PREPARATION OF PACKAGING COMPONENTS FOR STERILE DOSAGE FORMS • Improper handling of packaging materials in the preparation stage is one of the greatest sources of contamination by particulate matter. • A sterile package consists of primary and secondary packaging components. • Primary packaging components are in direct contact with the sterile product, such as ampoules, vials, syringes, syringe cartridges, squeeze bottles and rubber or plastic stoppers. • The primary components must be clean and sterile. There are numerous methods for cleaning primary packaging components. Containers • All containers for sterile preparations must be sterile, free of both particulate matter and pyrogens. • These containers should not interact physically or chemically with formulations to alter their required strength, quality, or purity. • Containers must also permit inspection of their contents. Packaging Construction Materials • Glass • Rubber • Plastic Glass Containers • • • • • • • Glass is the most popular material for sterile preparation containers. USP classifies glass as: Type I (borosilicate glass), Type II (soda-lime-treated glass), Type III (soda-lime glass), or NP (soda-lime glass unsuitable for parenteral containers). Different glass types vary in their resistance to attack by water and chemicals. • For pharmaceutical containers, glass must meet the USP test for chemical resistance. • Because most pharmacy personnel do not have the time or facilities to perform glass chemical interaction studies, they should use only Type I glass to minimize sterile preparation compatibilities. • Glass containers received in cardboard and chipboard boxes contain dust generated by these packaging materials. • This dust and other particulate matters are difficult to eliminate, frequently, the empty glass are vacuumed before washing. • Another approach to reduce troublesome particulates have been the use of Shrink wrapping. • Groups of empty glass containers are wrapped tightly together with plastic films before shipment, thus eliminating the contact of the glass with the cardboard cartons. • The glass containers are passed through a number of cycles in automatic washing equipment. • The air and water entering the washer should be filtered to reduce particulate contact with the containers during washing. • A 0.22 μm cartridge is the most common porosity, although 1 to 5 μm sizes are being used to give high flow rate. • Hot, pyrogen- free distilled water is used as the washing and rinsing fluid. • A typical wash cycle, allowing 1 minute for each step, would be: • Inside wash: hot filtered pyrogen- free water • Outside wash: hot filtered pyrogen- free water • Inside: filtered air • Inside wash: hot filtered pyrogen- free water • Outside wash: hot filtered pyrogen- free water • Inside: filtered air • Inside wash: hot filtered pyrogen- free water • Inside: filtered air • Outside: filtered air • The vials or ampoules are then removed in tray for sterilization. • There are continuous washing system in which the vials/ampoules are washed, sterilized, filled and sealed in one continuous operation. • After washing the glass components are sterilized by dry heat. • The sterile, depyrogenated glass containers are stored in covered stainless steel trays in a cool, humidity-controlled, clean-area under laminar airflow. • Siliconization is necessary to: • Facilitate the draining of solid products from the walls of the containers. This drainage factor may help improve the appearance of the product as well as help the dose uniformity by inhibiting drying of the solid portion of a suspension on the vial wall, resulting in a reduction of the solids delivered per volume of suspension. • Siliconization is carried out with freshly prepared aqueous emulsion of silicon which is sprayed into the vials via a standard vial washing machine. • The siliconized vials are then backed in a dry wall oven at 250 C° for 5 hours. • This backing procedure bakes the silicone onto the surface of glass container. • This procedure is done last in the processing step, so that it serves as a depyrogenating step as well. PLASTIC CONTAINERS • Plastic polymers can be used as sterile preparation containers but present three problems: • 1. Permeation of vapors and other molecules in either direction through the container. • 2. Leaching of constituents from the plastic into the preparation. • 3. Sorption of drug molecules onto the plastic. • Plastics must meet USP specifications for biological reactivity and physiochemicals. • Most plastic containers do not permit ready inspection of their contents because they are unclear. Most plastics also melt under heat sterilization. • Plastic containers, such as ophthalmic dispensers, are usually, washed in much the same manner as glass but are sterilized by means requiring low temperature because of the low melting point of the plastic used. • Polypropylene or high- density polyethylene parts, such as caps, can be steam sterilized. • Low density polyethylene plastics used for flexiblewalled ophthalmic packaging can’t be steam-sterilized, due to the distortion encountered during the normal autoclaving cycle. So they are usually sterilized with ethylene oxide. • Washed plastic components are placed in polyethylene bag that allow adequate penetration of the gas for sterilization and proper venting after sterilization to remove the sterilant. • Less than 1 ppm of ethylene oxide can be detected on suitable monitoring equipment. • Exposure to cobalt- 60 gamma rays or the highenergy electron beam source is another method for plastic sterilization. • Plastic syringes: are rarely used to package unit dosage injection. • The pharmaceutical industry has not marketed prefilled plastic syringes. • This is meanly due to potential plastic extractives, weight loss by vertue of water vapor loss, plastic-product interaction. • Such devices would be sterilized by a gas sterilant or by exposure to radiation. Closures • Rubber closures must be rendered sterile, free from pyrogens and surface particles. To meet these specifications, multiple washings and autoclaving are required. • Closures are made of natural, neoprene, or butyl rubber. Thus, the rubber sealing of a vial or the plug in a syringe is a complex material that can interact with the ingredients of a formula. • Rubber closures also are subject to coring. • Therefore, you should consult the literature standards when selecting a rubber closure for sterile preparations • Washing process: to remove dirt and/or surface contaminants from the rubber. • Detergents must be used carefully because residual amounts can be difficult to remove from the rubber. • Two problems are associated with the ordinary clothes washers: • 1- the tumbling action of the washer produces abrasion, resulting in excess particle formation. • 2- The gravity drain at the bottom of the washer forces the dirty effluent liquid to be drained through the clean stoppers at the end of the wash cycle. • The problem of gravity drain has been eliminated by adding an overflow rinse cycle to float dirt and debris away from the stoppers toward the top of the liquid surface and out to a separate drain system. This prevents drainage of wash water back through the clean bed of closures (HUBER WASHER). • One disadvantage of this washer is the tumbling action of the inner basket. This action may cause the stoppers to abrade against each other or against drum. • CAPSOLUT WASHER: • Has eliminated both the drain and abrasion problems. • It gently agitates the stoppers via filtered air, which is directed toward a basket containing the stoppers. • The dirt or debris floats to the surface while the tank is being flushed with clean water from below. • The debris is removed by overflow through a drain system at the top of the tank. • The washing time and temp. of the rinse water will depend on the type, size and quality of rubber components being washed/load. • A 0.22 μm cartridge-type filter is used and the filter is checked periodically for integrity and/or clogging. • After washing the rubber components are packed in clean glass, polypropylene, nonshedding synthetic bags or stainless steel containers with sealable tops. • Sterilization: • - by autoclaving (moist heat), rapid heat penetration • -Dry heat (slow heat penetration)may dry and crack the rubber • Ethylene oxide may be difficult to release from the rubber matrix within a practical time period. • Underheating may not produce an adequate microbial kill. • Overheating may cause tackiness or decomposition of the rubber. • Siliconization: • -To facilitate insertion of the rubber components into container openings via highspeed automatic filling and sealing equipment. • Without siliconization, shingling or jamp-up of the rubber stoppers because of the high friction of untreated rubber. Cleaning and Sterilization of Vials • 1. Vials are cleaned and sterilized before filling. Following procedure is used for cleaning • and sterilization of vials. • 2. Soak the vial with detergent solution overnight to remove any sticking particles, grease, etc. • 3. Wash with tap water three to four times till soap solution is completely removed. • 4. Remove surface alkalinity using 1.0% hydrochloric acid solution. • 5. Again wash the vial using tap water till free from alkalinity. • 6. Rinse with de-ionized water and finally with distilled water. • 7. Cleaned vials are sterilized by dry heat sterilization at 200°C for 4 hours. • 8. Cool sterilized vials at room temperature under the closed condition prior to filling the vials. Cleaning and Sterilization of Rubber closures • 10. Rubber closures are boiled with 1.0% solution of liquid detergent for 30 minutes. • 11. Wash with tap water till free from detergent. • 12. Boil for 30 min. using 1.0% solution of hydrochloric acid. • 13. Wash to make them free from acid. • 14. Boil the acid washed rubber closures with 1.0% sodium carbonate solution and wash till free alkali. • 15. Treat rubber stoppers with double strength bacteriostatic solution. • 16. Wash three to four times using pyrogen free water. • 17. Sterilize by autoclave at 115°C for 30 minutes.