Section Phar 15.35 - Sterilization methods(1) Sterilization methods employed shall sterilize while maintaining its physical and chemical stability and the packaging integrity of the compounding sterile preparations. The efficacy of sterilization and depyrogenation of container closure systems performed in the pharmacy shall be established, documented, and reproducible.(2) Pre-sterilization requirements shall meet all of the following: (a) During all compounding activities that precede terminal sterilization, including weighing and mixing, compounding personnel shall be garbed and gloved in the same manner as when performing compounding in an ISO Class 5 environment. All pre-sterilization procedures shall be completed in an ISO Class 8 or better environment.(b) Immediately before use, all nonsterile measuring, mixing, and purifying devices used in the compounding process shall be thoroughly rinsed with sterile, pyrogen-free water and then thoroughly drained or dried.(3) Sterilization shall be performed utilizing one of the following methods: (a)Sterilization by filtration. Sterilization by filtration involves the passage of a fluid or solution through a sterilizing grade membrane to produce a sterile effluent. Filtration may not be used when compounding a suspension when the suspended particles are removed by the filter being used. This method shall meet all of the following: 1. Sterile filters used to sterile filter preparations shall meet all of the following requirements: a. Be pyrogen-free and have a nominal pore size of 0.22 microns.b. Be certified by the manufacturer to retain at least 10 7 microorganisms of a strain of Brevundimonas diminuta per square centimeter of upstream filter surface area under conditions similar to those in which the compounded sterile preparations will be filtered.c. Be chemically and physically stable at the compounding pressure and temperature conditions.d. Have sufficient capacity to filter the required volumes.e. Yield a sterile filtrate while maintaining pre-filtration pharmaceutical quality, including strength of ingredients of the specific compounded sterile preparations.2. The filter dimensions and liquid material to be sterile filtered shall permit the sterilization process to be completed rapidly without the replacement of the filter during the filtering process.3. When compounded sterile preparations are known to contain excessive particulate matter, one of the following shall occur:a. A pre-filtration step using a filter of larger nominal pore size.b. A separate filter of larger nominal pore size placed upstream of the sterilizing filter to remove gross particulate contaminants before the compounding sterile compound is passed through the sterilizing grade filter.4. Sterilization by filtration shall be performed entirely within an ISO Class 5 or better air quality environment.5. Filter units used to sterilize compounded sterile preparations shall be subjected to the manufacturers' recommended post-use integrity test.(b)Sterilization by steam heat. The process of thermal sterilization using saturated steam under pressure shall be the method for terminal sterilization of aqueous preparations in their final, sealed container closure system. The effectiveness of steam sterilization shall be established and verified with each sterilization run or load by using biological indicators, physicochemical indicators and integrators. This method shall meet all of the following: 1. All materials shall be directly exposed to steam under adequate pressure for the length of time necessary, as determined by use of appropriate biological indicators, to render the items sterile. The duration of the exposure period shall include sufficient time for the compounded sterile preparation to reach the sterilizing temperature.2. The compounded sterile preparation and other items shall remain at the sterilizing temperature for the duration of the sterilization period. The sterilization cycle shall be designed to achieve a sterility assurance level of 10 -6.3. Compounded sterile preparations shall be placed in trays which allow steam to reach the compounded sterile preparations without entrapment of air. Paper, glass, and metal devices or items shall be wrapped in low lint protective fabric, paper, or sealed in envelopes that will permit steam penetration and prevent post sterilization microbial contamination.4. Immediately before filling ampules and vials, solutions shall be passed through a filter having a nominal pore size of not larger than 1.2 microns for removal of particulate matter.5. Sealed containers shall be able to generate steam internally. Stoppered and crimped empty vials shall contain a small amount of moisture to generate steam. Deep containers, including beakers and graduated cylinders, shall be placed on their sides to prevent air entrapment or have a small amount of water placed in them.6. Porous materials and items with occluded pathways shall only be sterilized by steam if the autoclave chamber has cycles for dry goods.7. The steam supplied shall be free of contaminants and generated using clean water.8. The seals on the doors of autoclave chambers shall be examined visually every day they are used for cracks or damage and the seal surfaces shall be kept clean.9. A data recorder or chart shall be used to monitor each cycle and the data shall be reviewed to identify cycle irregularities in temperature or exposure time.10. Materials in direct contact with the compounded sterile preparation shall undergo a depyrogenation process before being sterilized using steam heat unless the materials used are certified to be pyrogen-free.(c)Sterilization by dry heat. Dry heat sterilization shall be used only for those materials that cannot be sterilized by steam or filtration. The effectiveness of dry heat sterilization shall be verified using appropriate biological indicators and temperature sensing devices. This method shall meet all of the following:1. The duration of the exposure period shall include sufficient time for the compounding sterile preparation or items to reach the sterilizing temperature. The compounded sterile preparation and items shall remain at the sterilizing temperature for the duration of the sterilization period.2. Heated air shall be evenly distributed throughout the chamber.3. Sufficient space shall be left between materials to allow for good circulation of the hot air.4. The oven shall be equipped with temperature controls and a timer.5. A data recorder or chart shall be used to monitor each cycle and the data shall be reviewed to identify cycle irregularities in temperature or exposure time.6. Materials shall first undergo a depyrogenation process before being sterilized using dry heat, unless the materials used are certified to be pyrogen-free.(4) Dry heat depyrogenation shall be used to render glassware and other thermostable containers pyrogen free. The duration of the exposure period shall include sufficient time for the items to reach the depyrogenation temperature. The items shall remain at the depyrogenation temperature for the duration of the depyrogenation period. The effectiveness of the dry heat depyrogenation cycle shall be established and verified annually using endotoxin challenge vials to demonstrate that the cycle is capable of achieving at least a 3-log reduction in endotoxins.Wis. Admin. Code Pharmacy Examining Board Phar 15.35
Adopted by, CR 16-085: cr. Register April 2018 No. 748, eff. 11/1/2018