Chapter Phar 15

Phar 15.35(3)(a) (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:

Phar 15.35(3)(a)1. 1. Sterile filters used to sterile filter preparations shall meet all of the following requirements:

Phar 15.35(3)(a)1.a. a. Be pyrogen-free and have a nominal pore size of 0.22 microns.

Phar 15.35(3)(a)1.b. b. Be certified by the manufacturer to retain at least 107 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.

Phar 15.35(3)(a)1.c. c. Be chemically and physically stable at the compounding pressure and temperature conditions.

Phar 15.35(3)(a)1.d. d. Have sufficient capacity to filter the required volumes.

Phar 15.35(3)(a)1.e. e. Yield a sterile filtrate while maintaining pre-filtration pharmaceutical quality, including strength of ingredients of the specific compounded sterile preparations.

Phar 15.35(3)(a)2. 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.

Phar 15.35(3)(a)3. 3. When compounded sterile preparations are known to contain excessive particulate matter, one of the following shall occur:

Phar 15.35(3)(a)3.a. a. A pre-filtration step using a filter of larger nominal pore size.

Phar 15.35(3)(a)3.b. 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.

Phar 15.35(3)(a)4. 4. Sterilization by filtration shall be performed entirely within an ISO Class 5 or better air quality environment.

Phar 15.35(3)(a)5. 5. Filter units used to sterilize compounded sterile preparations shall be subjected to the manufacturers’ recommended post-use integrity test.

Phar 15.35(3)(b) (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:

Phar 15.35(3)(b)1. 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.

Phar 15.35(3)(b)2. 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.

Phar 15.35(3)(b)3. 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.

Phar 15.35(3)(b)4. 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.

Phar 15.35(3)(b)5. 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.

Phar 15.35(3)(b)6. 6. Porous materials and items with occluded pathways shall only be sterilized by steam if the autoclave chamber has cycles for dry goods.

Phar 15.35(3)(b)7. 7. The steam supplied shall be free of contaminants and generated using clean water.

Phar 15.35(3)(b)8. 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.

Phar 15.35(3)(b)9. 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.

Phar 15.35(3)(b)10. 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.

Phar 15.35(3)(c) (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:

Phar 15.35(3)(c)1. 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.

Phar 15.35(3)(c)2. 2. Heated air shall be evenly distributed throughout the chamber.

Phar 15.35(3)(c)3. 3. Sufficient space shall be left between materials to allow for good circulation of the hot air.

Phar 15.35(3)(c)4. 4. The oven shall be equipped with temperature controls and a timer.

Phar 15.35(3)(c)5. 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.

Phar 15.35(3)(c)6. 6. Materials shall first undergo a depyrogenation process before being sterilized using dry heat, unless the materials used are certified to be pyrogen-free.

Phar 15.35(4) (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.

Phar 15.35 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Phar 15.36 Phar 15.36 Inspection, sterility testing and antimicrobial effectiveness.

Phar 15.36(1) (1) Physical inspection.

Phar 15.36(1)(a) (a) At the completion of compounding, the compounded sterile preparation shall be inspected by performing all of the following:

Phar 15.36(1)(a)1. 1. Visually inspect the container closure for leakage, cracks in the container, or improper seals.

Phar 15.36(1)(a)2. 2. Visually check the compounded sterile preparation for phase separation.

Phar 15.36(1)(a)3. 3. Each individual injectable unit shall be inspected against a lighted white background and a black background for evidence of visible particulates or other foreign matter or discoloration.

Phar 15.36(1)(b) (b) For compounded sterile preparations which will not be dispensed promptly after preparation, an inspection shall be conducted immediately before it is dispensed for any defects, including precipitation, cloudiness, or leakage, which may develop during storage.

Phar 15.36(1)(c) (c) Compounded sterile preparations with any observed defects shall be immediately discarded or marked and segregated from acceptable units in a manner that prevents them from being dispensed.

Phar 15.36(2) (2) Sterility Testing.

Phar 15.36(2)(a) (a) The membrane filtration method shall be used for sterility testing unless it is not possible due to the compounded sterile preparation formulation. The direct inoculation of the culture method shall be used when the membrane filtration method is not possible.

Phar 15.36(2)(b) (b) If a preparation may be needed before the results of sterility testing have been received, the pharmacy shall daily observe the incubating test specimens and immediately recall the dispensed preparations when there is any evidence of microbial growth in the test specimens. The patient and the prescriber to whom a potentially contaminated compounded sterile preparation was administered shall be notified immediately of the potential risk.

Phar 15.36(2)(c) (c) Positive sterility test results shall prompt a rapid and systematic investigation into the causes of the sterility failure, including identification of the contaminating organism and any aspects of the facility, process or personnel that may have contributed to the sterility failure. The investigation and resulting corrective actions shall be documented.

Phar 15.36(2)(d) (d) All Category 2 compounded sterile preparations made from one or more nonsterile ingredients, except those for inhalation and ophthalmic administration, shall be tested to ensure that they do not contain excessive bacterial endotoxins.

Phar 15.36(2)(e) (e) Notwithstanding par. (d), a compounded sterile preparation does not need to be tested for bacterial endotoxins if the material is stored under cool and dry conditions and one of the following:

Phar 15.36(2)(e)1. 1. The certificate of analysis for the nonsterile ingredient lists the endotoxins burden, and that burden is found acceptable.

Phar 15.36(2)(e)2. 2. The pharmacy has predetermined the endotoxins burden of the nonsterile ingredient and that burden is found acceptable.

Phar 15.36(3) (3) Antimicrobial effectiveness. Compounded sterile preparations containing a preservative added by the compounder shall pass an antimicrobial effectiveness testing with the results obtained on the specific formulation before any of the compounded sterile preparation is dispensed. The test may be conducted only once on each formulation in the particular container-closure system in which it will be stored or dispensed. The antimicrobial effectiveness test shall occur at one of the following times:

Phar 15.36(3)(a) (a) At the completion of the sterility test.

Phar 15.36(3)(b) (b) At the time of preparation for compounded sterile preparations which have not undergone a sterility testing.

Phar 15.36 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Phar 15.37 Phar 15.37 Beyond use dating.

Phar 15.37(1) (1) Sterility and stability considerations shall be taken into account when establishing a BUD. Either Category 1 and 2, or low, medium, and high-risk compounding preparation standards may be used, but not a combination of the two within the same pharmacy. The following dates and times for storage and initiation of administration of the compounded sterile preparations shall apply:

Phar 15.37(1)(a) (a) For compounded sterile preparations including components from conventionally manufactured products, the BUD shall not exceed the shortest expiration of any of the starting components. If the compounded sterile preparation includes non-conventionally manufactured products, the BUD may not exceed the shortest BUD of any of the starting components.

Phar 15.37(1)(b) (b) For Category 1 compounded sterile preparations, one of the following:

Phar 15.37(1)(b)1. 1. May not exceed 12 hours when the preparation is stored at controlled room temperature.

Phar 15.37(1)(b)2. 2. May not exceed 24 hours when the preparation is stored in a refrigerator.

Phar 15.37(1)(c) (c) For aseptically processed Category 2 processed sterile preparations, one of the following:

Phar 15.37(1)(c)1. 1. No sterility testing performed or sterility testing not passed, and prepared with one or more nonsterile starting components, one of the following:

Phar 15.37(1)(c)1.a. a. Within 1 day when the preparation is stored at controlled room temperature.

Phar 15.37(1)(c)1.b. b. Within 4 days when the preparation is stored in a refrigerator.

Phar 15.37(1)(c)1.c. c. Within 45 days when the preparation is stored in a freezer.

Phar 15.37(1)(c)2. 2. No sterility testing performed or sterility testing not passed, and prepared with only sterile starting components, one of the following:

Phar 15.37(1)(c)2.a. a. Within 4 days when the preparation is stored at controlled room temperature.

Phar 15.37(1)(c)2.b. b. Within 10 days when the preparation is stored in a refrigerator.

Phar 15.37(1)(c)2.c. c. Within 45 days when the preparation is stored in a freezer.

Phar 15.37(1)(c)3. 3. Sterility testing performed and passed, one of the following:

Phar 15.37(1)(c)3.a. a. Within 30 days when the preparation is stored at controlled room temperature.

Phar 15.37(1)(c)3.b. b. Within 45 days when the preparation is stored in a refrigerator.

Phar 15.37(1)(c)3.c. c. Within 60 days when the preparation is stored in a freezer.

Phar 15.37(1)(d) (d) For Category 2 compounded sterile preparations, terminally sterilized by a validated procedure, one of the following:

Phar 15.37(1)(d)1. 1. No sterility testing performed or sterility testing not passed, one of the following:

Phar 15.37(1)(d)1.a. a. Within 14 days when the preparation is stored at controlled room temperature.

Phar 15.37(1)(d)1.b. b. Within 28 days when the preparation is stored in a refrigerator.

Phar 15.37(1)(d)1.c. c. Within 45 days when the preparation is stored in a freezer.

Phar 15.37(1)(d)2. 2. Sterility testing performed and passed, one of the following:

Phar 15.37(1)(d)2.a. a. Within 45 days when the preparation is stored at controlled room temperature.

Phar 15.37(1)(d)2.b. b. Within 60 days when the preparation is stored in a refrigerator.

Phar 15.37(1)(d)2.c. c. Within 90 days when the preparation is stored in a freezer.

Phar 15.37(2) (2) The BUD established in sub. (1) may not be exceeded or extended for compounded sterile preparations without verifiable supporting valid scientific sterility and stability information that is directly applicable to the specific preparation or compound.

Phar 15.37(3) (3) For compounded sterile preparations which have been assigned a BUD based upon storage in a freezer, the integrity of the container-closure system with the specific compounded sterile preparation in it shall have been demonstrated for 45 days at frozen storage. The container-closure integrity test may be conducted only once on each formulation in the specific container closure-system in which it will be stored or dispensed.

Phar 15.37(4) (4) When a preservative is added, the compounded sterile formulation shall pass antimicrobial effectiveness testing that shall include inoculation of standardized microorganisms, incubation serial sampling, and calculation of the changes in colony forming unit concentrations in terms of log reduction. The results of antimicrobial effectiveness testing shall be obtained before any of the compounded sterile preparation is dispensed. Preservatives shall not be used as a substitute for good compounding practices.

Phar 15.37(5) (5) For low-risk level compounded sterile preparations, in the absence of passing a sterility test:

Phar 15.37(5)(a) (a) Within 48 hours when the preparation is stored at controlled room temperature.

Phar 15.37(5)(b) (b) Within 14 days when the preparation is stored in a refrigerator.

Phar 15.37(5)(c) (c) Within 45 days when the preparation is stored in a freezer.

Phar 15.37(5)(d) (d) For products prepared in an airflow workbench not located in a buffer area, administration shall begin within 12 hours or less of preparation.