Chapter Phar 15

Phar 15.17 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Subchapter II — Non-sterile Compounding

Phar 15.20 Phar 15.20 Component Selection.

Phar 15.20(1) (1) Components with an expiration date from the manufacturer or distributor may be used before the expiration date provided all of the following:

Phar 15.20(1)(a) (a) The component is stored in its original container under conditions to avoid decomposition.

Phar 15.20(1)(b) (b) There is minimal exposure of the remaining component each time component is withdrawn from the container.

Phar 15.20(2) (2) Components without an expiration date assigned by the manufacturer or supplier shall be labeled with the date of receipt and assigned a conservative expiration date, not to exceed three years after receipt, based upon the nature of the component and its degradation mechanism, the container in which it is packaged and the storage conditions.

Phar 15.20(3) (3) Components transferred to another container which shall provide integrity that is minimally equivalent to the original container and shall be identified with all of the following:

Phar 15.20(3)(a) (a) Component name.

Phar 15.20(3)(b) (b) Original supplier.

Phar 15.20(3)(c) (c) Lot or control number.

Phar 15.20(3)(d) (d) Transfer date.

Phar 15.20(3)(e) (e) Expiration date.

Phar 15.20 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Phar 15.21 Phar 15.21 Assigning BUD.

Phar 15.21(1) (1) The BUD shall not be later than the expiration date on the container of any component.

Phar 15.21(2) (2) Only in the absence of stability information that is applicable to a specific drug product and preparation, the maximum BUD for a non-sterile compounded drug preparation that is packaged in a tight, light-resistant container is as follows:

Phar 15.21(2)(a) (a) For nonaqueous formulations stored at controlled room temperature, the BUD shall not be later than the time remaining until the earliest expiration date of any active pharmaceutical ingredient or 6 months, whichever is earlier.

Phar 15.21(2)(b) (b) For water-containing oral formulations, the BUD shall not be later than 14 days when stored in a refrigerator.

Phar 15.21(2)(c) (c) For water-containing semisolid mucosal liquid, topical, or dermal formulations, stored at controlled room temperature, the BUD shall not be later than 30 days.

Phar 15.21(3) (3) Assignment of BUD shall include an assessment of the need for antimicrobial agents or storage in a refrigerator to protect against bacteria, yeast, and mold contamination introduced during or after the compounding process.

Phar 15.21 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18.

Subchapter III — Sterile Compounding

Phar 15.30 Phar 15.30 Definitions. In this subchapter:

Phar 15.30(1) (1) “Ante area” means an ISO Class 8 or better area where personnel hand hygiene and garbing procedures, staging of components, order entry, labeling and other high particulate generating activities are performed. The ante-area is the transition area between the unclassified area of the facility and the buffer area.

Phar 15.30(2) (2) “Buffer area” means an ISO Class 7 or ISO Class 8 if using an isolator or cleaner area where the primary engineering control that generates and maintains an ISO Class 5 environment is physically located.

Phar 15.30(3) (3) “Category 1” means a compounded sterile preparation compounded with a primary engineering control in a segregated compounding area.

Phar 15.30(4) (4) “Category 2” means a compounded sterile preparation compounded with a primary engineering control in a classified area.

Phar 15.30(5) (5) “Clean” means to physically remove debris, dirt, dust, and other impurities from surfaces or objects using a cleaning agent with a detergent.

Phar 15.30(6) (6) “Compounded sterile preparation” means a compounded final preparation intended to be sterile through the BUD.

Phar 15.30(7) (7) “Compounded stock solution” means a compounded solution to be used in the preparation of multiple units of a finished compounded sterile preparation.

Phar 15.30(8) (8) “Critical site” means a location that includes any component or fluid pathway surfaces or openings that are exposed and at risk of direct contact with air, moisture, or touch contamination.

Phar 15.30(9) (9) “Disinfect” means the killing of microorganisms when used according to the disinfectant’s label.

Phar 15.30(10) (10) “HEPA” means high-efficiency particulate air.

Phar 15.30(10m) (10m) “High-risk level compounded sterile preparations” means preparations compounded from non-sterile ingredients or from ingredients that are incorporated using non-sterile equipment before terminal sterilization, or from commercially manufactured sterile products that lack effective antimicrobial preservatives and whose preparation, transfer, sterilization, and packaging is performed in air quality worse than ISO class 5 for more than one hour. High-risk level compounded sterile preparations include water containing preparations that are stored for more than six hours before terminal sterilization.

Phar 15.30(11) (11) “ISO Class 5” means conditions in which the air particle count is no greater than a total of 3,520 particles of 0.5 micrometers and larger per cubic meter of air that is supplied by HEPA or HEPA-filtered air.

Phar 15.30(12) (12) “ISO Class 7” means conditions in which the air particle count is no greater than a total of 352,000 particles of 0.5 micrometers and larger per cubic meter of air that is supplied by HEPA or HEPA-filtered air.

Phar 15.30(13) (13) “ISO Class 8” means conditions in which the air particle count is no greater than a total of 3,520,000 particles of 0.5 micrometers and larger per cubic meter of air that is supplied by HEPA or HEPA-filtered air.

Phar 15.30(14) (14) “Isolator” means an enclosure that provides HEPA-filtered ISO Class 5 unidirectional air operated at a continuously higher pressure than its surrounding environment and is decontaminated using an automated system. An isolator uses only decontaminated interfaces or rapid transfer ports for materials transfer.

Phar 15.30(14g) (14g) “Low-risk level compounded sterile preparations” means preparations compounded with aseptic manipulations entirely within ISO class 5 or better air quality using only sterile ingredients, products, components, and devices. The low-risk level sterile compounding process involves only transfer, measuring, and mixing, using no more than three commercially manufactured sterile products, and not more than two entries into one sterile container or package to make the compounded sterile preparations.

Phar 15.30(14r) (14r) “Medium-risk level compounded sterile preparations” means preparations compounded under low-risk level conditions but which require multiple individual or small doses of sterile products to be combined or pooled to prepare compounded sterile preparations that will be administered either to multiple patients or to one patient on multiple occasions. The medium-risk level sterile compounding process includes complex aseptic manipulations other than single volume transfer, and requires an unusually long duration, such as that required to complete dissolution or homogeneous mixing.

Phar 15.30(15) (15) “Primary engineering control” means a device or zone that provides an ISO Class 5 environment for sterile compounding.

Phar 15.30(16) (16) “Restricted access barrier system (RABS)” means an enclosure that provides HEPA-filtered ISO Class 5 unidirectional air that allows for the ingress or egress of materials through defined openings that have been designed and validated to preclude the transfer of contamination, and that generally are not to be opened during operations. RABS include compounding aseptic isolators and compounding aseptic containment isolators.

Phar 15.30(17) (17) “Sterility assurance level of 10-6” means an equivalent to a probability that one unit in a million is nonsterile.

Phar 15.30(18) (18) “Segregated compounding area” means a designated, unclassified space, area, or room that contains a primary engineering control.

Phar 15.30(19) (19) “Urgent use compounded sterile preparation” means a preparation needed urgently for a single patient and preparation of the compounded sterile preparation under Category 1 or Category 2 requirements would subject the patient to additional risk due to delays.

Phar 15.30 History History: CR 16-085: cr. Register April 2018 No. 748 eff. 11-1-18; CR 22-007: cr. (10m), (14g), (14r) Register July 2022 No. 799, eff. 8-1-22.

Phar 15.31 Phar 15.31 Facility design and environmental controls.

Phar 15.31(1) (1) General. Facilities shall meet all of the following requirements:

Phar 15.31(1)(a) (a) Be physically designed and environmentally controlled to minimize airborne contamination from contacting critical sites.

Phar 15.31(1)(b) (b) Be accessible only to designated personnel.

Phar 15.31(1)(c) (c) Have a heating, ventilation, and air conditioning system controlling the temperature and humidity.

Phar 15.31(2) (2) Segregated compounding area. A segregated compounding area shall meet all of the following requirements:

Phar 15.31(2)(a) (a) Be located in an area away from unsealed windows and doors that connect to the outdoors, or significant traffic flow.

Phar 15.31(2)(b) (b) Be located in an area which is not adjacent to construction sites, warehouses, and food preparation areas.

Phar 15.31(2)(c) (c) Have a defined perimeter.

Phar 15.31(2)(d) (d) Locate the primary engineering control at least one meter from any sink.

Phar 15.31(3) (3) Classified area. A classified area shall meet all of the following:

Phar 15.31(3)(a) (a) The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets shall be smooth, impervious, free from cracks and crevices, and nonshedding.

Phar 15.31(3)(b) (b) Work surfaces shall be constructed of smooth, impervious materials. All work surfaces shall be resistant to damage from cleaning and sanitizing agents.

Phar 15.31(3)(c) (c) Junctures where ceilings meet walls shall be covered, caulked, or sealed to avoid cracks and crevices in which microorganisms and other contaminate can accumulate. All areas in ceilings and walls where the surface has been penetrated shall be sealed.

Phar 15.31(3)(d) (d) Ceilings that consist of inlaid panels shall be impregnated with a polymer to render them impervious and hydrophobic and shall either be caulked or weighted and clipped.

Phar 15.31(3)(e) (e) Walls shall be constructed of a durable material, panels locked together and sealed or of epoxy-coated gypsum board.

Phar 15.31(3)(f) (f) Floors shall have a covering that shall be seamless or have heat-welded seams and coving to the sidewall. There shall be no floor drains.

Phar 15.31(3)(h) (h) Ceiling lighting fixtures shall have exterior lens surfaces which are smooth, mounted flush, and sealed.

Phar 15.31(3)(i) (i) Carts shall be constructed of stainless steel wire, nonporous plastic or sheet metal with cleanable casters.

Phar 15.31(3)(j) (j) Tacky mats may not be used in a classified area.

Phar 15.31(3)(k) (k) HEPA filters and unidirectional airflow shall be used to maintain the appropriate airborne particulate classification.

Phar 15.31(3)(L) (L) The classified area shall measure not less than 30 air changes per hour of which at least half shall be HEPA-filtered fresh air.

Phar 15.31(3)(m) (m) For classified areas physically separated through the use of walls, doors, and pass-throughs, a minimum differential positive pressure of 0.02-inch water column is required to separate each classified area. If a pass-through is used, only one door shall be opened at a time. A pressure gauge or velocity meter shall be used to monitor the pressure differential or airflow between classified areas with results documented at least daily.

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.