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

1. PARENTERALS MANUFACTURING LAYOUT EQUIPMENTS Swapnil Sanghavi

3. PARENTERAL

4. IRRIGATING PREPARATION

5. DIAGNOSTIC AGENTS

6. ALLERGIC EXTRACTS

7. SURGICALS

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

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.

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 pHNo absorption is necessary

23. and package components

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

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.

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.

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.

68. Automatic Intelligent Light Inspection Machine

70. Transferred through an intermittent transport section.

71. liquid filling section which fill the vials with predetermined quantity.

73. Vial Inspection Machine

74. Vial Labeling Machine

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 MachinePharmaceutical 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.

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)

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.

100. Volume filled

101. Temp for heat sterilized product

102. Environmental control tests

104. Pyrogen test

105. Particulate test

106. Sterility test.

107. Uniformity of weight.

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

113. Expensive

114. Laborious

115. Dose dependent.

117. 5 particulates of 25 μm per mlLight 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.

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