For implementing manufacturing, filling and closing processes, barrier technologies are currently the most commonly used technologies for regulated markets such as Europe, the US and Japan. Whether existing clean rooms are operated with new or upgraded filling and packaging technology or if the enterprise makes investments in completely new manufacturing processes, including sterile and barrier technologies, a universe of options is available to pharmaceutical manufacturers.
For processing medicines that do not allow terminal sterilisation in the container, the scope of feasible approaches reaches from various RABS systems to isolator technology. RABS systems in particular come in numerous variants. Contamination protection begins with ‘simple / low’ and ends with ‘complex / high’, whereby contained systems offer the same minimal leakage rate as isolator systems.
Optimum suitability of a system for a certain application ultimately depends on a variety of factors, while universally valid decision scenarios hardly exist. Too many factors influence the complexity of all preconditions. Moreover, each company has its own customised safety concepts that lead to preference of a specific technological approach.
Barrier technologies – RABS and isolators
Ubiquitous features of RABS are rigid machine cladding, doors with safety locks and glove ports. As a matter of principle, RABS must be installed in a class B clean room. Each RABS has an air circulation system, with the option of implementing pressure zones, possibly with temperature control. Class A conditions are required within the RABS itself.
In practice, further distinction by passive RABS, active RABS and active cRABS is common. The distinction primarily refers to the design of the protective housing and venting concept. A passive RABS has no intrinsic venting technology but is vented via the ventilation technology of the clean room. A laminar flow ceiling above the protective housing of the machine is responsible for the unidirectional displacement air flow. Via this ceiling, air is fed into the protective housing and then released back into the clean room in a controlled ‘flow’ underneath the manufacturing process.
An active RABS has its inherent venting technology where the laminar flow system, which is operating independently from the clean room ventilation system, is positioned directly on top of the protective housing. The laminar flow suctions the air from the surrounding, passing the air through a HEPA filter, followed by laminarisation of the air stream. Then the air is guided over the manufacturing process and – in analogy to passive RABS – released into the surroundings via controlled flow. In this process, the room’s ventilation system and the RABS cycle operate independently from each other.
An active cRABS comes with its own venting technology, which, as a rule, is completely separated from the surroundings’ ventilation system. The exhaust air is returned either by external exhaust air channels or via double walls and/or double screens. Because it is a contained and hermetical system, the active cRABS can be operated under pressure (product protection) or vacuum (operator protection – not suitable for aseptic processes).
As the process is carried out in a completely sealed environment with its own venting technology, the manufacturing process allows random zoning, for example structuring into various pressure zones. The system supports control of temperature and air humidity. A filling and closing machine with isolator is a completely closed system operated under class D clean room conditions. The isolator’s most important feature is the total seclusion of the operator from the aseptic process zone. In addition, the individual process zones of the isolator can be entirely isolated from each other.
The products are conveyed from one zone to the next through so-called ‘mouse holes’. This allows implementation of pressure cascades between the individual process steps. Within the isolator, the air flow always streams into one defined direction and, like in the cRABS, is completely secluded and operates independently from its surroundings. As a rule, an isolator is furnished with its own ventilation and/or air condition to control temperature and relative humidity. An isolator indispensably needs suitable equipment to ensure sterile transfer of products, primary packaging materials and other components into the protected area. In addition, automatic and repeatable bio-decontamination (sterilisation) by evaporated H2O2 is required.
Aseptic quality and operator protection
Among the RABS variants and isolator technologies, the isolator achieves optimum sterility assurance level (SAL). It not only provides the relevant barrier technology, but the method additionally offers an automated and safe bio decontamination process. For this very reason, the American FDA prefers the isolator solution to RABS. When processing highly active pharmaceuticals, the issue of operator protection inevitably arises. Here, isolator technology is considered the safest solution, too. An alternative, however, could be an active cRABS, also a hermetical system with comparably low leakage rates. Depending on occupational exposure limit (OEL) values, and other machine and building-related protective regulations, cRABS also offers suitable protection.
Strengths and drawbacks of barrier technologies
If aseptic quality and/or operator protection themselves do not imperatively require an isolator system, additional factors have to be included in the decision making. One of the issues needing clarification are the clothes changing procedures to be complied with in context with the barrier technologies. RABS technologies are always installed in a clean room and mandatorily demand compliance with the relevant clothing regulations to prevent operators from becoming potential contamination sources. Changing clothes, however, takes considerably longer for clean room staff than for isolator machine operators. Moreover, the requirements to operating skills differ. Multiple standard operating procedures (SOPs) apply to clean room operation, but they are easy to learn.
Operating RABS in a clean room, however, involves additional steps required for handling the transfer equipment for the pharmaceutical products, materials and glove ports. Operating an isolator machine thus requires skills that are significantly more complex. In addition to these qualifications, the operator needs an understanding for the line’s automated processes, including those of the decontamination devices. The more comprehensive operator software that accompanies such a high degree of automation also raises the yard stick for the operating staff, and the required skills have to be imparted by training and
The type of containment has great influence on the flexibility of the operating processes, not only with regard to the clothes changing procedures of staff but also to the defined automated manufacturing processes on machines and/or glove ports. If needed, RABS systems support opening doors randomly, for example to remove jams, remedy errors or carry out disinfection. After disinfection and once the doors are closed, routine operation can continue. In most cases, the surfaces of the RABS are cleaned manually. The filling systems inside the RABS often come with automated cleaning and sterilisation devices (CIP/SIP). The doors of isolator systems can be opened for changeover and preparation of a batch and/or a campaign.
This step, however, is followed by the automated bio-decontamination and CIP / SIP procedures – and they take a long time. Work effort for RABS and isolators, however, is identical with regard to monitoring particle and micro-biological contamination. Investment costs: does the customer’s site already have clean rooms? To be able to reach class B clean room properties – as required for RABS lines – investments into building and HVAC technologies may become necessary. Building-related investment costs for setting up RABS systems are high and have to be calculated into the costs for the RABS equipment. Machine investment costs for RABS systems without restructuring expenses, however, are lower than for an isolator system. Not only the time-consuming clothes changing procedure has a significant impact on operating costs.
In addition, monitoring costs, and energy costs for the HVAC technology in particular, have tangible effects on the cost side. If isolators are used, frequent format changeovers and the related time-consuming mandatory decontamination cycles can quickly bloat operating costs. Validation costs for setting up an isolator system are high, because the automatic decontamination equipment has to be qualified and valuated. In addition, isolator machines are complex automated systems with correspondingly high validation costs. For both systems, for example also for the RABS systems as well, the transfer processes for products and materials have to be described and evaluated.