (µm) in diameter . HEPA filters are composed of a mat of randomly arranged fibres. These fibres are typically composed of fiberglass and possess diameters between 0.5 and 2.0 micron. The air space between HEPA filter fibres is much greater than 0.3 μm. 15

TYPES OF PARENTERAL DOSAGE FORM:

TYPES OF PARENTERAL DOSAGE FORM SOLUTION: Solutions of drug are suitable for parenteral administration are referred as injections. They are manufactured by dissolving the drug and suitable excipients, adjusting the pH, filtration through 0.22µm membrane and autoclaving the final product. These are of two types: a) Large Volume Parenterals (LVP) b) Small Volume Parenterals (SVP) 16

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SUSPENSIONS : It is one of the most difficult parenteral dosage form. It can be injected through a 18 to 21 gauge needle. Formulation consists of active ingredients suspended in aqueous solution. Two methods are used to prepare parenteral suspension: a) Sterile vehicle & powders are combined aseptically. b) Sterile solutions are combined and the crystals formed in-situ. E.g.: Penicillin G procaine injectable suspension USP Sterile Testosterone injectable suspension USP 17

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SYRINGEABILITY : It refers to the handling characteristics of a suspension while drawing and manipulating it in a syringe. INJECTABILITY : It refers to the properties of the suspension during injection. 18

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EMULSIONS : An emulsion is a dispersion of two or more immiscible liquids. It includes following types: water-in-oil emulsions of allergenic extracts (subcutaneously) Oil-in-water sustained-release depot preparations (intramuscularly) 19

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DRY POWDERS : Many drugs are physically or chemically unstable and hence formulated as dry powders, which can be reconstituted in solution by addition of water. Sometimes it may be an aqueous suspension such as ampicillin trihydrate and spectinomycin hydrochloride. 20

FORMULATION:

FORMULATION VEHICLES: The most widely used solvent used for parenteral production is water for injection . WFI is an aqueous vehicle which is prepared by distillation or reverse osmosis. Non-aqueous vehicles used for parenteral products are fixed oils such as:- corn oil, cottonseed oil, peanut oil, sesame oil etc. 21

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ANTIOXIDANTS: These are used to maintain product stability by being oxidized. E.g.: -Ascorbic acid -Cysteine -Sodium bisulfite -Monothioglycerol -Sodium metabisulfite -Tocopherols 22

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ANTIMICROBIALS: They are used to inhibit the growth of micro-organisms. E.g.: -Benzalkonium chloride -Benzyl alcohol -Chlorobutanol -Metacresol etc. BUFFERS: These are used to maintain the pH of the product. 23

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E.g.: -Acetates -Citrates -Phosphates etc. TONICITY AGENTS: E.g.: - S odium chloride -Dextrose etc. 24

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PROTECTANT: Protectants are added to a formulation to protect against loss of activity or to prevent loss of ingredients by adsorption. E.g.: -Sucrose -Glucose -Lactose -Maltose -Human Serum Albumin etc. 25

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SURFACTANTS: E.g.: -Polysorbate 80 -Polysorbate 20 -Lecithin -Sorbitan mono-oleate etc. CHELATING AGENTS: E.g.: -Salts of ethylenediamine tetra-acetic acid. -Salts of edetate disodium. -Citric acid & tartaric acid. 26

EQUIPMENTS:

EQUIPMENTS Various equipments are used in the manufacturing of parenteral products: 27

MIXING APPARATUS:

MIXING APPARATUS 28

BOTTLE FILLING MACHINE:

BOTTLE FILLING MACHINE 29

CLOSURE MACHINE:

CLOSURE MACHINE 30

AUTOMATED VIAL FILLING MACHINE:

AUTOMATED VIAL FILLING MACHINE 31

AMPOULE SEALING MACHINE:

AMPOULE SEALING MACHINE 32

PROCESS OF MANUFACTURING:

PROCESS OF MANUFACTURING 33 FREEZE DRYING OR LYOPHILIZATION : Lyophilization or freeze drying is a process in which water is removed from a product after it is frozen and placed under vacuum , allowing the ice to change directly from solid to vapor. The process consists of three processes; i) freezing, ii) primary drying and iii) secondary drying.

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Steps include in this process are: Drugs and excipients are dissolved in suitable solvent. Sterilize the solution by passing through 0.22 microns filter. Filling individual container and place under aseptic conditions. Transfer the containers to lyophilizer and loading into the chamber under aseptic conditions. Freezing the solution by placing it in freeze-drying chamber. Apply vacuum and heat to the chamber to evaporate water from frozen state. 34

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Primary drying : In this a receding boundary can be observed in the vial as the thickness of the frozen layer decreases. In this ice is removed by direct sublimation method. Secondary drying : It consists of removal of water by diffusion and desorption. It is used to remove the water that did not freeze during freezing process. 35

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ADVANTAGES: Ease of processing a liquid, which simplifies aseptic handling. Enhanced stability of a dry powder. Removal of water without excessive heating of the product. Enhanced product stability in a dry state. Rapid and easy dissolution of reconstituted product. 36

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DISADVANTAGES: Increased handling and processing time n eed for sterile diluent upon reconstitution Cost and complexity of equipment. 37

FREEZE DRYING MACHINE:

FREEZE DRYING MACHINE 38

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2) ASEPTIC CRYSTALLIZATION AND DRY POWDER FILLING : It includes: Drug is dissolved in a suitable solvent and filtered through a filtration membrane. A second solvent is added for crystallization and precipitation of drug. Crystals are collected on a funnel, washed and dried by vacuum drying. After drying milling or blending of drug crystals takes place. The powder is then transferred to dry-powder-filling equipment and filled into vials. 39

DRY POWDER FILLING MACHINE:

DRY POWDER FILLING MACHINE 40

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3) SPRAY DRYING : It includes following steps: The drug solution is sterile filtered and metered into the drying chamber. Here it passes through an atomizer that creates an aerosol of small droplets of liquid. Aerosol comes into contact with a stream of hot sterile gas. The solvent evaporates and drug is collected as a powder in the form of hollow spheres . The powder is then filled into vials using conventional powder-filling equipment. 41

SPRAY DRYING MACHINE:

SPRAY DRYING MACHINE 42

STABILITY & QUALITY CONTROL:

STABILITY & QUALITY CONTROL Temperature Light Humidity Packing material. Formation of precipitate. Change of odor. Interaction b/w products & container closure. 43

QUALITY CONTROL:

QUALITY CONTROL CLARITY TEST: Clarity is tested by visual inspection of containers under light and observed against a black & white background. It is based on the principle of light scattering & electrical resistance which are used to count particles and particle size distribution. Coulter-Counter method & Filtration method are used for monitoring particulate matter. 44

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STERILITY TESTING: The solution of the product under investigation is carefully filtered via a hydrophobic-edged membrane filter. The resulting membrane is washed to get rid of any possible ‘traces of antibiotic’ that would have been sticking to the surface of the membrane intimately . Finally , the segregated microorganisms are transferred to the suitable culture media under perfect aseptic environment . no growth- passes the test growth- retesting is done- no growth- passes the test 45

PYROGEN TESTING::

PYROGEN TESTING: RABBIT TEST : It is based on the fever response of rabbits. If a pyrogenic substance is injected into the vein of a rabbit, a temperature elevation will occur within 3 hours. It is used for both gram +ve and gram -ve bacterias. 46

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LAL TEST : LAL is cell lysate of amoebocyte of Limulus Polyphemus (horse shoe crab). Solution of the preparation is made with WFI . LAL reagent is added to it, incubate at 37 0 c for 1 hr . Firm gel formation indicates presence of pyrogens . It is used only for gram –ve bacteria. 47

LEAKAGE TEST::

LEAKAGE TEST: This test is usually performed by producing a negative pressure within an incompletely sealed ampule. Ampule is submerged entirely in a deeply colored dye solution(1% methylene blue solution). After carefully rinsing the dye solution from outside, color from the dye will be visible within a leakage . 48

SAFETY TEST::

SAFETY TEST: Particularly for biological products. 49

PACKAGING:

PACKAGING Glass: i) soda-lime glass. ii) borosilicate. 2 . Plastic: i) Ampoules. ii) Vials. iii) Cartridges. iv) Automatic injector. 50

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3 . Rubber closure with aluminium caps: i) Small volume parenterals: less than 100ml ii) Large volume parenterals : more than 100ml 51

MARKETED PRODUCTS:

MARKETED PRODUCTS 52

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REFERENCES:

REFERENCES Gilbert Banker and Christopher Rhodes, “Modern Pharmaceutics” 4th edition. Remington: The Science and Practice of Pharmacy, vol.-1, 20 th edition, Pg. no.- 780-805. Leon Lachman, Herbert A. Lieberman and Joseph L. Kanig, “The Theory and Practice of Industrial Pharmacy”, Pg. no.-639-676. 54

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