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Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
Parenteral preparation, equipments and layout
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Parenteral preparation, equipments and layout

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A seminar about Manufacturing, equipments and preparation of layout of parenterals... useful for M.Pharm. students.....regards...Swapnil Sanghavi

A seminar about Manufacturing, equipments and preparation of layout of parenterals... useful for M.Pharm. students.....regards...Swapnil Sanghavi

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  • 1. PARENTERALS
    MANUFACTURING
    LAYOUT
    EQUIPMENTS
    Swapnil Sanghavi
  • 2. Introduction
    • Sterile- Absolute termas the state of freedom from all viable organism.
    Type of sterile preparations
    • OPTHALMIC
    • 3. PARENTERAL
    • 4. IRRIGATING PREPARATION
    • 5. DIAGNOSTIC AGENTS
    • 6. ALLERGIC EXTRACTS
    • 7. SURGICALS
    • 8. RADIO PHARMACEUTICALS
  • Parenteral: The dosage form for conveying a drug by means of injection through the skin or mucous membranes.
    Parenteral drugs are administered directly into the veins, muscles or under the skin, or more specialized tissues such as the spinal cord.
    Circumvented the highly efficient first line body defense that is skin and mucus membrane.
    Thus they should be free from microbial contamination and should have high purity.
  • 9. COMMON TERMINOLOGY
    Aseptic-“without sepsis” Used to designate a practical level of sterility.
    Parenteral
    Sterile
    Alert level- An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions.
    Action Level- An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.
    HVAC- Heating, ventilation, and air conditioning.
    Laminar flow of air- Airflow moves in a single direction and in parallel layers at constant velocity.
  • 10. COMMON TERMINOLOGY
    ULPA filter : Ultra-low penetration air filter with minimum 0.3 µm particle retaining efficiency of 99.999 percent.
    LVP : A liquid intended for infusion and hermetically sealed in a container of greater than 100 ml volume.
    SVP : A parenteral preparation hermetically sealed in a container of 100 ml or less volume.
    Pyrogen : The fever producing lipid associated with polysaccharide or polypeptide of microbial origin.
    Sterilization : A process designed to completely eliminate or destroy all living microorganism.
    Process validation:
    SAL :
  • 11. SOME IMPORTANT PARENTERAL PREPARATION
    IV Admixturesconsist of one or more sterile drug products added to an IV fluid.
    Used for
    Drugs intended for continuous infusion
    For drugs that may cause irritation or toxicitywhen given by direct IV injection.
    IV fluids
    These fluids have multiple uses,
    Vehicles in IV admixtures
    Provide means for reconstituting sterile powders
    Serve as the basis for correcting body fluids and electrolyte disturbances
    For administering parenteral nutrition
  • 12. Dextrose: Generally, a solution of 5% dextrose in water
    pH of 5% dextrose ranges from 3.5-6.5. Instability may result if it is combined with an acid sensitive drug.
    In higher conc. (e.g. 10% solution in water), dextrose provides a source of carbohydrate in parenteral nutrition solutions.
    Should used cautiously in patients with diabetes mellitus.
    Sodium chloride :usually given as 0.9% solution called as normal saline solution.
    • Sterile sodium chloride for injection:
    Used as vehicle in IV admixtures and fluid for electrolyte replacement.
    • Bacteriostatic sodium chloride for injection:
    It contains an agent that inhibits bacterial growth (e.g. Benzyl alcohol, Propylparaben. Methyl papaben), allowing its use in multiple dose preparation.
  • 13. Water
    Used for reconstitution and for dilution of IV solutions such as dextrose and sodium chloride.
    Water suitable for parenteral preparations include sterile water for injection and bacteriostatic water for injection.
    Ringer solutions
    Used for fluid and electrolyte replacement.
    Commonly administered to post surgical patients.
    It contains sodium lactate, sodium chloride, potassium chloride, and calcium chloride.
  • 14. Electrolyte preparation
    Ions present in both intracellular and extracellular fluid.
    Surgical and medical patients who can not take food by mouth or who need nutritional supplementation require the addition of electrolytes in hydrating solutions or parenteral nutrition solutions.
    Dialysate
    Used in paients with disorder as renal failure, poisoining, and electrolyte disturbances.
    In peritoneal dialysis, a hypertonic dialysis is infused directly into peritoneal cavity via a surgically implanted catheter. It contains Dextrose and electrolyte, which removes the harmful substances by osmosis and diffusion.
  • 15. Irrigating solutions
    Not intended for infusion into the venous system.
    • Topical administration
    Used in irrigating wounds, moistening dressings, and cleaning surgical instruments.
    • Infusion of irrigating solutions
    Surgeons performing urological procedure often use irrigating solution to perfuse tissues in order to maintain the integrity of surgical field, remove blood, and provide a clear field of view.
  • 16. Parenteral preparation
    Intravenous, Intraspinal, Intramuscular, Subcutaneous, and Intradermal.
    Intravascular route complete drug availability occurs immediately
    • For all other routes, at least a blood vessel wall, and usually one or more tissue cell walls, must be permeated before the drug can enter the circulation.
    • 17. Most often this occurs by passive diffusion and is most favourable when the drug has bothlipophilic and hydrophilic properties, with the former being predominant.
    • 18. So with nonvascular injection, absorption is also affected by such factors
    • 19. Size and number of blood vessels supplying the tissue,
    • 20. Physical & chemical properties of drug
    • 21. Characteristic of the dosage form as whether it is a solution, suspension or emulsion
    • 22. Nature of vehicle & its pH
    No absorption
    is necessary
  • 23. and package components
  • 24.
  • 25. TYPES OF PROCESSING
    Terminal sterilization
    The product in its final container is subjected to a sterilization process such as heat or irradiation.
    In most cases, the product, container, and closure have low bio-burden, but they are not sterile.
    Aseptic process 
    The drug product, container, and closure are first subjected to sterilization methods separately, as appropriate, and then brought together.
    Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment.
  • 26. Types of Operations for Terminally Sterilized Products
    Note
    Grade A and B correspond to with class 100, M 3.5, ISO 5
    Grade C correspond to with class 10000, M 5.5, ISO 7
    Grade D correspond to with class 100000, M 6.5, ISO 8
  • 27. Types of Operations for Aseptic preparations
    Note
    Grade A and B correspond to with class 100, M 3.5, ISO 5
    Grade C correspond to with class 10000, M 5.5, ISO 7
    Grade D correspond to with class 100000, M 6.5, ISO 8
  • 28.
  • 29. Parameters to be taken into consideration in the Design of a Parenteral Production Facility:
    Environmental factors such as site selection, area planning, space planning, design and construction features, traffic flow of personnel and supplies, and service features.
    Site selection
    Criteria for site selection
    Basic factors
    Pharmaceutically important factors
    land availability, land cost,
    construction cost, taxes,
    utility costs, labor availability,
    labor cost and so on.
    Requires special consideration
    because of unique
    pharmaceutical needs.
  • 30. Basic plant requirement includes an adequate supply of raw materials, transportation availability, market proximity, adequate utilities, and labor supply.
    Minimizing shipping may aid in minimizing potential contamination, material degradation due to ageing or lack of environmental control (e.g. temp. & humidity).
    Area planning it depends on
    Type of production
    Batch operations -Suited to small production volume & minimum financial investment is necessary.
    Advantages
    Product quality, consistency, and homogeneity are relatively easily controlled.
    Production documentation is easy.
    Disadvantages
    Economically undesirable because it is labor intensive and does not exploit the economies of volume.
  • 31. Continuous operations: It is suited to very high volume production requirements.
    It requires more space and more complex equipments.
    Advantages
    Minimizes shortcoming of batch operations; labor, production time, and environmental exposure of the product.
    Since the intermediate material handling steps are eliminated, the potential for product contamination during those steps is no longer exists.
    Disadvantages
    Product quality assurance is difficult.
    It is very difficult to document the ingredients or process cyclefor a product produced in a continuous process.
  • 32. Container size
    SVPs and LVPs obviously requires different space considerations.
    All the production equipment has container size limitations- large container requires large equipments and more space.
    Environment control needs
    For aseptic filling process
    Sterilization and
    Depyrogenation of
    containers before filling,
    normally hot air oven
    or autoclave.
    Provision must
    be made for
    Filling requires
    An aseptic environment with
    the attendant support rooms
    Inspection and Packaging
  • 33. Non aseptic filling, followed by terminal sterilization, normally requires less rigid environmental control.
    Terminal sterilization
    Eliminates the
    sterilization prior
    to filling
    Following to
    filling and sealing
    An accumulation and segregation
    area is required to accumulate
    the product for transfer to the
    next process step
  • 34. Product characteristics
    Liquids are probably the easiest product to handle.
    Emulsion may require compounding areas close to filling lines to ease transfer problems. Pumping systems will be very critical.
    Suspension will require a means of maintaining a homogenous mixture prior to filling.
    To minimize the time the suspension resides in piping, reservoir, and pump system, filling rate should be kept high and the distance from compounding to filling should be minimized.
  • 35. Zone 7
    WHITE
    BLACK
    GRAY
    Environmental control zone groupings
    Zones as per cGMP
    Zone 7:- Filling line
    Zone 6:- Filling area
    Zone 5:- Weighing, mixing & transfer area.
    Zone 4:- Clean area
    Zone 3:-General production
    Zone 2:- Warehouse
    Zone 1:- Exterior
    7
    1
    Zones as per Gazette of India
    White zone:-Final step ( filling of parenteral)
    Grey zone:-weighing, Dissolution & filtration.
    Black zone:-Storage, Worst area from contamination view point
  • 36. Space requirements
  • 37. Personnel flow
    Discontinuous and crowded flow patterns can decrease production efficiency, increase security problems, and increase the problems of maintaining a clean environment.
    Personnel flow path from zone to zone must be such that access to higher level of cleanliness is only through change rooms, gowning rooms, locker rooms, or other areas as may be required to prepare the personnel for the cleaner area.
    Access should be restricted.
    × Design
    1
    3
    4
    2
    √ Design
    2
    1
    3
    4
  • 38. CHANGE ROOM
  • 39. FILLING AREA
    The product & sterilized components are exposed to room environment.
    Therefore these areas are specially constructed, filtered, and maintained to prevent environmental contamination.
    Clean room must meet several requirements:
    The room should undergo 15-20 air changes per hour.
    HEPA filters are to clean the air entering the room.
    HEPA filters remove all airborne particles of size 0.3 or larger with an efficiency of 99.97%.
    Maintaining higher air pressure (+ve pressure) within the critical area to minimize infiltration of airborne contaminants from outside.
    Adjacent rooms of different grades should have a pressure differential of 10 - 15 Pascals.
  • 40. Care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or equipment to a zone of higher product risk. A warning system should be provided to indicate failure in the air supply.
    Counters in the clean room should be made of stainless steel or other non-porous, easily cleaned material.
    Walls and floors should be free from cracks or crevices and have rounded corners. If the walls or floors are to be painted, epoxy paint is used.
    The air flow should move with uniform velocity along parallel lines. The velocity of the air flow is 90 ± 20 ft/m3.
    Providing temp. & humidity controls appropriate to the product being manufactured.
  • 41.
  • 42. Environmental control
  • 43. PERSONNEL & GOWNING
    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.
    Clothing
    Uniform is made up of Dacron and Span polyethylene.
    Hats & masks are sometimes made of special parchment paper.
    Foot wearsplastic and rubber material.
  • 44. Air handling system
    Air Classification as per Schedule M
    Air Classifications by USFDA guideline on Sterile Drug Products
  • 45. Air Classifications as per WHO 2002
    As per ISO
  • 46. As per British Pharmacopoeial Codex
  • 47. QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (circular flow)
  • 48. QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (parallel flow)
  • 49. Layout for Aseptic Production
    Material
    Entry
    Pdt.
    Exit
    Soln
    Prepn
    Area
    Unidirectional
    Clean Zone
    Aseptic
    Filling zone
    Clean
    Changing
    Room
    Entry
    Oven
    Equipment &
    Component
    Prepn
    Area
    Auto
    clave
    Aseptic
    Receiving
    Area
    Comp.
    Entry
    Hatch
  • 50. Layout for Terminal Sterilization
    Solution
    Prepn
    Area
    Solution
    Prepn
    Area
    Material
    Entry
    Terminal
    Sterilization
    Material
    Entry
    Terminal
    Sterilization
    lamimar flow
    Unidirectional
    Clean Zone
    Clean Filling Area
    Clean Filling Area
    Clean
    Changing
    area
    Clean
    Changing
    area
    Equipment &
    Component prepn
    Area
    Equipment &
    Component prepn
    Area
    Comp.
    Entry
  • 51. EQUIPMENTS
  • 52. The following equipments as pre Schedule-M are recommended:
    Manufacturing area
    Storage equipment for ampoules, vials bottles and closures.
    Washing and drying equipment.
    Dust proof storage cabinet
    Water still.
    Mixing and preparation tanks or other containers.
    The tanks or containers shall be made of either glass or such materials as will not react with the liquid.
    Mixing equipment where necessary.
    Filtering equipment.
    Hot air sterilizer.
  • 53. Aseptic filling and sealing rooms
    Benches for filling and sealing.
    Bacteriological filters.
    Filling and sealing unit under laminar flow work station.
    General Room
    Inspection table.
    Leak testing table.
    Labeling and packing benches.
    Storage of equipment including cold storage and refrigerators if necessary.
  • 54. Sterile Garment Cabinet
    Stainless steel
    Ensure a clean storage space by making use of UV disinfectant and heating through IR lamps.
    These cabinets may be designed in horizontal air flow system and clean air through HEPA filters
  • 55. Cooler or Cold Storage
  • 56. HEPA Filter
    HEPA filters can remove at least 99.97% of airborne particles 0.3 µm in diameter.
    HEPA filters are composed of a mat of randomly arranged fibres (poly-vinylidene fluoride -PVDF)
    Key metrics affecting function are fibre density and diameter, and filter thickness.
    The air space between HEPA filter fibres is much greater than 0.3 μm. The common assumption that a HEPA filter acts like a sieve where particles smaller than the largest opening can pass through is incorrect.
    Smaller pollutants and particles are mainly trapped (they stick to a fibre) by one of the following three mechanisms
    Interception
    Impaction
    Diffusion
  • 57. Laminar flow hoods
    Clean air work benches are specially designed to ensure the aseptic preparation of sterile products.
    Air flow rates
    0.3 m/s (vertical)
    0.45 m/s (horizontal)
    Introduction of personnel, equipment, and material into the work area provides sources of particulate matter which may contaminate the product.
    Very small particles are not heavy enough to settle due only to the force of gravity, but instead are carried and directed by air currents. and if there is turbulent air, particles may be driven into product.
    Laminar air flow velocity satisfactorily sweeps the area yet does not create unacceptable turbulence.
  • 58. Types of containers
    Ampoules
    They are intended for single use only.
    Because glass particles may become dislodged during ampoule opening, the product must be filtered before it administered.
    Limitation
    Unsuitability for multiple-dose use
    The need to filter solutions before use
    Other safety considerations
  • 59. Vials
    Glass or plastic containers are closed with a rubber stopper and sealed with an aluminum crimp.
    Advantages over ampoules.
    They can be designed to hold multiple doses (if prepared with a bacteriostatic agent).
    It is easier to remove the product.
    They eliminate the risk of glass particle contamination during opening.
    Drawbacks
    Multiple withdrawals (as with multiple-dose vials) may result in microbial contamination.
  • 60. Double Chambered Vials
    Some drugs that are unstable in solution are packaged in vials in powder form and must be reconstituted with sterile sodium chloride for injection before use.
    Some of this drugs come in vials that contain a double chamber.
    Top chamber- sterile water for injection
    Bottom chamber- unreconstituted drug
    Both chambers are separated by a rubber closure.
    To dislodge the inner closure and mix the contents of the compartments, external pressure is applied to the outer rubber closure.
  • 61. Prefilled syringes
    Designed for quickest administration and maximum convenience.
    Drugs administered in an emergency (e.g.atropine, epinephrine) may be available for immediate injection when packaged in prefilled syringes.
  • 62. Rubber Stopper Washing Machine
  • 63. Syringe Filling Machine
    Characteristics
    Barrier isolators
    In-process check weighing
    Filling : rotary piston pumps.
    0.2 to 29 ml.
    Filling :
    -- All types of syringe including glass, plastic can be filled.
    -- 300 to 600 syringes in a minute.
  • 64. Ampoule Washing Machine
    PROCESS
    • Water is sprayed onto the ampoules.
    • 65. Turned to an angle of 180 degree with their mouth downward to remove water.
    • 66. Finally the ampoules are filled with compressed air to remove residual water.
    • 67. Certain machines have a high temperature zone meant for killing any bacteria.
  • Vial Washing And Sterilizing Machine
  • 68. Automatic Intelligent Light Inspection Machine
  • 69. Vial Filling Machine
    Fill vials and bottles
    liquids, viscous material and suspensions and powders.
    PROCESS
    • The machine comprises of an intake section which loads the vials.
    • 70. Transferred through an intermittent transport section.
    • 71. liquid filling section which fill the vials with predetermined quantity.
    • 72. Finally the filled and rubber stoppered vials are released and discharged.
  • Fully automated inspection systems
    58/94
  • 73. Vial Inspection Machine
  • 74. Vial Labeling Machine
  • 75. Ampoule Filling Machine
    Note = vertical laminar air flow, plastic curtain.
    • Filling range of these machines is normally between 1ml to 20 ml.Features of Ampoule Filling Machines
    • 76. Accommodate a variety of ampoules in terms of shapes and size.
    • 77. 'no ampoule no fill' capability
    • 78. Check weight mechanism of the machine helps to maintain consistency in each batch.
    • 79. Sealing is done either by laser sealing system or conventional gas flame. Application of Ampoule Filling Machine
    Pharmaceutical
    Neutraceutical
  • 80. SIP System
    For in-line sterilization of various processing equipments.
    Handling various biological solutions and mixtures requires cleaning and sterilizing these equipments from time to time as they are susceptible to contamination.
    Proper SIP integration with pharmaceutical equipment is very important for the overall success of the operation.
  • 81. ANTIMICROBIAL EFFICACY OF A SILVER-ZEOLITE MATRIX COATING ON STAINLESS STEEL
    A silver and zinc-containing zeolite matrix (AgION) used as a coating for stainless steel.
    Test against- e coli, s aereus, p aeroginosa etc.
    Result:- The silver-zeolite mixture reduced microbial colony-forming units upto 84.536 – 99.999% after 4 h exposure, and upto 99.992-100% after24 h in all cases.
  • 82. FILTERS IN FILTRATION STERILIZATION
    Millipore’s Airvent filters
    Constructed with a PTFE membrane.
    These filters have been qualified to withstand at least 40 SIP cycles at 135 °C for 30 minutes.
    Millipore’s Durapore filters
    Constructed with a PVDF membrane
    These filters have been qualified to withstand 5 to 30 SIP cycles at 135 °C for 30 minutes
    Verification of integrity of filter
    Bubble point method
    Diffusive flow
    Pressure hold test
  • 83. Bubble Point Test
  • 84. Test Method
    1. Record the filter part number(s), lot number, and product information. Also include physical observations.
    2. Wet the filter to be tested with the appropriate solvent (water for hydrophilic filters, alcohol for hydrophobic filters).
    3. Place the wetted filter in the appropriate housing.
    4. Connect the outlet fitting from the compressed air pressure regulator to the upstream side of the test filter.
    6. Connect a piece of flexible tubing from the downstream port of the test filter into a beaker filled with water.
    7. Starting from zero pressure, gradually increase the pressure to the test filter using the pressure regulator.
    8. Observe the submerged end of the tubing for the production of bubbles as the upstream pressure is slowly increased in 0.5 psig increments. Note the rate that the bubbles appear for the end of the submerged tube.
    9. The bubble point of the test filter is reached when bubbles are produced from the tube at a steady rate. Record the pressure to the nearest 0.5 psig as indicated on the pressure gauge.
  • 85. STANDARAD OPERATION PROCEDURE
    For aseptic filling:-
    • Check all sterilized material has indicator and expiration date.
    • 86. Open sterilized container, filling assembly and tubing on LAF bench.
    • 87. Connect the tubing of filling lines.
    • 88. Connect solution tank to the inlet of the filling assembly.
    • 89. Connect the nitrogen over lay in tank for pre and post flushing.
    • 90. Pump the solution in filling tubing up to the filling nozzle (remove any air bubble)
    • 91. After that wipe the filling nozzle with 70%alcohol.
    • 92. Switch on the machine.
    S.O.P FOR OTHER MENUFACTURING PROCESSES IS SAME AS THAT OF NON STERILE DOSAGE FORMS
  • 93. VALIDATION
    Purpose : To minimize this reliance on end product sterility testing.
    Three principle involved in validation process.
    To built sterility in the product.
    To demonstrate the maximum level of probability that the processing and sterilization method have establish sterility to all units of product batch.
    To provide greater assurance and support to the result of the end product sterility.
  • 94. Validation
    Pre-processing quality control test
    In process quality control test
    Finished product quality control test
    Pre-processing quality control test:-
    Raw material testing and assays
    Packaging material test (glass, plastic, rubber etc)
    sterility test and media fill (process simulation test )
  • 95. Tests for containers
    (a).For Glass containers.
    (i). Test for hydrolytic resistance.
    (ii). Arsenic test.
    (b). For Plastic container.
    (i). Non volatile matter.
    (ii). Sulphated ash.
    (iii). Heavy metals.
    (iv). Buffering capacity.
    (v). Biological test. (Adverse reaction or toxicity)
  • 96. Media fill (process simulation test):-
    • Evaluation of the environment along with the process, the operator and the equipment is the media fill.
    Procedure
    • Sterile Trypticase soy broth is filled into sterile container under condition simulating as for a product.
    • 97. Entire lot at least 3000 unitsis incubated at suitable temp for 14 days.
    • 98. To pass the test not more than 0.1% of the unit may show growth.
    • 99. This is very stringent evaluation of an aseptic fill process and is considered to be the most evaluative test available.
  • In Process Quality Control Test
    • Conductivity measurement
    • 100. Volume filled
    • 101. Temp for heat sterilized product
    • 102. Environmental control tests
    • 103. Visual inspection
  • Finished product quality control test
  • Leak test
    To detect incompletely sealed ampoules.
    Principle
    10% methylene blue or 0.1% FDC red one or red two.
    Generally combined with autoclave.
    Disadvantage
    Leakage of 15 micron in diameter or smaller is not detected.
    Vial and bottles are not subjected to this test.
  • 109. Pyrogen test
  • 110. LAL test
    Limulus amoebocyte test or bacterial Endotoxin test for the validation of depyrogenation process.
    Reagent - LAL reagent (limulus Polyphemus)
    Reaction -In presence of Endotoxin a firm gel is formed within 60 min when incubated at 370 C.
    CHARACTERISTIC
    Test tube scale.
    Only pyrogen of gram negative bacteria detected.
    Semi quantitative test.
    Sensitivity in terms of Endotoxin unit.
    In-vitro test.
    Doesn’t measure fever producing potential of Endotoxin.
    Sensitivity varies with different microbial source of LAL.
  • 111. LAL TESTER
  • 112. Pyrogen test- Fever response of rabbit
    Sham testis performed to select the proper animals for the main tests.
    Rabbit test - Qualitative fever response test.
    Procedure
    Test solution is injected into the vein of rabbit. Temperature elevation is seen for 3 hrs.
    Disadvantage
  • Particulate test
    USP
    Visually inspected- all (WHITE AND BLACK )
    Any with visible particle is discarded.
    Large volume parental
    • 50 particles of 10μm
    • 117. 5 particulates of 25 μm per ml
    Light obscuration particle count test
    Microscopic particle count test
  • 118. HVAC Validation
    Features of HVAC affect product quality (sterility).
    HEPA integrity
    Certification: by filter manufacturer indicates that filter is capable of removing all particulate matter equal to or greater than 0.3 in size with an efficiency of 99.97%.
    Installation: a certified filter if improperly installed will not perform its function & provides a false sense of security.
    Integrity testing: A popular method for certifying integrity of filter installation uses polydisperse aerosol, created by blowing air through liquid Dioctyl phthalate, introduced into upstream of HEPA filter followed by scanning the entire downstream of filter face with a probe nozzle of an aerosol photometer.
    This testing will indentify “leaks” caused by damage due to mishandling or faulty construction.
    Small leaks can be repaired with a suitable silicone based compound without removing filter.
  • 119. HVAC Validation (Cont.)
    Airflow resistance : Caused by dirty filter may reduce airflow volume, thereby reducing the air change rate in critical areas.
    Airflow resistance is expressed as pressure differential between the air pressure upstream of the filter and the downstream air filter.
    If the filters are not changed when they reach the maximum resistance as specified by manufacturer, they may begin to lose their physical integrity or rupture, thereby releasing some of the dust they have accumulated.
    Airborne particle control
    Particle count surveys should be performed at regular intervals.
    Airflow direction
    Determination of unidirectional flow involves measuring the parallelism of air flow generating from HEPA filter throughout the work zone.
    This can be accomplished using an isokinetic smoke generator & measuring devices to determine offset from straight line flow.
  • 120. HVAC Validation (Cont.)
    Room pressure difference
    Special monitoring devices which measure the pressure differential are connected directly to an alarm system that will cause a visual signal (flashing light) or an audible signal (Alarm buzzer) to report a deviation outside a prescribed range of pressure differential.
    Temp. & Humidity control
    Cleanroom Environmental Monitoring
  • 121. Packaging of finished product
    Packaging material.
    (1) Glass
    (2) Plastic
    Plastic is more preferred over glass as packaging material for no of reasons.
    - Ease to form
    - High quality
    - Freedom of design
    E.g.--Polypropylene, PVC, Polystyrene, Nitrile polymers.
  • 122. USP requirements for packaging.
    Single dose container should not be more than 1 liter.
    Intra-spinal and intra-cisternal administered product must be in single dose container.
    In case of multiple dose container dose should not be more than 30 ml.
  • 123. BFS Technology
    It refers to the technology and related equipment and procedures in which the formation of the container, its filling with liquid pharmaceutical material, and subsequent formation and application of a seal for container are achieved aseptically in an uninterrupted sequence of operations without exposure to nonsterile environments between poerations.
  • 124. BFS Technology
    Extrusion
    An endless sterile plastic tube is continuously extruded from the melted granulate in the filling cavity of the mould.
    Blowing
    • Final container is produced by sterile air pressure from Blow and Fill nozzle.
  • BFS Technology
    Filling
    After the container is formed inside the mould, sterile liquid product is introduced into the container.
    Sealing
    • Final container is sealed in place by closing of the seal-mould form onto the container top.
  • BFS Technology
    Mould opening
    Upon completion of filling and sealing steps, the mould is separated, producing the sterile filled and sealed container.
  • 125. ADVANTAGEOVER CONVECTIONAL ASEPTIC FILLING
    There is no need to purchase and stock a range of pre-fabricated container and closures.
    Cleaning and sterilizing pre-fabricated container and closures are not required. A clean sterile container is made with in the BFS machine.
    The cost of material transport, storage and inventory controlis reduced.
    Validation requirement are reduced.
    There is a large choice of neck and opening device shapes.
    Saving floor space.
    Less labourintensive than conventional one.
    Thecode number and variables can be mouldedinto container it-self
    With blow-fill-seal, you produce a one-piece, aseptically filled container with a built-in safety seal..
    The blow-fill-seal process is suitable for heat-sensitive products.
  • 126. .
    Asep-Tech ® Model 603 Blow/Fill/Seal Packaging Machine System
  • 127. QUESTIONS ASKED
    Differentiate Master formula record (MFR), Batch manufacturing record (BMR) and standard operating procedure (SOP) by giving a suitable example of a compendia injection product (MARCH- 2004 ).
    Give qualitative and quantitative lay out, manufacturing steps with suitable equipments, important IPQC parameter, and packaging records and post marketing surveillance reports for sterile products. (JULY- 2004 )
    Discuss the department layout, schedule ‘M’ requirement, validation parameters, and PMS report for sterile LVPs?(29th September, 2004 )
    What is the importance of Bio film removal on product quality?( march 2005)
    What are the facilities, environment control and air handling system with different types of classification ?( march 2005)
    Discuss clean room concept and level of protection in brief?(2005)
    How will you evaluate the package for different sterile DF? Give the legal requirement for keeping their records and reports? (sep 2006)
    Discuss the qualities , national ,international standard for clean room? Discuss the pressure differential in the pharma. plant ?(sep 2006)
    Validation of the steam sterilizer and importance of the D, Z, F value? (sep 2006)
    QC. Of aseptic area (may 2003)
    Give detail lay-out of SVP and area and equipment requirement as per CGMP ? (may 2003)
  • 128. REFERENCES
    1. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon Lachman, Vol-1.
    2. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon Lachman, Vol-2.
    3. Drugs & Cosmetics Act 1940.
    4. The theory and Industrial pharmacy by Leon Lachman, Third edition
    5. Pharmaceutical science by Remington, 20th edition
    6. Pharmaceutical process Validation by Loftus & Nash: 29-90.
    7. Sterile Pharmaceutical Manufacturing by Groves Gisan.
    8. www.fda.gov.
    9. American Journal of Hospital Pharmacy, Vol. 38, Issue 8, 1144-1147
    10. Dispensing for pharmaceutical students; 10 th edition; by:-S J Carton
    11.www.GMP.online.coms
    12.www.ispc.org
    13.www.whqlibdoc.who.org
    14.www.dwscientific.co.uk
    15.www.pharmamachines.com
    16.www.bascotech.com
    17.www.getthatmag.com
    18.www.fabtecheng.com
    19.www.ahind.com
    20.www.nkambica.com
  • 129. THANK YOU

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