The California Board of Pharmacy has released the language for the proposed regulations amending several sections of the law pertaining to pharmacy compounding for sterile and non-sterile practice. This executive summary focuses on summarizing the major changes put forth and less so on grammatical changes inserted for the purpose of distinguishing pharmacy compounding from manufacturing. Section titles are shown in their proposed language.
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Title 16 Article 4.5
Section:
1735.1. Compounding Definitions
Amended to include definitions for:
Ante-area
Batch - means compounding of two or more finished drug preparation units produced during the same continuous cycle of compounding and shall include any multiple dose vials prepared for administration to more than one patient
Beyond Use Date
Buffer area
Cleanroom
Controlled cold temperature
Controlled freezer temperature
First air
Gloved fingertip sampling
Integrity - all aspects of quality including sterility, packaging, chemical stability and potency, handling and transport and storage are maintained throughout the drug preparation process, and until the beyond use date provided on the label
Media-fill test
Parenteral
Personal protective equipment
Potency - added reference to range specified by USP37-NF32, 37th revision
Preparation
Prescriber's Office
Process validation
Product
Primary Engineering Control (PEC)
Segregated compounding area
Smoke test
1735.2. Compounding Limitations and Requirements; Self-Assessment
Amended to clarify provisions for prescriber's office compounding. An order for a compounded medication must be ordered and paid for by the prescriber using a purchase order or other order form that lists the number of patients seen or to be seen in the prescriber office for whom the drug is needed or anticipated, and quantity for each patient sufficient for treatment in the office or for furnishing of no more than a 72 hour supply. The order must be delivered to the prescriber office and signed for by the prescriber. The pharmacy may not dispense an amount beyond which they can reasonably and safely compound.
Further limitations found in this section are inserted from the recently amended Section 503A of the Food, Drug and Cosmetic Act (FDCA). No pharmacy or pharmacist shall compound a drug that:
1. is classified by the FDA as demonstrably difficult to compound
2. appears on a FDA list of drugs that have been withdrawn or removed from the market because such drugs or components of such drugs have been found to be unsafe or not effective; or
3. is a copy of essentially a copy of one or more drug products, unless that drug product appears on an ASHP or FDA list of drugs that are in short supply at the time of compounding and at the time of dispense. The pharmacy shall retain a copy of the documentation of the shortage in the pharmacy records for three years.
Compounding master formula records must contain the rationale or reference source for determining the maximum allowable beyond use date.
A compounding self-assessment must be completed for a change of location.
Ingredients that lack a supplier's expiration date are subject to following limitations:
1. such ingredients cannot be used for any non-sterile preparations more than 3 years after the date of receipt by the pharmacy unless documented inspection or analytical testing indicates that the ingredient has retained its purity and quality for use, considering the container in which it is packaged and the storage conditions.
2. the same is stated for sterile preparations no more than 1 year after the date of receipt by the pharmacy, unless inspection or analytical testing indicates otherwise.
1735.3. Recordkeeping for Compounded Drug Preparations
Pharmacy records for compounded preparations must include storage information. Procuring ingredients should be, whenever possible, through FDA registered supplier.
Certificates of purity or analysis must be matched to the product received.
If records are stored only electronically, on magnetic media, or in any other computerized form, the records shall be maintained as specified by Business and Professions Code section 4070 subsection (c).
1735.4. Labeling of Compounded Drug Preparations
Preparations packaged into unit-dose containers that are too small for a label compliant with all requirements should at a minimum contain the name of the compounding pharmacy and dispensing pharmacy, if different, in addition to currently established components.
1735.5. Compounding Policies and Procedures
The pharmacy shall follow its policies and procedures and failure to follow these policies and procedures shall constitute grounds for disciplinary action.
The annual review of the policies and procedures by the pharmacist in charge shall be documented, signed and dated.
There should be evidence that the staff has been educated and trained on all policies and procedures.
A written plan for preparation recall to be included and proof that all affected doses can be accounted for as part of the recall.
There should be procedures for evaluating, maintaining, certifying, cleaning, and disinfecting the facility used for compounding, and for training on these procedures as part of the training and competency evaluation process.
Dates of any revisions to the policy and procedure manual shall be approved by the pharmacist-in-charge, signed and dated.
There shall be policies and procedures for storage of compounded sterile preparations in the pharmacy and daily documentation of all room, refrigerator, and freezer temperatures.
There shall be policies and procedures regarding ensuring appropriate functioning of refrigeration devices, monitoring refrigeration device temperatures, and actions to take regarding any out of range temperature variations.
1735.6. Compounding Facilities and Equipment
Amended to specify definition of equipment to include any equipment that weighs, measures or transfers ingredients for compounding to be calibrated prior to use per manufacturer's specifications.
1735.8 Compounding Quality Assurance
Amended to include a written procedure for responding to out-of-range temperature variations, including for preparations furnished to patient care areas.
ARTICLE 7. STERILE COMPOUNDING
1751. Sterile Compounding; Compounding Area; Self-Assessment
The designated compounding area shall be in a restricted location where traffic has no impact on the performance of primary engineering controls (ISO 5). All ISO classified environments must be certified at least every 6 months.
Sinks and drains shall not be present in an ISO Class 7 or better environment, nor within three feet of an ISO Class 5 PEC or better located in a segregated compounding area. A sink may be located in an ante-area.
1751.1. Sterile Compounding Recordkeeping Requirements
The are amendments listing the required record keeping components for results of hand hygiene and garbing assessment, media fills, viable air sampling, and surface sampling.
Daily documentation of controlled temperature for all rooms and refrigerators / freezers for storage as well as air pressure differentials, and/or air velocity between adjoined ISO classified rooms/environments associated with PEC or containment isolators.
Logs or documentation for inspection of expired and recalled products and/or ingredients.
Pharmacies compounding sterile preparations for future use pursuant to section 1735.2, in addition to requirements in 1735.3, must make and keep records indicating the name of the preparation, lot number, amount and date on which the preparation was provided to a prescriber.
Records maintained and stored electronically must comply with Business and Professions Code section 4070 subsection (c).
1751.3 Sterile Compounding Policies and Procedures
There shall be written policies and procedures for proper use of equipment and supplies, training staff in all aspects of the preparation of sterile preparations including:
- didactic training and knowledge/competency assessments including hand hygiene and garbing, cleaning and disinfection of controlled areas, proper aseptic technique
- an environmental sampling plan including viable air sampling, surface and gloved fingertip sampling, and nonviable particle sampling
- for compounding aseptic isolators and compounding aseptic containment isolators, documentation of the manufacturer's recommended purge time
-media fill test procedure
- compounded sterile drug preparation stability and beyond use dating
- visual inspection and other final quality checks
- conduct of personnel in controlled areas
- use and maintenance of primary engineering controls that create direct compounding area
- daily and monthly cleaning and disinfection schedule for controlled environment
- airflow considerations and pressure differential monitoring
- temperature and humidity monitoring in compounding and controlled storage areas
- facility management including certification and prevention maintenance of controlled environments and related equipment
- assigning of beyond use date requirements
- use of automated compounding devices (if applicable)
- hazardous drug employee training and safety program
- hazardous drug handling, storage, labeling and transport
- hazardous drug compounding techniques
- hazardous drug spill, deactivation and waste management
- preparing sterile solutions from non-sterile components (if applicable)
- disposal of packaging materials, used syringes, containers, and needles to enhance sanitation and avoid accumulation
- action levels for colony-forming units (CFUs) detected during viable surface testing, glove fingertip sampling and volumetric air sampling
(Pharmacies subject to an institutional infection control policy may follow that policy as it relates to cleaning schedules and the alternation of disinfectants in lieu of complying with requirements in this subparagraph)
For sterile batch compounding:
- use of master formulas and compounding work sheets
- appropriate documentation
- appropriate sterility and bacterial endotoxin testing
For non-sterile to sterile compounding:
- sterilization methods
- end-product evaluation and testing
1751.4. Facility and Equipment Standards for Sterile Compounding
Cleaning and disinfecting of surfaces in the ISO Class 5 PEC shall occur frequently, including the beginning of each shift, before and after each batch, after a spill and when surface contamination is known or suspected.
Counters, cleanable work surfaces, and floors shall be cleaned with a germicidal detergent and water and disinfected with a suitable agent (i.e. isopropyl alcohol) daily. Walls, ceilings, storage shelving, tables and stools shall be cleaned in the same manner, at least monthly.
Included provision for use of an aseptic containment isolator outside of an ISO 7 buffer area if the isolator provides ISO 5 air during a particle sampling count approximately 6-12 inches upstream of critical exposure site, not more than 3250 particles (0.5 microns and larger) per cubic meter during material transfer, recovery time to achieve ISO 5 air is documented and used to create procedures that allow for ample recovery time after material transfer before and during compounding operations.
To compound sterile preparations containing hazardous drugs, a negative pressure PEC must be used and certified every 6 months by a qualified technician. Pharmacies utilizing a negative pressure buffer area and PEC for the purpose of compounding hazardous drugs must use this PEC exclusively for hazardous drugs, otherwise non-hazardous preparations compounded in this area must be labeled with the same requirements as hazardous drugs. A laminar flow hood may be installed outside of this negative pressure area, or on the clean side of the line of demarcation from the ISO 7 ante-room, at least six feet from the sink to be exempted from this r.
All hazardous drug preparations compounded in an aseptic containment isolator must comply with the same provisions for personnel garbing in a controlled environment.
Containment isolators that are certified to provide ISO 5 air during dynamic operation conditions during transfer and compounding may be placed in a non-ISO classified room. Compounding of this nature requires the same personnel garbing and hygiene requirements as if working in a laminar flow hood, including the donning of sterile gloves over the isolator gloves. These sterile gloves must also be changed by each individual whenever continuous compounding is ceased and before compounding resumes.
Viable air sampling and surface testing shall be performed at least monthly for low and medium-risk and at least weekly for high-risk compounding. All sampling tests should occur under similar conditions as routine compounding. When results exceed action levels, the pharmacy shall identify CFUs to at least the genus level, and conduct an investigation including review of cleaning and compounding operations.
The pharmacy shall have a comfortable and well-lighted working environment of 20 degrees Celsius or cooler. Humidity levels should be consistent ASHRAE Standard 55 (30-65%RH).
1751.5. Sterile Compounding Attire
Personal protective equipment (PPE) includes facial hair covers when applicable. All PPE should be donned and removed within the ante-area. PPE should be applied from activities considered dirtiest to cleanest, beginning with shoe covers, head cover, face mask, washing of hands and elbows, then donning the non-shedding gown. Hand, wrist or finger jewelry shall not be worn.
Sterile gloves that have been tested for compatibility with disinfection with isopropyl alcohol are required. Hands must be cleansed with a persistently acting alcohol-based product followed by the donning of sterile gloves in the ante or buffer-area. Gloves must be routinely disinfected with the agent (i.e. sterile 70% IPA) before entering the PEC and after contact with non-sterile objects. Gloves must also be routinely examined for holes, punctures or tears and replaced immediately if such are detected.
Individuals with rashes, sunburn, weeping sores, conjunctivitis, active respiratory infections, or wearing cosmetics shall not be permitted into compounding areas until these conditions are remedied.
1751.6. Sterile Compounding Consultation; Training of Sterile Compounding Staff
Media fill test must be as complicated as the most complex manipulations performed by staff and contain the same amount of volume transferred during the selected manipulations.
1751.7. Sterile Compounding Quality Assurance and Process Validation
Media used for personnel media fill tests must have demonstrated the ability to support and promote growth. Samples must be incubated according to manufacturer's recommendations.
The initial gloved fingertip test should be conducted after the initial hand hygiene and garbing procedure and demonstrate 3 successful test results prior to permission for sterile compounding (zero CFUs).
Revalidating must include 3 media fill tests per day for 3 consecutive days for an annual revalidation.
All personnel competencies must be revalidated at least every 12 months for individuals performing sterile to sterile (low and medium-risk) compounding and at least every 6 months for individuals compounding non-sterile to sterile (high-risk) ingredients, in addition to the currently established criteria for revalidating.
Batch produced (see proposed CA definition) sterile preparations from one or more non-sterile ingredient must follow USP definition for pyrogen testing. Testing must demonstrate sterility and an acceptable level of pyrogens prior to dispensing.
In the circumstance where a 'high-risk' batch-produced preparation is needed for immediate dispensing, where failure to dispense may results in loss of life or intense suffering, the preparation may be dispensed prior to receipt of these test results if there are written procedures in place that include the following:
1. Prior to dispensing:
- the physician is notified of the inability to conduct the required testing
- suggest an alternative preparation or product to the prescriber
- procure the prescriber's written consent to dispense given the circumstances
2. and subsequent to dispensing:
- daily observation of the incubating test specimen are made
and
- there is an immediate recall of the dispensed compounded sterile preparation's when there is any evidence of microbial or pyrogen growth resulting
Any dispensing under these circumstances shall only be done in such a quantity as necessary to meet the immediate need and circumstance, and is documented according to written policies and procedures
1751.8. Beyond Use Dating for Sterile Compounded Drug Preparations
All sterile compounded preparation must have a beyond use date that does not exceed the expiration date of any individual component. The USP <797> risk level definitions are provided in this section, indicating that a preparation which falls into the USP classified risk level, in the absence of a sterility test, may not exceed its respective beyond use date.
Guidelines are also provided for sterile preparations compounded in a segregated compounding area, restricted to using only sterile ingredients.
Sterile preparations containing hazardous components that are prepared outside of a negative pressure environment are granted a beyond use date of 12 hours.
Any sterile preparation that is compounded outside of an ISO 5 environment, or a PEC that does not meet the requirements for ISO 5 environment, the preparation must be labeled "for immediate use only" and granted a one-hour beyond use date. If not used within one hour, the preparation must be discarded. This type of compounding shall only be utilized in situations where there is an immediate need for compounded sterile preparations where failure to dispense such may result in loss of life or intense suffering, and only in a quantity to meet such a need. This compounding must be conducted according to written policies and procedures.
1751.9. Single-Dose and Multi-Dose Containers; Limitations on Use
This new section is added to include the USP <797> definitions, requirements, and limitations for storage of single-dose vials and ampules, and multi-dose vials.