PARENTERALSINTRODUCTIONParenterals :- are Sterile, Pyrogen free preparations injected through skin or mucous membrane into internal body compartment.

Parenteral productsA. 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

Types of sterile products processing1 Terminally sterilised prepared, filled and sterilised 2 Sterilised by filtration 3 Aseptic preparation

Manufacture of sterile preparations 1. Terminally sterilised:- usually involves filling and sealing product containersunder high-quality environmental conditions. 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. In most cases, the product, container, and closure have low bio-burden, but they are not sterile. The product in its final container is then subjected to a sterilization process such as heat or irradiation.

2. Sterilisation by Filtration:o o o o o o Previously sterilized container are taken. Filters having nominal pore size 0.22 m 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. Aseptic Preparation :- In an 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 Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination and thus necessitates careful control. Note:- In area occupied by personal, the air must be exchanged with the frequent intervals.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.

SPECIFIC REQUIREMENTS FOR MANUFACTURE OF PARENTERAL PREPARATIONS (SMALL VOLUME INJECTABLES AND LARGE VOLUME PARENTERALS)

As per schedule M .

[1] General :- Sterile products, being very critical and sensitive in nature a veryhigh degree of precautions, prevention are needed for its preparation.Dampness, 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, air, active materials and in the maintenance of hygienic environment.

[2] Building and Civil Works: The building-built on proper foundation with standardized materials Location of services like water, steam, gases etc. shall be such that their servicing or repair shall not pose any threat to the integrity of the facility. Water lines shall not pose any threat of leakage to any of the manufacturing area. The manufacturing areas-clearly separated into support areas & preparation areas. 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. Wooden pallets, fiberboard drugs, cardboard and other particle shedding materials shall not be taken inside the preparation areas.

General points to be in consideration for ASEPTIC Areas Walls, floors and ceiling-impervious, non-shedding, non-flaking and non-cracking. Flooring-unbroken, provided with a cove both at the junction between the wall and the floor & wall and ceiling. Epoxy should done in aseptic area, Walls-shall be flat. Light-fittings and air-grills-shall flush with the walls and not hanging from ceiling. Doors & Windows-made of non-shedding material preferably Aluminium or Steel material. Doors shall open towards the higher-pressure area so that they close automatically due to air pressure. The furniture-smooth, washable and made of stainless steel or any other appropriate material

[3] GarmentsThe garments-made of non-shedding and tight weave material, single piece with fastenings at cuffs, neck and at legs to ensure close fit. Trouser legs shall be tucked inside the cover boots. Design-include a hood (head-cover) or a separate hood which can be tucked inside the over-all. Zips (if any) shall be of plastic material. 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.

footwear- of suitable plastic or rubber material, daily cleaned with a bactericide. Garment changing procedures shall be documented and operators trained in this respect.

[4] Area planning:1). Type of production

Depends on

Batch operations: suited to small production volume & minimum financial investment. Advantages: 1.Product quality, consistency, and homogeneity are relatively easily controlled. 2. Production documentation is easy. Disadvantages: 1.Economically undesirable because it is labor intensive and does not exploit the economies of volume. Continuous operations: it is suited to very high volume production requirements. it requires more space and more complex equipments. Advantages: 1. Minimizes shortcoming of batch operations; labor, production time, and environmental exposure of the product. 2. Since the intermediate material handling steps are eliminated, the potential for product contamination during those steps no longer exists. Disadvantages: 1. 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.

2). Container sizeSVPs and LVPs obviously requires different space considerations. All the production equipment has container size limitations- large container requires large equipments and more space.

3). Environment control needs

4). Product characteristicsLiquids 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.

5). Space requirements[QUANTITATIVE LAYOUT OF PARENTERAL MANUFACTURING ]FUNCTION Square meter Production Warehouse Utility Quality control Administration Maintenance Employee services Security Total 11,094 7,606 1,716 1,716 1,018 1,014 1,014 39 24,607 Area Percentage 45.1 30.9 4.1 7.0 4.1 4.5 4.1 0.9 100.0

6). 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, 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. In a parenteral plant degree of access should be restricted. Planning for visitors and nonproduction employees in advance can prevent or lessen many future problems, particularly in critical area. A glassed mezzanine or balcony provides absolute isolation, yet may give excellent view of process.

[5] Environmental control zone groupings1st. Zones as per the cGMP: Zone 7:- Filling line Zone 6:- Filling area Zone 5:- Weighing, mixing & transfer area. Zone 4:- Clean area Zone3:-General production Zone 2:- Warehouse Zone 1:- Exterior

1st. 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, Dissolution & filtration. 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 personal flow and restricted access to aseptic and critical environment. Minimum movement of personal. Adequate operation procedure for personal. Adequate sterilization procedure Barrier 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 Adequate material control and selection Material Adequate sterilization and filtration procedure Adequate air filtration system Air Adequate monitoring of air cleanliness level. Adequate air system validation procedure.AIR HANDLING SYSTEM (AHU)

CRITICAL AREAS Aseptic feeling area Sterilized component unloading area Change room

GRADES B C D

The filter Configuration in the AHU shall be suitably designed to achieve the Grade of air as given in Table1. TABLE I AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTS. Grade Maximum number of permitted particles per cubic metre equal to or above. AT REST IN OPERATION 0.5m 3520 35,200 3,52,000 35,20,000 5m 29 293 2,930 29,300 0.5m 3500 3,52,000 35,20,000 Not (c) defined 5m 29 2,930 29,300 Not defined (c)

A B (a) C (a) D (a)

Notes : (a) In order to reach the B, C and D air grades, the number of air changes shall be related to the size of the room and the equipment and personnel present in the room. The air system shall be provided with the appropriate filters such as HEPA for Grade A, B and C. the maximum permitted number of particles in the at rest condition shall approximately be as under: Grade A corresponds with Class 100 or M 3.5 or ISO Class 5; Grade B with Class 1000 or M 4.5 ISO Class 6; Grade C with Class 10,000 or M 5.5 or ISO Class 7; Grade D with Class 100,000 or M 6.5 or ISO Class 8. (b) The requirement and limit for the area shall depend on the nature of the operation carried out. (c) Type of operations to be carried out in the various grades are given in Table II and Table III as under. 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

TABLE III Types of operations to be carried out in the various Grades for terminally sterilized products. Grade A C Types of operations for terminally sterilized products. Filling of products, which are usually at risk Placement of filling and sealing machines, preparation of solutions when usually at risk. Filling of product when unusually at risk. Moulding, blowing (pre-forming) operations of plastic containers, preparations of solutions and components for subsequent filling

D

The recommended frequencies of periodic monitoring shall be as follows(As per Schedule - 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: >0.5 m Clean Area ISO Microbiological Microbiological Classification Designation particles/m3 Active Air Settling Plates (0.5 um Action Action Levelsc,d particles/ft3) Levelsc(cfu/m3 ) (diam. 90mm; cfu/4 hours) 100 5 3,520 1e 1e 1000 6 35,200 7 3 10,000 7 352,000 10 5 100,000 8 3,520,000 100 50 1. Air Classification as per Schedule M Grade Maximum permitted number of particles/m3 equal or above at rest in operation 0.5m 5.0m 0.5m 5.0m 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

2. Air Classifications by USFDA guideline on Sterile Drug Products Microbiological Limit Clean Area