parenteral part-II

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PARENTERALS MANUFACTURING LAYOUT & Environmental Condition

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Introduction Sterile - Absolute term as the state of freedom from all viable organism. Type of sterile preparations OPTHALMIC PARENTERAL IRRIGATING PREPARATION DIAGNOSTIC AGENTS ALLERGIC EXTRACTS SURGICALS RADIO PHARMACEUTICALS

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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 .

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Aseptic- “without sepsis” Used to designate a practical level of sterility. 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. COMMON TERMINOLOGY

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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. COMMON TERMINOLOGY

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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. 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 SOME IMPORTANT PARENTERAL PREPARATION

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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, Propyl paraben . Methyl papaben ), allowing its use in multiple dose preparation.

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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.

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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.

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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.

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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. Most often this occurs by passive diffusion and is most favourable when the drug has both lipophilic and hydrophilic properties , with the former being predominant. So with nonvascular injection , absorption is also affected by such factors Size and number of blood vessels supplying the tissue, Physical & chemical properties of drug Characteristic of the dosage form as whether it is a solution, suspension or emulsion Nature of vehicle & its pH No absorption is necessary

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Production facilities: Clean- up area Preparation area Aseptic area Quarantine area Finishing and packaging area Sterile area

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S T O C K R O O M COMPOUNDING AREA CLEAN UP AREA ASEPTIC AREA QUARANTINE AREA STERILIZATION STORAGE AND TRANSPORT PACKING AND LABELLING LAY OUT OF PARENTERAL MANUFACTURING AREA

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

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Preparation area: The ingredients are mixed & preparation is prepared for filling Not essential that the area is aseptic Strict precaution is taken to prevent contamination from outside Cabinets & counters: SS Ceiling & walls : sealed & painted

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Aseptic area: Filtration & filling into final containers & sealing is done The entry of outside person is strictly prohibited To maintain sterility, special trained persons are only allowed to enter & work Person who worked should wear sterile cloths Should be subjected for physical examination to ensure the fitness Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or treated with aseptic solution and there should not be any toxic effect of this treatment

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

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Temperature & humidity control Positive pressure air through HEPA filter

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Horizontal Laminar Airflow Cabinet

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Personnel Major source of contamination Specially trained Restriction of number of personnel Protective clothing • Sterile, impervious, non-fibre shedding

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

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

Parameters to be taken into consideration in the Design of a Parenteral Production Facility: : 

Parameters to be taken into consideration i n 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.

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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.

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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 cycle for a product produced in a continuous process.

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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 Provision must be made for Sterilization and Depyrogenation of containers before filling, normally hot air oven or autoclave. Filling requires An aseptic environment with the attendant support rooms Inspection and Packaging

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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

TYPES OF PROCESSING: 

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.

Types of Operations for Terminally Sterilized Products: 

Types of Operations for Terminally Sterilized Products Grade Types of Operations for Terminally Sterilized Products A & B Filling of products, when unusually at risk C Placement of filling and sealing machines, preparation of solutions, when unusually at risk. D moulding , blowing (pre-forming) operations of plastic containers, Preparation of solutions and components for subsequent filling 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

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Grade Types of Opeartions for Aseptic Preparations A Aseptic preparation and filling B Background room conditions for activities requiring Grade A C Preparation of Solution to be filtered D Handling of components after washing 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

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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.

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Environmental control zone groupings 1 7 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 Zones as per cGMP Zones as per Gazette of India WHITE GRAY BLACK White zone :-Final step ( filling of parenteral) Grey zone :-weighing, Dissolution & filtration. Black zone :-Storage, Worst area from contamination view point Zone 7

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Space requirements FUNCTION Area Square meter Percentage Production 11,094 45.1 Warehouse 7,606 30.9 Administration 1,018 4.1 Utility 1,716 4.1 Quality control 1,716 7.0 Maintenance 1,014 4.5 Employee services 1,014 4.1 Security 39 0.9 Total 24,607 100.0

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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 . 1 4 3 2 × Design 1 4 3 2 √ Design

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CHANGE ROOM

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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 .

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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/m 3 . Providing temp. & humidity controls appropriate to the product being manufactured.

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Sources Control People Total body covering in critical area and partial covering in non critical area. Adequate personal flow and restricted access to aseptic and critical environment. Minimum movement of personal. Adequate operation procedure for personal . Barrier Adequate sterilization procedure Protective laminar flow equipment Barrier and separation between high risk and low risk operation . Adequate operation procedure to assure proper handling, cleaning, and sterilization of machinery and equipment Material Adequate material control and selection Adequate sterilization and filtration procedure Air Adequate air filtration system Adequate monitoring of air cleanliness level. Adequate air system validation procedure . Environmental control

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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 wears plastic and rubber material .

Air handling system : 

Air handling system Clean Area Classification <0.5 µm Particles/ft3 <0.5 µm Particles/mt3 Microbiological Limit cfu/ft3 cfu/m3 100 100 3,500 <1 <3 1000 1000 35,000 <2 <7 10000 10000 350,000 <3 <18 100000 100000 3,500,000 <25 <88 Grade Maximum permitted number of particles/m3 equal or above at rest in operation 0.5µm 5.0µm 0.5µm 5.0µm A 3,520 29 3,500 29 B 35,200 293 3,52,000 2,930 C 3,52,000 2,930 35,20,000 29,300 D 35,20,000 29,300 not defined not defined Air Classification as per Schedule M Air Classifications by USFDA guideline on Sterile Drug Products

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Grade ISO Class Particle/cum Class(SI) A 5 100 3.5 M 3.5(filling) B 6 1000 35 M 4.5 C 7 10000 350 M5.5 (preparation) D 8 100000 3500 M 6.5 Grade Maximum Number Permitted / M3 Particles Microorganisms 0.5µm 5.0µm A (LAF) 3,500 0 <1 B 3,500 0 5 C 3,50,000 2,000 100 D 3,500,000 20,000 500 Air Classifications as per WHO 2002 As per ISO

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Class Maximum microorganism 1(A)HEPA filter every where <1 1(B)only at station 5 2 100 3 500 As per British Pharmacopoeial Codex

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& package components

QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (circular flow): 

QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (circular flow)

QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (parallel flow): 

QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (parallel flow)

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Material Entry Sol n Prep n Area Oven Auto clave Equipment & Component Prep n Area Hatch Comp. Entry Clean Changing Room Aseptic Receiving Area Entry Unidirectional Clean Zone Aseptic Filling zone Pdt. Exit Layout for Aseptic Production

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Material Entry Solution Prep n Area Clean Changing area Equipment & Component prep n Area Clean Filling Area Terminal Sterilization lamimar flow Material Entry Solution Prep n Area Clean Changing area Equipment & Component prep n Area Comp. Entry Clean Filling Area Terminal Sterilization Unidirectional Clean Zone Layout for Terminal Sterilization

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Destruction or removal of viable microorganisms Heat - Moist/dry heat Filtration Gas - Ethylene oxide Radiation - UV, ionising 4. Sterilization

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• Utilizes heated, saturated steam, under pressure Steam – facilitates penetration of heat throughout the load by creating changes in pressure on condensation More effective at killing microbes than dry heat i(a). Moist Heat Sterilization (Autoclave)

Possible time-temperature relationships: 

Possible time-temperature relationships Pressure (lb/in 2 ) Temperature ( ° C) Minimum holding time (min) 10 115-116 30 15 121-123 15 20 126-129 10 32 134-138 3

Applications of Moist Heat sterilisation: : 

Applications of Moist Heat sterilisation: Preparations and materials that can withstand the required temperatures Not sensitive to moisture Penetrated by the steam (N.B. with aqueous products water is provided by the vehicle) Generally NOT used for oils, fats, anhydrous powders

i(b). Dry heat sterilization (hot air oven): 

i (b). Dry heat sterilization (hot air oven) 160 °C for >2 hours Can vary this – i.e. higher temp for shorter periods or vice versa Consider size, type of product, heat distribution characteristic Application: Heat-stable, non-aqueous preparations , powders, oils, and dry equipments

ii. Filtration: 

ii. Filtration Removes most bacteria, moulds, and particles, but may allow viruses, small bacteria, and pyrogens to pass through Application: aqueous products that cannot be heat sterilized Cannot be used for suspensions or small volumes of potent drugs Only used when other methods are not suitable

iii. Ethylene Oxide: 

iii. Ethylene Oxide Active against all microbes Activity depends on concentration, temperature, humidity, and length of exposure Application: Suitable for thermolabile + moisture-sensitive substances , and can sterilize a wide range of materials Disadvantages: slow, high running costs, hazards associated with flammability + toxicity, potential production of toxic substances with some materials

iv. Radiation:: 

iv. Radiation: Application: Tends to be used for articles not sterilisable by other methods – syringes, catheters, etc. Not usually used for pharmaceuticals as can cause destruction of product, colour changes, alterations in texture or solubility May be useful for sterilizing vaccines without loss of antigenicity

STANDARAD OPERATION PROCEDURE: 

STANDARAD OPERATION PROCEDURE For aseptic filling :- Check all sterilized material has indicator and expiration date. Open sterilized container, filling assembly and tubing on LAF bench . Connect the tubing of filling lines . Connect solution tank to the inlet of the filling assembly. Connect the nitrogen over lay in tank for pre and post flushing. Pump the solution in filling tubing up to the filling nozzle (remove any air bubble) After that wipe the filling nozzle with 70%alcohol. Switch on the machine. S.O.P FOR OTHER MENUFACTURING PROCESSES IS SAME AS THAT OF NON STERILE DOSAGE FORMS

VALIDATION: 

VALIDATION Purpose : T o 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.

Validation: 

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 )

Tests for containers : 

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)

Media fill (process simulation test):-: 

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. Entire lot at least 3000 units is incubated at suitable temp for 14 days . To pass the test not more than 0.1% of the unit may show growth. 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 : 

In Process Quality Control Test Conductivity measurement Volume filled Temp for heat sterilized product Environmental control tests Visual inspection

Finished product quality control test : 

Finished product quality control test Leaker test Pyrogen test Particulate test Sterility test. Uniformity of weight. Uniformity of content

Evaluation of parenteral preparations: 

Evaluation of parenteral preparations Particulate matter test Leakage test Clarity test Assay pH Identification test Turbidity Content uniformity Weight variation test Sterility test Bacterial endotoxin test (LAL test) Pyrogen test

What is sterile preparation?: 

What is sterile preparation? Sterility – absence of viable microorganism Sterility Testing Particulate matter Clarity Test Pyrogen-free Pyrogen Testing Quality Control

I. Sterility Testing: 

I. Sterility Testing Membrane filtration Direct inoculation of the culture medium II. Clarity Test Visual or automatic inspection for particulate matter Microscopic examination

III. Pyrogen Testing: 

III. Pyrogen Testing Pyrogens are bacterial products such as endotoxin Can cause fever, activate coagulation system, alter carbohydrate lipid metabolism, produce shock and death Main source of contamination of products is water

III. Pyrogen Testing: 

III. Pyrogen Testing i. LAL (limulus amoebocyte lysate) test for endotoxin Utilises extract from blood cells of horseshoe crab Contains an enzyme and protein system that clots in the presence of endotoxin

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Extract from blood cells (Amoebocyte lysate) Enzyme + protein Horseshoe crab (Limulus polyphemus) Endotoxins ~ 30 mins Coagulation - Formation of gel Solution of test parenteral product

III. Pyrogen Testing: 

III. Pyrogen Testing ii. Rabbit test Based on temperature rise of rabbits compared to controls following an injection of the test product 1. Control Temperature 2. Injection of test solution 3. Record of temperature after injection

3. Quality Control: 

Environmental testing Microbial monitoring Air quality & airflow Testing of raw materials Documentation 3. Quality Control Air velocity monitoring

Leak 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.

Pyrogen test : 

Pyrogen test

LAL test : 

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 37 0 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.

LAL TESTER : 

LAL TESTER

Pyrogen test- Fever response of rabbit : 

Pyrogen test- Fever response of rabbit Sham test is 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 Biological variation Expensive Laborious Dose dependent. Not for anti pyretic drug.

Particulate test : 

Particulate test USP Visually inspected- all (WHITE AND BLACK ) Any with visible particle is discarded. Large volume parental 50 particles of 10μm 5 particulates of 25 μm per ml Light obscuration particle count test Microscopic particle count test

HVAC Validation : 

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.

HVAC Validation (Cont.): 

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.

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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 Sr.No Test Frequency 1 Particle Monitoring in air 6 monthly 2 HEPA Filter Integrity Testing Yearly 3 Air Changes Rate Calculation 6 Monthly 4 Air Pressure Differentials Daily 5 Temperature and Humidity Daily 6 Microbiological monitoring by settle plates and / or swabs in aseptic areas Daily, and at decreased frequency in other areas HVAC Validation (Cont.) Cleanroom Environmental Monitoring

Packaging of finished product : 

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 .

USP requirements for packaging.: 

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.

REFERENCES: 

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

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