In the past year, the attention of the world has been focused on the threat from terrorist attacks and, in particular, the danger from the release of chemical or biological weapons, of which anthrax has had perhaps the greatest coverage. Additionally, there is growing awareness of the risk of contagious diseases spreading from developing countries due to increasing business, leisure travel and refugee migration across continents. Although to the casual observer it may seem that the proliferation of biological agents is a recent phenomenon, nothing could be further from the truth. As long ago as the 4th century BC, the Spartans used sulphur fumes against enemy soldiers, while during the Middle Ages it was not unusual for infected animal and human corpses to be catapulted into towns that were under siege. More recently, the use of various types of poison gas killed or incapacitated around one million troops during the First World War, while in the 1940s the British government carried out research into biological entities and dangerous pathogens with testing of anthrax on sheep on the remote Scottish island of Gruinard. The island remained contaminated for 50 years and was only declared safe in 1990. Since the Second World War the pace of research into biological and chemical weapons has intensified, while outbreaks of naturally occurring pathogens, such as ecoli, anthrax and ebola, especially in Africa and other developing regions, has increased considerably. As a result, there is a rising demand for both research and effective containment facilities. Indeed, in the past few years, we have seen the emergence of a new bio-defence sector to counteract the darker side of biotechnology which, in common with the nuclear industry, has the ability to be used for good or ill.
Today's pharmaceutical and healthcare sectors face a wide range of technical, commercial and legislative challenges, all of which impact on the design, construction and use of containment facilities.
The main areas of application for containment facilities are:
- high containment laboratories (for minor organisms)
- hospital contagious diseases units
- potent drug manufacturing
- biotechnology R&D
- emergency outbreaks and bio-terrorism attacks.
Levels of containment There are four different containment levels: CL1, CL2, CL3 and CL4, the latter being the most stringent. These are also referred to as Cat 1 to Cat 4. Containment level 1 (CL1) requires no special features beyond those suitable for a professionally designed and functional laboratory. Biological safety cabinets are not required within these zones and work may be done in the laboratory environment on an open bench top. Any containment is achieved through the use of the standard operating procedures that would normally be employed in the running of any microbiology laboratory. Containment level 2 (CL2), primary and secondary, is similar to level 1 and is suitable for work involving agents of a moderate hazard to personnel and the environment. Agents requiring CL2 facilities are not generally transmitted by the airborne route, but care must be taken to avoid splashes or aerosols (aerosols can settle on bench tops and become an ingestion hazard by contamination of the hands). Primary containment devices such as biological safety cabinets and centrifuges with sealed rotors or safety cups are to be used, as well as personal protective equipment. Environmental contamination must also be minimised by installing hand washing sinks and decontamination facilities (autoclaves). Secondary containment is controlled and contained by the physical properties of the area, to avoid leakage of any spillages and fumigants. Containment level 3 (CL3) applies to diagnostic, research and clinical laboratories, production facilities or teaching laboratories handling agents requiring CL3. These agents typically include Bacillus anthracis, Brucella abortus and Canis, and may be transmitted by the airborne route, often needing only a low infectious dose to produce serious or life-threatening diseases. CL3 emphasises the need for additional primary and secondary barriers to minimise the release of infectious organisms into the immediate laboratory and the environment. Other features to prevent transmission of CL3 organisms include appropriate respiratory protection, HEPA filtration of exhausted laboratory air and strictly controlled laboratory access. In addition, all cultures and other regulated wastes must be decontaminated before disposal by an approved method of decontamination, such as autoclaving. Strict fumigation procedures should also be initiated to decontaminate the laboratory after each campaign. It is worth noting that many existing facilities may not have all the safeguards currently recommended to meet bio-safety level 3 (e.g. access zones, separate change/showering facilities and decontamination showers/airlocks). Containment level 4 (CL4) is the maximum containment available and is suitable for facilities manipulating dangerous and exotic agents that pose a high individual risk. These agents include Lassa fever and ebola, and have the potential for aerosol transmission, with a low infectious dose producing serious and often fatal diseases – often where there is no treatment or vaccine available. This level of containment is normally represented by an isolated unit within an existing facility, that is functionally and, when necessary, structurally independent of other areas. CL4 emphasises maximum containment of the infectious agent through complete sealing of the facility, with a negative pressure environment (-70). Research scientists must be isolated from the pathogen either by containing individuals in positive pressure suits or containing the pathogen within a Class III biological safety cabinet; Class II biological safety cabinets can also be used with one piece positive pressure personnel suites ventilated via HEPA filtered circulatory unit packs. All liquid wastes must be contained and treated before release into a dedicated decontamination holding/treatment vessel. Solid wastes have to be bagged and autoclaved at source before leaving the laboratory and then be incinerated.
The design process The theoretical development of a containment facility is generally straightforward, being dependent on the products manufactured, the type and specification of the equipment available and the production throughputs and flexibility required. In practice, however, the process can become increasingly complex, as people, product variables, regulatory and pharmaceutical legislation and operational and budget requirements are introduced. As there may be many systems, structural configurations, technologies and products involved, it is important that all relevant personnel are involved from the outset in the facility design. Achieving 'buy-in' or ownership at an early stage will effectively help to minimise both overall costs and the time required before the facility is fully operational, as it will eliminate, for example, the need for reworking design layouts or incorrectly specified equipment. The design contractors should also be involved as part of the overall team, helping to develop the initial user requirement specification (URS). This needs to be a short definition of the processes, equipment, operations, capacities and environmental criteria required for the facility.
Material and people flows In the URS the designers and facility operators and users need to review the flows around the GA boundaries to assess the optimum layout for regulatory compliance, efficient operation and to minimise cross contamination. It is, for example, easier to simplify the flows in new facilities, but can be more difficult in retrofit projects, where compromises may need to be made due to space or cost constraints. Here, procedures or controls may have to be put in place to avoid cross contamination where waste, people, raw materials and finished goods have to share common areas.
Process equipment Typically, this will include both the specific equipment required for handling and processing products in the laboratory, and the systems and structural equipment, such as decontamination showers, autoclaves and freezers. The URS therefore needs to clearly define which equipment is to be used, what options it will have and, if a new process, what downstream or associated areas still need to be developed. This will enable the design team to anticipate and accommodate equipment changes during the design process. The decision whether to make a piece of equipment a fixed part of the structure or skid mounted (common with bio-pharmaceutical equipment) also needs to be taken and reviewed early in a project, as it will have a significant impact on the layouts, programme and costs. In addition, the URS should include the materials and finish of the structure itself; for example, walls and ceilings may need to be impervious, with coved abutments, while floors are likely to require special coverings, doors need to be constructed from steel, GRP or be gas tight and, in CL3 and CL4 suites, there should be no windows. It is also important to consider the impact that different containment levels will have on the complexity and cost of the design process. For example, process systems may have to be adapted to accommodate the collection and treatment of effluent and vent gasses, while the need for high specification equipment seals, which are resistant or impermeable to aggressive liquids and gasses, may add considerably to start-up costs. Similarly, the facility may need to be designed to encompass positive and negative pressure systems, with changing and decontamination areas, while the required sampling and materials handling methodologies will also need to considered at an early stage. One final issue that is often overlooked at the primary design stage of high containment facilities is the impact that fumigation processes will have on the operability and downtime of each laboratory. It should, for example, be recognised that a typical fumigation procedure will take at least 12 hours, with area preconditioning to a determined and stable temperature, fumigation, soak, degassing and purging. Regardless of the level of containment, the laboratory should, in addition to the mandatory requirements that have to be addressed, also be designed to meet standards or guidelines produced by bodies such as the Advisory Committee on Dangerous Pathogens (ACDP), Advisory Committee on Genetic Modification (ACGM), HSE, BSI and relevant professional organisations. Equally as important, consideration must be given both to performance criteria and validation processes for the laboratory, as it is essential that these are set up and operated effectively if the facility is to be truly accountable. Similarly, the issues of production flexibility and facility security and, in the event of a breach of security, remedial measures, should be given a high priority from the outset. Table 1 outlines a typical design process and the key objectives at each stage.
Growing trends There are a number of evolving trends that are driving the global growth of containment facilities. In particular, organisations are seeking to increase the flexibility of individual sites, so that facilities can be reconfigured to match changing business needs. Similarly, new facilities are often modular in design, some with containerised clean rooms and interchangeable wall and ceiling panel systems, and are now being cloned across country borders to allow dual site flexibility and security. There is also considerable technology crossover from other industries, which is changing the nature of delivery systems and manufacturing equipment. One benefit of this is that it is leading to shorter project delivery times so that vaccines can be brought to market faster. These trends are set to continue as the handling and treatment of pathogens and bio-chemical substances that are harmful to the health of people and animals increases over the next decade. This will be driven by the age-old need to combat disease, with the development of new and increasingly potent drugs, requiring ever more careful handling, plus dangerous clinical research into vaccines and treatments for HIV, CJD, cancer and contagious diseases. Additionally, the growing threat of biological terrorism and chemical warfare will demand that new and often radical defence strategies be evolved, including the discovery and development of vaccines for dangerous pathogens and bio-chemical agents.
For further information contact Richard Paley/Ian Pearson from the Pharmaceutical division of Bovis Lend Lease. Tel: +44(0)161 495 6600
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