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Brian Midcalf
BPharm FRPharmS
Pharmaceutical Isolator Working Party Chairman
Although this was the seventh conference organised by the Pharmaceutical Isolator User Group, it was the first conference to be organised with The Parenteral Society. The combination of the two organising bodies was intended to attract more industry speakers and delegates – an objective that was achieved as the numbers of delegates from the NHS and the industry were about equal. Those attending, a total exceeding 120, participated freely in a pleasant and sociable environment, which offered a blend of more general education to presentation of the latest technical research.
The conference started with an evening seminar on the Sunday evening to provide an overview of the technology of the pharmaceutical isolator, introducing the terminology that was likely to be used in the following three days.
An American perspective
After an introduction and overview of the potential uses of isolators by the chairman, Brian Midcalf, Carmen Wagner of Strategic Compliance International Inc commented on the applications of isolators in North America and reviewed the history, current status and trends.
She noted that in North America the definition of an isolator is very focused, while it is far more flexible in Europe. It is important to have an agreement on terminology since the definition will drive the requirements for use. In North America, typically isolators are operated under positive pressure. It is recognised that operators do not enter the work area and work is accomplished remotely. Air is not exchanged with the surrounding environment, except through a microbial retentive filter or HEPA filter.
Isolators are usually decontaminated in a quantifiable manner and by a method that can be validated. Rapid-transfer ports are used to introduce materials into the enclosure, but only after such materials have been decontaminated or sterilised.
Isolators provide effective separation between the controlled workspace and the operator and are a substantial improvement over barrier systems and glove boxes. The decontamination process is much more effective than for barriers, and isolators can be gassed. Prevention of direct personnel access to the work area provides an opportunity to increase control of sterile product manufacturing and the efficiency of operation, eliminate gowning, and reduce the cost and the frequency or amount of environmental monitoring. Carmen illustrated these points by identifying a number of companies that had pursued this approach to their advantage.
Current applications include the handling of “germ-free animals”, sterile clinical manufacturing or commercial production and containment in both hospital and biotechnology establishments.
From a survey of 199 establishments, Carmen identified the rate of use of isolators that were soft- or hard-wall units and those using filling lines with half-suits. Many more companies were using cleanroom classification grade D (US 100,000) than grade C (US 10,000). Companies using isolators for sterility testing placed their systems in controlled but unclassified rooms. Most production isolator and sterility testing isolator systems use hydrogen peroxide vapour for decontamination. Orders for new isolators in Europe have been twice that in North America over the last six years, and orders for isolators used for filling operations have decreased in the last two years. More manufacturers are producing their own isolators, and the link between production line and isolator manufacturers is growing stronger. The use of two-piece gloves without pleats is typical, and use of a second inner glove is also common. Better transfer technologies (eg, DPTE bags or SafePass) are now available.
Carmen noted that the implementation of isolator technology has been slower in the USA and more difficult in a conservative industry. The FDA, while remaining supportive, is cautious. Isolators used for sterility testing are state-of-the-art, and applications in aseptic manufacturing continue to expand but still present challenges as there is some scepticism about initial cost savings and acceptance by authorities.
Dr Wagner created considerable interest in her presentation, which generated discussion on the relative status of isolators on either side of the Atlantic.
Choice of construction materials
Caroline Coles of Pharminox delivered a paper on some of the materials used in the construction of isolators and why they might be chosen. She indicated that a range of materials are used for the separative device itself, transfer devices and access devices, and to ensure the right level of visibility into the controlled workspace. An isolator framework should be strong enough to provide a barrier, be cleanable and comply with relevant standards and guidelines. The materials used should not compromise the product or the operator by leaking excessively, shedding particles, reacting with substances or creating static.
This guidance is endorsed by standards like ISO 14644 Part 7 (“Separative Devices”) EN 388, EN 374, EN 421 (gloves), and regulatory bodies such as the MHRA and FDA, and forms part of EC GMP 2002 (Orange Guide), the PIC/S Recommendation PI 014-1 June 2002: Isolators used for aseptic processing & sterility testing, the FDA’s Sterile drug products produced by aseptic processing (draft) 2002, HSE, ACDP, COSHH and the new Yellow Guide.
She noted that the separative device, if rigid and constructed from stainless steel, is very strong; however, while it looks as though it can withstand pressure, the strength is only as good as the seals and gaskets, which can blow at pressures of 250Pa or more.
Isolators used for radiopharmacy have a lead shield incorporated in their structure. Metals used in isolator construction include stainless steel, which should have at least 10.5% chromium content, which oxidises to form a passive chromium oxide layer and prevents further oxidation or rusting. Austenitic (nonmagnetic) steels have greater corrosion resistance, and 304 is suitable for nonproduct contact areas, 316L with added molybdenum for greater chloride resistance and Hastelloy.
The surface finish needs some understanding. Passivation treatment with acid (removal from the metal’s surface of iron contaminants that would otherwise accelerate corrosion) accelerates the formation of a protective oxide layer, and polishing with abrasives from coarse to fine grades is used to apply the finish. The surface characteristic or roughness average (Ra) is measured in microns. Electropolishing is an electrochemical process that removes a layer of material, including the Beilby layer. Surfaces can be damaged by the welding process, scratches, ferritic contamination and poor cleaning practices.
Other rigid materials that can be used include epoxy-coated stainless or mild steel, aluminium, lead shielding (for radiopharmacy), acrylics (Perspex, Plexiglass) to enhance optical quality, which can be cemented to themselves to form boxes, glass (safety glass for windows), glass-reinforced plastic (fibreglass) for trays and Microban.
Flexible components include PVC (polyvinyl chloride; optical quality on the face visors), which is attached to the base tray by steel-cored PVC strip or other suitable fastenings. PVC, in contrast to common belief, is surprisingly strong and can withstand considerable pressures. It is prone to “outgas”, releasing absorbed sporicidal gassing agent after a gassing process has been completed. It is vulnerable to some cleaning agents that may leach out the plasticiser and to damage by sharp objects, but it can be patched.
Referring to transfer devices, Caroline discussed rapid transfer containers or “mini-isolators”, which can be made from all the materials mentioned above. She noted that rigid containers can be made of steel, which is relatively heavy, or of plastics, which are lightweight, such as polypropylene or polycarbonate, which is a thermoplastic and prone to static, or of rigid (polymerised) PVC.
Flexible containers can be made from plastic films or polymers such as polyethylene or Tyvek (high- density polyethylene: HDPE) and are usually designed to be disposable. Consideration should be given to sterilisation methods, product contact, temperature and pressure.
Critical parts, such as seals and gaskets, are very vulnerable, especially to sporicidal gassing and mechanical distortion, and need special consideration. Teflon is poor mechanically but can be used to advantage as a coating. Nylon, a polyamide plastic, is destroyed by hydrogen peroxide. Other gasket materials include PTFE (polytetrafluoroethylene), rubber (which is vulnerable to some chemicals) and silicone rubber.
Addressing HEPA (high-efficiency particulate air filtration) filter construction, Caroline noted that they are usually made from glass fibres formed into a high-density paper, not the cellulose variety. Housings must not be constructed of shedding materials such as wood, plywood, hardboard or medium- density fibreboard (MDF).
With a human operator, gauntlets, sleeves, gloves and half-suits will be required, and Caroline cautioned that the operator may have strong opinions on how suitable these are. If the operator is a robot, it will rarely have an opinion! Gloves and gauntlets can be made from: natural rubber latex, which has excellent handling qualities but is susceptible to many chemicals and may be allergenic; nitrile; EPDM (ethylene propylene diene monomer), which needs to be checked for product compatibility; neoprene, which is strong; Viton (a PTFE polymer), which needs to be checked for product compatibility; and Hypalon, which resists hydrogen peroxide and almost everything else, although it is expensive. Some materials used for access devices are more vulnerable than others, so need changing more frequently. Sleeves and half suits may be constructed of PVC, which is often layered and backed but should not be too heavy for sustained operator comfort. Helmets can either have a clear visor or be made entirely of clear plastic.
Caroline concluded with some comments on looking after the isolator. All materials have some vulnerability to cleaning materials, and excessive contact should be avoided. Your supplier should be able to provide information or advice. Spills should be cleaned up immediately and probably washed down with water afterwards. Parts should be replaced routinely as advised by the designer. Remember that steel is only stainless if you treat it correctly, and that plastics are usually tougher than they look.
Materials: a technical review
A specialist view relating to materials used in the construction of isolators was presented by Volker Sigwarth of Skan AG, Switzerland. Volker related his past year’s research on the surface characteristics of materials and how these can present different challenges to microbial decontamination procedures. He had performed a study to measure the suitability of different materials for hydrogen peroxide decontamination, and described the materials studied and the equipment and methods used to assess the microbiological system and decontamination process. The effect of different carrier materials on the inactivation of spores was key to the study. Volker found there were fluctuations in resistance caused by system materials in commercially available biological indicators. There were reproducibly different resistances on different carrier materials, and some materials seem to be unsuitable for peroxide decontamination.(1)
In the next issue we will be including highlights from presentations looking at standards, biological indicators and surface decontamination.
Reference
- Sigwarth V, Stärk A. Effect of carrier materials on the resistance of spores of Bacillus stearothermophilus to gaseous hydrogen peroxide. PDA J 2003;57(1).
