Containment Levels and Facility Design

By Ian Pearson
Containment, by definition, is the action of preventing a hostile force from expanding into other areas. In the biotech and pharmaceutical arenas, this takes on significant proportions, particularly in clean room or laboratory environments, extending to the very fundamentals of building design, validation and process management, and determining the success of pivotal research and development (R&D) projects.
Containment encompasses the procedural steps required to manage biological or chemical agents within a known and fixed parameter; this includes the measures employed to prevent both the release of these agents, which often present a hazard to the surrounding environment, and the ingress of contaminants into a sensitive and controlled process.


Figure 1: Containment level one (CL1).
These umbrella statements cover many different disciplines and doctrines, but essentially convey a simple message of 'safety first.' The main areas of application for containment facilities are:
  • high containment laboratories for minor organisms
  • contagious disease units
  • potent drug manufacturing
  • emergency outbreaks and bioterrorism attacks
  • biotechnology R&D.

The practicalities of fulfilling a containment policy mean that biopharm and pharmaceutical management teams must complete meticulous and careful planning before developing or building holding envelopes around primary containment isolators or enclosures. It also requires the establishment of specific validation and performance criteria, and the assurance of intrinsically safe and flexible operations.
Depending on the level of containment required, this could materialize in the form of designated airline supply points within movement zones, ergonomically designed containment suites, dedicated fumigation ports and/or HVAC (heating, ventilating, air conditioning) HEPA (high efficiency particulate air) filtration. The determining factor is the level to which the facility must be adequately contained.
Levels of containment There are four primary facility containment levels for the control of biological agents. Each contains explicit stipulations that have a fundamental impact on the design and planning of new and existing clean room or laboratory environments.


Figure 2: Containment level two (CL2).
Containment level one (CL1). As the first level of containment is intended for organisms or processes that present a low risk to researchers and the surrounding environment, CL1 areas typically require few specially designed features beyond those that would normally be specified for a microbiology laboratory (Figure 1). For example, within CL1 containment zones, there is no requirement for biologically safe cabinets, meaning that work can be done on open worktops. Containment is essentially achieved through good practice and standard operating procedures (SOPs). Other CL1 specifications include washable walls covered with epoxy or emulsion paint, laminate-faced doors, epoxy, polyurethane and vinyl floors, recessed or teardrop light fittings and trespa, laminate, corian or epoxy lab worktops.


Key points for successful containment
Containment level two (CL2). Similar to CL1, this designation relates to agents and organisms that present a moderate risk but are usually not transmitted in air. In such areas, care should be taken to avoid the generation of splashes or aerosols, which can settle on work surfaces and become an ingestion hazard by contamination of the skin; hand washing should be actively encouraged. Similar to CL1 areas, there is no need for an airlock or mechanical ventilation, although inward airflow and safety cabinet ventilation are often recommended (Figure 2). Primary containment is achieved through biological safety cabinets, personal protective equipment and centrifuges with sealed rotors or safety cups. Once again, washable walls, laminated doors, epoxy, polyurethane and vinyl floors, and recessed lights are among the standard fitting requirements.
Unlike CL1, however, CL2 areas require hand washing sinks and decontamination facilities (autoclaves), SOPs and provisions for containing leakage from spillage and fumigants. Secondary containment is controlled and contained by the physical properties of the facility.


Figure 3: Containment level three (CL3).
Containment level three (CL3). CL3 containment generally applies to diagnostic, research and clinical laboratories, production facilities, or teaching laboratories handling agents such as Bacillus anthracis (anthrax), Brucella abortus (bovine brucellosis) and Brucella canis (canine brucellosis), that can be transmitted in air and often need only a low infectious dose to produce serious or life-threatening diseases. Consequently, the demands placed on CL3 facilities are far more stringent. For example, additional primary and secondary barriers are necessary to minimize the possibility of infectious organisms reaching the immediate laboratory and the outside environment (Figure 3).
Specific measures include respiratory protection, HEPA filtration of exhausted laboratory air and strictly controlled access to laboratory areas. In addition, all cultures and regulated wastes should be decontaminated before disposal by an approved method, such as autoclaving, and strict fumigation procedures to decontaminate the laboratory should be initiated after each session.
The severity of the organisms contained in CL3 areas means laboratory suites must be partially isolated and include a separate airlock, shower room and changing facilities. Other requirements include airtight perimeter HEPA filtration and steriglazed washable walls.
Containment level four (CL4). The most rigorous containment classification is CL4, which relates to dangerous and exotic agents that pose a high individual risk. These agents include Lassa fever and Ebola, which have the potential for aerosol transmission and can produce serious or fatal diseases at low infectious doses. Often, with such agents, there is no treatment or vaccine available.


Figure 4: Containment level four (CL4).
CL4 encapsulates the maximum containment safeguards and follows the doctrine embracing unit isolation, negatively pressurized environments and Class III biological safety cabinets. CL4 stipulations are so extreme that there are fewer than ten facilities in the world that have so far been validated to this level. 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 (Figure 4). CL4 emphasizes maximum containment of the infectious agent through complete sealing of the facility, with a negative pressure environment (270 Pa). 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 that are 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.
Planning and design The planning and design strategy will be driven by the processes or products involved; the type, performance and specification of the equipment available; and the production throughputs and flexibility required. In principle, the process is generally straightforward and comprises concept design, client definition, performance design and detailed design - with each stage becoming increasingly rigorous; for example, working from concept layouts to full definition of the engineering solution.
Although the principle may be straightforward, the implementation can be complex, as people, product variables, regulatory and pharmaceutical legislation and operational and budget requirements are introduced.
Ultimately, there may be many systems, structural configurations, technologies and products involved, so it is important that all relevant personnel, from drug development, production, quality, logistics and maintenance departments, as well as process and construction engineering, are involved from the outset in the facility design. Achieving buy-in from all parties at an early stage will minimize overall costs and the time required before the facility is fully operational; for example, eliminating the need for reworking design layouts or the risk of 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 define the processes, equipment, operations, capacities and environmental criteria required for the facility, reflecting appropriate standards and legislation.
Material and people flows In the URS, the design and construction engineers and contractors, plus facility managers and users need to review the flows around the containment areas and boundaries to assess the optimum layout for regulatory compliance, efficient operation and to minimize cross-contamination. It is generally easier to simplify the flows in new facilities, but can be more difficult in retrofit projects, where compromises may need to be made because of space or cost constraints. Here, special 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 define clearly 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. The decision whether to make a piece of equipment a fixed part of the structure or skid mounted (common with biopharmaceutical equipment) also needs to be taken and reviewed early in a project, as it will have a significant impact on the layout, programme and costs.
It is also important to consider the impact that different containment levels will have on the complexity and possible cost of the project. For example, process systems may have to be adapted to accommodate the collection and treatment of effluent and vent gasses, whereas the need for high specification equipment seals, which are resistant or impermeable to aggressive liquids and gasses, may add considerably to start-up costs.
Buildings The URS should also include the materials and finish of the structure; for example, walls and ceilings may need to be impervious, with coved abutments, whereas floors are likely to require special coverings, doors to be constructed from steel, GRP (glass-reinforced plastic) or be gas-tight and, in CL3 and CL4 suites, windows are not a preferred option, particularly within CL4 environments.
Similarly, the facility may need to be designed to encompass positive and negative pressure systems, with changing and decontamination areas, whereas the required sampling and materials handling methodologies will also need to considered at an early stage - as they may have a considerable impact on the layout of the facility.
One final issue that is often overlooked at the primary design stage of high containment facilities is the impact of fumigation processes on the operability and downtime of each laboratory. It should, for example, be recognized that a typical fumigation procedure will take at least 12 h, with area preconditioning to a determined and stable temperature, fumigation, soak, degassing and purging.
Standards and validation Regardless of the level of containment, the laboratory should, in addition to the mandatory requirements that have to be addressed, 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), the Health and Safety Executive (HSE), the British Standards Institution (BSI) and relevant professional organizations. Additionally, process equipment must comply with the international and, possibly, national standards of the country in which the facility operates; for example, BS EN 1822 or Eurovent 4/4 for HEPA filters and BS EN 12469:2000 for biosafety cabinets will be required for CL1 and above, and COSHH (control of substances hazardous/harmful to health) 1999, ACDP Guidance (CL1–CL4) and HAZOP (hazard and operability) will be applicable at all levels.
Perhaps as importantly, 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, are of utmost importance and should be given a high priority from the outset.
To achieve comprehensive validation and compliance, a facility must satisfy criteria relating to training, documentation, resource management and equipment validation - to name but a few. Managing the smooth progression of a validation study, and thereby avoiding costly setbacks, is an often-difficult feat to achieve and is frequently left to a single project manager to complete. However, as we have seen with containment classification, the influence of rudimentary considerations extends throughout the entire process, and it is, therefore, more effective, in terms of both results and cost control, to recruit a management team that can oversee the entire project and formulate an end-to-end solution.
Lessons learnt During the past few years, our consultants have been involved at all levels in many different containment projects. As a result, there are a few lessons that have been learnt and that should be considered for new projects.
From the outset, make use of the most appropriate tools to deliver optimum results quickly and within budget; if manual analysis is the most effective route then do not allow the project to be sidetracked by unnecessarily complex computer-based processes; conversely, processes such as CAD (computer-aided design) and CFD (computational fluid dynamics) can provide valuable early stage solutions to evaluate process and ventilation flows.
The impact of noise and vibration, both on working conditions and, potentially, on the long-term integrity of processes and the facility itself, are often overlooked and should be considered from the outset. Similarly, it is essential to be realistic about the ongoing operation of the containment facility, so that future expansion, modification or possible decontamination are all factored into the design phase - a small increase in investment during the initial construction stage may save a far larger sum in the future.
In terms of process engineering, the cost of treating liquid and solid effluents will invariably account for a significant proportion of the budget, particularly in CL3 and CL4 facilities. In addition, the challenge of interfacing information technology (IT) systems, particularly when existing legacy systems are involved and the connections between process equipment are from different manufacturers, can often take a disproportionate amount of time to resolve.
One final word of advice: no matter how simple or complex the project appears, success or failure depends on the degree of consideration given to the detail. It is often easier to focus on wider strategic or technical issues than the day-to-day planning, construction, operation and maintenance of a containment facility. Yet, it is the details that must be dealt with effectively and in a planned, structured manner. Achieve this successfully and you will meet your objectives - be they commercial, technical or marketing.

Figure 1: Containment level one (CL1).
Figure 2: Containment level two (CL2).
Key points for successful containment
Figure 3: Containment level three (CL3).
Figure 4: Containment level four (CL4).

3 comments:

Arpita mohapatra said...

Software validation is a part of the design validation for a finished device, but is not separately defined in the Quality System regulation.
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Barsharani Jena said...

Perhaps as importantly, 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. more information

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