parenteral manufacturing basic information

PARENTERALS

QUANTITATIVE AND QUALITATIVE LAYOUTS OF PARENTERAL MANUFACTURING Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli1Parenterals :- 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 Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli2 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.

C. Electrolyte preparation

D. Dialysate Used in patients with disorder as renal failure, poisoning, and electrolyte disturbances. In peritoneal dialysis,

E. Irrigating solutions Not intended for infusion into the venous system. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli3GMP Requirements for Sterile Products Specific points relating to minimizing risks of contamination. Microbiological Particulate matter Pyrogen Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli4General 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 Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli5

Planning & SchedulingDr. Tushar Gohil, S.L.P.T.P.M.C., Amreli6

Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli7Types of sterile products processing 1 Terminally sterilised prepared, filled and sterilised 2 Sterilised by filtration 3 Aseptic preparation Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli8Manufacture of sterile preparations

Terminally sterilised:- Usually involves filling and sealing product containers under 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli92. Sterilisation by Filtration:- o Previously sterilized container are taken. o Filters having nominal pore size 0.22 m or less are used for filtration o Remove bacteria and moulds but Not viruses & Mycoplasmas o Double filter layer or second filtration o No fibre shedding or asbestos filters o Filter integrity testing Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli103. 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. 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli11SPECIFIC 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 very high 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli12[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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli13General 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 Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli14[3] Garments The 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli15[4] Area planning: Depends on 1). Type of production Batch operations

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

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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli162). 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli173). Environment control needs

Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli18

Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli194). 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli205). Space requirements [QUANTITATIVE LAYOUT OF PARENTERAL MANUFACTURING ]

Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli216). 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. Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli22




Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli26Grade 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.





Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli31CLEAN ROOM An area with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area

























Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli56Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli57REFERENCES www.GMP.online.coms Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth Avis, Leon Lachman, Vol-1. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth Avis, Leon Lachman, Vol-2 Drugs & Cosmetics Act 1940. www.ispc.org www.whqlibdoc.who.org The theory and Industrial pharmacy by Leon Lachman, Third edition Aseptic Pharmaceutical Manufacturing by M.J.Groves Pharmaceutical science by Remington, 20th edition Pharmaceutical process Validation by Loftus & Nash: 29-90. Sterile Pharmaceutical Manufacturing by Groves Gisan. www.fda.gov. American Journal of Hospital Pharmacy, Vol. 38, Issue 8, 1144-1147 Dispensing for pharmaceutical students; 10 th edition; by:-S J Carton www.dwscientific.co.uk www.pharmamachines.com www.bascotech.com www.getthatmag.com www.fabtecheng.com www.ahind.com www.nkambica.com Dr. Tushar Gohil, S.L.P.T.P.M.C., Amreli58Thank You

parenteral manufacturing basic information

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