Hospital Pharmacist Saint Germain-en-Laye
University of Pharmacy
GERPAC (Groupe d’Evaluation et de Recherche sur la Protection en Atmosphère Contrôlée)
French Association of Hospital Pharmacists
Aseptic compounding includes the mixing of substances to prepare a medication for one patient, such as reconstitution, dilution, admixture and repackaging.
The compounding process commonly used in hospital pharmacy is aseptic transfer in a closed system, defined by the American Society of Health-System Pharmacists (ASHP) as:(1)
“The movement of sterile products from one container to another in which the container-closure system and transfer devices remain intact throughout the entire transfer process, compromised only by the penetration of a sterile pyrogen-free needle or cannula through a designated stopper or port to effect transfer, withdrawal or delivery.”
This method minimises microbiological contamination during the compounding process.
Specific installations are required to ensure aseptic compounding. Controlled areas are classified according to their airborne particles grade. Annex 1 of the EU Guide to Good Manufacturing Practice (EU GMP)2 gives airborne particulate classification in four grades (see Table 1). The EU GMP classification corresponds approximately to the US Federal 209E and the ISO Classifications.
Two technical concepts are suitable for attaining the quality required for aseptic compounding:
- Laminar airflow in a cleanroom.
- The isolator.
Laminar airflow hood in a cleanroom
Laminar airflow provides clean air to the work area by the use of a high-efficiency particulate air (HEPA) filter (see Figure 1). The air passes through the HEPA filter in a laminar flow fashion (the purified air flows out over the entire work surface in parallel lines at a uniform velocity). Horizontal or vertical laminar airflow can be used for aseptic compounding. Vertical laminar airflow is commonly used for aseptic compounding of hazardous drugs (eg, cytotoxics), with a vertical glass panel in front of the hood to limit projection risks.
A cleanroom is always required around the laminar airflow hood because room air may be highly contaminated by personnel working in the area. EU GMP recommends a grade-B zone around the hood for aseptic compounding, but if closed-system transfer is applied a grade-C zone around the hood would be sufficient. In addition, specific garments and gloves are required for aseptic compounding.
An isolator is a small airtight, sterile, controlled area. The physical barrier is made of a plastic wall (soft or rigid). The air filtration consists of an entry HEPA filter and one outlet HEPA filter, which both protects the outer environment (containment of hazardous drugs) and the inside of the isolator from outside microbiological contaminants. Isolators can be ventilated with positive or negative (only rigid wall) air pressure relative to the adjacent environment. As a PDA (Parenteral Drug Association) technical report suggested in 2001,(3) aseptic compounding must be performed only in positive air pressure isolators. For aseptic compounding of toxic drugs, isolators in positive air pressure must be permanently enclosed with the use of transfer systems. Two main configurations are available, with or without halfsuit. The configuration with halfsuit (see Figure 2a) has four gloves for two operators and a 3m(3) volume, which allows room for storage of sterile products. The configuration without halfsuit (see Figure 2b) measures approximately 1m(3) with four gloves or more and requires the use of a transfer isolator to solve the sterile storage problem.
The sterilisation process is performed using a gas sterilising agent (peracetic acid [APA] or hydrogen peroxide [H(2)O(2)]). In hospital pharmacies, APA is the main gas sterilising agent used because of the high cost of H(2)O(2) sterilisers and the easier management of the APA sterilisation process.
End-products and waste from the unit are removed in sterile plastic containers connected to an interlocked door (see Figure 2c). These plastic containers are sealed with the end-product inside to create an airtight sterile plastic bag. Then the preparation is delivered in a closed system to wards and the patient, minimising the risk of microbiological contamination during transfer. Waste products can be placed in special closed containers attached to the isolator, which are directly disposed of without risk of contamination.
Quality control of aseptic compounding
To improve safety in aseptic compounding a specific quality assurance system is required. In the pharmaceutical industry, the batch is one production per thousand of the same product. In hospital pharmacies, the batch consists of a specific preparation for one patient. So the main problem hospital pharmacists have with the batch is end-product evaluation – because the end-product cannot be destroyed for control, conventional sterility testing and chemical analysis are not available. Steps must be taken to ensure adequate installation, operation and performance.
Assessing the installation
Evaluation of both laminar airflow and isolators must include assessment of the air ventilation and filtration systems, and particle and microbiological contamination control.
For laminar airflow the quality of the airflow must be ensured by assessing air laminarity controls and air velocity, and for the cleanroom, pressure, temperature and air change rate need to be appraised. For isolators, the integrity of the airtight enclosure, the positive air pressure and the efficiency of the sterilisation process should be monitored. Hospital pharmacies commonly use a gas detection leak test for integrity testing, which uses ammonia as a tracer. Biological indicators are distributed on the inner surfaces of the isolator to assess the efficiency of the sterilisation process. A three-log reduction in biological indicators known to be resistant to the gas/vapour method is often employed.
Controlled areas must be assessed periodically in order to verify that the necessary technical targets have been met. Monitoring for microbiological contamination must be performed daily in controlled areas. Recommended EU GMP limits are shown in Table 2.
Process evaluation is another important step that needs to be taken to ensure the sterility of the end-product and the lack of cross-contamination between drugs. Process simulation testing is carried out in the same manner as that of normal production, except that an appropriate microbiological growth medium is used in place of the drug. Evaluation of cross-contamination between different drugs must also be performed. Because of the use of many different drugs within the same controlled area, process simulation testing is carried out using a tracer instead of the drugs.
Quality control of compounding must be carried out to double-check every step in the preparation process – reconstitution, withdrawal and dilution. All batch numbers of initial drugs and diluents must be noted on the preparation worksheet and compared with the final product. Quality control analysis ensures the identity, strength and quality of the end-product. It is performed by trained personnel independent of the handlers.
The end-product is released by the pharmacist after it has been compared with the drug order forms, preparation worksheets and control worksheets with the end-product. Observation of the end-product will detect leaks or bag failure. Any nonconformities must be analysed and corrective action, such as policies and procedures re-evaluation, taken.
Pharmacy personnel preparing or dispensing sterile products must receive suitable didactic and experimental training and pass the competency evaluation through both demonstration and testing (written and practical).This training must include good manufacturing practice, the quality assurance system and monitoring of the equipment. The programme must be based on theory and practice using various tools such as films and CD-Rom. The training programme includes, in particular, aseptic technique, critical area contamination factors, environmental monitoring, equipment, proper gowning and gloving techniques, and proper conduct in controlled areas. Assessment of personnel must be regularly done; process simulation testing is a useful tool to ensure competence.
Aseptic compounding in the hospital pharmacy must follow the healthcare industry recommendations. This includes the use of suitable technologies and a specific quality assurance system.
Some principles must be adapted to meet the specificity and constraints of hospital compounding, but the result must guarantee a sterile end-product for each patient.
- ASHP. Guidelines on quality assurance for pharmacy prepared sterile products. Am J Health-Syst Pharm 2000;57:1150-69.
- European Commission. Good manufacturing practice. Brussels: EC; 1998.
- Technical report N°34. Design and validation of isolator systems for the manufacturing and testing of health care products. PDA J Pharm Sci Technol 2001;55:1-24.
EU Good Manufacturing Practice
French association of hospital pharmacists who perform aseptic compounding of toxic drugs in controlled areas
Parenteral Drug Association
American Society of Health-System Pharmacists
United States Pharmacopeia
European GERPAC Congress
Lourdes, France September 2003