(A) The purpose of this section is to provide standards for the preparation, labeling, storing, dispensing and distribution of sterile preparations by pharmacies and other facilities permitted by the board.
(B) Compounded sterile preparation (CSP) microbial contamination risk level is assigned according to the corresponding probability of contamination.
(1) A low-risk level CSP is compounded under the following conditions:
(a) The CSP must be compounded with aseptic manipulations entirely within ISO Class 5 or better air quality using only sterile ingredients, products, components, and devices with the exception of radiopharmaceuticals as stated in Section 40-43-87.
(b) The compounding only may involve transfer, measuring, and mixing manipulations using not more than three commercially manufactured packages of sterile products and not more than two entries into one sterile container or package of sterile product or administration container or device to prepare the CSP.
(c) For a low-risk level preparation, in the absence of passing a sterility test or process validation, the storage periods should not exceed the following time periods before administration and with proper storage:
(i) not more than forty-eight hours at controlled room temperature;
(ii) not more than fourteen days at a cold temperature; and
(iii) not more than forty-five days in solid frozen state.
(2) A low-risk level CSP prepared in a PEC and that cannot be located within an ISO Class 7 or better buffer area requires a twelve-hour or less BUD. A low-risk level CSP with a BUD of twelve hours or less must meet the following criteria:
(a) PECs must be certified and maintain ISO Class 5 for exposure to critical sites and must be in a segregated compounding area restricted to sterile compounding activities that minimize the risk of CSP contamination.
(b) The segregated compounding area must not be in a location that has unsealed windows or doors that connect to the outdoors or high traffic flow, or that is adjacent to construction sites, warehouses, or food preparation.
(c) Personnel shall follow all procedures outlined in subsection (F) prior to compounding. A sink may not be located adjacent to the ISO Class 5 PEC and must be separated from the immediate area of the ISO Class 5 PEC device.
(d) The specifications for cleaning and disinfecting the sterile compounding area, personnel training and responsibilities, aseptic procedures, and air sampling must be followed as described in subsection (F).
(3) A medium-risk level CSP occurs under low-risk conditions when one or more of the following conditions exist:
(a) Multiple individual or small doses of sterile products are combined or pooled to prepare CSPs that will be administered either to multiple patients or to one patient on multiple occasions.
(b) The compounding process includes complex aseptic manipulations other than the single-volume transfer.
(c) The compounding process requires an unusually long duration, such as that required to complete dissolution or homogeneous mixing.
(d) In the absence of passing a sterility test or process validation, the storage periods should not exceed the following time periods before administration and with proper storage:
(i) not more than thirty hours at controlled room temperature;
(ii) not more than nine days at a cold temperature; and
(iii) not more than forty-five days in solid frozen state.
(4) A CSP is considered high-risk if it is compounded under the following conditions due to contamination or high risk of becoming contaminated:
(a) Nonsterile ingredients and products are incorporated or a nonsterile device is employed before terminal sterilization.
(b) Any of the following are exposed to air quality worse than ISO Class 5 for more than one hour:
(i) sterile contents of commercially manufactured products;
(ii) CSPs that lack effective antimicrobial preservatives; and
(iii) sterile surfaces of devices and containers for the preparation, transfer, sterilization, and packaging of CSPs.
(c) Presterilization procedures for high-risk level CSP, such as weighing and mixing, are completed in an ISO Class 8 or better environment.
(d) Preparations are appropriately sterilized before dispensing.
(e) For a high-risk level preparation, in the absence of passing a sterility test or process validation, the storage periods should not exceed the following time periods before administration and with proper storage:
(i) not more than twenty-four hours at controlled room temperature;
(ii) not more than three days at a cold temperature; and
(iii) not more than forty-five days in solid frozen state.
(5) The immediate-use CSP provision stated here only may be used for situations where a need for emergency or immediate patient administration of a CSP exists. An immediate-use preparation may not include a medium-risk level or a high-risk level CSP. An immediate-use CSP is exempt from the requirements described in subsection (B)(1) if:
(a) The compounding process involves simple transfer of commercially manufactured packages of sterile nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers' original containers into any one container or package of sterile infusion solution or administration container or device.
(b) The compounding procedure is a continuous process not to exceed one hour unless otherwise required for preparation.
(c) During preparation, aseptic technique is followed and, if not immediately administered, the finished CSP is under continuous supervision to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other CSPs, and direct contact of outside surfaces.
(d) Administration begins no later than one hour following the start of the preparation of the CSP.
(e) Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the CSP must bear a label listing the patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared the CSP, and the exact one-hour BUD and time.
(f) If administration has not begun within one hour following the start of preparing the CSP, the CSP must be discarded.
(C) The compounding area of the facility must meet the facility requirements relative to the risk level of preparations they prepare.
(1) Facility design and environmental control must be designed to minimize airborne contamination from contacting critical sites.
(a) A PEC must maintain ISO Class 5 or better conditions while compounding.
(b) The PEC HEPA-filtered air must be supplied in critical areas at a velocity sufficient to sweep particles away from the compounding area.
(2) The buffer area must maintain at least ISO Class 7 conditions under dynamic operating conditions.
(a) The room must be segregated from surrounding, unclassified spaces to reduce the risk of contaminants being blown, dragged, or otherwise introduced into the HEPA-filtered airflow environment.
(b) For buffer areas not physically separated from the ante areas, the principle of displacement airflow must be employed. The displacement concept shall not be used for high-risk compounding.
(c) The PEC must be placed out of the traffic flow in a manner to avoid conditions that could adversely affect its operation.
(d) Cleaning materials must be nonshedding and dedicated for use only in the sterile compounding area.
(e) Only the furniture, equipment, supplies, and other material required for the compounding activities to be performed may be brought into the buffer area, and they must be nonpermeable, nonshedding, cleanable, and resistant to disinfectants. They must be cleaned, then disinfected before brought into the area.
(f) The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets in the buffer area must be smooth, impervious, and nonshedding in order to promote cleanliness.
(g) The buffer area shall not contain sources of water or floor drains with the exception of emergency safety devices.
(3) An ISO Class 7 buffer area and ante area supplied with HEPA-filtered air must have air changes per hour (ACPH) of not less than thirty.
(4) HEPA-filtered supply air should be introduced at the ceiling and returns must be mounted low on the wall, creating a general top-down dilution of area air.
(5) The floors in the clean and ante areas are cleaned by sweeping and mopping on each day of operation when no aseptic operations are in progress.
(6) The environment for compounding must contain an ante area that is ISO Class 8 quality air or better. Areas participating in high-risk compounding must have a separate ante area. Supplies and equipment must be removed from shipping cartons outside of the ante area, and must be wiped with a sanitizing agent before being transported to the clean room.
(7) Placement of a PEC must be based on the following:
(a) an LAFW, BSC, CAI, and CACI only may be located within a restricted access ISO Class 7 buffer area; and
(b) a CAI and CACI only may be placed in an ISO Class 7 buffer area unless the isolator maintains ISO Class 5 during dynamic operating conditions.
(8) The buffer area designated for placement of the ISO Class 5 PEC must be constructed to allow visual observation.
(9) The buffer area may not be used for storage of bulk supplies and materials.
(10) Maintain areas at temperatures and humidity levels to ensure the integrity of the drugs prior to their dispensing as stipulated by the USP/NF or the labeling of the manufacturer or distributor, or both.
(11) A sink with hot and cold running water readily accessible to the sterile preparations preparation area with immediate availability of germicidal skin cleanser and either an air blower or nonshedding single-use towels for hand drying must be available to all personnel preparing sterile pharmaceuticals.
(D) Environmental quality and control practices include:
(1) Giving the highest priority in a sterile compounding practice to the protection of critical sites by precluding physical contact and airborne contamination.
(2) Performing viable and nonviable environmental air sampling testing every six months as part of a comprehensive quality management program and:
(a) as part of the commissioning and certification of new facilities and equipment;
(b) as part of the recertification of facilities and equipment; or
(c) in response to identified problems with the sterility of end preparations.
(3) Engineering control performance verification procedures must be performed by a qualified individual no less than every six months and when the device or room is relocated or altered. Certification documents must be retained for two years.
(4) Certification that each ISO classified area is within established guidelines for total particle counts must be performed no less than every six months and whenever the LAFW, BSC, CAI, or CACI is relocated or the physical structure of the buffer area or ante area has been altered. Testing must be performed by qualified operators.
(5) All certification records must be maintained and reviewed by pharmacy personnel to ensure that the controlled environments are in compliance.
(6) A pressure gauge or velocity meter must be installed to monitor the pressure differential or airflow between the buffer area and the ante area and between the ante area and the general environment outside the compounding area.
(a) The pressure between the positive ISO Class 7 or better buffer area, the ante area, and the general pharmacy area may not be less than a 0.02 inch water column.
(b) The pressure between the negative ISO Class 7 or better buffer area, the ante area, and the general pharmacy area may not be less than a -0.01inch water column. For negative pressure buffer areas, the ante area must be ISO Class 7 or better.
(c) The results must be reviewed and documented on a log maintained either electronically or manually at least every work shift or by a continuous recording device.
(7) An appropriate facility-specific environmental sampling procedure must be followed for airborne viable particles based on a risk assessment of compounding activities performed.
(a) The documentation must include sample location, method of collection, volume of air sampled, time of day, and action levels.
(b) Evaluation of airborne microorganisms using volumetric collection methods in the controlled air environments, including LAFWs, CAIs, clean room or buffer areas, and ante areas, must be performed by properly trained individuals for all compounding risk levels. Impaction is the preferred method of volumetric air sampling.
(c) For all compounding risk levels, air sampling must be performed at locations prone to contamination during compounding activities and during other activities such as staging, labeling, gowning, and cleaning. Locations must include zones of turbulence within LAFW and other areas where air turbulence may enter the compounding area.
(d) Corrective actions must be taken when CFU counts for each ISO classification are exceeded, or when microorganisms are identified that are potentially harmful to patients receiving CSPs.
(E)(1) All hazardous CSPs must be compounded and prepared in an ISO Class 5 environment in a BSC or CACI with the exception of radiopharmaceuticals as stated in Section 40-43-87. Hazardous drugs may not be prepared in a laminar airflow workbench or a compounding aseptic isolator.
(2) Appropriate personal protective equipment must be worn by personnel compounding hazardous agents.
(3) Written procedures for disposal and handling spills of hazardous agents must be developed.
(4) There must be immediate access to emergency spill supplies wherever hazardous drugs are prepared.
(5) A hazardous CSP must be identified with warning labels in accordance with state and federal requirements.
(6) A hazardous CSP must be packaged for handling and delivery in a manner that minimizes the risk of rupture of the primary container and ensures the stability, sterility, and potency of the solution.
(7) A hazardous drug must be handled with caution at all times during receiving, distribution, stocking, inventorying, preparation for administration, and disposal.
(8) Documentation that personnel have been trained in the compounding, handling, and disposal of hazardous agents must be available. This documentation must be updated annually. The training must include the following if applicable:
(a) safe aseptic manipulation practices;
(b) negative pressure techniques when utilizing a BSC or CACI;
(c) correct use of CSTD devices;
(d) containment, cleanup and disposal procedures for breakages and spills; and
(e) treatment of personnel contact and inhalation exposure.
(F) Policies and procedures must be developed and implemented for the pharmacy. These policies and procedures must include the following as applicable:
(1) annual training and evaluation of sterile compounding personnel to include skills observation of antiseptic hand cleansing, other personnel cleansing, media-fill challenge, glove fingertip testing, cleaning of compounding environment, donning protective garb, maintaining or achieving sterility of CSPs;
(2) semiannual media-fill test representative of high-risk compounding must be performed by all personnel authorized to prepare high-risk CSPs;
(3) cleaning and disinfecting of the sterile compounding areas and devices with supporting documentation;
(4) ensuring identity, quality, and purity of ingredients;
(5) sterilization methods for high-risk CSPs;
(6) establishment of appropriate storage requirements and BUDs;
(7) measuring, mixing, dilution, purification, packaging, and labeling;
(8) unpackaging and introducing supplies into the sterile compounding environment;
(9) compounding activities that require the manipulation and disposal of a hazardous material;
(10) expiration dating of single-dose and multiple-dose containers;
(11) quality control and quality assurance of CSP processes;
(12) material safety data sheets;
(13) use of investigational drugs;
(14) written procedures outlining required equipment calibration, maintenance, monitoring for proper function, and controlled procedures for use of the equipment and specified time frames for these activities must be established and followed. Results from the equipment calibration, semiannual certification reports, and routine maintenance must be kept on file for two years;
(15) patient training and competency in managing therapy in the home environment;
(16) safety measures to ensure accuracy of CSPs; and
(17) compounding logs for nonpatient-specific CSPs.
(G) Compounding personnel:
(1) may not introduce food or drinks into the ante areas, buffer areas, or segregated compounding areas; and
(2) shall ensure that all CSPs are checked by a pharmacist before dispensing.
(H) In addition to references currently required in a pharmacy, at least one current reference on compatibility and stability of sterile pharmaceuticals must be available.
(I) All sterile pharmaceuticals prepared for dispensing must be labeled in accordance with Section 40-43-86 and include:
(1) name, address, and telephone number of the pharmacy for outpatients and name of the facility for inpatients;
(2) dating of a nonadditive solution if the manufacturer's protective cover, if applicable, is removed before dispensing;
(3) name of prescribing physician;
(4) room number and bed of patient, if applicable; and
(5) special handling, storage requirements, or both.
(J) Bulk or unformulated drug substances and added substances or excipients must be stored in tightly closed containers under temperature, humidity, and lighting conditions that are either indicated in official monographs or approved by suppliers. The date of receipt by the compounding facility must be clearly and indelibly marked on each package of ingredients. After receipt by the compounding facility, packages of ingredients that lack a supplier's expiration date cannot be used after one year unless either appropriate inspection or testing indicates that the ingredient has retained its purity and quality for use in CSPs.
(K) When sterile pharmaceuticals are provided to home care patients, the dispensing pharmacy may supply a nurse with emergency drugs if a physician has authorized the use of these drugs by a protocol or prescription drug order for use in an emergency situation, such as anaphylactic shock.
(L) A licensed health care professional may possess noncontrolled legend drugs or devices such as water for injection, normal saline for an IV, and heparin flushes to facilitate in the administration of prescribed CSPs.
(M) There must be a system that requires an institutional or home infusion pharmacist to be available twenty-four hours a day for a patient, nursing agency, or physician to which the pharmacy is providing services.
HISTORY: 1998 Act No. 366, Section 1; 2018 Act No. 143 (H.3926), Section 3, eff March 20, 2018.
Effect of Amendment
2018 Act No. 143, Section 3, rewrote the section, revising and broadening associated standards relating to the handling of sterile preparation by pharmacies.