It seems intuitive that the manufacture of pharmaceutical products must be free of all contamination risk. After all, patients must rely on the safety of the final product. Looking back, as early as 1822 a French pharmacist demonstrated that physicians could use solutions that contained chlorides of lime or soda as disinfectants. He concluded independently that the hands of health personnel spread puerperal fever and that sterilization measures could be taken to prevent transmission of pathogens.
Today, almost 200 years later and with approximately 2200 commercial production lines in conventional cleanrooms in operation worldwide (1), we still deal with the introduction of the human element as we seek the highest possible level of sterility and the prevention of cross contamination in aseptic manufacturing. In the highly competitive and global world of parenteral manufacturing, along with ever-growing costs and increasingly stricter regulatory demands, optimized processes to reduce contamination sources are essential.
Since the early 1990s, two systems emerged that have helped the manufacturer assure a higher level of contamination-free product--the isolator and the restricted access barrier system, commonly referred to as RABS. The isolator was the first system developed to help enable a high level of sterility. By definition, the isolator allowed for full isolation of the machinery from the environment. Such units help keep the processing of the product separate from human intervention.
In the earlier phase of its development, technical issues and discussions around validation of sterilization or decontamination of the isolator were a problem. These issues have since been overcome and vast improvements have helped make the isolator a safe and proven process that is used in over 430 commercial lines (1). However, the limitation of the isolator continues to be lengthy changeover time. Thus, isolators are most effective in mono-lines that run the same product continuously, especially products requiring containment such as potent/cytotoxic drugs.
The second manufacturing system developed in the mid-90s was the RABS (see Figure 1). Recently, the demand for RABS lines has become more prominent. A primary reason for this development is the enhanced flexibility RABS offers beyond the isolator. RABS can allow for faster start-up time, ease of changeover, and reduced capital costs, particularly with retrofits and renovations. As a result, today there are approximately 250 RABS units in operation worldwide.
What is a RABS?
With the emergence of RABS among contract development and manufacturing organizations, agencies involved in overseeing those manufacturers, such as FDA, demanded that a more precise definition of RABS be put into place to ensure consistency among its users. They believed that simply installing restricted access barrier hardware in the manufacturing facility does not create a RABS. In 2005, FDA commissioned a study group to develop a definition and determine what elements need to be included to ensure that a RABS system is truly in place before a manufacturer can make such a claim. The International Society for Pharmaceutical Engineering (ISPE) study group consisted of experts from major manufacturers including Bosch Packaging Technologies, Pfizer, Merck, GSK, and Vetter, along with members of FDA.
By the definition developed by this ISPE group (2), any system claiming to be a RABS must include quality-designed equipment, and all operators must receive comprehensive training in key practices such as proper gowning practice. Additionally, all RABS must also include the following:
• A barrier to prevent human intervention directly into the critical zone
• Airflow for an ISO 5, at least in the critical zone
• Glove ports and transfer ports used for interventions (see Figure 2)
• High-level disinfection
• Highly automated processes and well-defined procedures for rare open-door interventions.
The system goes beyond encasing the production lines from the environment only. RABS combines the high aseptic safety of an isolator with the flexibility of a conventional cleanroom. The inclusion of rare open-door interventions in the definition often leads to criticism. These interventions, however, are not considered a best practice.
Best practices for RABS
RABS provides a level of separation between the operator and product that affords product protection superior to traditional systems. However, to operate a RABS cleanroom successfully, several best practices must be followed.
No open-door intervention allowed. During operation, the barriers may not be compromised; lifting the separation can lead to contamination and increased risk to the product. Therefore, when aseptic operations are carried out in a RABS, it is the intent to fully eliminate the need to open RABS doors. If the filling is interrupted with an open-door intervention, a complete cleaning and line clearance must be carried out, and the batch is eliminated.
During the line set-up stage, all machine parts and formats must be installed with the barrier closed by using a special glove-portal system. Thorough mock-up studies when designing a machine are essential. Such studies allow a well thought-through configuration of the machine and the barrier around it that allows the operator to reach all areas within the machine using the gloves. The mock-up studies simulate all routine operations and potential interventions on the machine. Operators of different departments (e.g., engineering and quality assurance) join forces to ensure the mock-up studies are as effective as possible.
High-level disinfection. Disinfection after each production batch must be completed. Once the filling process and the monitoring of the microbiological environment have been completed, the barriers are opened for cleaning. This is followed by a high-level disinfection with a sporicidal agent (e.g., peroxide suspension), which generates oxygen radicals to avoid build-up of resistance.
Integrity of gloves. Following production, all gloves must be tested for integrity and sterilized. Using a pressure-decay test, the gloves are removed and tested for even the smallest damage that could compromise the system. If the gloves are found to be airtight, they can be cleaned, steam-sterilized, and remounted back into the glove ports for use in the next production batch.
Aseptic transfer systems for zone transition. Materials and formats are only carried into the ISO 5 area using aseptic transfer systems. Any parts used in the production, including any raw materials such as syringes and stoppers, are sterilized in steam or dry heat and double packed. The outer packaging is sprayed with a sterilizing agent containing alcohol before being transferred to the ISO 5 area through a lock, and the outer packaging is removed. All steps are performed using the glove portal system. Packaging materials are also put into sterilized bags and placed in special containers. The containers are sprayed down prior to introduction so when they are opened inside the barrier, the content is exposed to ISO 5 conditions only.
A RABS process is secure, with both a cleanroom design and aseptic safety comparable to an isolator, but with a higher degree of flexibility. Automation of the system reduces variability due to operators and makes the entire process reproducible. At Vetter’s Ravensburg South production facility, for example, approximately 4 million media-fill units were filled over 7 years in 3 different cleanrooms with RABS units with no resulting contaminated units.
The RABS system is a proven and effective approach to favorably impact cleanliness in the finished product. RABS is also one of the most effective and efficient responses to current and future challenges in the manufacturing of aseptic products.
1. J. Lysfjord, “Current aseptic processing trends with the use of isolators and RABS,” presentation at the European Compliance Academy (Dusseldorf, Germany, 2012).
2. J. Lysfjord, Pharm. Eng. 25 (6) (2005).
About the Author
Joerg Zimmermann is director of Process Development and Implementation at Vetter, www.vetter-pharma.com