PARENTERALSINTRODUCTION Parenterals :- are Sterile, Pyrogen free preparations injected through skin or mucous membrane into internal body compartment. Parenteral products A. IV Admixtures consist 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 toxicity when given by direct IV injection. B. 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 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: o Used as vehicle in IV admixtures and fluid for electrolyte replacement. ▶ Bacteriostatic sodium chloride for injection: o It contains an agent that inhibits bacterial growth (e.g. Benzyl alcohol, Propyl paraben. Methyl papaben), allowing its use in multiple dose preparation. 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. C. Electrolyte preparation ▶ Ions present in both intracellular and extra cellular 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. D. Dialysate ▶ Used in patients with disorder as renal failure, poisoning, 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. E. 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. GMP Requirements for Sterile Products ▶ Specific points relating to minimizing risks of contamination. – – – Microbiological Particulate matter Pyrogen General Requirements ▶ Production in clean areas ▶ Airlocks for entry – Personnel entry. – Material entry ▶ Separate areas for operations – – – – Component preparation Product preparation Filling Sealing etc… ▶ Level of cleanliness ▶ Filtered air ▶ Air classification: Grade A, B, C and D. ▶ Laminar air flow: – Air speed (horizontal versus vertical flow) – Number of air changes – Air samples ▶ Conformity to standards ▶ Work station and environment ▶ Barrier technology and automated systems . Filters having nominal pore size 0. and then brought together. and closure have low bio-burden. 2.Types of sterile products processing 1 Terminally sterilised → prepared.Fresh outside or recycled air must be first filtered to remove particulate matter and than HEPA filters are used to get CLASS-100 air systems. containers.In area occupied by personal. In most cases. the air must be exchanged with the frequent intervals. Terminally sterilised:. Sterilisation by Filtration:o o o o o o Previously sterilized container are taken. filled and sterilised 2 Sterilised by filtration 3 Aseptic preparation Manufacture of sterile preparations 1. components. but they are not sterile. Aseptic Preparation :. as appropriate. the product.In an aseptic process. The product in its final container is then subjected to a sterilization process such as heat or irradiation. Products are filled and sealed in this type of environment to minimize the microbial and particulate content of the in-process product and to help ensure that the subsequent sterilization process is successful. it is critical that containers be filled and sealed in an extremely high-quality environment Before aseptic assembly into a final product.usually involves filling and sealing product containers under high-quality environmental conditions. or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control.22 µm or less are used for filtration Remove bacteria and moulds but Not viruses & Mycoplasmas Double filter layer or second filtration No fibre shedding or asbestos filters Filter integrity testing 3. container. the individual parts of the final product are generally subjected to various sterilization processes. and closure are first subjected to sterilization methods separately. the drug product. SPECIFIC REQUIREMENTS FOR MANUFACTURE OF PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES AND LARGE VOLUME PARENTERALS) . Note:. Any manual or mechanical manipulation of the sterilized drug. Because there is no process to sterilize the product in its final container. container. →Operations like removal of outer cardboard wrappings of primary packaging materials shall be done in the de-cartoning areas which are segregated from the washing areas. floors and ceiling-impervious. fiberboard drugs. →The manufacturing areas-clearly separated into support areas & preparation areas. air. washable and made of stainless steel or any other appropriate material [3] Garments →The garments-made of non-shedding and tight weave material. →Design-include a hood (head-cover) or a separate hood which can be tucked inside the over-all.As per schedule –M . single piece with fastenings at cuffs. provided with a cove both at the junction between the wall and the floor & wall and ceiling. → Light-fittings and air-grills-shall flush with the walls and not hanging from ceiling. non-flaking and non-cracking. being very critical and sensitive in nature a very high degree of precautions.Sterile products. → Doors & Windows-made of non-shedding material preferably Aluminium or Steel material. [1] General :. → The furniture-smooth. .Dampness. shall be such that their servicing or repair shall not pose any threat to the integrity of the facility. neck and at legs to ensure close fit. Water lines shall not pose any threat of leakage to any of the manufacturing area. cardboard and other particle shedding materials shall not be taken inside the preparation areas. →Gloves-made of latex or other suitable plastic materials & long enough to cover wrists completely and allow the over-all cuff to be tucked in. Trouser legs shall be tucked inside the cover boots. prevention are needed for it‟s preparation. non-shedding. [2] Building and Civil Works: – →The building-built on proper foundation with standardized materials →Location of services like water. dirt and darkness are to be avoided to ensure aseptic conditions in all there shall be strict compliance in the prescribed standards especially in the matter of supply of water. General points to be in consideration for ASEPTIC Areas → Walls. Doors shall open towards the higher-pressure area so that they close automatically due to air pressure. → Flooring-unbroken. Epoxy should done in aseptic area. Walls-shall be flat. steam. active materials and in the maintenance of hygienic environment. Zips (if any) shall be of plastic material. →Wooden pallets. gases etc. Disadvantages: 1. →All the production equipment has container size limitations.→footwear. .Economically undesirable because it is labor intensive and does not exploit the economies of volume. Disadvantages: 1. production time. daily cleaned with a bactericide. Advantages: 1.Product quality. Advantages: 1. 2). Production documentation is easy. Minimizes shortcoming of batch operations. 2. Since the intermediate material handling steps are eliminated. it requires more space and more complex equipments.of suitable plastic or rubber material. 2. labor.large container requires large equipments and more space. →Garment changing procedures shall be documented and operators trained in this respect. [4] Area planning: 1). Continuous operations: it is suited to very high volume production requirements. the potential for product contamination during those steps no longer exists. Container size →SVPs and LVPs obviously requires different space considerations. and environmental exposure of the product. Type of production Depends on Batch operations: suited to small production volume & minimum financial investment. consistency. and homogeneity are relatively easily controlled. Product quality assurance is difficult. 2. It is very difficult to document the ingredients or process cycle for a product produced in a continuous process. 3). and pump system. Environment control needs 4). . Suspension will require a means of maintaining a homogenous mixture prior to filling.filling rate should be kept high and the distance from compounding to filling should be minimized. 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. reservoir. To minimize the time the suspension resides in piping. locker rooms. or other areas as may be required to prepare the personnel for the cleaner area. In a parenteral plant degree of access should be restricted.014 1.094 7. and increase the problems of maintaining a clean environment.0 6). increase security problems.1 0. Space requirements [QUANTITATIVE LAYOUT OF PARENTERAL MANUFACTURING ] FUNCTION Square meter Production Warehouse Utility Quality control Administration Maintenance Employee services Security Total 11.9 4. yet may give excellent view of process. Personnel Movement The movement of personnel should be planned during the design of individual plant areas. Discontinuous and crowded flow patterns can decrease production efficiency.1 4.607 Area Percentage 45.5 4.9 100. Personnel flow path from zone to zone must be such that access to higher level of cleanliness is only through change rooms. A glassed mezzanine or balcony provides absolute isolation.5).1 30. gowning rooms. particularly in critical area.0 4.716 1.014 39 24.606 1.018 1. Planning for visitors and nonproduction employees in advance can prevent or lessen many future problems.716 1.1 7. . Adequate personal flow and restricted access to aseptic and critical environment. Black zone:-Storage. Worst area from contamination view point Environmental control : Sources Control People Total body covering in critical area and partial covering in non critical area. Adequate sterilization procedure Barrier Protective laminar flow equipment Barrier and separation between high risk and low risk operation. Zone 4:. cleaning.Warehouse Zone 1:. Zones as per Gazette of India WHITE BLACK GRAY ZONES AS PER GAZZETE OF INDIA White zone:-Final step ( filling of parenteral) Grey zone:-weighing.Filling area Zone 5:. Minimum movement of personal. AIR HANDLING SYSTEM (AHU) CRITICAL AREAS Aseptic feeling area Sterilized component unloading area Change room GRADES B C D . and sterilization of machinery and equipment Adequate material control and selection Material Adequate sterilization and filtration procedure Adequate air filtration system Air Adequate monitoring of air cleanliness level.Filling line Zone 6:. Adequate air system validation procedure.Exterior 1st. Adequate operation procedure for personal.Clean area Zone3:-General production Zone 2:. Zones as per the cGMP: Zone 7:.[5] Environmental control zone groupings 1st.Weighing. Adequate operation procedure to assure proper handling. mixing & transfer area. Dissolution & filtration. 000 35.300 Not defined (c) A B (a) C (a) D (a) Notes : (a) In order to reach the B.5 or ISO Class 5. Grade C with Class 10. The air system shall be provided with the appropriate filters such as HEPA for Grade A.52. TABLE I AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS.000 5µm 29 293 2.5 or ISO Class 7. the maximum permitted number of particles in the “at rest” condition shall approximately be as under: Grade A corresponds with Class 100 or M 3.000 Not (c) defined 5µm 29 2.930 29.5 or ISO Class 8. C and D air grades.52. TABLE II TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS Grade A B C D Types of operations for aseptic preparations Aseptic preparation and filling Background room conditions for activities requiring Grade A Preparation of solution to be filtered Handling of components after washing .20.5µm 3500 3. B and C.000 or M 5.000 35. (b) The requirement and limit for the area shall depend on the nature of the operation carried out.200 3.000 or M 6. Grade B with Class 1000 or M 4.930 29. Grade D with Class 100. Grade Maximum number of permitted particles per cubic metre equal to or above.20.5 ISO Class 6.The filter Configuration in the AHU shall be suitably designed to achieve the Grade of air as given in Table1. AT REST IN OPERATION 0.5µm 3520 35. the number of air changes shall be related to the size of the room and the equipment and personnel present in the room. (c) Type of operations to be carried out in the various grades are given in Table II and Table III as under.300 0. 52.000 29.0µm A 3. preparations of solutions and components for subsequent filling D The recommended frequencies of periodic monitoring shall be as follows(As per Schedule .500 29 B 35. 90mm.5µm 5. Filling of product when unusually at risk.300 D 35.520 1e 1e 1000 6 35. Filling of products.5 µm Clean Area ISO Microbiological Microbiological Classification Designation particles/m3 Active Air Settling Plates (0.M) :Particulate monitoring in air 6 Monthly Air change rates 6 Monthly HEPA filter integrity testing (smoke testing) Yearly Air Pressure differentials Daily Temperature & Humidity Daily Microbiological monitoring by settle plates and/or swabs in Daily aseptic areas AIR CLASSIFICATION AS PER CDER – Centre For Drug Evaluation & Research: >0.000 7 352. preparation of solutions when usually at risk.520.000 2. blowing (pre-forming) operations of plastic containers.20. cfu/4 hours) 100 5 3.930 35.300 Not defined not defined .000 10 5 100.000 29. which are usually at risk Placement of filling and sealing machines. Air Classification as per Schedule M Grade Maximum permitted number of particles/m3 equal or above at rest in operation 0.000 2.520 29 3.000 100 50 1.20.d particles/ft3) Levelsc(cfu/m3 ) (diam.200 7 3 10.5µm 5.52.200 293 3.930 C 3.TABLE III Types of operations to be carried out in the various Grades for terminally sterilized products.000 8 3. Grade A C Types of operations for terminally sterilized products.0µm 0.5 um Action Action Levelsc. Moulding. 000 Microorganisms <1 5 100 500 4.5 (preparation) M 6.5(filling) M 4.5 35 350 3500 Class(SI) M 3.2.000 <25 <88 3. thus maintaining the necessary air pressure differential to prevent the entry of airborne contamination.500. CHANGE ROOM Entrance to a change room is normally through vestibules whose doors are electrically interlocked so that both can not open simultaneously. Air Classifications as per ISO Grade ISO Class A 5 100 B 6 1000 C 7 10000 D 8 100000 Particle/cum 3.5 3) DESIGN CONCEPTS 1.5 µm <0.5 µm Classification Particles/ft3 Particles/mt3 cfu/ft3 cfu/m3 100 100 3.500 <1 <3 1000 1000 35.500 3.000 3. Air Classifications as per WHO 2002 Grade Maximum Number Permitted / M3 Particles A (LAF) B C D 0.500 3.50.5 M 5.000 5. Automatic or foot operated controls for water and soap eliminate hand contact with contaminated surfaces.500. wash sinks are provided for scrubbing hands and forearms. Air Classifications by USFDA guideline on Sterile Drug Products Microbiological Limit Clean Area <0.000 <2 <7 10000 10000 350. .0µm 0 0 2.000 20.5µm 3. Upon entry in the change room.000 <3 <18 100000 100000 3. where the product & sterilized components are exposed to room environment. Special filtered driers are available to minimize the creation of particulate contamination. 2. aseptic gloves are put on and sanitized. As a final gowning step. . FILLING AREA: It is the most critical area in parenteral plant. Therefore these areas are specially constructed. and maintained to prevent environmental contamination. filtered. Commercial hand driers may create undesired airflow patterns. After the hands are dry. hands are dried by hot air blowers. garments are taken from dispensers and donned while moving across a dressing bench. Next. & humidity controls appropriate to the product being manufactured.97%. constructed and used in such a way as to reduce the introduction. Counters in the clean room should be made of stainless steel or other nonporous. The velocity of the air flow is 90 ± 20 ft/m3. HEPA filters are to clean the air entering the room. The air flow should move with uniform velocity along parallel lines. Maintaining higher air pressure(+ve pressure) within the critical area to minimize infiltration of airborne contaminants from outside. HEPA filters remove all airborne particles of size 0. LAY OUT OF CLEAN ROOM STANDARDS FOR CLEAN ROOM . Adjacent rooms of different grades should have a pressure differential of 10 . operation or equipment to a zone of higher product risk. Care should be taken to ensure that air flows do not distribute particles from a particle-generating person.3 or larger with an efficiency of 99. generation and retention of contaminants within the area QUALITIES OF CLEAN ROOM The room should undergo 15-20 air changes per hour. easily cleaned material. epoxy paint is used. Walls and floors should be free from cracks or crevices and have rounded corners. If the walls or floors are to be painted. Providing temp. CLEAN ROOM An area with defined environmental control of particulate and microbial contamination. A warning system should be provided to indicate failure in the air supply.15 Pascals. 3m m 0.0 35 350 NA NA NA NA 7.000 NA NA NA 7 70 700 Selected ISO 209 airborne particulate cleanliness classes for cleanrooms and clean zones. numbers (N) ISO ISO ISO ISO ISO ISO ISO ISO ISO 1 2 3 4 5 6 7 8 9 Maximum concentration equal to and larger than 0.Federal Standard 209 CLASS 1 10 100 1.5 75 750 NA NA NA 3 30 300 NA NA NA 1 10 100 1.000 MEASURED PARTICLE SIZE (MICROMETERS) 0.000 100.2m m 10 2 100 24 1 000 237 10 000 2 370 100 000 23 700 1 000 000 237 000 limits (particles/m^3 of air) for particles the considered sizes shown below 0.000 10.2 0.000 10.5m m 1m m 5.3 0.1 0.5 5.0m m 10 102 1 020 10 200 102 000 4 35 352 520 200 000 000 000 3 35 352 3 520 35 200 8 83 832 8 320 8 83 832 320 200 000 000 29 293 2 930 29 300 293 000 .000 100.1m m 0. QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (circular flow) QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (parallel flow) . Exit Unidirectional Clean Zone Soln Prepn Area Material Entry Aseptic Filling zone Clean Changing Room Oven Auto clave Aseptic Receiving Area Equipment & Component Prepn Area Entry Hatch Comp. Entry .LAYOUT FOR TERMINAL STERILIZATION Pdt. Water still. o Laminar air flow velocity satisfactorily sweeps the area yet does not create unacceptable turbulence. particles may be driven into product. o For laminar air flow work station the air flow rates shall be 0. 1. Mixing equipment where necessary. and material into the work area provides sources of particulate matter which may contaminate the product.and if there is turbulent air. Bacteriological filters. 10. Filtering equipment.3 meter per second (vertical) and 0. Dust proof storage cabinet 4. Straining or Sieving 2. 7. . vials bottles and closures. 11. equipment. Interception 4. 2. o Very small particles are not heavy enough to settle due only to the force of gravity. Laminar air flow hoods are generally used in conjunction with clean rooms.3. LAMINAR AIR FLOW UNIT o HEPA (HIGH EFFICIENCY PARTICULATE AIR filtration) HEPA Filter HEPA filters are composed of a mat of randomly arranged fibers (polyvinylidene fluoride -PVDF) Key metrics affecting function are fiber density and diameter. Benches for filling and sealing. Washing and drying equipment. Mixing and preparation tanks or other containers. 3. Diffusion Laminar flow hoods: These are clean air work benches are specially designed to ensure the aseptic preparation of sterile products. b) Aseptic filling and sealing rooms 9. Filling and sealing unit under laminar flow work station. Impaction 3. LIST OF EQUIPMENTS( as per schedule-M) The following equipment's is recommended: a) Manufacturing area: 1.45 (horizontal) o Introduction of personnel. Storage equipment for ampoules. 8. 5. and filter thickness There are four basic mechanism in which fibrous air filter remove contamination from the airstream. 6. Hot air sterilizer. but instead are carried and directed by air currents. Storage of equipment including cold storage and refrigerators if necessary. 12. 13. Leak testing table. Because glass particles may become dislodged during ampoule opening. the product must be filtered before it administered. Multiple withdrawals(as with multiple-dose vials)may result in microbial contamination. Prefilled syringes -These designed for quickest administration and maximum convenience. ampoules are opened by breaking the glass at a score line on the neck. This system eliminates the need to enter the vial twice.epinephrine) may be available for immediate injection when packaged in prefilled syringes. Ampoules: They are intended for single use only. external pressure is applied to the outer rubber closure. They can be designed to hold multiple doses (if prepared with a bacteriostatic agent).and large volume parenterals (LVP).. those . is recommended for the basic installation. It is easier to remove the product. 14. They eliminate the risk of glass particle contamination during opening. those having a volume of 100 ml. An area of minimum sixty square meters partitioned into suitable sized cubicles with air lock arrangement. Labeling and packing benches. Types of containers: 1.g. 2. 15. (b) To dislodge the inner closure and mix the contents of the compartments.c) General Room. Advantages over ampoules. Drawbacks The rubber stopper may become cored. Infusion solutions are divided into two categories : small volume parenterals (SVP).atropine. 3. Vials are glass or plastic containers are closed with a rubber stopper and sealed with an aluminum crimp.(a) The top chamber containing sterile water for injection is separated from the unreconstituted drug by a rubber closure. Some of this drugs come in vials that contain a double chamber. thereby reducing the risk or microbial contamination. the need to filter solutions before use and other safety considerations have markedly reduced ampoule use. 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. Inspection table. 4. Because of their unsuitability for multiple-dose use. Drugs administered in an emergency (e. Ampoule Washing Machine PROCESS Water is sprayed onto the ampoules. These cabinets may be designed in horizontal air flow system and clean air through HEPA filters Syringe Filling Machine Characteristics • Barrier isolators • In-process check weighing • Filling : rotary piston pumps. EQUIPMENTS Sterile Garment Cabinet Made up of Stainless steel.having a volume of 100 ml or greater. Finally the ampoules are filled with compressed air to remove residual water. liquid filling section which fill the vials with predetermined quantity. Ensure a clean storage space by making use of UV disinfectant and heating through IR lamps. • Handling various biological solutions and mixtures requires cleaning and sterilizing these equipments from time to time as they are susceptible to contamination.2 to 29 ml • All types of syringe including glass. Infusion solutions are used for the intermittent or continuous infusion of fluids or drugs. viscous material and suspensions and powders. Certain machines have a high temperature zone meant for killing any bacteria. PROCESS The machine comprises of an intake section which loads the vials. • Proper SIP integration with pharmaceutical equipment is very important for the overall success of the operation. Turned to an angle of 180 degree with their mouth downward to remove water. . Finally the filled and rubber stoppered vials are released and discharged. • Filling Rate: 300 to 600 syringes in a minute. • Volume: 0. Vial Filling Machine • Fill vials and bottles • liquids. SIP System • For in-line sterilization of various processing equipments. plastic can be filled. Transferred through an intermittent transport section. 536 – 99. • These filters have been qualified to withstand at least 40 SIP cycles at 135 °C for 30 minutes.aeroginosa etc. FILTERS IN FILTRATION STERILIZATION Millipore’s Airvent filters • Constructed with a PTFE membrane. • Result:.992-100% after 24 h in all cases. p.999% after 4 h exposure. 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.The silver-zeolite mixture reduced microbial colony-forming units upto 84. 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 Bubble Point Test .aereus.e. and upto 99.coli. • Test against. s. . Record the pressure to the nearest 0. 5.O. • To built sterility in the product. Connect solution tank to the inlet of the filling assembly. gradually increase the pressure to the test filter using the pressure regulator. 3. 4. Switch on the machine. 6. 8. Wet the filter to be tested with the appropriate solvent (water for hydrophilic filters. Three principle involved in validation process. filling assembly and tubing on LAF bench. 7. • To provide greater assurance and support to the result of the end product sterility. alcohol for hydrophobic filters).5 psig as indicated on the pressure gauge. 2. Starting from zero pressure. Place the wetted filter in the appropriate housing. S. STANDARAD OPERATION PROCEDURE For aseptic filling: Check all sterilized material has indicator and expiration date. Note the rate that the bubbles appear for the end of the submerged tube. Connect the nitrogen over lay in tank for pre and post flushing.Test Method 1. Record the filter part number(s).P FOR OTHER MENUFACTURING PROCESSES IS SAME AS THAT OF NON STERILE DOSAGE FORMS VALIDATION Purpose: To minimize this reliance on end product sterility testing. Connect the tubing of filling lines. Pump the solution in filling tubing up to the filling nozzle (remove any air bubble) After that wipe the filling nozzle with 70%alcohol. and product information. Observe the submerged end of the tubing for the production of bubbles as the upstream pressure is slowly increased in 0. Connect a piece of flexible tubing from the downstream port of the test filter into a beaker filled with water.5 psig increments. • To demonstrate the maximum level of probability that the processing and sterilization method have establish sterility to all units of product batch. Connect the outlet fitting from the compressed air pressure regulator to the upstream side of the test filter. The bubble point of the test filter is reached when bubbles are produced from the tube at a steady rate. lot number. Open sterilized container. Also include physical observations. (iii). To pass the test not more than 0. (i). Procedure Sterile Trypticase soy broth is filled into sterile container under condition simulating as for a product. Sulphated ash. Biological test. Test for hydrolytic resistance. In Process Quality Control Test Conductivity measurement Volume filled Temp for heat sterilized product Environmental control tests Visual inspection . Heavy metals.It includes a) Pre-processing quality control test b) In process quality control test c) Finished product quality control test Pre-processing quality control test a) Raw material testing and assays b) Packaging material test (glass. the operator and the equipment is the media fill. (iv). Arsenic test. For Glass containers. (b). Entire lot at least 3000 units is incubated at suitable temp for 14 days . (ii). plastic. (ii). For Plastic container. (Adverse reaction or toxicity) Media fill (process simulation test) Evaluation of the environment along with the process. rubber etc) c) sterility test and media fill (process simulation test) Tests for containers (a). (v). Non volatile matter. Buffering capacity. This is very stringent evaluation of an aseptic fill process and is considered to be the most evaluative test available. (i).1% of the unit may show growth. In presence of Endotoxin a firm gel is formed within 60 min when incubated at 370 C. Particulate test USP Visually inspected.Qualitative fever response test. Not for anti pyretic drug.all (WHITE AND BLACK ) Any with visible particle is discarded. o CHARACTERISTIC • Test tube scale. Disadvantage Leakage of 15 micron in diameter or smaller is not detected. LAL test Limulus Amoebocyte Lysate test or bacterial Endotoxin test for the validation of depyrogenation process. • Sensitivity varies with different microbial source of LAL. • In-vitro test.Fever response of rabbit • Sham test is performed to select the proper animals for the main tests. Reagent . Generally combined with autoclave. • Semi quantitative test.LAL reagent (limulus Polyphemus) Reaction . • Sensitivity in terms of Endotoxin unit.1% FDC red one or red two. Procedure • Test solution is injected into the vein of rabbit. • Doesn‟t measure fever producing potential of Endotoxin. Disadvantage Biological variation Expensive Laborious Dose dependent. Temperature elevation is seen for 3 hrs. Uniformity of weight. Vial and bottles are not subjected to this test. Principle 10% methylene blue or 0. • Rabbit test . • Only pyrogen of gram negative bacteria detected. . Finished product quality control test Leaker test Pyrogen test Particulate test Sterility test. Pyrogen test. Uniformity of content Leak test • To detect incompletely sealed ampoules. Microscopic particle count test USP requirements for packaging. This manufacturing technology includes economies in container closure processing and reduced human intervention . Large volume parental 50 particles of 10μm 5 particulates of 25 μm per ml Particulate count is done by: 1. • In case of multiple dose container dose should not be more than 30 ml. and sealed in a continuous operation. filled. • Single dose container should not be more than 1 liter. BFS Technology Blow-fill-seal (BFS) technology is an automated process by which containers are formed. • Intra-spinal and intra-cisternal administered product must be in single dose container. Light obscuration particle count test 2. • Less labour intensive than conventional one. • With blow-fill-seal. • Validation requirement are reduced. Extrusion • An endless sterile plastic tube is continuously extruded from the melted granulate in the filling cavity of the mould. A clean sterile container is made with in the BFS machine. List of equipments:. • The cost of material transport. producing the sterile filled and sealed container. the mould is separated.Most BFS machines operate using the following steps.(mostly utilized in industry) Asep-Tech® Model 603 Blow/Fill/Seal Packaging Machine System PKV316 Vial and BFS container for Leak Detector Single chamber Autoclave Unit STERILIZER Sterilizing Tunnel • . • Saving floor space. Sealing • Final container is sealed in place by closing of the seal-mould form onto the container top. Filling • After the container is formed inside the mould. 5. Mould opening • Upon completion of filling and sealing steps. 2. • The blow-fill-seal process is suitable for heat-sensitive products. • There is a large choice of neck and opening device shapes. ADVANTAGE OVER CONVECTIONAL ASEPTIC FILLING There is no need to purchase and stock a range of pre-fabricated container and closures. Blowing • Final container is produced by sterile air pressure from Blow and Fill nozzle. 4. 3. sterile liquid product is introduced into the container. you produce a one-piece. 1. • The code number and variables can be moulded into container it-self. storage and inventory control is reduced. • Cleaning and sterilizing pre-fabricated container and closures are not required. aseptically filled container with a built-in safety seal. __________________________ Room________________________________ date exposed_____________________ Media__________________________ Date Time Incubation Temp. Humidity (in substances) case of hygroscopic Plate no Duration Location No. of colonies .Master formula records Name of the product________________________________________ Name and Weight of API ____________________________________ Name and Weight of Ingredient _______________________________ Description of equipment ____________________________________ Statement of theoretical yield_________________________________ Process and packaging procedure_____________________________ A description of container____________________________________ closure and packaging material _______________________________ In process control during processing ___________________________ In process control during packaging____________________________ Precaution to be taken______________________________________ Environmental control Product_______________________________ lot no. Of officer_______________________________________________ If sterilized by dry heat or autoclave: . date _____________________Date of expiry_________________ Requisition slip Sr no Ingredients Item code Standards ATR no Label claim Qty required Qty issued Preparation of equipment & containers Description of containers _______________________________________ Q/C report of container ________________________________________ Date ________________________ Equipment used__________________ Cleaning agent used ___________________________________________ Cycle of washing: _____________________________________________ Sign.Batch Manufacturing Records Name of the company:-_______________________________________ Address:-___________________________________________________ Name of the product _________________________________________ Active pharmaceutical ingredient ______________________________ M F R No. __________________________________________________ Batch No._____________________ Batch size ____________________ Mfg. Visual inspection: Description ________________________________________________________ Total no of filled. attained Temp. sealed & sterilized containers rejected __________________ Nature of defects ____________________________________________________ Name of worker who examined: . Of officer_______________________________________________ Time Filling started Filling completed IPQC records 1. Time when oven switched off Filtration & filling:Equipments used for filtration ___________________________________ Date__________________________ Time_________________________ Result of test or analysis of solution_______________________________ Equipment used for filling_______________________________________ Date________________________________________________________ Sign.Articles Date Time when started oven Desired temp. _______________________________________________ (ii). Printed packaging material received __________________________________ Result of bulk finished products ________________________________________ Sign. Of officer _____________________________________________________ Reconciliation of labeling and packaging material Quantity of material received___________________________________________ Quantity of material destroyed__________________________________________ Quantity of material used _____________________________________________ Quantity of material returned___________________________________________ Date of release____________________ quantity release____________________ Signature of supervisor _______________ QAQC records . _______________________________________________ Batch Packaging & Labeling Records Product name_______________________ Batch no _______________________ Strength___________________________ batch size ______________________ Category___________________________ mfg date _______________________ MFG no____________________________ exp date _______________________ Batch Packaging & Labeling Records Description of packaging______________________________________________ Pre-coding of labels & printed packaging materials.(i). ________________________________________________ (ii). of pre-coded ____________________________________________________ (ii). examined & verified by _______________________________________________ No. Sterility “The reduction of anticipated levels of contamination in a load to the point where the probability of survival is less than 10-6. and filtration. irradiation. introduced into upstream of HEPA filter followed by scanning the entire downstream . 1. created by blowing air through liquid Dioctyl phthalate.” Examples of sterilization methods are : steam treatment at 121℃. Linen ----by means of steam under pressure of 15 .Visual inspection records 2.97%.” EQUIPMENT Single chamber Autoclave Unit Steam Sterilize Item: Surgical Instruments Dressing materials.1.20 PSI (Adjustable) HVAC Validation Features of HVAC affect product quality (sterility). that destroys or eliminates all viable microbes including resistant bacterial spores from a fluid or a solid. flushing with a sterilizing solution such as hydrogen peroxide (H 2O2) or ozone (O3). Pyrogen test Sterilization “The act or process.3 in size with an efficiency of 99. physical or chemical. Uniformity of weight 4. C) Integrity testing: A popular method for certifying integrity of filter installation uses polydisperse aerosol. Uniformity of content 3. HEPA integrity a) Certification: by filter manufacturer indicates that filter is capable of removing all particulate matter equal to or greater than 0. dry heat at 230℃. Injection liquids. b) Installation: a certified filter if improperly installed will not perform its function & provides a false sense of security. Specially used for thermal destruction processes. d) Airflow resistance : Caused by dirty filter may reduce airflow volume. F-VALUE AND Z-VALUE 1) D value: Quantitative expression of the rate of kill of the microorganism . B is the slope of the linear line in the graph D value is of the linear slope: D=1/B FRACTION NEGATIVE METHOD:. Airflow resistance is expressed as pressure differential between the air pressure upstream of the filter and the downstream air filter. D. they may begin to lose their physical integrity or rupture. If the filters are not changed when they reach the maximum resistance as specified by manufacturer. SURVIVOR CURVE METHOD:. The Z value is the reciprocal of the slope resulting from the plot of the logarithm of the D value was obtained.VALUE . gas concentration etc Log N =A + Bt. thereby releasing some of the dust they have accumulated. thereby reducing the air change rate in critical areas.uses replicate samples containing identical spore population treated in identical manner and determining the number of sample still showing growth following treatment and incubation. . -it is not applicable to ethylene oxide sterilization.N is number of surviving organism.Temp.of filter face with a probe nozzle of an aerosol photometer.The time or dose required for the one log reduction in the microbial population.Airborne particle control Particle count surveys should be performed at regular intervals. Required for one log reduction in D value. 2. → Small leaks can be repaired with a suitable silicone based compound without removing filter. →This testing will indentify “leaks” caused by damage due to mishandling faulty construction. Where: . 2 ) Z value:-for validation of heat sterilization process. Validation of the steam sterilizer a) Validation on the basis of microbial death kinetic.based upon plotting the log no of surviving organism versus and independent variable such as time. A is the y intercept. determination & recording of heat distribution within the chamber is of prime importance. Procedures Steam Dry heat Gas Species B.4-5 3) F value:-The equivalent time at temp T delivered to a unit of product calculated using a specified value of z.Subtills var. METHODS USED FOR VALIDATION 1) PHYSICAL METHODS 2) BIOLOGICAL INDICATORS 3) CHEMICAL METHODS Z=(T2-T1/LOGD1-LOGD2) 1) PHYSICAL METHODS A. The most commonly used equipment consists of the resistance temperature detectors or thermocouples measuring systems. F0 is equivalent time at temp of 121oC delivered to a unit of product calculated using a specified value of z equal to 10. 2) BIO-INDICATORS FOR VALIDATION OF STERILIZER Bio-indicators are preparations of microorganisms innoculated into the product.Dosimeters for radiation sterilization Perspex (Polymethacrylate) strips.its current application is limited to steam sterilization. ▶ II) Media fill (process simulation test) Evaluation of the environment along with the process. .FOR SPORES. or suspended in a liquid medium and sealed in ampoules for steam sterilization. niger B.PRESSURE SENSOR They should be chosen to fit the purpose of the instrument C.MEASURING DEVICES FOR HEAT: For heat sterilizers. Sporogenes B. niger .REFERENCE TEMP T. adsorbed onto paper strips or glass beads. stearothermophilus Cl. F0=Δt Σ10 (T-T0)/Z T0. subtilis var. including autoclaves and dry heat sterilizers. B.10-15 NON SPORES. the operator and the equipment is the media fill.PRODUCT TEMP Where Δt time interval between product temp measurements T. Temperature set point for validation_________ 7. Revalidation date:_____________________ 5. 2.Radiation B. Mechanically checking. Dependability. Temperature range for validation___________ 8. RESULTS SUMMARY SHEET 1. B. pumilus. Location: Building_____________________ 3. upgrading & qualifying the Sterilizer unit. specification of frequency and types of operation to be repeated at regular intervals. proper installation & lack of Contamination. Validation date:_______________________ 4. Sphaericus 3) CHEMICAL METHODS based on ability of steam. Autoclave identification number:___________ 2. All instruments used in studying the steam sterilizer such as temperature & pressure instrumentations must be calibrated.heat. to alter the chemical &physical characteristic of substances. cereus. BROWN‟S TUBE KLINTEX PAPER BOWIE DICK TEST TEST TABLET FILTER PAPER STRIP VALIDATION PLANS For all sterilization procedures a coherent validation plan should be developed.etc. This plan should include: QUALIFICATION OF THE STERILIZER Installation qualification Operation qualification PRODUCT VALIDATION Compatibility of the sterilization process with the given equipment Development of the sterilization cycle PROCESS VALIDATION Specification of the data to be routinely collected & evaluated Revalidation. Description of process validated____________ 6.e. The autoclave must be checked for quality. VALIDATION OF STEAM STERILIZER 1. Cycle validated_______________________ 9. 3. Validation records stored in archives_________ . i. B. ▶ www.com ▶ www.who.org ▶ The theory and Industrial pharmacy by Leon Lachman. Z. national.co. and packaging records and post marketing surveillance reports for sterile products. How will you evaluate the package for different sterile DF? Give the legal requirement for keeping their records and reports? (sep 2006) 7. What are the facilities. F value? (sep 2006) REFERENCES ▶ www.Give qualitative and quantitative lay out.bascotech.com ▶ www.com ▶ www.Groves ▶ Pharmaceutical science by Remington.10.fda.com ▶ www.online.com ▶ www.dwscientific. Vol-2 ▶ Drugs & Cosmetics Act 1940. Discuss clean room concept and level of protection in brief?(2005) 6. plant ?(sep 2006) 8. by:-S J Carton ▶ www. 20th edition ▶ Pharmaceutical process Validation by Loftus & Nash: 29-90. ▶ www. Validation of the steam sterilizer and importance of the D. international standard for clean room? Discuss the pressure differential in the pharma. Vol-1.fabtecheng. ▶ Sterile Pharmaceutical Manufacturing by Groves Gisan. manufacturing steps with suitable equipments.J. validation parameters. What is the importance of Bio film removal on product quality?( march 2005) 4.ahind.nkambica. 10 th edition. ▶ American Journal of Hospital Pharmacy. important IPQC parameter. Issue 8. 38. Vol.getthatmag. Leon Lachman. Discuss the qualities.uk ▶ www. ▶ Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth Avis. and PMS report for sterile LVPs?(29th September. environment control and air handling system with different types of classification ?( march 2005) 5.com .whqlibdoc.org ▶ www. 1144-1147 ▶ Dispensing for pharmaceutical students. Revalidation records stored in archives________ QUESTIONS BANK 1.ispc. 2004 ) 3. Leon Lachman.2004 ) 2. schedule „M‟ requirement.GMP. Discuss the department layout.gov. (JULY.pharmamachines.coms ▶ Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth Avis. Third edition ▶ Aseptic Pharmaceutical Manufacturing by M.