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Modern Problems

Tue, 09/25/2012 - 10:41am
Joerg Zimmermann, Vetter

Manufacturers of parenteral drugs face a host of challenges. Among the biggest issues are cost and competitive pressures, as well as stricter regulatory demands. One way to meet these challenges is through the use of Restricted Access Barrier Systems (RABS) in aseptic filling. RABS solutions provide high quality and safety standards and enable flexible and efficient production processes.

Pharmaceutical and biotech companies are increasingly under pressure. Reasons for this are highly competitive markets due to sustained globalization in the pharmaceutical and biotech world, the loss of patent protection for many blockbuster drugs, and competition from generic drugs and biosimilars. They have to reduce costs, optimize processes and at the same time develop innovative drugs and get them to market quickly and successfully. By the same token, official agencies like the FDA and EMA are demanding higher reliability and quality from drugs. One option is optimizing processes and conditions in production. For instance, using Restricted Access Barrier Systems (RABS) for the aseptic filling of parenterals offers considerable advantages.

New Solutions

Many modern drug substances made using biotechnological processes are extremely sensitive to environmental impact and require highly classified areas for manufacturing. One reason, terminal sterilization is not possible in the case of these parenterals. Nevertheless, for a high level of sterility assurance, sources of contamination must be excluded as much as possible. One convincing approach is to separate production staff physically from the manufacturing processes. Two solutions have emerged since the mid-1990s: the isolator and RABS.

Favoring Isolators

The isolator, which kept processing completely separate, seemed to be the way to go early on. However, technical issues and long discussions about how to validate the sterilization or decontamination of isolators meant teething problems for the isolator as a system. These issues have now been overcome and safe and proven processes have been established. The filling machines form a separate ISO 5 cleanroom or higher, which is operated in an environment class ISO 8. Gowning procedures are simpler and costs in time and money can be saved in daily operations. Today there are approximately 2,200 production lines worldwide operating in conventional cleanrooms and about 430 isolators lines, say the experts. From the mid 90s until the nearby past far fewer filling lines were equipped with RABS. In contrast to isolators, the physical barriers with RABS are somewhat limited. Hence, RABS lines have to be installed in at least ISO 7 class cleanrooms. Until recently, only about 70 systems of this type were operating world-wide.

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Illustration of a passive RABS system.
Source: Robert Bosch GmbH, Packaging Technology

RABS is Flexible

Lately, however, demand for RABS lines has increased noticeably. Currently, about 250 systems in facilities are operating with RABS. One reason for its growing popularity is its greater flexibility compared to isolators. One of the design features of the isolator systems is an automized bio-decontamination of all machine parts and surfaces in the aseptic processing area before each production. As a rule, the physical separation must be lifted for product change-over. For decontamination, automatic systems usually with hydrogen peroxide vapor are used. This is aseptically safe, but depending on the system, it can last from three to ten hours. Isolators, therefore, are well suited for products manufactured in large quantities or high potent drugs like cytotoxic drugs. Large quantity products allow for longer production runs and campaigns, favoring isolators, while for high potent drugs, operator protection becomes equally important as product protection. For smaller batches as well as lines that are not geared towards manufacturing of a single product, isolators will not be very economical. What’s needed, instead, are plants that are flexible regarding formats and numbers of filled drug-delivery systems and can be equipped quickly. RABS lines are a solution, because they do allow for rapid change over from one product to the other in as little as 6 hours, when done properly.

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 As with all operations, the replenishment of stoppers into conveyers is
done through gloveports installed in the machine cover.
Source: Vetter Pharma International GmbH

What is RABS?

RABS lines make a lot of sense in light of the ever-growing need for efficiency. Companies with no RABS experience can still rely on proven technology. Thanks to their flexibility, RABS lines found favor in the mid-1990s with contract development and manufacturing organizations (CDMO) like Vetter. Official agencies started demanding a more precise definition, however. The FDA commissioned a study group made up of industry experts to make a determination. The group included representatives from the FDA, Bosch Packaging Technologies, Pfizer, GSK and Vetter. In 2005, it published its definition within the framework of the ISPE. A RABS line had to include the following:

• a barrier to prevent human intervention directly into the critical zone

• air flow for an ISO 5 environment at least in the critical zone

• glove ports and transfer ports used for interventions

• high-level disinfection = sporicidal disinfection

• highly automated processes and proper procedures for rare open-door interventions

The aim of RABS is to combine the high aseptic safety of an isolator with the flexibility of a conventional cleanroom. The definition shows that RABS solutions go beyond merely encasing the production lines. As the illustration of the passive RABS shows, a barrier keeps the production line isolated from the environment. Air flows downward around the machine. It blows through orifices from the ISO 5 area underneath the barrier into the ISO 7 area. From there it is redirected, filtered and steered back into the air circulation system. As with the isolator, intervening with the machine is only done using installed gloves.

How to Run a RABS Cleanroom Successfully

A dividing wall separating the operator and the aseptic production area does not suffice. Four main points are necessary to use a RABS line flexibly and safely and make it a best-practice. 

1. During operations, the barriers may not be opened. This applies to the line set-up stage as well. All machine parts and formats have to be installed with the barrier closed and using the gloves. Lifting the separation can lead to contamination. The filling would then have to be interrupted and a complete cleaning and line clearance carried out. The filling can then proceed as a separate batch only.

2. After filling, disinfection with a sporocide must be carried out. Once the manufacturing and monitoring of the microbiological environment has been completed, the barriers are opened for cleaning. This is followed by a high-level disinfection, for example using a peroxide suspension, which generates oxygen radicals and thus avoids build-up of resistance.

3. Gloves have to be tested for integrity and sterilized. After production is finished, the gloves are removed and tested for integrity for example using a pressure decay test. This allows one to spot the tiniest holes. If the gloves are airtight, they can be cleaned, sterilized and mounted back into the gloveports.

4. Using aseptic transfer systems for zone transisition. Materials and formats are only carried into the ISO 5 area using aseptic transfer systems: All parts and raw materials (e.g. syringes and stoppers) are sterilized in steam or dry heat and doubly packed. Prior to being transferred to the ISO 5 area, the outer packaging is sprayed with an alcoholic agent. They are then transferred to the ISO 5 area through a lock, and the outer packaging is removed. All following steps are performed using the gloves. Packaging materials are also put into sterilizable bags and placed in Steriset-containers. These boxes are also sprayed down prior to introduction. When they are opened inside the barrier, their content is exposed to ISO 5 only.

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RABS separates production staff physically from the
manufacturing processes. During operations, the barrier
may not be open and all interventions take place using
the gloves.
Source: Vetter Pharma International GmbH

Successful Handling

Complying with these instructions can produce a high level of aseptic safety. For example, in the past 8 years, about 3 million units have been filled at one of the Vetter RABS lines with zero contaminated units. The result is the aseptic safety of an isolator but with high flexibility. Therefore RABS lines are able to serve as an effective response to current and future challenges in aseptic manufacturing. 

 

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About the author: Joerg Zimmermann studied pharmacy in Freiburg, Germany and Cardiff, Wales. He joined Vetter in 1994 as assistant head of production. His first responsibilities were process development and new product introductions with a focus on lyophilization process development. For the last 10 years, Joerg was responsible for the Vetter Site in Langenargen as Director of production, a site with 5 filling lines for aseptically prefilled injection systems. In September 2010 he changed back into the role of Director Process Development and Implementation.

  

 

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