Ensuring the safe transfer of active pharmaceutical ingredients (APIs) and formulation ingredients during high potency and aseptic processing is vital to both the quality of final products and the sterility of manufacturing processes. The most challenging aspect of handling these components lies in the transfer of materials from process to process, with operator error and human contaminants posing the greatest risks to product contamination. This has fuelled the need for new transfer methods that are both enclosed and minimize the requirement for operator intervention. This article explores the advantages associated with sterile transfer valve technology, and more specifically, looks at the emerging benefits being achieved through the adoption of split butterfly valve (SBV) technology.

Managing risks
The transfer of materials into and out of the aseptic core is one of the greatest potential sources of contamination. If managed incorrectly, a potential bridge can be created with the external environment. To manage the risks, there needs to be an understanding about where potential hazards occur. As previously mentioned, the most common source of contamination is from people; a fully gowned operator may release as many as 10,000 colony-forming units per hour. As human intervention is present at almost every stage of pharmaceutical manufacturing processes, solutions to counter these potential risks are vital.

Regulations and standards for cleanroom environments have gone some way to alleviating and managing the risks. Ranging from grade A to grade D, there are various approaches associated with each grade, from closed to open handling of a sterile product. In a grade A environment, less than one colony forming unit (CFU) is allowable meaning there is no contamination. The advent of sealed transfers using SBV has enabled the downgrading of the external environment as it creates an internal grade A environment of its own, the benefits of which will be discussed below.

SBV technology
To overcome challenges during high potency and aseptic processing, several techniques have been introduced to manage the associated risks and provide assurance of product sterility. SBV uses hydrogen peroxide gas to bio-decontaminate on the two mating surfaces before product transfer. These valves consist of two halves, the active (Alpha) unit and the passive (Beta) unit. Typically, the active unit is attached to the stationary process equipment, such as a formulation vessel or filling line, and the passive unit is attached to the mobile container, such as a flexible bag or rigid intermediate bulk container (IBC).

The two halves of the valve create a sealed chamber by partially docking the two ‘butterfly’ disc faces. This allows decontamination to take place in a closed environment. The decontamination media is applied as small droplets, which are dropped onto a hot plate and vaporized, before being blown into an air stream and into the sealed space between the passive and active discs. This happens before the valve docks, which is when the elimination of viable microorganisms takes place.

Biological indicators holding one million spores are placed inside the chamber as part of the validation process to determine the appropriate decontamination cycle. The biological indicator is then removed afterwards and tested to determine the survival of any spores. If no spores grow, the process has worked and the unwanted microbes have been killed meaning that the area can be classified as contaminant-free.

In short, SBV achieves improved sterility assurance by applying the principles of separation and decontamination. Separation measures protect the critical line before, during and after transfer, while eliminating manual intervention by minimizing the exposure of the operator to the product/critical area. Decontamination delivers a validated approach, eliminating reliance on previous ‘spray and hope’ methodologies.

The benefits of SBV
Adoption of the technology means that manufacturers can benefit from a closed handling method that not only achieves the required sterility assurance level (SAL) and reduces the requirement for manual intervention, but also offers the opportunity to reduce the resource associated with cleaning and validating large volume areas.

SBV enables APIs to be processed while ensuring the safety of the operating environment by maintaining the required Occupational Exposure Limit (OEL), protecting sensitive products and helping to eliminate cross contamination. The method eliminates dust in the processing of raw materials and reduces cleaning requirements and associated downtime.
In addition, SBV with integrated bio-decontamination provides a validated, repeatable 6-log reduction at the point of fill, as the conditions and the transfer space are consistent, something that cannot be guaranteed with a traditional spray and wipe approach. The de-contamination process using the hydrogen peroxide gas reduces the spore count so that a (10-6) reduction in microbiological contamination is achieved on the exposed faces of the valve. This means there is no risk of the final connection being contaminated. This is a common concern for operators who are using the wiping approach, as contaminants can come into contact with the surfaces that have just been de-contaminated, particularly as operators are intervening.

Processing time varies between six and 30-minutes depending on the gassing system utilized. This is extremely fast when compared to a conventional airlock approach to transfer into the aseptic core, which would typically be in the region of 30 minutes to one-hour due to the surface area and volume being transported. This makes the production process more efficient, helping to maximize product output.

SBV technology also demonstrates improved ergonomics over alternatives that rely on working alongside barrier isolation. The sealed system removes the requirement for the use of glove ports and reduces associated handling issues that can be challenging for the operator. Significant cost savings can also be realized as valve technology is as much as three to five times cheaper than isolators, while ongoing running and maintenance costs are reduced thanks to the downgrading of the external environment that it supports. For example, it is less restrictive and time consuming to enter into a grade D room than a grade A room. As a result, this can speed up production and is a more cost-effective way to operate.

SBV is now being applied to several applications including product transfer for non-terminally sterilized products, adding bulk powder to formulation vessels, as well as direct transfer from process dryers into immediate containers and then into filling lines.

Closing thought
The development of SBV technology has increased its suitability for a wide range of industry applications where not only dust control and containment is a concern but where product flow, yield and sterility issues are also prominent. As an alternative to the industry’s current reliance on high classification cleanrooms and isolators in aseptic manufacturing processes, the adoption of SBV can not only achieve time and cost savings as the surrounding environment can be downgraded, but it can bring improved sterility assurance and reduced opportunity for operator introduced contamination. Offering a validated methodology to transform the way that containment and sterility is achieved during aseptic processing, SBV is helping to transform operator safety and the quality of final drug products. 

---

Christian Dunne is the global product manager for ChargePoint Technology for the aseptic range of products. Over the past 15 years, Christian has been creating innovative solutions for the pharmaceutical, biotech, cell therapy and fine chemical industries in the form of high containment and aseptic process solutions. For the past four years, Christian has been working with ChargePoint Technology on the advancement of its split butterfly range of solutions in the aseptic and containment fields, handling high potent/sterile powders and small-scale components, where both product and operator protection are paramount.