Designing a Monitoring Program
Development and verification of the effectiveness of standard operating procedures is the foundation of the CSP quality management program. However, it is the ongoing monitoring of the CSP compounding environment, the techniques and daily practices of personnel, and the quality characteristics of the CSPs that provides assurance of quality.
It is necessary to periodically test all components of the CSP system including the proper functioning of equipment and the skills of personnel. However, annual or semi-annual testing cannot assure ongoing proper functioning of equipment or routine compliance of personnel.
The CSP Compounding Environment
Critical compounding environment is designed to exclude particulate contamination and to be easily cleaned and disinfected. There are usually three levels of control which progress from the uncontrolled general environment through progressively cleaner environments to the critical work zone. It is customary for the first level of control to be an ISO Class 8 anteroom where gowning and staging of materials occurs (however, this is required to be ISO Class 7 if there is a hazardous compounding lab accessible from the anteroom). Personnel and materials then progress to the ISO Class 7 buffer zone housing the ISO Class 5, unidirectional airflow primary engineering controls.
The following monitoring procedures are recommended to assure the continuous acceptability of the environment. All of the following supporting data are to be recorded:
- Verification of pressurization
- Critical work zone disinfection and cleaning logs; at least daily for other surfaces
- Refrigerator temperature
- Compounder and other precision equipment calibration
- Line clearance, general cleanliness and trash management, or as required to maintain a clean and uncluttered work environment
- Surface monitoring for microbial contamination
- Airborne microbial contamination
- Inanimate airborne particle count monitoring
- Verify removal of expired supplies
The skills and practices of personnel are the most critical component of CSP quality. Monitoring frequency will depend upon the amount of time spent in the CSP process. Recommended monitoring includes:
- Observation for compliance with SOPs.
Assessment of Aseptic Technique Form
- Testing of glove tips for microbial contamination
- Gown testing for microbial contamination
- Work surface testing for adequate cleaning and disinfection
Compounded Sterile Preparation Quality
Compounded sterile preparations must meet the requirements for sterility, apyrongenicity, identity, and purity set forth in USP chapters. As with other aspects of the quality management system, there are tests that can be performed on the product as well as process monitoring procedures to assure that the preparations meet requirements.
Process Monitoring and Pre-Release Checks
These observations and checks should ALWAYS be performed and all discrepancies identified should be recorded.
- Ongoing observation of compounding personnel for proper hygiene and gowning
- Ongoing observation of compounding personnel for aseptic technique
- Ongoing observation of environment for cleanliness
- Label/original order cross-check
- Calculation check
- Verification of all component label information to include both manufacturer's information and pharmacy labeling such as reconstitution diluent, initials, amount, and beyond-use-dating
- Verification of plunger position
- Verification of any required auxiliary labeling
- Check for container integrity
- Check for particulates
Preparation Quality Testing
Sterility— Although sterility and other preparation quality testing of CSPs is not mandated by USP <797>, in virtually every other quality assurance system known to industry, end-product quality testing in some form is required to physically prove the consistency of product specifications. It is therefore recommended that a representative sampling of the sterility of all CSPs be carried out in accord with a cumulative-sum control-based end- product sterility sampling plan using USP <71>-compliant methods.
Testing should incorporate a pharmacy-friendly testing system (i.e. no extraneous pumps, tubing, connections, filter housings, or any other component foreign to the institution's actual CSP process) which eliminates all false-positive results by design. The pharmacy-friendly sterility testing system should incorporate only the usual and customary components of the CSP process (i.e. syringes, needles, and vials), and require only actual manipulations used in normal compounding, thus ruling out any false-positive result attributable to unfamiliar materials, techniques, or manipulations.
Also, end-product testing should be performed only by the end-product’s original compounder, thereby eliminating possible intervention by any other person into the testing result. This method establishes the testing outcome to be the result solely of the compounder's aseptic manipulations as they occur within the continuum of his or her aseptic technique.
Identity/Purity— There are many methods available for testing the quantity of one or more components of CSPs. Care should be taken, however, if the hospital microbiology lab is used. The equipment involved is often designed and calibrated for human specimens and may not provide accurate results on pharmacy samples. Be sure you and your lab manager understand the principles behind any method you use, and that lab personnel who perform testing are proficient in the skills required. The limits of precision of the test method must also be appropriate for the acceptable result range.
Apyrogenicity— Generally, this testing is only performed on high-risk preparations. Pyrogen testing requires specialized skills, and controls must be run for the results to be meaningful. For this reason, unless sufficient numbers of tests are being performed to maintain tester proficiency and make the running of controls economical, it may be preferable to use a contract service to verify apyrogenicity.
Clean Room Testing Procedures
Minimum Frequency: 6 Months
- Measurement of airflow and determination of both installation air changes and filtration air changes
- Pressurization (or, for soft-wall installations, flow rate across openings
- Total particulate burden for ISO Classification
- Airborne microbial contamination
- Filter integrity upon any installation, and if there is a possibility that damage has occurred.
- Smoke visualization of airflow and recovery patterns if there is non-random distribution of particulate of microbial contamination that cannot be explained by activities and equipment placement
Personnel Testing Procedures
Low- and Medium-Risk Minimum Frequency: Annually
High-Risk Minimum Frequency: 6 Months
Both a written test of knowledge and a practical skills evaluation conducted using a growth-medium simulation must be conduct annually for personnel compounding low- and medium-risk verifications. High-risk procedures require semi-annual verification.