Quality Control Officer
Departement de Pharmacie Clinique
Institut Gustave Roussy
An isolator can be defined as a sterile system consisting of a closed area with no unfiltered air exchange between the enclosure and the environment.(1) It can be defined as a physical barrier and a microbiological airtight closure between preparation and both operator and environment. Isolators should be considered according to two parameters:
- The levels of confinement and sterility of the working area.
- The possibility of carrying out airtight transfers to remove manufactured drugs and pharmaceutical waste or to introduce new materials, as transfers can be particularly sensitive operations.
Pharmaceutical isolators are essentially made of five components, each of which involves a different technology.(2)
The enclosure, which delineates the controlled workspace, can be flexible (PVC; polyvinylchloride) or rigid (PMMA; polymethylmetacrylate acrylic).
Transfer devices for transferring materials in and out of the controlled workspace can include hoppers (attached to the principal enclosure), rapid transfer ports (RTPs), transfer containers, dynamic systems (positive or negative pressure) and closed systems.
The access device, which allows entry to the controlled workspace, includes gloves and gauntlets. Two to four working stations (opposite or side by side) are usually available.
The sterilisation system allows for sterilisation of the isolator and of the materials entering and leaving it through gassing with bactericidal, fungicidal and sporicidal agents. Peracetic acid is commonly used in pharmaceutical isolators. Hydrogen peroxide is still only used by pharmaceutical industries for aseptic manufacturing. A steriliser is required to vaporise the agent. Time of sterilisation is defined according to the sterilised volume and the method used. Liquid cleaning (by spraying, swabbing or dunking) ensures surface decontamination.
The ventilation and evacuation systems have to replace at least 20 times the volume of the air present in the isolator per hour.(3) The ventilation system comprises two high-efficiency particulate air (HEPA) filter units installed upstream (for air filtration with retention of at least 99.97% of particles of 0.3 m in diameter) and downstream (to retain contaminated particles). To protect the HEPA filter, prefilters are required.
Table 1 shows the advantages and drawbacks of each configuration. When choosing a system, pharmacists need to consider the following items:
- Ergonomics and accessibility depend on whether the enclosure is rigid or flexible. Rigid enclosures are solid, and security is also improved. In any case, ergonomic features must ensure a comfortable working environment.
- Positive or negative pressure can be used according to the drug being manufactured. Negative pressure (with rigid enclosure only) is essential to manufacture oral cytotoxic drugs in powder form, while positive pressure is less restrictive and can be used in the manufacture of injectable drugs. The benefits of negative pressure need to be studied further.
- Peracetic acid or hydrogen peroxide as sterilising agents, depending on time and performance of sterilisation required. These compounds have comparable sporicidal, fungicidal and bactericidal properties (through an oxidising mechanism).(4) Vaporisation of peracetic acid is the sterilisation process mostly used in hospital pharmacies, although this compound must be manipulated with caution due to toxicities such as skin irritations, spasms or pulmonary congestions when inhaled.
- Design: volume, number of positions for manufacturing according to the production flow.
- Accessories (eg, fridge, shelves).
- Working organisations need to be chosen depending on the type of cytotoxic drugs being prepared. Large isolators (>5m(3)) comprise a sterile stocking area, which allows for flexibility during the preparation process. These sterile areas are fitted out with a half suit and have 24-48 hours autonomy range. Smaller isolators (<3m(3)) require continuous work with continuous sterilisation.
- Medicoeconomics (eg, operational costs) must be considered.
- Quality and maintenance costs offered by the manufacturer need to be evaluated.
Isolators are available in a wide range of configurations and sizes. Isolators with important volume of controlled workspace allow for sterile stocking with optimised cycles of sterilisation, while smaller isolators are better suited for the “forward moving” method. To reduce time of sterilisation and rinse cycle, manufacturers offer the possibility to install a small sterilisation chamber to ensure quick sterilisation in 15 minutes with vaporised peracetic acid for manufacturing of 5âˆ’10 therapeutic products per cycle. This could be reduced to less than 10 minutes if using a new process that includes a spray of peracetic acid (Sieve(R)), but the 6-log reduction of contamination needs to be confirmed in further studies.
Hydrogen peroxide is as effective as peracetic acid to destroy bacteria, and could be used in the hospital pharmacy setting.
- Bonnes pratiques de preparation a l’hopital. July 2002 Project.
- Midcaf B. Isolators: protecting operator and product.HPE 2003;10:63-4.
- Les isolateurs: qualification. Paris, France: ASPEC; 2002.
- Bounoure F, Fiquet H, Arnaud P. Comparison of hydrogen peroxide and peracetic acid as isolator sterilization agents in a hospital pharmacy.Am J Health-Syst Pharm 2006;63:451-5.
- Fiche toxicologique N123. Peroxyde d’hydrogene et solution aqueuse. INRS:1992.
- Fiche toxicologique N239. Acide peracetique. INRS:2001.