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The author reviews current approaches to sterile containment and compares several sealed transfer and barrier techniques, including isolators, restricted access barrier systems, and split butterfly valve technology.
This article was published in Pharmaceutical Technology Europe,Volume 30, Issue 7, July 2018
The manufacture of sterile drug forms must be subjected to strict controls to minimize the risk of contamination by micro-organisms, endotoxins, and particles. Because the presence of something unwanted in a dosage form can pose serious risks, legislation demands that steps be taken to reduce these risks that threaten product quality and ultimately patient safety.
Pharmaceutical manufacturing environments are open to multiple sources of contamination from the air filtration systems to the process of materials transfer and the fact that a fully gowned operator can create more than 10,000 colony forming units an hour. As a result, measures need to be taken to ensure the safe and sterile transfer of APIs and formulation ingredients during aseptic processes. This article reviews current approaches to sterile containment and compares several sealed transfer and barrier techniques, including isolators, restricted access barrier systems (RABS), and split butterfly valve (SBV) technology.
Sealed transfers and barrier technologies have been designed to contain aseptic manufacturing processes. They provide a robust alternative to conventional “cleanroom only” methods of handling sterile products, ensuring that pharmaceuticals are not exposed to viable organisms or particulate contamination, while also protecting operators from potent compounds.
RABS have been designed to enhance the aseptic processes carried out in conventional cleanrooms. These systems put a physical barrier between operators and processing lines, while still offering the flexibility to interact with the process. To enable the use of a less restrictive barrier, RABS are required to be set up in class ISO 7 cleanrooms, which means they do not require their own bio-decontamination system.
Two different types of RABS are commonly used in today’s manufacturing facilities. The first are active RABs, which actively pull air from outside the cleanroom environment, filtering and extracting it so that the RABS is completely isolated. The second type are standard passive RABS that use a cleanroom’s heating, ventilation, and air conditioning (HVAC) system.
RABS bring their own unique advantages by enabling operators to maintain a distance from the process, while allowing the cabinet to be opened if further intervention is required. Processes can also be quickly turned around to suit different batch sizes and requirements.
Isolators create an airtight barrier or enclosure around an aseptic processing line, hence, providing complete separation between the product and the operator/cleanroom environment. Operators perform tasks through half-suits or glove ports, enabling manipulation to be undertaken within the space from outside the enclosure without compromising integrity.
The clean environment is maintained through a combination of techniques, including the use of positively pressurized chambers with closed loop control. High-efficiency particulate air (HEPA) is supplied to the chamber in a laminar flow and ensures that particulate generation is suppressed and removed efficiently, while integrated bio-decontamination systems provide a validated sterility assurance level (SAL) of 10-6 on the chamber surfaces.
Due to the high-performance requirements for these enclosures, integrated pressure decay tests have become the norm during start-up and prior to any bio-decontamination phase, with the leak of the chamber being a key factor in the classification of the device. More information can be found via ISO14644 (1) on leak rates for separative devices.
Isolators and RABS both offer rigid wall environments that provide a physical and aerodynamic barrier between the operator and the sterile drug manufacturing process. While both provide an ISO 5 cleanroom environment, they each have their own unique advantages and limitations.
One of the major benefits that isolators have over most RABS is that the interior can be decontaminated through an automated process. This allows for repeatable and consistent high-level bio-decontamination providing increased SALs over conventional cleanroom manufacturing. Comparably, most RABS rely on the use of manual cleaning processes.
A limitation of isolators is that they can create difficulties in transferring materials in and out of the cabinet. This system can require a docking isolator to be connected and its interior sanitized before materials can be transferred. The qualification of hydrogen peroxide vapour systems in isolators can also be difficult. As a result, there is a need to suspend everything within the cabinet to remove any hidden surfaces.
In comparison to isolators, RABS can ensure faster start-up times, while also improving the ease of changeover. They can also bring increased operational flexibility and reduced validation expenditure. Isolators, however, offer the advantage of higher integrity chambers for a more robust closed solution.
As an alternative handling technique to these more traditional barrier techniques, many manufacturers are finding that an SBV approach can provide a more practical option in achieving assurance of product sterility.
SBV technology enables a product to be transferred from one container, process vessel, isolator, or RABS to another without compromising sterility. The valve consists of two parts: the active half and the passive half. Generally, the active half will be attached to the receiving vessel, with the passive half attached to the discharging drum or container, such as an intermediate bulk container (IBC) or flexible bag. When the two halves of the “butterfly” disc are brought together, a single disc is created, which allows product to flow on the internal surface of each half. When the passive and active halves are detached, the external face remains clean and can be safely exposed to the process environment.
Decontamination is able to take place in a closed environment using SBV. A gap is created between the discs when the two halves are connected, which enables hydrogen peroxide gas to be flushed through. Chemical indicators are used to validate the process and ensure that full coverage of the enclosure is obtained. Biological indicators also ensure a six-log reduction in microbiological contamination has been achieved.
The SBV approach offers manufacturers a closed handling method that reduces the resource associated with cleaning and validating large areas and minimizes the need for manual intervention, all while achieving the necessary SAL. By reducing cleaning requirements, the technique results in less downtime.
Depending on the gassing system used, processing times when employing SBV technology can range between four and 30 minutes, which represents a significant time-saving in comparison to conventional airlock systems or isolators that generally require four to six hours. The aseptic SBV also makes it possible to downgrade the surrounding cleanroom environment because of the integrity of the approach, again generating further time and cost savings.
The key to advanced aseptic processing is the elimination and absolute control of all sources of contaminants, including human-generated contaminants. The selection of an appropriate barrier containment technique will be dependent on several factors, including the requirements of individual manufacturing facilities and the types of products being processed. Choosing the right contamination control platform requires considerable research into what a product needs for an effective process design.
While ease of decontamination and a high degree of sterility assurance can be readily achieved using isolators, RABS bring increased operational flexibility and speed of changeover which appeals to manufacturers that need to adapt to varying requirements from different customers. Aseptic SBV technology not only complements and works in harmony with these solutions, but can, in many circumstances, eliminate the need for other methods.
For manufacturers who require high-speed commercial manufacture, barrier isolation technologies may make business sense. For smaller batch sizes, a more flexible RABS solution may be more suited to the process.
ISO 14644-7: Cleanrooms and Associated Controlled Environments-Part 7: Separative Devices (Clean Air Hoods, Gloveboxes, Isolators, and Mini-Environments) (2004), www.iso.org/obp/ui/#iso:std:iso:14644:-7:ed-1:v1:en.
Pharmaceutical Technology Europe
Vol. 30, No. 7
When referring to this article, please cite it as C. Dunne, "Aseptic Transfer Technology: Weighing Up the Advantages of Varying Approaches for Sterile Drug Manufacturing," Pharmaceutical Technology Europe 30 (7) 2018.
Christian Dunne is global product manager for ChargePoint AseptiSafe.