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While isolators may offer advantages in high-speed commercial manufacturing lines, RABS continues to be a flexible alternative solution for small-scale production of drugs for clinical use.
In any cleanroom environment, there are multiple potential sources of contamination, which include but are not limited to the incoming air system, materials transfer, and the process operators. In a well-designed and controlled operation, the people entering the area present one of the main sources of bacteria. The need to distance the operator from the open processing has led to the use of restricted access barrier systems (RABS) or isolators to provide a barrier between the drug product and its handler. There is an ongoing debate among quality and production experts in the contract manufacturing space over which solution to employ in the cleanroom environment. Typical factors to consider include the type of product being manufactured and the stage in the drug development process that a contract manufacturing organization (CMO) is operating in. This article reviews the role of RABS in a small-scale aseptic manufacturing environment and explores factors for vendors to consider when selecting a CMO partner.
Aseptic processes in the cleanroom are designed to minimize the exposure of the core sterile operation to the potential microbiological hazards of the manufacturing process. Isolators have traditionally been used in aseptic pharmaceutical manufacturing environments with the aim of protecting operator safety, as well as reducing the risk of contaminants reaching the drug product. An isolator is a fully sealed unit that is often sanitized using vaporized hydrogen peroxide (VHP). The handling of drug substances and the filling of vials take place within a closed system that completely isolates the operator and the surrounding environment from the drug product. Isolators were first implemented as a means of protecting operators from the drug substance they are handling. They are often the preferred solution in cases that involve pathogenic agents and higher-risk materials that need absolute containment within a high-potency working area. Isolators are also suited to large-scale manufacturing environments that use fixed automated processes and require minimal intervention by the operator. Although used successfully by some CMOs across the industry, there are, however, a number of limitations associated with VHP isolators. Given that the isolator is a closed system, it can be difficult to transfer materials in and out of the unit. Routinely, it is necessary to connect a smaller docking isolator, which itself is further sanitized using VHP in isolation before moving materials across. This process can be cumbersome, restrictive, and lacks the flexibility for the operator or engineer to rapidly intervene in the event of unexpected issues. The qualification of VHP systems in isolators can also be challenging. For example, VHP is a surface sanitant, meaning when a unit is gassed with the substance, it only hits the exposed surfaces. As an item is moved, it may expose further surfaces that have not been exposed to the sanitizing gas. As a result, there is a need to suspend significant portions of the load within the cabinet to minimize the obscured surfaces. In addition, residual VHP within isolator cabinets has the potential to negatively interact with the drug product itself, leading to potential degradation. In particular, there is evidence that biologics can be more sensitive to VHP. While development work could be conducted upfront to help to understand how a drug substance may react to VHP, this level of research may not be feasible in cases where drug products are being manufactured for first-in-man clinical studies and may take several months to manufacture using biotechnological processes.
RABS is another way to distance the operator from the open aseptic processing, using a barrier and dynamic airflow. The RABS cabinet is a simple idea, combining the barrier part of the isolator to minimize the risk of the operator potentially contaminating the drug product, while still allowing the flexibility to interact with the process outside of a sealed, gassed, isolator unit. Broadly speaking, RABS can be divided into open or closed systems, with open systems subdivided as active or passive. Passive RABS recycles air from the surrounding environment (i.e., the unit does not have a dedicated air supply). The benefits of passive RABS are the ease of installation and the simpler room balancing. Active RABS are still open by design but use a dedicated air supply, independent of the surrounding area air supply. Both of these types of RABS are classified as open because they push the supplied air out of the cabinet into the surrounding area-they do not provide operator protection if required. Closed RABS offers operator protection by the use of controlled supply and exhaust systems preventing passage of the filtered air directly into the surrounding area. The RABS cabinet concept was born out of a need for technology that could be more easily applied to manual open processing. While isolators are well suited to cases where there is an automatic filling system requiring minimal intervention, when conducting manual or semi-automated filling, there is often a requirement to go in and out of the open part of the process on an ongoing basis. This is particularly the case for CMOs handling small-sized batches, complex filling procedures, and/or challenging substances, where frequent process changeovers need to be accomodated. The operational benefits of using RABS are clear. The operator can maintain a distance from the process, but if there is a significant intervention required, the cabinet may be opened to perform the activities in a controlled manner. Also, RABS makes it significantly quicker to turnaround the process to suit different batch sizes and requirements. This feature can allow the CMO to offer a quicker filling solution to help a client get their product ready for clinical trials and to meet tight deadlines. From a quality control (QC) standpoint, RABS have also been shown to produce nil non-viable particle counts during routine operations.
Despite the clear benefits of the isolator and the RABS cabinet set-up, neither are an absolute regulatory requirement. It is possible to meet the demands of GMP standards by having Grade A open cabinets at the point of fill and a Grade B aseptic background environment without requiring a physical barrier between the operator and drug substance. Instead, the use of RABS or an isolator is recommended by regulatory guidance documents as something that should be considered. In practice, if a manufacturer is expanding or building a new facility to perform a task such as aseptic vial filling in the United Kingdom, the Medicines and Healthcare products Regulatory Agency (MHRA) may strongly suggest that a RABS cabinet or isolator system is implemented. This approach is defined to assist the manufacturer with ongoing process qualification and reliable operation.
The increasing uptake of RABS and similar systems and the attention they are receiving from regulatory bodies suggest that they may eventually become part of the legislation in the future. There are, however, a number of reasons why the use of RABS may be challenging. RABS is not suitable for every drug product and process. For example, RABS may not always be workable in cases where complex major interventions or significant manual handling are required, or if fixed equipment needs to be adjusted to be used at different angles, or if the fixed process needs to be viewed from varying angles, meaning that multiple product or process changeovers need to take place. In addition, it is important to remember that many CMOs have existing systems that have already been validated and approved in situ. Inevitably, many CMOs may push back on something that is going to require a significant financial investment in terms of equipment, training, and process validation when strictly speaking, the regulations do not yet stipulate the use of such systems. In addition, operational changes of this scale have the potential to impact productivity, as processes must be qualified again. Costs and continuity of supply are among other wider considerations. Whether or not RABS becomes a legal requirement, it is clear that their use in place of more cumbersome VHP isolators can deliver significant time savings to certain parts of the industry, speeding up the manufacturing process and offering the flexibility to deliver product in a responsive manner, without compromising on quality. While isolators continue to offer advantages to CMOs dealing with big outputs and high-speed commercial manufacturing lines, RABS continues to offer an alternative solution for small-scale CMOs that focus on the manufacture of drugs for clinical use. While the speed of product changeover is a key factor for the majority of commercial manufacturers, small-scale CMOs also require the operational ease and flexibility to use different manufacturing processes to be able to offer clients rapid access to their manufacturing capabilities. In summary, the motivation to adopt RABS is distinctly different depending on where in the wider drug-development process a CMO chooses to position itself competitively. RABS supports the achievement of quality standards of the highest order while offering additional operational flexibility, meaning that its application across the industry is no doubt set to continue.
Outsourcing Resources Supplement
August 2016 Pages: s24-s27
When referring to this article, please cite it as F. Weston, "Debating the Role of RABS and Isolators in Aseptic Manufacturing,"
Outsourcing Resources 2016 Supplement, Pharmaceutical Technology