3 Colo. Code Regs. § 719-1-21.00.00

Current through Register Vol. 47, No. 8, April 25, 2024

Section 3 CCR 719-1-21.00.00 - COMPOUNDING

The purpose of this Rule is to codify the compounding of preparations to assure that they are of acceptable strength, quality and purity.

If the pharmacist compounds a preparation according to the manufacturer's labeling instructions, then further documentation is not required. All other compounded preparations require further documentation as set forth in this Rule.

Compounding of investigational products may be exempt from sections of Rule 21.00.00 when compounding is restricted to utilizing ingredients that are regulated by the Federal Food and Drug Administration through an Investigational Review Board (IRB) and when the IRB- approved protocol requires deviation from this Rule.

21.00.10 Limitations and Record-Keeping.

a. No non-controlled substance preparation shall be compounded in advance in such quantity as may exceed a ninety-day supply or is necessary to accurately compound the preparation. A ninety-day supply shall be determined by the average number of dosage units dispensed or distributed of said preparation during the previous six month period. All prescription drug outlets shall comply with all applicable federal laws and rules pertaining to the compounding and dispensing of controlled substance preparations, including any federal laws or rules pertaining to compounding controlled substance preparations in anticipation of immediate need.

b. No expired components may be used in compounding. No component may be used which will expire prior to the beyond-use date of the final compounded product. No expired final compounded product shall be dispensed or distributed.

c. All records required to be maintained pursuant to this Rule 21.00.00 may be maintained electronically so long as such records are maintained in a uniform and readily retrievable manner, are printable upon request of the Board or its inspectors, and can be reviewed at a viewable rate that may customarily be reviewed when otherwise in hard-copy form.

21.00.20 Casual Sales/Distribution of Compounded Products.

a. Unless otherwise allowed by state and federal law, nonresident prescription drug outlets shall not distribute compounded products into Colorado pursuant to 21 U.S.C. secs. 331(a), 353(b) and 355(a).

b. Unless otherwise allowed by state and federal law, nonresident prescription drug outlets registered in Colorado may dispense compounded products and ship them into Colorado only pursuant to valid, patient-specific prescription orders.

c. A nonresident prescription drug outlet may distribute a compounded product to a Colorado-licensed veterinarian who is located in Colorado and authorized by law to prescribe the drug only if:

i) The nonresident prescription drug outlet provides the Board with a copy of the outlet's most recent report detailing an inspection by the National Association of Boards of Pharmacy Verified Pharmacy Program, for which third-party inspection the nonresident prescription drug outlet shall obtain and pay for on an annual basis, and the Board approves the inspection report as satisfactorily demonstrating proof of compliance with the Board's own inspection procedures and standards;

ii) The nonresident pharmacy provides a copy of the most recent inspection of the nonresident pharmacy by the agency that regulates pharmaceuticals in the state of residence; and

iii) The nonresident prescription drug outlet provides the Board, on an annual basis, with a copy of the outlet's current manufacturer registration obtained from the Drug Enforcement Administration.

d. Distribution of a compounded product to a Colorado-licensed veterinarian may be for the purpose of dispensing by the receiving veterinarian only if:

i) The compounded product is necessary for the treatment of an animal patient's emergency medical condition; and

ii) As determined by the veterinarian, the veterinarian cannot access, in a timely manner, the compounded product from a prescription drug outlet or nonresident prescription drug outlet.

21.00.30 Definitions. When used in this Rule 21.00.00, the following words and terms shall have the following meanings, unless the context clearly indicates otherwise.

a. Active Pharmaceutical Ingredient (API): Chemicals, substances or other components of preparations intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in human or other animals or for use as dietary supplements.

b. Batch (Lot): Multiple units of the same compounded preparation in a single discrete process, by the same individuals, carried out during one limited time period.

c. Beyond-Use Date (BUD): A date after which a compounded preparation should not be stored, used or transferred and is determined from the date the preparation is compounded.

d. Biological Safety Cabinets (BSC): A ventilated cabinet often used for preparation of hazardous drugs. These cabinets are divided into 3 general classes (Class I, Class II, Class III). Class II BSCs are further divided into types (Type A1, Type A2, Type B1, and Type B2).

e. Component (ingredient): Any substance which is contained in a compounded preparation.

f. Compounding:

(1) The combining, admixing, diluting, pooling, reconstituting other than as provided in the manufacturer's labeling or otherwise altering a drug product or bulk drug substance of one or more active ingredients with one or more other substances, or the assembling of a finished device:

(a) Formulated for use on or for the patient as the result of a practitioner's prescription drug order, chart order, or initiative, based on the relationship between the practitioner, patient, and pharmacist in the course of professional practice; or

(b) For the purpose of, or as an incident to, research, teaching, or chemical analysis and not for sale or dispensing; or

(c) In anticipation of prescription orders based on routine, regularly-observed prescribing patterns.

(2) Compounding does not include the preparation of copies of commercially available drug products. Compounded preparations that produce, for the patient, a significant difference between the compounded drug and the comparable commercially available drug product as determined, by the prescriber, as necessary for the medical best interest of the patient are not copies of commercially available products. "Significant differences" may include, but are not limited to, the removal of a dye for medical reasons (such as allergic reaction), changes in strength, and changes in dosage form or delivery mechanism. Price differences are not a "significant" difference to justify compounding.

g. Containment Ventilated Enclosures (CVE): A full or partial enclosure that uses ventilation principles to capture, contain, and remove airborne contaminants through HEPA filtration and prevent their release into the work environment.

h. Designated Person: One or more individuals assigned to be responsible and accountable for the performance and operation of the facility and personnel as related to the preparation of non-sterile and sterile preparations

i. Preparation or Product: A compounded drug dosage form, a compounded dietary supplement, or a finished device.

j. Quality Assurance (QA): Set of activities used to ensure that the processes used in the preparation of non-sterile or sterile drug products lead to products that meet predetermined standards of quality.

k. Quality Control (QC): Set of testing activities used to determine that the ingredients, components and final non-sterile or sterile drug products prepared meet pre-determined requirements with respect to strength, identity, quality, and purity.

l. Repackaging: The subdivision or transfer of a product from one container or device to a different container or device. Repackaging does not constitute compounding, whether or not the product being repackaged was previously compounded.

m. SOPS: Standard operating procedures.

n. Stability: Extent to which a preparation retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding.

o. USP/NF: The current edition of the United States Pharmacopeia/National Formulary.

p. Validation: Documented evidence providing a high degree of assurance that specific processes will consistently produce a product meeting predetermined specifications and quality attributes.

n. Vehicle: A component for internal or external use that is used as a carrier or diluent in which liquids, semisolids, or solids are dissolved or suspended. Examples include, but are not limited to, water, syrups, elixirs, oleaginous liquids, solid and semisolid carriers, and proprietary products.

21.10.00 Compounding of Non-Sterile Preparations.

21.10.00 Scope

Compounded nonsterile preparations (CNSPs) that must comply with this rule include, but are not limited to the following dosage forms:

a. Solid oral preparations

b. Liquid oral preparations

c. Rectal preparations

d. Vaginal preparations

e. Topical preparations (i.e., creams, gels, and ointments)

f. Nasal and sinus preparations intended for local application (i.e., nasal sprays and nasal irrigation)

g. Otic preparations (excluding use in perforated eardrums)

21.10.10 Policy and Procedure Manual.

a. A manual, outlining policies and procedures encompassing all aspects of non-sterile compounding shall be available for inspection at the pharmacy. The manual shall be complied with and shall be reviewed on an annual basis. Such review shall be signed and dated or electronically approved if version and approval histories are available by the pharmacist manager. In the event the pharmacist manager changes, the new manager shall review, sign, and date the manual within 30 days of becoming pharmacist manager. The pharmacist manager shall ensure compliance with the manual.

a.b. All personnel who conduct or oversee compounding activities must be trained in the facility's SOPs and be responsible for ensuring that they are followed.

b. The policy and procedure manual shall address at least the following:

(1) Responsibility of compounding personnel;

(2) Verification of compounding accuracy;

(3) Personnel training and evaluation in compounding skills;

(4) Garbing Requirements and cleaning and sanitation for reusable equipment

(4) Environmental quality and control;

(5) Labeling and recordkeeping;

(6) Finished preparation release check;

(8) Storage and beyond-use dating;

(8) (10) Packaging and Transporting

(9) Adverse event reporting and recalls; and

(10) Quality assurance and quality control programs.

21.10.20 Personnel Education, Training and Evaluation.

a. The compounding facility must designate one or more individuals to be responsible and accountable for the performance and operation of the facility and personnel for the preparation of CNSPs. The designated person(s) must be identified in the facility's SOPs. If the compounding facility has only one person responsible for all compounding in the facility, then that person is the designated person.

b. Pharmacy personnel who compound or have direct oversight of compounding personnel compounding CNSPs must complete training initially and every 12 months. Other personnel, who do not compound and only perform functions such as in-process checks, final verification, or dispensing of CNSPs, must undergo training as required by the facility's policy and procedure manual. Documentation records of this training shall be retained for the previous 2 years.

c. Before beginning to compound CNSPs independently or have direct oversight of compounding personnel, personnel must complete training and be able to demonstrate knowledge of principles and competency of skills for performing nonsterile manipulations as applicable to their assigned tasks in at least the following core competencies:

1) Hand hygiene

2) Garbing

3) Cleaning and sanitizing

4) Handling and transporting components and CNSPs

5) Measuring and mixing

6) Proper use of equipment and devices selected to compound CNSPs

7) Documentation of the compounding process.

d. Documentation of completion of training of personnel shall be retained at the pharmacy and be available for inspection.

21.10.25 Personal Hygiene and Garbing

a. Personnel engaged in compounding must maintain appropriate hand hygiene and maintain appropriate cleanliness required for the type of compounding performed.

b. Before entering the compounding area, compounding personnel must remove any items that are not easily cleanable and that might interfere with garbing, including:

(1) Remove personal outer garments (e.g., bandanas, coats, hats, and jackets)

(2) Remove all hand, wrist, and other exposed jewelry, including piercings that could interfere with the effectiveness of garbing or hand hygiene (e.g., watches or rings that may tear gloves)

(3) Remove earbuds or headphones

c. The designated person(s) may permit accommodations provided that the quality of the environment and CNSP will not be affected. All accommodations should be documented.

d. Personnel must perform the following procedures necessary for appropriate hand hygiene when entering the compounding area to compound:

(1) Wash hands with soap and water for at least 30 seconds

(2) Dry hands completely with disposable towels or wipers

(3) Don gloves

e. Gloves must be worn for all compounding activities. Gloves must be inspected for holes, punctures, or tears and must be replaced immediately if such defects are detected.

f. Other garb (e.g., shoe covers, head or hair covers, facial hair covers, face masks, and gowns) must be appropriate for the type of compounding performed and should be worn as needed for the protection of personnel from chemical exposures and for prevention of CNSP contamination.

g. Garbing requirements and frequency of changing garb must be determined by the facility and documented in the policy and procedure manual.

h. Garb should be removed when leaving the compounding area. If gowns are worn, they may be reused if not damaged or soiled. If gowns are to be reused, they must remain in the compounding area.

i. Garb must be stored in a manner that minimizes contamination.

j. The policy and procedure manual must describe cleaning and sanitization procedures for reusing goggles, respirators, and other reusable equipment.

21.10.30 Environmental Quality and Controls.

a. For entities that compound both nonsterile and sterile preparations (e.g., presterilization procedures), the respective PECs/C-PECs must be placed in separate rooms, unless those PECs/C-PECs used for nonsterile compounding are sufficiently effective that the room can continuously maintain ISO 7 classification throughout the nonsterile compounding activity. If the PECs/C-PECs used for sterile and nonsterile compounding are placed in the same room, they must be placed at least 1 meter apart and particle-generating activity must not be performed when sterile compounding is in process. The area used for non-sterile compounding should be decontaminated, cleaned and disinfected before resuming sterile compounding.

b. The compounding area shall be designed, arranged, used, and maintained to prevent adventitious cross-contamination.

c. Non-sterile compounding areas shall be separate and distinct from any sterile compounding area.

d. The entire compounding area is to be well-lighted. Heating, ventilation, and air conditioning systems are to be controlled to avoid decomposition of chemicals.

e. Storage areas shall provide an environment suitably controlled to ensure quality and stability of bulk chemicals and finished preparations.

f. All components, non-freestanding equipment, and containers shall be stored off of the floor and in a manner to prevent contamination and permit inspection and cleaning of the compounding / dispensing area.

g. Compounding areas shall be maintained in a clean, orderly, and sanitary condition.

h. Adequate washing facilities are to be provided, including hot and cold running water, soap or detergent, and air driers or single-service towels. The sink used for cleaning of equipment used in nonsterile compounding must be emptied of all items unrelated to compounding and must be cleaned if visibly soiled before being used. The plumbing system shall be free of defects that could contribute to contamination of any compounded preparation.

i. Purified water or better quality water, e.g., sterile water for irrigation, shall be used for compounding nonsterile preparations when formulations indicate the inclusion of water. Purified water shall also be used for rinsing equipment and utensils used in compounding.

j. Sewage, trash, and other refuse in the compounding area are to be disposed of in a safe, sanitary, and timely manner.

k. Special precautions shall be taken to clean equipment and compounding areas meticulously after compounding preparations that contain allergenic ingredients.

21.10.35 Cleaning and Sanitization

a. Cleaning and sanitizing shall be completed with the following minimum frequencies:

b. Work surfaces shall be cleaned and sanitized at the beginning and end of each shift on days when compounding occurs, after spills, and when surface contamination (e.g., from splashes) is known or suspected and between compounding CNSPs with different components.

c. Floors shall be cleaned daily on days when compounding occurs, after spills, and when surface contamination is known or suspected.

d. Walls and ceilings shall be cleaned when visibly soiled, after spills, and when surface contamination (e.g., from splashes) is known or suspected

e. Storage shelving shall be cleaned every 3 months, after spills, and when surface contamination (e.g., from splashes) is known or suspected.

f. Devices and equipment used in the compounding operation shall be cleaned and sanitized before each use and between compounding CNSPs with different components.

g. If a CVE or BSC is used, it must be cleaned and sanitized at the beginning and end of each shift on days when compounding occurs, after spills, and when surface contamination is known or suspected. The horizontal work surface of the CVE or BSC shall be cleaned between compounding CNSPs with different components. Clean and sanitize under the work surface of a BSC monthly.

h. Cleaning and sanitizing agents must be selected and used with consideration of compatibilities, effectiveness, and minimal potential to leave residues.

i. If cleaning and sanitizing are performed as separate steps, cleaning must be performed first.

j. Documentation of cleaning shall be maintained and be available for inspection at the outlet for at least two years.

21.10.40 Equipment.

a. The equipment and components used for compounding a CNSP must be suitable for the specific compounding process.

b. Equipment shall be of suitable composition so that surfaces that contact components, in-process material, or drug products shall not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the desired result.

c. Equipment and devices used in the compounding or testing of compounded preparations must be inspected prior to use and, if appropriate, verified for accuracy as recommended by the manufacturer at the frequency recommended by the manufacturer or at least every 12 months, whichever is more frequent.

d. Equipment must be stored in a manner that minimizes the risk of contamination and must be located to facilitate equipment use, maintenance, and cleaning.

e. Equipment must be cleaned in compliance with these Rules.

f. If a CVE or BSC is used, it must be certified at least every 12 months according to manufacturer specifications.

g. Written procedures outlining required equipment, calibration, appropriate maintenance, monitoring for proper function, controlled procedures for use of the equipment and specified time frames for these activities shall be established and followed. Results of equipment calibration and appropriate maintenance reports shall be kept on file at the outlet for at least two years from the report date. These results shall be available for inspection.

21.10.60 Components.

a. Compounding personnel shall ascertain that ingredients for compounded products are in compliance with Rule 21.00.10 and are of the correct identity and appropriate quality using the following information: vendors' labels, labeling, certificates of analysis, direct chemical analysis, and knowledge of compounding facility storage conditions. No expired components may be used in compounding. No component may be used which will expire prior to the beyond-use date of the preparation.

b. Ingredients used in a compounded preparation shall either originate from FDA-approved sources, when available, or be USP/NF grade substances, when such sources are not available and identified on the FDA drug shortage list.

c. If neither USP/NF grade substances nor FDA-approved substances are available, or when food, cosmetics, or other substances are, or must be used, the substance shall be of a chemical grade in one of the following categories:

(1) Chemically Pure (CP);

(2) Analytical Reagent (AR); or

(3) American Chemical Society (ACS); or

(4) Food Chemical Codex.

d. For all ingredients, unless FDA-approved, the pharmacist shall establish purity and stability by obtaining a certificate of analysis from the supplier. The certificate of analysis, when applicable, shall be maintained at the prescription drug outlet for at least two years from the date of preparation.

e. For components that do not have expiration dates assigned by the manufacturer or supplier, a pharmacist shall clearly and legibly label the container with the date of receipt and assign a conservative expiration date, not to exceed three years after receipt, to the component based on the nature of the component and its degradation mechanism, the container in which it is packaged, and the storage conditions. A pharmacist shall clearly and legibly label the container with the assigned expiration date. In no event shall the labeled date of receipt or assigned expiration date be later altered after originally labeling the container.

f. A manufactured drug product may be a source of active ingredient. Only manufactured drugs from containers labeled with a lot number and an expiration date are acceptable as a potential source of active ingredients. When compounding with manufactured drug products, the compounder must consider all ingredients present in the drug product relative to the intended use of a compounded preparation.

g. Drug preparations that have been withdrawn or removed from the market for safety reasons shall not be compounded. Such preparations may be compounded exclusively for veterinary use provided no documentation exists which indicates that the preparation is unsafe for such use.

h. Purified water or better quality, e.g., sterile water for irrigation, must be used for compounding nonsterile drug preparations when formulations indicate the inclusion of water.

i. Any ingredient regulated by the FDA through an Investigational Review Board (IRB) is exempt from Rule 21.10.60 provided the research requirements for the receipt of the ingredient is followed and meets the requirements of section 12-280-131(2), C.R.S.

21.10.65 Drug Preparation Containers

a. Pharmacy personnel shall ensure that the containers and container closures used in the packaging of compounded preparations meet all applicable USP requirements and, when available, compounding monographs.

b. The containers and closures shall be made of suitable clean material in order not to alter the quality, strength, or purity of the compounded preparation in any way.

c. The containers and closures shall be stored off of the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. The containers and closures shall be stored in such a way as to permit inspection and cleaning of the compounding / dispensing area.

21.10.70 Finished Preparation Release Checks.

a. Physical Inspection

(1) Written procedures for physical inspection of compounded preparations shall be followed. Immediately after compounding, and prior to dispensing or distribution, each product shall be inspected for evidence of particulates or other foreign matter, container-closure integrity, and any other apparent visual defect. Defective product shall be segregated from other product and shall not be dispensed or distributed.

b. Compounding Accuracy Checks

(1) Written procedures for double-checking compounding accuracy shall be followed for every compounded product during preparation and immediately prior to release. Outlets which compound shall have at least the following written procedures for verifying the correct identity and quality of compounded products prior to dispensing or distribution:

(2) At the completion of compounding, before releasing and dispensing, the CNSP must be visually inspected to determine whether the physical appearance of the CNSP is as expected (e.g., color, texture, physical uniformity). Some CNSPs, as noted in their MFR, also must be visually checked for certain characteristics (e.g., emulsions must be checked for phase separation). The CNSP must be visually inspected to confirm that the CNSP and its labeling match the CR and the prescription or medication order. The inspection also must include a visual inspection of container closure integrity (e.g., checking for leakage, cracks in the container, or improper seals).

21.10.80 Storage and Beyond-Use Dating.

a. Completed compounded preparations that are not immediately dispensed or distributed shall be stored according to the guidelines in the formulation record.

b. In the absence of stability information that is applicable to the lowest and highest dose or concentration of a specific preparation compounded at the outlet, the following maximum beyond-use dates are to be used for non-sterile compounded preparations that are packaged in tight, light-resistant containers and as indicated:

(1) For nonpreserved aqueous dosage forms, the beyond-use-date shall not exceed 14 days under refrigeration.

(2) For preserved aqueous dosage forms, the beyond-use date shall not exceed 35 days at controlled room temperature or under refrigeration;

(3) For non-aqueous oral liquids, the beyond-use-date shall not exceed 90 days at controlled room temperature or under refrigeration

(4) For all other non-aqueous dosage forms, the beyond-use date shall not exceed 180 days at controlled room temperature or under refrigeration.

(5) The beyond-use-date of the CNSP must not exceed the shortest remaining expiration date of any of the commercially available starting components

(6) When there is supporting valid scientific stability information that is directly applicable to the specific preparation, the beyond-use date may be extended to that indicated in the scientific information for aqueous and non-aqueous dosage forms up to 180 days.

(7) If the beyond-use-date of an aqueous CNSP is extended beyond the BUD indicated in Rule 21.10.80(1)(2), the CNSP must be tested for antimicrobial effectiveness or align with antimicrobial effectiveness provided by an FDA-registered facility or published in peer-reviewed literature, as long as the formulation and container closure materials are the same as those tested. Antimicrobial effectiveness testing may be performed on a low concentration and a high concentration of the active ingredient in the formulation to establish preservative effectiveness across various strengths of the same formulation (e.g., bracketing).

(8) Any literature used to extend the beyond-use-date shall be readily retrievable and be available for inspection.

21.10.90 Master Formulation Record.

a. For each compounded preparation, a uniform, readily retrievable formulation record shall be maintained and available for inspection for two years from the date last utilized, documenting:

(1) The official or assigned name, strength or activity, and dosage form of the compounded preparation;

(2) Calculations needed to determine and verify quantities or concentrations of components and doses of APIs, if applicable;

(3) All ingredients and their quantities;

(4) References to support the assigned BUD;

(5) The equipment and supplies used to compound the preparation;

(6) Complete instructions for preparing CSNPs that shall include:

(a) Order of mixing;

(b) Mixing temperatures or other environmental controls:

(c) Duration of mixing; and

(d) Other factors pertinent to the replication of the preparation as compounded;

(7) Sample labeling information which shall include, in addition to other required information;

(a) Generic name and quantity or concentration of each API;

(b) Assigned BUD;

(c) Storage and handling (e.g. shake well) conditions; and

(d) Assigned prescription or control number, whichever is applicable;

(8) The container closure systems as used in dispensing;

(9) Packaging and storage requirements;

(10) Physical description of final product; and

(11) Procedures for quality control, if applicable.

21.11.00 Compounding Record.

a. For each compounded product prepared, a record shall be maintained and available for inspection for two years on the original order, or on a separate, uniform, and readily retrievable record documenting the following:

(1) The official or assigned name and strength or activity and dosage form of the CNSP;

(2) Formulation record reference for the preparation;

(3) Names and corresponding quantities of all components used in the preparation;

(4) Sources, lot numbers, and expiration dates of each component;

(5) Total number of dosage units compounded;

(6) Name of the individuals who compounded the preparation;

(7) Name of the pharmacist who approved the preparation;

(8) Batch (lot) number assigned, if multiple units compounded;

(9) Date prepared;

(10) Assigned BUD;

(11) Assigned prescription number(s) or control number(s), whichever is applicable;

(12) Storage conditions;

(13) Calculations, if applicable;

(14) Physical description of the final product;

(15) Results of quality control procedures, if applicable;

(16) Documentation of any quality control issues and any adverse reactions or preparation problems reported by the patient or caregiver; and

(17) Duplicate label(s) should be readily retrievable for auditing and inspection purposes as was attached to the container of the finished compounded preparation.

21.11.10 Labeling of Non-Sterile Compounded Preparations.

a. Labeling of non-sterile compounded products dispensed pursuant to a prescription order or LTCF chart order shall include at least the following:

(1) All requirements of section 12-280-124, C.R.S.;

(2) Batch (lot) number, if appropriate;

(3) Assigned BUD;

(4) Storage directions when appropriate; and

(5) A clear statement that this product was compounded by the pharmacy, except for radiopharmaceuticals prepared from FDA-approved, commercially available kits and/or drug products.

b. Labeling of non-sterile compounded products dispensed pursuant to a hospital chart order shall include at least the following:

(1) All requirements of section 12-280-124, C.R.S.;

(2) Batch (lot) number, if appropriate;

(3) Assigned BUD; and

(4) Storage directions, when appropriate.

c. Labeling of non-sterile compounded products made in anticipation of orders shall include at least the following:

(1) Name and address of the outlet;

(2) Name and strength of the drug(s) / active ingredient(s) in the final product;

(3) Total quantity in package;

(4) Assigned BUD;

(5) Batch (lot) number;

(6) Specific route of administration;

(7) Storage directions, when appropriate;

(8) "Rx only"; and

(9) "This product was compounded by the pharmacy", except for radiopharmaceuticals prepared from FDA-approved, commercially available kits and/or drug products.

d. Labeling of non-sterile compounded products distributed within hospitals as floor stock shall include at least the following:

(1) Name of the outlet;

(2) Name and strength of the drug(s);

(3) Total quantity in package;

(4) Quantity of active ingredient in each dosage unit;

(5) Assigned BUD;

(6) Batch (lot) number;

(7) Specific route of administration; and

(8) Storage directions, if appropriate.

21.11.20 Quality Assurance and Quality Control. Patient Monitoring, Adverse Events Reporting, and Product Recall.

a. A formal, written quality assurance and quality control program must exist and address:

(1) Adherence to procedures

(2) Prevention and detection of errors and other quality problems

(3) Evaluation of complaints and adverse events, and

(4) Appropriate investigations and corrective actions

b. The quality assurance and quality control program must be reviewed every 12 months by the designated person (s) and this review must be documented.

c. Outlets which compound shall provide patients and other recipients of compounded preparations with a way to address their questions, complaints, and report any concerns that they may have with these preparations.

d. The outlet shall have written policies describing specific instructions for receiving, acknowledging; and for recording, or filing, and evaluating reports of adverse events and of the quality of preparation claimed to be associated with compounded preparations.

e. Outlets which compound must have procedures in place to address notification about and recall of dispensed CNSP.

f. The pharmacist manager shall report to the Board in writing significant errors related to compounded preparations such as those that result in serious personal injury or death of a patient.

g. If a compounded preparation is believed to be defective in any way, or if the Board or Federal Food and Drug Administration makes a written request for a recall of a specific preparation, the outlet shall immediately recall any product dispensed or distributed. Any product remaining in the outlet shall be immediately quarantined and shall not be dispensed or distributed. Recall records shall include at least the following:

(1) Product name, strength, dosage form;

(2) Reason for recall;

(3) Amount of product made;

(4) Date made; and

(5) Amount of product dispensed or distributed.

h. The outlet shall conduct tests, as appropriate, on the recalled product to identify reason product was defective. Results of these tests shall be retained at the outlet.

i. Adverse event reports and product recall records shall be retained and available for inspection at the outlet for at least two years.

21.11.25 CNSP Packaging and Transporting

a. An outlet that compounds must have a policy or procedure to describe the packaging of CNSP.

b. If transporting CNSPs, the facility must have written SOPs to describe the mode of transportation, any special handling instructions, and whether temperature monitoring devices are needed.

21.20.00 Compounding of Sterile Products (CSPs).

21.20.10 Definitions. In addition to the definitions set forth above in Rule 21.00.30, when used in these Rules 21.20.00 et seq., 21.21.00 et seq., and 21.22.00 et seq., the following words and terms shall have the following meanings, unless the context clearly indicates otherwise.

a. Anteroom: An ISO Class 8 (Class 100,000) or better area where personnel perform hand hygiene and garbing procedures, staging of components, order entry, labeling, and other activities which generate particulates. It is a transition area that provides assurance that air flows from clean to dirty areas.

b. Aseptic Processing: A mode of processing pharmaceutical and medical products that involves the separate sterilization of the product and of the packaging and the transfer of the product into the container and its closure under at least ISO Class 5 conditions.

c. Biological Safety Cabinet (BSC): A ventilated containment unit for personnel, product, and environmental protections having an open front with inward airflow for personnel protection, downward HEPA filtered laminar airflow for product protections, and HEPA filtered exhausted air for environmental protections.

d. Buffer Area: An ISO Class 7 (Class 10,000), or an ISO Class 8 for the preparation of radiopharmaceuticals, area where the primary engineering control is physically located. Activities conducted in this area include the preparation and staging of components and supplies when compounding sterile products. This area may also be referred to as a buffer or core room, buffer or cleanroom areas, buffer room area, buffer or clean area.

e. Class 100 Environment (ISO Class 5): An atmospheric environment which contains less than one hundred (100) particles 0.5 microns in diameter per cubic foot of air, according to federal standards.

f. Class 10,000 Environment (ISO Class 7): An atmospheric environment which contains less than ten thousand (10,000) particles 0.5 microns in diameter per cubic foot of air, according to federal standards.

g. Class 100,000 Environment (ISO Class 8): An atmospheric environment which contains less than one hundred thousand (100,000) particles 0.5 microns in diameter per cubic foot of air according to federal standards.

h. Clean Room: A room in which the concentration of airborne particles is controlled to meet a specified airborne particulate cleanliness class. Microorganisms in the environment are monitored so that a microbial level for air, surface, and personnel is not exceeded for a specified cleanliness class.

i. Compounding Aseptic Containment Isolator (CACI): A compounding aseptic isolator (CAI) designed to provide worker protection from exposure to undesirable levels of airborne drug throughout the compounding and material transfer process and to provide an aseptic environment for compounding sterile preparations. Air exchange with the surrounding environment should not occur unless the air is first passed through a microbial retentive filter (HEPA minimum) system capable of containing airborne concentrations of the physical size and state of the drug being compounded. Where volatile drugs are prepared, the exhaust air from the isolator should be appropriately removed by properly designed building ventilation.

j. Compounding Aseptic Isolator (CAI): A closed system made up of solid walls, an air-handling system, and transfer and interaction devices. The walls are constructed so as to provide surfaces that are cleanable with covering between wall junctures. The air-handling system provides HEPA filtration of inlet air. Transfer of materials is accomplished through air locks, glove rings, or ports. Transfers are designed to minimize the entry of contamination. Manipulations can take place through either glove ports or half suits. A barrier isolator is designed for compounding sterile products. It is designed to maintain an aseptic compounding environment within the isolator throughout the compounding and material transfer process. Air exchange into the isolator from the surrounding environment should not occur unless it has first passed through a HEPA filter.

k. Compounded Sterile Products (CSPs): A preparation intended to be sterile that is created by combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug product or bulk drug substance. Such products may include, but are not limited to:

(1) Injections, including infusions

(2) Irrigations for internal body cavities (i.e., any space that does not normally communicate with the environment outside of the body, such as the bladder cavity or peritoneal cavity). [NOTE-Irrigations for the mouth, rectal cavity, and sinus cavity are not required to be sterile.]

(3) Ophthalmic dosage forms

(4) Aqueous preparations for pulmonary inhalation. [NOTE-Nasal dosage forms intended for local application are not required to be sterile.]

(5) Baths and soaks for live organs and tissues

(6) Implants

l. Compounding does not include mixing, reconstituting, or other such acts that are performed in accordance with directions contained in approved labeling or supplemental materials provided by the product's manufacturer if:

(1) The product is prepared as a single dose for an individual patient; and

(2) The approved labeling includes information for the diluent, the resultant strength, the container closure system, and storage time.

m. Critical Area: An ISO Class 5 environment.

n. Critical Sites: Include sterile ingredients of CSPs and locations on devices and components used to prepare, package, and transfer CSPs that provide opportunity for contamination.

o. Hazardous Drugs: A pharmaceutical product that has the capability of direct toxic action on living tissue that can result in severe leucopenia and thrombocytopenia, depression of the immune system and the alteration of a host's inflammatory response system.

p. Disinfectant: An agent that frees from infections. It is usually a chemical agent but sometimes a physical one. It destroys disease-causing pathogens or other harmful microorganisms but may or may not kill bacterial spores. It refers to substances applied to inanimate objects.

q. High-Efficiency Particulate Air (HEPA) filter: A filter composed of pleats of filter medium separated by rigid sheets of corrugated paper or aluminum foil that direct the flow of air forced through the filter in a uniform parallel flow. HEPA filters remove 99.97% of all particles three-tenths (0.3) microns or larger. When HEPA filters are used as a component of a horizontal or vertical-laminar-airflow workbench, an environment can be created consistent with standards for a class 100 clean room.

r. Media-Fill Test: A test which is used to qualify aseptic technique of compounding personnel or processes and to ensure that the processes used are able to produce sterile product without microbial contamination. A microbiological growth medium such as soybean-casein digest medium (SCDM) is substituted for the actual drug product to simulate admixture compounding.

s. Multiple-Dose Container: A multiple-unit container for articles or preparations intended for parenteral administration only. These containers usually contain antimicrobial preservatives. The beyond-use date (BUD) for an opened or entered multi-dose container with antimicrobial preservatives is twenty-eight days, unless otherwise specified by the manufacturer.

t. Parenteral: A sterile preparation of drugs for injection through one or more layers of skin.

u. Pharmacy Bulk Package: A container of a sterile preparation for parenteral use that contains multiple single doses. The contents of the package are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes. The closure shall by penetrated only one time after constitution with a suitable sterile transfer device or dispensing set, which allows measured dispensing of the contents. The pharmacy bulk package is to be used only in a suitable work area such as a laminar flow hood or an equivalent clean air compounding area. Such container shall be labeled with the following:

(1) The name, strength and quantity of drug or base solution;

(2) The statement "Pharmacy Bulk Package-Not For Direct Infusion;"

(3) Information on the proper technique to assure safe use of the product; and

(4) A statement limiting the time frame in which the container may be used once it has been entered, provided it is held under the labeled storage conditions.

v. Primary Engineering Control (PEC): A device or room that provides an ISO Class 5 environment for the exposure of critical sites when compounding CSPs. Such devices include, but are not limited to, laminar airflow workbenches (LAFWs), biological safety cabinets (BSCs) and compounding aseptic isolators (CAIs), and compounding aseptic containment isolators (CACIs).

w. Process Validation or Simulation: Microbiological simulation of an aseptic process with growth medium processed in a manner similar to the processing of the product and with the same container or closure system.

x. Segregated Compounding Area: A part of the designated compounding / dispensing area that is a specifically designated space, either a demarcated area or room, and that is restricted to preparing Category 1 CSPs. Such area shall contain a device that provides unidirectional airflow of ISO Class 5 air quality for preparation of CSPs and shall be void of activities and materials that are extraneous to sterile compounding.

y. Single-Dose Container: A single-unit container for articles or preparations intended for parenteral administration only. It is intended for single use and is labeled as such. Examples include, but are not limited to, prefilled syringes, cartridges, fusion-sealed containers, and closure-sealed containers when so labeled.

z. Sterile Pharmaceutical: A dosage form free from living microorganisms.

aa. Sterilization: A validated process used to render a product free of viable organisms.

bb. Sterilizing Grade Filter Membranes: Filter membranes that are documented to retain 100% of a culture of 107 microorganisms of a strain of Brevundimonas (Pseudomonas) diminuta per square centimeter of membrane surface under a pressure of not less than 30 psi (2.0 bar). Such filter membranes are nominally at 0.22 or 0.2 micrometer porosity, depending on the manufacturer's practice.

cc. Sterilization by Filtration: Passage of a fluid or solution through a sterilizing grade filter to produce a sterile effluent.

dd. Terminal Sterilization: The application of a lethal process (e.g. steam under pressure or autoclaving) to sealed containers for the purpose of achieving a predetermined sterile assurance level of usually less than 10-6, or a probability of less than one in one million of a non-sterile unit.

ee. Temperatures:

1. Frozen means temperatures between twenty five degrees below zero and ten degrees below zero Celsius (-25 and -10 degrees C.) or thirteen degrees below zero and fourteen degrees Fahrenheit (-13 and 14 degrees F.).

2. Refrigerated means temperatures between two and eight degrees Celsius (2 and 8 degrees C.) or thirty-six and forty-six degrees Fahrenheit (36 and 46 degrees F.).

3. Room temperatures mean room temperatures between fifteen and thirty degrees Celsius (15 and 30 degrees C.) or fifty-nine and eighty-six degrees Fahrenheit (59 and 86 degrees F.).

ff. Unidirectional Flow: An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed to reproducibly sweep particles away from the critical processing or testing area.

21.20.16 Allergen Extracts as CSPs

a. Licensed allergenic extracts are mixed and diluted to prepare prescription sets for administration to patients. A prescription set is a vial or set of vials of premixed licensed allergenic extracts for subcutaneous immunotherapy that have been diluted with an appropriate diluent for an individual patient.

b. Rules for compounding allergenic extracts are applicable only when:

1. The compounding process involves transfer via sterile needles and syringes of conventionally manufactured sterile allergen products and appropriate conventionally manufactured sterile added substances; and

2. Manipulations are limited to penetrating stoppers on vials with sterile needles and syringes and transferring sterile liquids in sterile syringes to sterile vials

c. Personnel Qualification for Compounding Allergenic Extract Prescription Sets.

1. Before being allowed to compound, all compounding personnel must complete training and competency and be able to demonstrate knowledge and principles of sterile compounding. This includes successful completion of:

(a) A didactic test on sterile compounding skills

(b) A gloved fingertip and thumb sampling on both hands no fewer than 3 separate times after performing complete hand hygiene and garbing procedures.

(c) A media-fill test

2. Annual personnel training must be completed and documented, including:

(a) A didactic test on sterile compounding skills

(b) A gloved fingertip and thumb sampling on both hands after performing complete hand hygiene and garbing procedures.

(c) A media-fill test

3. Personnel who have failed competency evaluations or who have not compounded in 6 months must be re-evaluated in competencies before resuming compounding duties

d. Personnel Hygiene and Garbing for Compounding Allergenic Extract Prescription Sets

1. Before beginning compounding of allergenic extract prescription sets, personnel must perform hand hygiene and garbing procedures

2. The minimum garb requirements include:

(a) A low-lint garment with sleeves that fit snugly around the wrists and an enclosed neck (e.g., gowns)

(b) A low-lint, disposable head cover that covers the hair and ears and, if applicable, a disposable cover for facial hair

(c) Face mask

(d) Sterile powder-free gloves

3. Throughout the compounding process, personnel must apply sterile 70% IPA onto all surfaces of the gloves and allow them to dry thoroughly.

e. Facilities for compounding allergenic extract prescription sets:

1. The compounding process must occur in an ISO Class 5 PEC or in a dedicated allergenic extract compounding area (AECA). The PEC or AECA used to compound allergenic extract prescription sets must be located away from unsealed windows, doors that connect to the outdoors, and traffic flow, all of which may adversely affect the air quality. Neither a PEC nor an AECA may be located where environmental control challenges (e.g., restrooms, warehouses, or food preparation areas) could negatively affect the air quality. The PEC or the work surfaces in the AECA must be located at least 1 m away from a sink. The impact of activities that will be conducted around or adjacent to the PEC or AECA must be considered carefully when designing such an area.

2. If used, the PEC must be certified at least every 6 months (see 5. Certification and Recertification).

3. If used, a visible perimeter must define the AECA.

a. Access to the AECA during compounding must be restricted to authorized personnel.

b. During compounding activities, no other activity is permitted in the AECA.

c. The surfaces of walls, floors, fixtures, shelving, counters, and cabinets in the AECA must be cleanable.

d. Carpet is not allowed in the AECA.

e. The surfaces in the AECA upon which the allergenic extract prescription sets are prepared must be smooth, impervious, free from cracks and crevices, and non-shedding to allow for easy cleaning and disinfecting.

f. Dust-collecting overhangs such as utility pipes, ledges, and windowsills, if present, must be easily cleanable.

g. The AECA must be designed and controlled to provide a well-lighted working environment, with temperature and humidity controls for the comfort of compounding personnel wearing the required garb.

4. Cleaning and Disinfecting for Compounding Allergenic Extract Prescription Sets

a. All interior surfaces of the PEC and all work surfaces of the AECA where direct compounding occurs must be cleaned and disinfected each day before compounding begins and when surface contamination is known or suspected. The horizontal work surface must be disinfected between each prescription set.

(1) If present, walls, doors, and door frames within the perimeter of the AECA must be cleaned and disinfected monthly and when surface contamination is known or suspected.

(2) Ceilings within the perimeter of the AECA must be cleaned and disinfected when visibly soiled and when surface contamination is known or suspected.

b. Vial stoppers on packages of conventionally manufactured sterile ingredients must be wiped with sterile 70% IPA to ensure that the critical sites are wet and allowed to dry before they are used to compound allergenic extract prescription sets.

6. Establishing BUDs for Allergenic Extract Prescription Sets

The BUD for the prescription set must be no later than the earliest expiration date of any allergenic extract or any diluent that is part of the prescription set, and the BUD must not exceed 1 year from the date the prescription set is mixed or diluted.

7. Labeling for Allergenic Extract Prescription Sets

a. The label of each vial of an allergenic extract prescription set must display the following prominently and understandably:

b. Patient name

c. Type and fractional dilution of each vial, with a corresponding vial number

d. BUD

e. Storage conditions

8. Shipping and Transporting Allergenic Extract Prescription Sets

a. If shipping or transporting allergenic extract prescription sets, compounding personnel must select modes of transport that are expected to deliver properly packed prescription sets in an undamaged, sterile, and stable condition. Inappropriate transport can adversely affect the quality of allergenic extract prescription sets.

b. When shipping or transporting allergenic extract prescription sets that require special handling, personnel must include specific handling instructions on the exterior of the container.

9. Documentation for Compounding Allergenic Extract Prescription Sets

a. All facilities where allergenic extract prescription sets are prepared must have and maintain written or electronic documentation to include, but not limited to, the following:

i. SOPs describing all aspects of the compounding process

ii. Personnel training records, competency assessments, and qualification records including corrective actions for any failures

iii. Certification reports of the PEC, if used, including corrective actions for any failures

iv. Temperature logs for refrigerator(s)

v. CRs for individual allergenic extract prescription sets

vi. Information related to complaints and adverse events including corrective actions taken

vii. Investigations and corrective actions

21.20.20 Definitions of Sterile Compounded Products Categories

a. Immediate Use CSPs:

(1) When all of the following conditions are met, compounding of CSPs for direct and immediate administration is not subject to the requirements for Category 1, Category 2, or Category 3 CSPs

(a) Aseptic techniques, processes, and procedures are followed, and written SOPs are in place to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, and mix-ups with other conventionally manufactured products or CSPs.

(b) Personnel are trained and demonstrate competency in aseptic processes as they relate to assigned tasks and the facility's SOPs.

(c) The preparation is performed in accordance with evidence-based information for physical and chemical compatibility of the drugs (e.g., approved labeling, stability and compatibility studies).

(d) The preparation involves not more than 3 different sterile products.

(e) Any unused starting component from a single-dose container must be discarded after preparation is complete. Single-dose containers must not be used for more than one patient.

(f) Administration begins within 4 h following the start of preparation. If administration has not begun within 4 h following the start of preparation, it must be promptly, appropriately, and safely discarded.

(g) Unless directly administered by the person who prepared it or administration is witnessed by the preparer, the CSP must be labeled with the names and amounts of all active ingredients, the name or initials of the person who prepared the preparation, and the 4-h time period within which administration must be completed.

b. Category 1 CSPs are compounded under the least controlled environmental conditions and therefore are assigned a BUD of 12 h or less at controlled room temperature or 24 h or less when refrigerated, if compounded in accordance with all of the applicable requirements for Category 1 CSPs

c. Category 2 CSPs require more environmental controls and testing than Category 1 CSPs and may be assigned a BUD of greater than 12 h at controlled room temperature or more than 24 h if refrigerated, but not exceed the limits established in these Rules, if compounded in accordance with all of the applicable requirements for Category 2 CSPs

d. Category 3 CSPs undergo sterility testing, supplemented by endotoxin testing when applicable, and have more requirements than Category 2 CSPs for personnel qualification, use of sterile garb, use of sporicidal disinfectants, frequency of environmental monitoring, and stability determination. Category 3 CSPs may be assigned longer BUDs than those set for Category 2 CSPs but not exceeding the limits in these Rules if compounded in accordance with all applicable requirements for Category 3 CSPs.

21.20.23 Single-Dose Containers, Multiple-Dose Containers, and Pharmacy Bulk Packaging.

a. Opened or needle-punctured single-dose containers shall be used within one hour if opened in worse than ISO Class 5 air quality. Single-dose containers exposed to ISO Class 5 air quality or cleaner air may be used up to twelve hours after initial puncture, as long as the labeled storage requirements during that 12-h period are maintained. Opened single-dose ampules must not be stored for any time period.

(1) Opened or needle-punctured single-dose containers shall be used within one hour if opened in worse than ISO Class 5 air quality. Needle-punctured single- dose containers exposed to ISO Class 5 air quality or cleaner air may be used up to twelve hours after initial puncture.

b. Multiple-dose containers must not be used for more than 28 days from the initial date of entering or opening, unless otherwise specified by the manufacturer.

c. Pharmacy bulk packages must be used according to the manufacturer's labeling The pharmacy bulk package must be entered or punctured only in an ISO Class 5 PEC

21.20.25 Radiopharmaceuticals as CSPs.

a. Production of radiopharmaceuticals for positron emission tomography (PET) shall comply with the most current Chapter 823 of the USP/NF < Radiopharmaceuticals for Positron Emission >.

b. Radiopharmaceuticals shall be compounded in conformity with Rules 21.20.25 below, Rule 12.00.00, and all other applicable sections of Rule 21.00.00.

(1) Radiopharmaceuticals compounded from FDA-approved, commercially sterile components in closed sterile containers and with a volume of 100 ml or less for a single-dose injection or not more than 30 ml taken from a multiple-dose container shall be designated as, and conform to, the standards for low risk CSPs.

(2) Radiopharmaceuticals shall be compounded using appropriately shielded vials and syringes in a properly functioning and certified ISO Class 5 PEC located in an ISO Class 8 or cleaner air environment to permit compliance with special handling, shielding, and negative air flow requirements.

(3) Radiopharmaceutical vials designated for multiple use, compounded with technetium-99m, exposed to an ISO Class 5 environment, and punctured by needles with no direct contact contamination may be used up to the time indicated by the manufacturer's recommendations.

(4) Technetium-99m/molybdenum-99 generator systems shall be stored and operated under conditions recommended by the manufacturer and applicable state and federal rules. Such generator systems shall be operated in an ISO Class 8 or cleaner air environment to permit special handling, shielding, and air flow requirements. To limit acute and chronic radiation exposure of inspecting personnel to a level that is as low as reasonably achievable (ALARA), direct visual inspection of radiopharmaceutical CSPs containing high concentrations of doses of radioactivity shall be conducted in accordance with ALARA.

21.20.30 Policy and Procedure Manual.

a. A manual, outlining policies and procedures encompassing all aspects of compounding shall be available for inspection at the pharmacy. This manual shall be complied with and shall be reviewed on an annual basis. Such review shall be signed and dated or electronically approved if version and approval histories are available by the pharmacist manager. In the event the pharmacist manager changes, the new manager shall review, sign, and date the manual within thirty days of becoming pharmacist manager. The pharmacist manager shall ensure compliance with the manual.

b. The policy and procedure manual shall address at least the following:

(1) Responsibility of compounding personnel, including designated person;

(2) Categories of compounding performed

(3) Development and maintenance of master formulation records;

(4) Initial and on-going training and competency of compounding personnel, persons with direct oversight of compounding personnel, and personnel who restock or clean sterile compounding areas;

(5) Garbing and Hand Hygiene, including garbing order and disinfection of re-usable equipment

(6) Environmental quality and control including review of temperature, humidity and pressure readings, microbiological air and surface monitoring;

(7) Aseptic technique, processes and procedures;

(8) Sterilization and depyrogenation methods

(9) Cleaning and disinfecting activities

(10) Calibration, maintenance, and cleaning of compounding equipment

(11) Labeling and recordkeeping;

(12) CSP release inspection and testing procedures;

(13) CSP handling, storage, packaging, shipping and transport;

(14) Adverse event reporting and recalls;

(15) Quality assurance program; and

(16) Quality control procedures, as appropriate.

21.20.50 Personnel Training and Evaluation:

a. Knowledge and Core Competency of Skill

b. Personnel who compound or have direct oversight of compounding personnel shall be initially trained and qualified by demonstrating knowledge and core competency of skill in compounding CSPs before they begin compounding or overseeing of compounding personnel.

c. Personnel who compound or have direct oversight of compounding personnel must complete training and be able to demonstrate knowledge of principles and competency skills for performing sterile compounding initially and every 12 months in the following:

(1) Hand hygiene

(2) Garbing

(3) Cleaning and disinfection

(4) Calculations, measuring, and mixing

(5) Aseptic technique

(6) Achieving and/or maintaining sterility (and apyrogenicity if compounding with nonsterile components)

(7) Use of equipment

(8) Documentation of the compounding process (e.g., master formulation and compounding records)

(9) Principles of high-efficiency particulate air (HEPA)-filtered unidirectional airflow within the ISO Class 5 area

(10) Proper use of PECs

(11) Principles of movement of materials and personnel within the compounding area

d. Competency in Garbing and Hand Hygiene

(1) Personnel who compound or have direct oversight of compounding personnel must complete an initial garbing competency evaluation no fewer than 3 separate times.

(2) After the initial garbing competency evaluations, compounding personnel must successfully complete the garbing competency at least one time every 6 months for personnel compounding Category 1 and Category 2 CSPs, and at least one time every 3 months for personnel compounding Category 3 CSPs. Personnel who have direct oversight of compounding personnel, but do not compound, must complete a garbing competency evaluation every 12 months.

(3) The garbing competency evaluation consists of a visual observation and gloved fingertip and thumb sampling (GFT) of both hands. The 3 completions must be in succession. Failure of any of the 3 initial garbing competency evaluations require repeat testing until successful completion of 3 in a row.

(4) Failure is indicated by any growth recovered from gloved fingertip and thumb sampling after garbing.

e. Competency Testing in Aseptic Manipulation

(1) Personnel who compound or have direct oversight of compounding personnel must successfully complete an aseptic manipulation competency before beginning to compound.

(2) For personnel compounding Category 1 and Category 2 CSPs, the aseptic manipulation competency must occur initially and at least every 6 months thereafter. For personnel compounding Category 3 CSPs, the aseptic manipulation competency must occur initially and at least every 3 months thereafter. Personnel who have direct oversight of compounding personnel must complete an aseptic manipulation competency evaluation annually.

(3) The aseptic manipulation competency evaluation consists of a visual observation, media-fill testing, followed by a post media-fill gloved fingertip and thumb sampling on both hands, and a post media-fill surface sampling of the direct compounding area to assess aseptic technique and related practices.

(4) A failure in the media fill, gloved fingertip and thumb sampling, or surface sample constitutes an overall failure of the aseptic manipulation competency.

(i) Failure of media-fill is indicated by visible turbidity or other visual manifestations of growth in the media following the incubation period.

(ii) A failure in the gloved fingertip and thumb sampling post media-fill is indicated by recovery of >3 cfu as a total from both hands.

(iii) A failure of the surface sampling of the direct compounding area post-media fill is indicated by exceeding surface sampling action levels listed in these Rules. If action levels are exceeded for the surface sampling of the direct compounding area post media-fill, an attempt must be made to identify any microorganism recovered to a genus level.

(iv) Personnel who fail required competencies must be immediately reinstructed and re-evaluated by expert compounding personnel to ensure correction of all aseptic practice deficiencies before resuming compounding. Results of the evaluation and corrective actions must be documented, and the documentation maintained to provide a record and long-term assessment of personnel competency.

f. Results of all trainings, competencies, and evaluations shall be retained and be available for inspection at the outlet for at least two years.

21.20.60 Environmental Controls.

a. Category 1, Category 2, and Category 3 CSPs must be compounded in an ISO Class 5 or better PEC. The PEC must be located in the buffer room of the cleanroom suite or the SCA. If compounding only Category 1 CSPs, the PEC may be placed in an unclassified SCA.

b. A buffer room must meet at least ISO Class 7 air quality.

c. Anterooms providing access only to positive-pressure buffer rooms must meet at least ISO Class 8 classification. Anterooms providing access to negative-pressure buffer rooms must meet at least ISO Class 7 classification.

d. The clean room suite should be maintained at a temperature of 68 degrees F(20 degrees C) or cooler and a relative humidity of 60% or less.

e. For the compounding of non-radiopharmaceuticals, all primary engineering controls shall be placed in a buffer area that is of air quality Class 10,000 (ISO Class 7) or better. If the PEC is a CAI or a CACI that provides isolation from the room and maintains ISO Class 5 conditions during dynamic operating conditions, including transferring ingredients, components, and devices into and out of the isolator and during preparation of CSPs, then it is not required to be placed in an ISO Class 7 buffer area. For the compounding of radiopharmaceuticals, all primary engineering controls shall be placed in a buffer area that is of air quality Class 100,000 (ISO Class 8) or better.

f. The surfaces of the ceiling, walls, floor, fixtures, shelving, counters, and cabinets in the buffer area or clean room shall be smooth, impervious, free from cracks and crevices and non-shedding. Junctures of ceilings to walls shall be coved or caulked. There shall be no sink or floor drains in the buffer area or clean room.

g. An anteroom shall be physically isolated from the buffer area or clean room. In this area, supplies are uncartoned and disinfected. Hand sanitizing and gowning occurs in this area. The anteroom must have a line of demarcation to separate the clean side from the dirty side.

h. For CSPs prepared from one or more non-sterile components, presterilization procedures such as weighing and mixing, shall be completed in no worse than an ISO Class 8 environment.

i. A pressure gauge shall be installed to monitor the pressure differential between the ISO Class 7 cleanroom and the ISO Class 8 anteroom and the anteroom and the general pharmacy area. The results shall be reviewed and documented on a daily basis. The pressure between the cleanroom and general pharmacy area shall not be less than 5 Pa (0.02-inch water column, w.c.). The pressure differential between the cleanroom and the anteroom shall be greater than the pressure differential between the anteroom and the general pharmacy area, except for the preparation of radiopharmaceuticals where there is no pressure differential.

21.20.70 Certification and Recertification of Compounding Areas.

a. Certification of the classified areas including the PEC must be performed initially, and recertification must be performed at least every six months and whenever the device or room is relocated or major service to the facility is performed. Certification must include:

(1) Airflow testing: Airflow testing is performed to determine acceptability of the air velocity, the room air exchange rate, and the room pressure differential in doorways between adjacent rooms to ensure consistent airflow and that the appropriate quality of air is maintained under dynamic operating conditions. The ACPH from HVAC, ACPH contributed from the PEC, and the total ACPH must be documented on the certification report.

(2) HEPA filter integrity testing: HEPA filters must be leak tested at the factory and then leak tested again after installation and as part of recertification.

(3) Total particle count testing: Total particle count testing must be performed under dynamic operating conditions using calibrated electronic equipment.

(4) Dynamic airflow smoke pattern test: Smoke pattern tests must be performed for each PEC during dynamic operating conditions to demonstrate unidirectional airflow and sweeping action over and away from the preparation(s).

b. Classified areas additionally must be recertified if there are changes to the area such as redesign, construction, replacement or relocation of any PEC, or alteration in the configuration of the room that could affect airflow or air quality

(1) Class 100 or better clean rooms and/or primary engineering controls shall be certified by qualified operators at least every twelve months and whenever the device or room is relocated or major service to the facility is performed. Certification records shall be maintained and be available for inspection at the outlet for at least two years from the certification date.

(2) Certification that each ISO classified area is within established guidelines shall be performed no less than every twelve months and whenever the primary engineering control is relocated or the physical structure of the buffer area or anteroom has been altered. The testing shall be performed by qualified operators using state-of-the-art electronic equipment with the following results:

(3) Not more than 3,520 particles 0.5 micrometer size and larger per cubic meter of air for any primary engineering control (ISO Class 5).

(4) Not more than 352,000 particles of 0.5 micrometer size and larger per cubic meter of air (ISO Class 7) for any buffer room; and

(5) Not more than 3,520,000 particles of 0.5 micrometer size and larger per cubic meter of air (ISO Class 8) for any anteroom/area.

c. Certification records shall be maintained and be available for inspection at the outlet for at least two years from the certification date.

21.20.75 Microbiological Air and Surface Monitoring

a. The microbiological air and surface monitoring program must include 1) viable impact volumetric airborne particulate sampling and 2) surface sampling.

b. Microbiological air and surface monitoring must be performed initially for sterile compounding facilities prior to initiating compounding.

c. Microbiological air and/or surface monitoring must be conducted in all classified areas during dynamic operating conditions to confirm that the required environmental quality is maintained. In addition to the specific sampling frequencies described in this section, sampling must be performed in the following circumstances:

(1) In conjunction with the certification of new facilities and equipment. After any servicing of facilities or equipment

(2) In response to identified problems (e.g., positive growth in sterility tests of CSPs)

(3) In response to identified trends (e.g., repeated positive gloved fingertip and thumb sampling results, failed media fill testing, or repeated observations of air or surface contamination)

(4) In response to changes that could impact the sterile compounding environment (e.g., change in cleaning agents)

d. Volumetric active air sampling using an impaction air sampler must be conducted in each classified area [e.g., ISO Class 5 PEC and ISO Class 7 and 8 room(s)] during dynamic operating conditions. For entities compounding Category 1 and Category 2 CSPs, this must be completed at least every 6 months. For entities compounding any Category 3 CSPs, this must be completed within 30 days prior to the commencement of any Category 3 compounding and at least monthly thereafter regardless of the frequency of compounding Category 3 CSPs. Air sampling sites must be selected in all classified areas. Sampling shall be performed at locations judged by compounding personnel to be the most prone to contamination.

e. All volumetric active air sampling should be conducted according to the manufacturers operating instructions for the air sampler.

f. Evaluate cfu counts from air samples against action levels. If levels measured during the viable air monitoring program exceed the levels for the ISO classification levels of the area sampled, the cause must be investigated, and corrective action must be taken. Data collected in response to corrective actions must be reviewed to confirm that the actions taken have been effective. The corrective action plan must be dependent on the cfu count and the microorganism recovered. If action levels are exceeded, an attempt must be made to identify any microorganism recovered down to the genus level. Action levels by ISO class per 1000 liters of air are:

(1) ISO 5: >1 cfu

(2) ISO 7: >10 cfu

(3) ISO 8: > 100 cfu

g. Surface sampling must be conducted in each classified area, including each room and the interior of each ISO Class 5 PEC and pass-through chambers connecting to classified areas. For entities compounding Category 1 and Category 2 CSPs, this must be completed at least monthly. For entities compounding any Category 3 CSPs, surface sampling of all classified areas, and pass-through chambers connecting to classified areas, must be completed prior to assigning a BUD longer than the limits established in these rules, and at least weekly on a regularly scheduled basis regardless of the frequency of compounding Category 3 CSPs. Additionally, surface sampling must be conducted within the PEC used to prepare Category 3 CSPs, at the end of each batch before cleaning and disinfection occurs, unless a self-enclosed robotic device is used. When a self-enclosed robotic device is used as the PEC to prepare Category 3 CSPs, surface sampling must be conducted at least once daily at the end of compounding operations, before cleaning and disinfection occurs.

h. Evaluate cfu count from surface samples against action levels. If levels measured during the surface sampling exceed the levels for the ISO classification levels of the area sampled, the cause must be investigated, and corrective action must be taken. Data collected in response to corrective actions must be reviewed to confirm that the actions taken have been effective. The corrective action plan must be dependent on the cfu count and the microorganism recovered. If action levels are exceeded, an attempt must be made to identify any microorganism recovered down to the genus level. Action levels by ISO class per sample are:

(1) ISO 5: >3 cfu

(2) ISO 7: >5 cfu

(3) ISO 8: > 50 cfu

i. Records of microbiological air and surface sampling tests and corrective action plans shall be maintained and be available for inspection at the outlet for at least two years from the testing date.

j. For buffer areas not physically separated from ante-areas, a velocity flow meter may be installed in place of a pressure gauge to monitor the displacement airflow to require an air velocity of forty feet per minute or more from the buffer area across the line of demarcation into the ante-area. The results shall be reviewed and documented on a daily basis.

21.20.80 Cleaning, Disinfecting and Applying Sporicidal Disinfectants and Sterile 70% IPA.

a. Surfaces in classified areas used to prepare Category 1, Category 2, and Category 3 CSPs must be cleaned, disinfected, and have sporicidal disinfectants applied according to the frequencies listed in rule 21.20.80.

b. The PEC and equipment inside the PEC must be cleaned and disinfected daily on days when compounding occurs and when surface contamination is known or suspected. Sporicidal disinfectant must be applied monthly for Category 1 and/or Category 2 compounding, and weekly for Category 3 compounding.

c. Work surfaces of removable work trays of the PEC, when applicable, must be cleaned and disinfected daily on days when compounding occurs, and have a sporicidal disinfectant applied monthly. All surfaces underneath the work tray must be cleaned, disinfected, and have a sporicidal disinfectant applied monthly.

d. The pass-through chambers, work surface(s) outside the PEC, and floors must be cleaned and disinfected daily on days when compounding occurs. Sporicidal disinfectant must be applied monthly for Category 1 and/or Category 2 compounding, and weekly for Category 3 compounding.

e. Walls, ceilings, doors, door frames, equipment outside the PEC(s) and storage shelving and bins shall be cleaned, disinfected and have a sporicidal disinfectant applied monthly.

f. After the disinfectant or sporicidal disinfectant is applied to the surface, the agent must be allowed to dwell for the minimum contact time specified by the manufacturer.

g. Cleaning, disinfecting and sporicidal agents used within the PEC must be sterile. When diluting concentrated cleaning and disinfecting agents for use in the PEC, sterile water must be used.

h. All cleaning and disinfecting supplies (e.g., wipers, sponges, pads, and mop heads) with the exception of tool handles and holders must be low lint. In addition, cleaning and disinfecting supplies used in the PEC must be sterile with the exception of tool handles and holders, which must be cleaned and disinfected prior to use in a PEC. Wipers, sponges, pads, and mop heads should be disposable. If disposable cleaning supplies are used, they must be discarded after each cleaning activity. Reusable cleaning tools must be made of cleanable materials (e.g., handles should not be made of wood or any other porous material) and must be cleaned and disinfected before and after each use. Reusable cleaning tools must be dedicated for use in the classified areas or SCA and must not be removed from these areas except for disposal.

21.20.90 Personal Hygiene and Garbing.

a. All personnel entering a compounding area where Category 1, Category 2, or Category 3 CSPs are prepared must take appropriate steps to minimize microbial contamination of the environment and of the CSPs, including hand hygiene, garbing, and consideration of needed materials to be brought into the compounding area

b. Individuals that may have a higher risk of contaminating the CSP and the environment (e.g., personnel with rashes, recent tattoos, oozing sores, conjunctivitis, or active respiratory infections) must report these conditions to the designated person(s). The designated person(s) is responsible for evaluating whether these individuals should be excluded from working in compounding areas before their conditions have resolved because of the risk of contaminating the CSPs and the environment.

c. Food (including mints, gum, etc.) and drinks must not enter anterooms, buffer rooms, or segregated compounding areas.

d. Before entering a compounding area, individuals must remove any items that are not easily cleanable or are not necessary for compounding. At a minimum, individuals must:

(1) Remove personal outer garments (e.g., bandanas, coats, hats, jackets, sweaters, vests)

(2) Remove all cosmetics because they shed flakes and particles

(3) Remove all hand, wrist, and other exposed jewelry, including piercings that could interfere with the effectiveness of garbing (e.g., the fit of gloves, cuffs of sleeves, and eye protection) or otherwise increase the risk of contamination of the CSP. Cover any jewelry that cannot be removed.

(4) Not wear earbuds or headphones

(5) Not bring electronic devices that are not necessary for compounding or other required tasks into the compounding area

(6) Keep nails clean and neatly trimmed to minimize particle shedding and avoid glove punctures. Nail products (e.g., polish, artificial nails, and extenders) must not be worn

(7) Wipe eyeglasses, if worn

e. The designated person(s) may permit accommodations to personnel preparation as long as the quality of the CSP and environment will not be affected. Accommodations must be documented.

f. Any person entering a compounding area where Category 1, Category 2, or Category 3 CSPs are prepared must wash hands and forearms up to the elbows with soap and water before initiating compounding activities. Brushes must not be used for hand hygiene. Hand dryers must not be used. To minimize the risk of extrinsic contamination, disposable soap containers must not be refilled or topped off.

g. The order of hand washing and garbing must be determined by the facility and documented in the facility's SOPs. Hands must be sanitized with alcohol-based hand rub before donning sterile gloves. Sterile gloves must be donned in a classified room or SCA.

h. Any person entering a compounding area where Category 1, Category 2, or Category 3 CSPs are prepared must be properly garbed. Garb must be donned and doffed in an order that reduces the risk of contamination. The required garb, manner of storage, and order of garbing must be determined by the facility and documented in the facility's SOPs.

i. When preparing Category 2 or Category 3 CSPs, all garb should be donned in a classified area before entering the buffer room. If hand hygiene is completed outside of a classified area, alcohol-based hand rub must be used prior to donning garb. Skin must not be exposed inside the ISO Class 5 PEC (e.g., gloves must not be donned or doffed inside the ISO Class 5 PEC exposing bare hands).

j. The minimum garbing requirements for preparing Category 1 and Category 2 CSPs include the following:

(1) Low-lint garment with sleeves that fit snugly around the wrists and an enclosed neck (e.g., gown or coverall)

(2) Low-lint covers for shoes

(3) Low-lint cover for head that covers the hair and ears, and if applicable, cover for facial hair

(4) Low-lint face mask. Sterile powder-free gloves

(5) If using a RABS (i.e., a CAI or CACI), disposable gloves should be worn inside the gloves attached to the RABS sleeves. Sterile gloves must be worn over the gloves attached to the RABS sleeve

k. Garb must be replaced immediately if it becomes visibly soiled or if its integrity is compromised. Gowns and other garb must be stored in a manner that minimizes contamination (e.g., away from sinks to avoid splashing). If compounding Category 1 and Category 2 CSPs, gowns may be reused within the same shift by the same person if the gown is maintained in a classified area or adjacent to, or within, the SCA in a manner that prevents contamination.

l. When personnel exit the compounding area, garb, except for gowns, cannot be reused and must be discarded or laundered before reuse. The facility's SOPs must describe disinfection procedures for reusing goggles, respirators, and other reusable equipment.

m. If the facility compounds Category 3 CSPs, additional garbing requirements must be continuously met in the buffer room in which Category 3 CSPs are prepared. The following additional garbing requirements must be followed in the buffer room where Category 3 CSPs are prepared for all personnel regardless of whether Category 3 CSPs are compounded on a given day:

(1) Do not allow any exposed skin in the buffer room (i.e., face and neck must be covered).

(2) All low-lint outer garb must be sterile, including the use of sterile sleeves over gauntlet sleeves when a RABS is used.

(3) Disposable garbing items must not be reused, and laundered garb must not be reused without being laundered and resterilized with a validated cycle.

(4) The facility's SOPs must describe disinfection procedures for reusing goggles, respirators, and other reusable equipment

n. Gloves must be sterile and powder free. Application of sterile 70% IPA to gloves must occur immediately before compounding and regularly throughout the compounding process. All gloves must be inspected for holes, punctures, or tears and must be replaced immediately if such defects are detected

o. The preceding subsections under 21.20.90 (d),(e), and (f) shall not apply if a public health order is in effect and consequently availability of required garbing equipment is not available or in short supply. Compounding personnel shall use compounding best practices outlined in a respective public health order, if applicable.

21.21.10 Components.

a. Compounding personnel shall ascertain that ingredients for CSPs are in compliance with these Rules and are of the correct identity and appropriate quality using the following information: vendors' labels, labeling, certificates of analysis, direct chemical analysis, and knowledge of compounding facility storage conditions. No expired components may be used in compounding. No component may be used which will expire prior to the beyond-use date of the finished CSP.

b. Ingredients used in a compounded preparation shall either originate from FDA-approved sources, when available, or be USP/NF grade substances when such sources are not available and identified on the FDA drug shortage list.

c. If neither USP/NF grade substances nor FDA-approved substances are available, or when food, cosmetics, or other substances are, or must be used, the substance shall be of a chemical grade in one of the following categories:

(1) Chemically Pure (CP);

(2) Analytical Reagent (AR); or

(3) American Chemical Society (ACS); or

(4) Food Chemical Codex.

d. For all ingredients, unless FDA-approved, the pharmacist shall establish purity and stability by obtaining a certificate of analysis from the supplier. The certificate of analysis, when applicable, shall be maintained at the prescription drug outlet for at least two years from the date of preparation.

e. A manufactured drug product may be a source of active ingredient. Only manufactured drugs from containers labeled with a lot number and an expiration date are acceptable as a potential source of active ingredients. When compounding with manufactured drug products, the compounder must consider all ingredients present in the drug product relative to the intended use of a compounded preparation.

f. Drug preparations that have been withdrawn or removed from the market for safety reasons shall not be compounded. Such preparations may be compounded exclusively for veterinary use provided no documentation exists which indicates that the preparation is unsafe for such use.

g. Sterile ingredients and components:

(1) A written procedure for physical inspection of ingredients and components prior to compounding shall be followed.

h. Non-sterile ingredients and components:

(1) When APIs are used:

(i) Must comply with the criteria in the USP-NF monograph, if one exists

(ii) Must have a COA that includes the specifications (e.g., compendial requirements for quality) and that test results for the component show that the API meets expected quality

(iii) Must be manufactured by an FDA-registered facility

(2) For all components other than APIs:

(i) Must comply with the criteria in the USP-NF monograph, if one exists

(ii) Must be accompanied by documentation (e.g., COA, labeling) that includes the specifications and test results and shows that the component meets the specifications

(iii) If non-USP or non-NF active ingredients, added substances, or excipients are utilized, a certificate of analysis from the supplier of the ingredient shall be maintained at the prescription drug outlet for at least two from the date of preparation.

(3) Component Receipt:

(i) Upon receipt of each lot of a component, the external packaging must be examined for evidence of deterioration and other aspects of unacceptable quality. Facility personnel must verify the labeling and condition of the component [e.g., whether the outer packaging is damaged and whether temperature-sensing indicators show that the component has been exposed to excessive temperature(s)].

(ii) Any component found to be of unacceptable quality must be promptly rejected, clearly labeled as rejected, and segregated from active stock to prevent use before appropriate disposal. Any other lots of that component from that vendor must be examined to determine whether the date of receipt by the compounding facility must be clearly marked on each API or added substance package that lacks a vendor expiration date. Packages of components (i.e., API and added substances) that lack a vendor's expiration date must be assigned a conservative expiration date, not to exceed 1 year after receipt by the compounding facility other lots have the same defect.

(4) Component evaluation before use:

(i) Compounding personnel must ascertain before use that components for CSPs are of the correct identity, appropriate quality, within expiry date and have been stored under appropriate conditions.

(ii) All components must be reinspected before use. All packages must be reinspected to detect container breaks, looseness of the cap or closure, and deviation from the expected appearance, aroma, and/or texture of the contents that might have occurred during storage. Sterile container closures must be visually reinspected to ensure that they are free from defects that could compromise sterility and that they are otherwise suitable for their intended use.

(iii) Any component found to be of unacceptable quality must be promptly rejected, clearly labeled as rejected, and segregated from active stock to prevent use before appropriate disposal. Any other lots of that component from that vendor must be examined to determine whether other lots have the same defect

(5) Component handling and storage:

(i) All components must be handled and stored in a manner that prevents contamination, mix-ups, and deterioration.

(ii) Components must be stored in closed containers under temperature, humidity, and lighting conditions consistent with those indicated in official monographs or specified by the suppliers and/or manufacturers.

(iii) Personnel must monitor temperature in the area(s) where components are stored either manually at least once daily on days that the facility is open or by a continuous temperature recording device to determine whether the temperature remains within the appropriate range. The results of the temperature readings must be documented on a temperature log or stored in the continuous recording device and must be retrievable. All monitoring equipment must be calibrated or verified for accuracy as recommended by the manufacturer or every 12 months if not specified by the manufacturer

(6) USE OF CSPs AS COMPONENTS

(i) Multiple-dose CSPs are required to meet the criteria for antimicrobial effectiveness testing. Multiple-dose CSPs must be stored under the conditions upon which its BUD is based (e.g., refrigerator or controlled room temperature). After a multiple-dose CSP is initially entered or punctured, the multiple-dose CSP must not be used for longer than the assigned BUD or 28 days, whichever is shorter. This time limit for entering or puncturing is not intended to restrict the BUD of the final CSP.

(ii) When a compounded single-dose CSP or CSP stock solution is used as a component to compound additional CSPs, the original compounded single-dose CSP or CSP stock solution must be entered or punctured in ISO Class 5 or cleaner air and must be stored under the conditions upon which its BUD is based (e.g., refrigerator or controlled room temperature). The component CSP may be used for sterile compounding for up to 12 h or its assigned BUD, whichever is shorter, and any remainder must be discarded. This time limit for entering or puncturing is not intended to restrict the BUD of the final CSP.

i. Any ingredient regulated by the FDA through an Investigational Review Board (IRB) is exempt from Rule 21.21.10 provided the research requirements for the receipt of the ingredient is followed and meets the requirements of section 12-280-131(2), C.R.S.

21.21.20 STERILIZATION AND DEPYROGENATION

a. sterilization method used must sterilize the CSP without degrading its physical and chemical stability

b. A description of the terminal sterilization and depyrogenation process, including the temperature, pressure (if applicable), duration, permissible load conditions for each cycle, and the use of biological indicators and endotoxin challenge vials (ECVs) must be included in the facility's SOPs

c. SOPs must include training and competency of personnel on all sterilization methods and equipment used by the facility. In addition, the SOPs must include a schedule and method for establishing and verifying the effectiveness of the terminal sterilization and depyrogenation methods selected, as well as the methods for maintaining and cleaning the sterilizing and depyrogenation equipment

21.21.21 Equipment.

a. Written procedures outlining required equipment, calibration, appropriate maintenance, monitoring for proper function, controlled procedures for use of the equipment and specified time frames for these activities shall be established and followed. Results of equipment calibration and appropriate maintenance reports shall be kept on file at the outlet for at least two years from the report date and shall be available for inspection.

b. Accuracy assessments of automated compounding devices (ACD) shall be conducted daily for each day used. At routine intervals, the pharmacist manager, or his or her designee, shall review these assessments to avoid potentially clinically significant cumulative errors over time. These assessments shall be documented and be maintained and available for inspection at the outlet for at least two years.

c. All equipment and Supplies (e.g., beakers, utensils, needles, syringes, filters, and tubing sets) should be of suitable composition such that the surfaces that contact components are not reactive or sorptive. Supplies in direct contact with the CSP must be sterile and depyrogenated.

21.21.30 CSP Release Checks and Tests.

a. Physical Inspection

(1) Finished CSPs shall be individually inspected after compounding pursuant to written procedures. Immediately after compounding, and prior to dispensing or distribution, each product shall be inspected for evidence of particulates or other foreign matter, container-closure integrity, precipitation, cloudiness, and any other apparent visual defect. Defective product shall be segregated from other product and shall not be dispensed or distributed.

b. Compounding Accuracy Checks.

(1) Written procedures for double-checking compounding accuracy shall be followed for every CSP during preparation and immediately prior to release. Outlets which compound CSPs shall have at least the following written procedures for verifying the correct identity and quality of CSPs prior to dispensing or distribution:

(a) Verification of label for accuracy;

(b) Correct identities, purities, and amounts of ingredients have been used; and

(c) Correct fill volumes in CSPs and correct quantities of filled units of the CSPs were obtained.

c. Sterility Testing.

(1) Category 1 CSPs do not require sterility testing. Sterility testing shall be done on Category 2 CSPs assigned a BUD that requires sterility testing and all Category 3 CSPs:

(a) If sterility testing is performed, the minimum quantity of each container to be tested for each media is specified in <71>

(b) The maximum batch size for all CSPs requiring sterility testing must be limited to 250 final yield units

(c) If the number of CSPs to be compounded in a single batch is less than the number of CSPs needed for testing as specified in <71>, additional units must be compounded to perform sterility testing as follows:

(i) If 1-39 CSPs are compounded in a single batch, the sterility testing must be performed on a number of units equal to 10% of the number of CSPs prepared, rounded up to the next whole number. For example:

(ii) If 1 CSP is compounded, 10% of 1 rounded up to the next whole number would indicate that 1 additional CSP must be prepared for sterility testing

(iii) If 39 CSPs are compounded, 10% of 39 rounded up to the next whole number would indicate that 4 additional CSPs must be prepared for sterility testing

(iv) If more than 40 CSPs are prepared in a single batch, the sample sizes specified in <71> must be used.

(v) If sterility testing is performed according to <71>, the Method Suitability Test from that chapter must be performed to ensure that contamination can be recovered. If performing sterility testing according to <71>, the Membrane Filtration method from that chapter is the method of choice when the CSP formulation permits. The preferred alternative is the <71>, Test for Sterility of the Product to Be Examined, Direct Inoculation of the Culture Medium method. If an alternative method is used for sterility testing, the method must be validated and demonstrated to be suitable for that CSP formulation.

(d) Sterility tests resulting in failures must prompt an investigation into the possible causes and must include identification of the microorganism, as well as an evaluation of the sterility testing procedure, compounding facility, process, and/or personnel that may have contributed to the failure. The source(s) of the contamination, if identified, must be corrected, and the facility must determine whether the conditions causing the sterility failure affect other CSPs. The investigation and resulting corrective actions must be documented product.

(2) When a Category 3 CSP is dispensed or distributed before receiving the results of the sterility test, there shall be a written procedure requiring daily observation of the incubating test specimens and requiring an immediate recall if there is any evidence of microbial growth. In addition, the patient and the practitioner of the patient to whom a potentially contaminated CSP was administered shall be notified of the potential risk. Positive sterility results shall prompt a rapid and systematic investigation of aseptic technique, environmental and other sterility assurance controls to identify sources of contamination and correct problems in the methods or processes.

d. Bacterial Endotoxin (Pyrogen) Testing.

(1) Category 1 injectable CSPs do not require testing for bacterial endotoxins. Category 2 injectable CSPs compounded from one or more nonsterile component(s) and assigned a BUD that requires sterility testing and Category 3 injectable CSPs compounded from one or more nonsterile component(s) must be tested to ensure that they do not contain excessive bacterial endotoxins (<85>).:

Category 2 injectable CSPs compounded from one or more nonsterile component(s) and assigned a BUD that does not require sterility testing should be tested for bacterial endotoxins. In the absence of a bacterial endotoxin limit in an official USP-NF monograph or other CSP formula source, the CSP must not exceed the endotoxin limit calculated as described in <85>; for the appropriate route of administration for humans. CSPs for nonhuman species must not exceed the endotoxin limit calculated as described in <85> based on the largest recommended dose and weight (or average weight for more than a single animal) of the target animal species unless a different limit is scientifically supported. CSPs administered epidurally should have the same endotoxin limit as that of intrathecally administered CSPs.

(2) The endotoxin test shall be compliant with the most current USP/NF Chapter 85 < Bacterial Endotoxins Test >. In the absence of a bacterial endotoxins limit in the official monograph or other CSP formula source, the CSP must not exceed the amount of USP/NF Endotoxin Units (EU per hour per kg of body weight) specified for the route of administration.

21.21.40 Storage and Beyond-Use Dating.

a. The temperature of drug storage areas of CSPs shall be monitored and recorded daily, either manually or electronically. Temperature records shall be maintained and be available for inspection for at least two years.

b. Finished CSPs that are not immediately dispensed or administered shall be refrigerated or frozen unless their chemical and physical stability are known to be adversely affected by cold or freezing temperatures.

c. Each CSP label must state the date, or the hour and date, beyond which the preparation must not be used and must be discarded (i.e., the BUD). The BUD is determined from the date and time that preparation of the CSP is initiated. The BUD is not intended to limit the time during which the CSP is administered (e.g., infused).

c. In the absence of sterility testing for each compounded batch compliant with the most current USP/NF Chapter 71 <Sterility Tests>, the beyond-use date (before administration) shall not exceed the following:

(1) Category 1 CSPs:

(i) Room temperature: No more than 12 hours

(ii) Refrigerated temperature: No more than 24 hours

(iii) Frozen: Not applicable

(2) Category 2 CSPs aseptically processed; no sterility testing; prepared from one or more nonsterile ingredients:

(i) Room temperature: 1 day

(ii) Refrigerated temperature: 4 days

(iii) Frozen:45 days

(3) Category 2 CSPs; aseptically processed; no sterility testing; prepared from only sterile ingredients:

(i) Room temperature: 4 day

(ii) Refrigerated temperature: 10 days

(iii) Frozen: 45 days

(4) Category 2 CSPs; aseptically processed; sterility testing performed and passed:

(i) Room temperature: 30 day

(ii) Refrigerated temperature: 45 days

(iii) Frozen: 60 days

(5) Category 2 CSPs; terminally sterilized; no sterility testing:

(i) Room temperature: 14 days

(ii) Refrigerated temperature: 28 days

(iii) Frozen: No more than 45 days

(6) Category 2 CSPs; terminally sterilized; sterility testing performed and passed:

(i) Room temperature: 45 days

(ii) Refrigerated temperature: 60 days

(iii) Frozen: No more than 90 days

(7) Category 3 CSPs; aseptically processed; sterility testing performed and passed:

(i) Room temperature: 60 days

(ii) Refrigerated temperature: 90 days

(iii) Frozen: 120 days

(8) Category 3 CSPs; terminally sterilized; sterility testing performed and passed:

(i) Room temperature: 90 day

(ii) Refrigerated temperature: 120 days

(iii) Frozen: 180 days

d. Proprietary bag and vial systems:

(1) Docking and activation of proprietary bag and vial systems in accordance with the manufacturer's labeling for immediate administration to an individual patient is not considered compounding and may be performed outside of an ISO Class 5 environment.

(2) Docking of the proprietary bag and vial systems for future activation and administration is considered compounding and must be performed in an ISO Class 5 environment

(3) Beyond-use dates (BUDs) for proprietary bag and vial systems must not be longer than those specified in the manufacturer's labeling

21.21.50 Master Formulation Record.

a. For each CSP, a uniform, readily retrievable master formulation record shall be maintained and available for inspection for two years from the date last utilized, documenting:

(1) The name, strength, or activity, and dosage form of the compounded preparation;

(2) All ingredients and their quantities;

(3) Type and size of container closure system(s);

(4) Complete instructions for preparing the CSP, including equipment, supplies, a description of the compounding steps, and any special precautions;

(5) Physical description of the final CSP;

(6) BUD and storage requirements;

(7) Reference source to support the stability of the CSP;

(8) Quality control (QC) procedures (e.g., pH testing, filter integrity testing); and

(9) Other information as needed to describe the compounding process and ensure repeatability (e.g., adjusting pH and tonicity; sterilization method, such as steam, dry heat, irradiation, or filter).

21.21.60 Compounding Record.

a. For each CSP prepared, a compounding record shall be maintained and available for inspection for two years on the original order, or on a separate, uniform, readily retrievable record documenting the following:

(1) Name, strength or activity, and dosage form of the CSP

(2) Date and time of preparation of the CSP

(3) Assigned internal identification number (e.g., prescription, order, or lot number)

(4) A method to identify the individuals involved in the compounding process and individuals verifying the final CSP

(5) Name of each component

(6) Vendor, lot number, and expiration date for each component

(7) Weight or volume of each component

(8) Strength or activity of each component

(9) Total quantity compounded

(10) Final yield (e.g., quantity, containers, number of units)

(11) Assigned BUD and storage requirements

(12) Results of QC procedures (e.g., visual inspection, filter integrity testing, pH testing;

(13) MFR reference for the CSP, if applicable

(14) Calculations made to determine and verify quantities and/or concentrations of component, if applicable.

21.21.70 Labeling of CSPs.

a. Labeling of CSPs made in anticipation of orders shall include at least the following:

(1) All requirements of section 12-280-124, C.R.S.;

(2) Batch (lot) number, if appropriate;

(3) Beyond-use date;

(4) If for parenteral administration, the following shall be included:

(a) Name of base solution; and

(b) Name and amounts of drugs added.

(5) Storage directions; and

(6) A clear statement that this product was compounded by the pharmacy, except for radiopharmaceuticals prepared from FDA-approved, commercially available kits and/or drug products.

b. Labeling of CSPs dispensed pursuant to a hospital chart order shall include at least the following:

(1) All requirements of section 12-280-124, C.R.S.;

(2) Batch (lot) number, if appropriate;

(3) Beyond-use date;

(4) If for parenteral administration, the following shall be included;

(a) Name of base solution; and

(b) Name and amounts of drugs added; and

(5) Storage directions.

c. Labeling of CSPs distributed to practitioners, other prescription drug outlets, or other outlets allowed by law shall include at least the following:

(1) Name of the outlet;

(2) Name and strength of the drug(s);

(3) Total quantity in package;

(4) Quantity of active ingredient in each dosage unit;

(5) Beyond-use date;

(6) Batch (lot) number;

(7) Specific route of administration;

(8) Storage directions;

(9) "Rx only"; and

(10) A clear statement that this product was compounded by the pharmacy, except for radiopharmaceuticals prepared from FDA-approved, commercially available kits and/or drug products.

d. Labeling of CSPs distributed within hospitals as floor stock shall include at least the following:

(1) Name of the outlet;

(2) Name and strength of the drug(s);

(3) Total quantity in package;

(4) Quantity of active ingredient in each dosage unit;

(5) Beyond-use date;

(6) Batch (lot) number;

(7) Specific route of administration; and

(8) Storage directions.

21.21.80 CSP HANDLING, STORAGE, PACKAGING, SHIPPING, AND TRANSPORT:

a. Processes and techniques for handling, storing, packaging, and transporting CSPs must be outlined in the facility's SOPs. Personnel who will be handling, storing, packaging, and transporting CSPs within the facility must be trained in accordance with the relevant SOPs, and the training must be documented.

b. CSPs must be handled in a manner that maintains CSP quality and packaging integrity. Conditions of storage areas must be monitored daily. Personnel must monitor conditions in the storage areas. When it is known that a CSP has been exposed to temperatures either below or above the storage temperature limits for the CSP, a designated person(s) must determine (e.g., by consulting literature or analytical testing) whether the CSP is expected to retain its integrity or quality. If this cannot be determined, it must be discarded

c. Compounding personnel must select appropriate shipping containers and modes of transport that are expected to deliver properly packed CSPs in an undamaged, sterile, and stable condition.

21.21.90 Patient Monitoring, Adverse Events Reporting, and Product Recall.

a. Outlets which compound CSPs shall provide patients and other recipients of CSPs with a way to address their questions and report any concerns that they may have with CSPs and their administration devices.

b. The outlet shall have written policies describing specific instructions for receiving, acknowledging, and dating receipts; and for recording, or filing, and evaluating reports of adverse events and of the quality of preparation claimed to be associated with CSPs.

c. The pharmacist manager shall report to the Board in writing significant errors related to compounded CSPs such as those that result in serious personal injury or death of a patient.

d. If a CSP is believed to be defective in any way, or if the Board or Federal Food and Drug Administration makes a written request for a recall of a specific preparation, the outlet shall immediately recall any product dispensed or distributed. Any product remaining in the outlet shall be immediately quarantined and shall not be dispensed or distributed. Recall records shall include at least the following:

(1) Product name, strength, dosage form;

(2) Reason for recall;

(3) Amount of product made;

(4) Date made; and

(5) Amount of product dispensed or distributed.

e. The outlet shall conduct tests, as appropriate, on the recalled product to identify the reason the product was defective. Results of these tests shall be maintained at the outlet for at least two years.

f. Adverse event reports and product recall records shall be retained and be available for inspection at the outlet for at least two years.

21.22.00 Quality Assurance Program.

a. Outlets that make CSPs shall have a formal written quality assurance (QA) program which shall provide a mechanism for monitoring, evaluating, correcting, and improving the activities and processes regarding the compounding of sterile products.

b. At a minimum, the written QA program shall include the following:

(1) Consideration of all aspects of the preparation, dispensing, and distribution of products, including environmental testing, work area cleaning effectiveness, validation results, etc;

(2) Describe specific monitoring and evaluation activities;

(3) Specification of how results are to be reported and evaluated;

(4) Identification of appropriate follow-up mechanisms when action limits or thresholds are exceeded;

(5) Recall procedures; and

(5) Delineation of the individuals responsible for each aspect of the QA program.

21.22.10 Hazardous Drug Preparation.

a. Hazardous drugs shall be compounded in a vertical flow, Class II biological safety cabinet (BSC) or CACI. Such BSC or CACI shall be placed in an ISO Class 7 area that is physically separated from other preparation areas and is negative pressure to adjacent positive pressure anteroom. If used for other products, the cabinet must be thoroughly cleaned;

b. Appropriate personnel protective equipment (PPE) shall be worn when compounding in a BSC or CACI and when using closed-system vial transfer devices (CSTDs). PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemo-type gloves, and compliance with manufacturers' recommendations when using a CACI;

c. Appropriate safety and containment techniques for compounding hazardous drugs shall be used in conjunction with the aseptic techniques required for preparing sterile products;

d. Appropriate disposal containers for used needles, syringes, and if applicable, hazardous waste from the preparation of chemotherapy agents and infectious waste from patients' homes. Disposal of hazardous waste shall comply with all applicable local, state and federal requirements;

e. Written procedures for handling major and minor spills and generated waste of hazardous agents must be developed and must be included in the policy and procedure manual; and

f. Prepared doses of hazardous drugs must be labeled with proper precautions inside and outside, and shipped in a manner to minimize the risk of accidental rupture of the primary container.

21.22.20 Exemption for Sterile Compounding of Products in Closed or Sealed System.

a. Pharmacists and pharmacies or other outlets where sterile compounding is provided may be exempt from this Rule when compounding is restricted to utilizing compounds or products that are contained only in a closed or sealed system and can be transferred or compounded within this self-contained system or topical products that require further transfer or combination in order to achieve a finished product without further modification of the product.

3 CCR 719-1-21.00.00

37 CR 18, September 25, 2014, effective 10/15/2014

38 CR 16, August 25, 2015, effective 9/14/2015

39 CR 04, February 25, 2016, effective 3/16/2016

39 CR 19, October 10, 2016, effective 11/14/2016

40 CR 04, February 25, 2017, effective 3/17/2017

40 CR 20, October 25, 2017, effective 11/14/2017

41 CR 16, August 25, 2018, effective 9/17/2018

42 CR 21, November 10, 2019, effective 11/30/2019

43 CR 10, May 25, 2020, effective 5/1/2020

43 CR 08, April 25, 2020, effective 5/15/2020

43 CR 15, August 10, 2020, effective 8/30/2020

43 CR 20, October 25, 2020, effective 11/14/2020

44 CR 04, February 25, 2021, effective 3/17/2021

44 CR 08, April 25, 2021, effective 5/15/2021

44 CR 21, November 10, 2021, effective 11/30/2021

45 CR 20, October 25, 2022, effective 9/29/2022

45 CR 21, November 10, 2022, effective 11/30/2022

46 CR 21, November 10, 2023, effective 11/30/2023