Chapter Phar 15

Phar 15.31(3)(mm) (mm) For classified areas not physically separated, no sterile compounded preparation may be compounded using any ingredient that was at any time non-sterile in a classified area not physically separated and all of the following shall be met:

Phar 15.31(3)(mm)1. 1. The buffer and ante areas shall be designated with a line of demarcation.

Phar 15.31(3)(mm)2. 2. The principle of displacement airflow shall be used with an air velocity of 40 feet per minute or more from the buffer area across the entire plane of the line of demarcation.

Phar 15.31(3)(n) (n) Devices and objects essential to compounding shall be located at an appropriate distance from the primary engineering control.

Phar 15.31(3)(p) (p) The ante area shall meet all of the following requirements:

Phar 15.31(3)(p)1. 1. Be capable of maintaining an ISO Class 8 air or higher.

Phar 15.31(3)(p)2. 2. Have a sink with running hot and cold running water.

Phar 15.31(3)(q) (q) The buffer area shall meet all of the following requirements:

Phar 15.31(3)(q)1. 1. Be capable of maintaining an ISO Class 7 air or better.

Phar 15.31(3)(q)2. 2. Only contain any of the following:

Phar 15.31(3)(q)2.a. a. Items, including furniture, equipment, and supplies, that are required for the tasks to be performed in the buffer area.

Phar 15.31(3)(q)2.b. b. Items that are smooth, impervious, free from cracks and crevices, nonshedding, and easily cleaned and disinfected.

Phar 15.31(3)(q)2.c. c. Items that have been cleaned and disinfected immediately prior to their being placed in the buffer area.

Phar 15.31(3)(q)3. 3. Does not contain any sinks.

Phar 15.31(3)(q)4. 4. Does not contain any course cardboard, external shipping containers, and nonessential paper.

Phar 15.31(4) (4) Primary engineering control. The primary engineering control shall be certified by an independent, qualified individual certified by the Controlled Environment Testing Association’s National Board of Testing or another Board approved entity prior to initial use and then every six months. It shall also be certified when any of the following occurs:

Phar 15.31(4)(a) (a) Redesign of the facility.

Phar 15.31(4)(b) (b) Replacement of the primary engineering control.

Phar 15.31(4)(c) (c) Relocation of the primary engineering control.

Phar 15.31 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Phar 15.32 Phar 15.32 Personnel hygiene, garbing and protective gear.

Phar 15.32(1) (1) Personnel suffering from rashes, sunburn, oozing tattoos or sores, conjunctivitis, active respiratory infection, or other active communicable disease shall be excluded from working in compounding areas until the condition is resolved.

Phar 15.32(2) (2) All personnel who engage in compounding sterile preparations shall comply with all of the following requirements before entering the compounding area:

Phar 15.32(2)(a) (a) Remove personal outer garments, all cosmetics, exposed jewelry and piercings, headphones, ear buds, and cell phones.

Phar 15.32(2)(b) (b) Abstain from eating, chewing gum or drinking in the compounding area or bringing food, gum, or drink into the compounding area.

Phar 15.32(2)(c) (c) Artificial nails, nail extenders or nail polish may not be worn while working in the compounding area. Nails shall be neat and trim.

Phar 15.32(2)(d) (d) Don personnel protective equipment and perform hand hygiene in the following order:

Phar 15.32(2)(d)1. 1. Low-lint, disposable shoe covers.

Phar 15.32(2)(d)2. 2. Low-lint, disposable covers for head and facial hair that cover the ears and forehead and face masks.

Phar 15.32(2)(d)3. 3. Eye shields, if required due to working with irritants or hazardous drugs.

Phar 15.32(2)(d)4. 4. Wash hands and forearms up to the elbows with unscented soap and water for at least 30 seconds. Hands and forearms to the elbows shall be completely dried using either lint-free disposable towels or wipes.

Phar 15.32(2)(d)5. 5. Don low lint disposable gown or overalls.

Phar 15.32(2)(d)6. 6. Prior to donning sterile gloves, hand antisepsis shall be performed using an alcohol-based hand rub with sustained antimicrobial activity following the manufacturers labeled instructions and application times.

Phar 15.32(3) (3) Gloves on hands and gauntlet sleeves on RABS shall be routinely inspected for holes, punctures, or tears and shall be replaced immediately if any are detected. Sterile gloves shall be donned over the RABS gloves.

Phar 15.32(4) (4) Disinfection of contaminated gloved hands shall be accomplished by wiping or rubbing sterile 70% isopropyl alcohol on all contact surface areas of the gloves and letting the gloved hands dry thoroughly. Routine application of sterile 70% isopropyl alcohol shall occur throughout the compounding process and whenever non-sterile surfaces, including vials, counter tops, chairs, and carts, are touched.

Phar 15.32(5) (5) When compounding personnel exit the buffer or segregated compounding area, a gown may be removed and retained in the ante area or segregated compounding area if not visibly soiled, to be worn again during the same work shift. Coveralls, shoe covers, hair and facial hair covers, face masks, eye shields, and gloves shall be replaced with new ones before re-entering the compounding area.

Phar 15.32(6) (6) Garbing items, including gowns, shall be segregated and stored before use in an enclosure to prevent contamination.

Phar 15.32(7) (7) Visibly soiled gowns shall be changed immediately.

Phar 15.32(8) (8) Gloves shall be sterile and powder free and tested by the manufacturer for compatibility with alcohol disinfection.

Phar 15.32 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Phar 15.33 Phar 15.33 Cleaning and Disinfecting the Compounding Area and Supplies.

Phar 15.33(1) (1) Compounding personnel are responsible determining the cleaning and disinfecting products to be used and for ensuring that the frequency of cleaning and disinfecting compounding area is done.

Phar 15.33(2) (2) Compounding personnel shall clean in accordance with the following:

Phar 15.33(2)(a) (a) Primary engineering control work surfaces, counters, floors and work surfaces in the buffer zone area, ante room and segregated compounding areas daily.

Phar 15.33(2)(b) (b) Walls, ceilings and storage shelving monthly.

Phar 15.33(2)(c) (c) When a spill occurs or the surface is visibly soiled.

Phar 15.33(2)(d) (d) Sporicidal agents shall be used at least weekly to clean compounding areas.

Phar 15.33(3) (3) Compounding personnel shall disinfect in accordance with the following:

Phar 15.33(3)(a) (a) Primary engineering control work surfaces at the beginning and end of each compounding business day and before each batch, but not longer than 4 hours following the previous disinfection when ongoing compounding activities are occurring.

Phar 15.33(3)(b) (b) When microbial contamination is known to have been or is suspected of having been introduced into the compounding area.

Phar 15.33(4) (4) All cleaning and disinfecting practices and policies for the compounding area shall be included in written standard operating procedures and shall be followed by all compounding and environmental services personnel.

Phar 15.33(5) (5) Cleaning, detergents and disinfection agents shall be selected and used with consideration of compatibilities, effectiveness, and inappropriate or toxic residues. The selection and use of disinfectants shall be guided by microbicidal activities, inactivation by organic matter, residue, and shelf life. Disinfectants shall have antifungal, antibacterial and antiviral activity. Sporicidal agents shall be used at least weekly to clean compounding areas.

Phar 15.33(6) (6) Storage sites for compounding ingredients and supplies shall remain free from dust and debris.

Phar 15.33(7) (7) Floors, walls, ceiling, and shelving in the classified and segregated compounding areas are cleaned when no aseptic operations are in progress. Cleaning shall be performed in the direction from cleanest to dirtiest areas.

Phar 15.33(8) (8) All cleaning tools and materials shall be low-lint and dedicated for use in the buffer room, ante room and segregated compounding areas. If cleaning tools and materials are reused, procedures shall be developed based on manufacturer recommendations that ensure that the effectiveness of the cleaning device is maintained and that repeated use does not add to the bioburden of the area being cleaned.

Phar 15.33(9) (9) Supplies and equipment removed from shipping cartons shall be wiped with a suitable disinfecting agent delivered from a spray bottle or other suitable delivery method. After the disinfectant is wiped on a surface to be disinfected, the disinfectant shall be allowed to dry, during which time the item shall not be used for compounding purposes.

Phar 15.33(10) (10) Entry points on bags and vials shall be wiped with small sterile 70% isopropyl alcohol swabs or comparable method for disinfecting, allowing the isopropyl alcohol to dry before piercing stoppers with sterile needles and breaking necks of ampules. The surface of the sterile 70% isopropyl alcohol swabs used for disinfecting entry points of sterile package and devices may not contact any other object before contacting the surface of the entry point. Particle generating material may not be used to disinfect the sterile entry points of packages and devices.

Phar 15.33(11) (11) When sterile supplies are received in sealed pouches designed to keep them sterile until opening, the sterile supplies may be removed from the covering pouches as the supplies are introduced into the ISO Class 5 primary engineering control without the need to disinfect the individual sterile supply items.

Phar 15.33 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18; CR 22-007: am. (10) Register July 2022 No. 799, eff. 8-1-22.

Phar 15.34 Phar 15.34 Immediate-use compounded sterile preparations. Immediate-use compounded sterile preparations are exempt from the requirements described for low-risk level, Category 1, and Category 2 compounding sterile preparations only when all the following criteria are met:

Phar 15.34(1) (1) The compounding process involves simple transfer of not more than three commercially manufactured sterile nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers’ original containers and not more than two entries into any one container or product of sterile infusion solution or administration container or device.

Phar 15.34(2) (2) Unless required for the preparation, the compounding procedure is a continuous process not to exceed 1 hour.

Phar 15.34(3) (3) During preparation, aseptic technique is followed and, if not immediately administered, the finished compound sterile preparation is under continuous supervision to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other compound sterile preparations, and direct contact of outside surfaces.

Phar 15.34(4) (4) Administration begins not later than 4 hours following the start of the preparation.

Phar 15.34(5) (5) Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the compounded sterile preparation shall bear a label listing patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared it, and the exact 4-hour BUD and time.

Phar 15.34(6) (6) If administration of the compounded sterile preparation has not begun within 4 hours following the start of preparation, it shall be promptly, properly, and safely discarded.

Phar 15.34 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18; CR 22-007: r. and recr. Register July 2022 No. 799, eff. 8-1-22.

Phar 15.35 Phar 15.35 Sterilization methods.

Phar 15.35(1) (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.

Phar 15.35(2) (2) Pre-sterilization requirements shall meet all of the following:

Phar 15.35(2)(a) (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.

Phar 15.35(2)(b) (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.

Phar 15.35(3) (3) Sterilization shall be performed utilizing one of the following methods:

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.