Sterilization manufacturing equipment

There is little published guidance to microbiological controls for non-sterile manufacture. Equipment and facilities should be designed to minimize the opportunities for contact with air, personnel, and water. 

Biologically derived products include fermentation products and genetically engineered materials. These products typically require sterile manufacturing areas. They require extensive air handling equipment and environmental controls. Ster-ilization/sanitation must be easily carried out. 

The manufacture of sterile products is universally acknowledged to be the most difficult of all pharmaceutical production activities to execute. When these products are manufactured using aseptic processing, poorly controlled processes can expose the patient to an unacceptable level of contamination. In rare instances contaminated products can lead to microbial infection resulting from products intended to hasten the patient s recovery. The production of sterile products requires fastidious design, operation, and maintenance of facilities and equipment. It also requires attention to detail in process development and validation to ensure success. This chapter will review the salient elements of sterile manufacturing necessary to provide acceptable levels of risk regarding sterility assurance. 

Uitrasonic emuisification can be used in different situations ranging from normai conditions to others requiring manufacturing equipment that can be readiiy cieaned and sterilized. This is especially important in the food or pharmaceutical fields, where the use of ultrasonic processing systems with aseptic production is indispensable with a view to avoid product contamination. New ultrasonic processing systems are continuously designed for this purpose [49],... 

The science that underpins steam sterilization is well known and has been long established. It is the preferred method of sterilization in the pharmaceutical industry it is used for sterilization of aqueous products in a wide variety of presentations, for sterilization of equipment and porous materials required in aseptic manufacture, in microbiology laboratories for sterilizing media and other materials, and for sterilization of massive systems of vessels and pipework [steam-in-place (SIP) systems]. Numerous rules and guidelines have been published on the topic, yet steam sterilization and particularly bio-validation of steam sterilization is still a subject for controversy and debate. 

Steam sterilization is widely used as a terminal process for drug products in glass ampules, vials, syringes, and plastic containers. It is also used for sterilizing closures, filters, manufacturing equipment, and cleaning equipment, etc. 

In finished product manufacturing areas, production personnel should be evaluated twice a year for their ability to maintain the sterility of the product by undergoing media fills where each employee manipulates sterile filling equipment and fills 300+ vials aseptically with sterile culture media. Additionally, personnel should be monitored daily for levels of contamination by ROD AC contact plates on fingers and other parts of the sterile gown. This requirement is becoming standard practice for bulk manufacturing personnel. 

The excipient manufacturer must document the sanitizing of critical processing equipment. Processes used for the sterilization of equipment must be validated. The manufacturer also needs to verify that no chemical interaction with the product occurs. 

Different products (including different batches of a product) shall not be manufactured in the same room at the same time. The culture tank, lyophilizer, filling and sealing equipment employed in the production of biological products shall not be used unless they are thoroughly cleaned and sterilized. Dedicated equipment, delivery pipes, containers, and others shall be provided for processing toxic medicinal materials. 

C. Facilities for the washing and sterilization of equipment utensils and containers prior to their use in manufacturing or testing. 

Manufacturing equipment and utensils should be thoroughly cleaned and when necessary, sterilized, and should be maintained in accordance with specific written directions. 

It is necessary to determine the bioburden and make cycle verification studies when ethylene oxide sterilization is used, as it is for other sterilization methods. The manufacturer of hospital sterilization equipment provides cycle recommendations based on the expected bioburden and the consideration of an appropriate safety factor. In ethylene oxide sterilization, it is necessary to determine if residues of the stefilant are absorbed by the sterilized article, and to examine the possible formation of other potentially toxic materials as a result of reaction with ethylene oxide. 

Provisions must be made for allowing residues of the stefilant absorbed by the product to dissipate by using aeration cabinets that have forced-air circulation at elevated temperatures. The amount of remaining absorbed stefilant should be determined before releasing the sterilized articles. If, as in the case of hospital sterilization, such studies are not feasible, the recommendations of the manufacturers of the articles sterilized or of the aeration equipment should be obtained. The permissible residue concentrations are 10—250 ppm, depending on the type of article and on its intended use. 

Dry heat is widely used to sterilize glassware and equipment parts in manufacturing areas for parenteral products. It has good penetration power and is not as corrosive as steam. However, heat-up time is... 

The design of equipment for use in controlled environment areas follows similar principles, whether for general injectable manufacturing or for the manufacturer of sterile ophthalmic pharmaceuticals. All tanks, valves, pumps, and piping must be of the best available grade of corrosion-resistant stainless steel. In general, stainless steel type 304 or 316 is preferable. 

In the design of equipment for the manufacture of sterile ophthalmic (and nonophthalmic) pharmaceuticals, manufacturers and equipment suppliers are turning to the advanced technology in use in the dairy and aerospace industries, where such concepts as CIP (clean-in-place), COP (clean-out-of-place), automatic heliarc welding, and electropolishing have been in use for several years. As a guide here, the reader is referred to the so-called 3A Standards of the dairy industry issued by the U.S. Public Health Service [267],... 

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