As market demand for advanced biopharmaceuticals continues to grow so do the demands placed upon modern aseptic processing, and primarily of parenterals such as vaccines. Quality of the final product remains of upmost importance, putting the techniques involved in ensuring sterility during manufacture under the spotlight. The current techniques adopted to ensure this fundamental requirement is met primarily consist of high classification cleanroom areas and barrier/isolator technology, coupled with validated sterilisation or decontamination processes to ensure both product and components within the critical areas can be maintained at the required sterility assurance level (SAL).
Arguably the most challenging aspect of handling components (such as vial stoppers) and powder-form product lies in the transfer of these materials from process to process. Personnel contaminants and operator error are among the greatest sources of microbial contamination, driving the need for the transfer method not only to be enclosed but also to ensure minimal operator intervention. Specific techniques are also required to achieve optimum results.
A current method for such batch transfer processes utilises alpha beta port technology, which offers a common transfer interface between processes. With any transfer device of this nature the decisive detail lies in how the device can eliminate or minimise the volume and frequency of interfacing surfaces that are first exposed outside the critical area and subsequently exposed inside the process, thus decreasing the risk of bioburden. The device must be adapted to allow steam sterilisation or decontamination in place while ensuring a sealed environment before, during and after the transfer.
Split butterfly valve (SBV) technology is new being used in aseptic processing and offers a multitude of process benefits
An alternative transfer technology has now been adapted to solve these issues in aseptic handling. Traditionally, the split butterfly valve (SBV) has been used as an operator safety device within fine chemical and solid dose pharma production, minimising the amount of airborne particulate when transferring toxic ingredients. Now this technology is being used in aseptic processing and offers a multitude of process benefits. Unlike most comparable systems, some novel SBV designs allow them to be autoclaved offline, steam sterilised and bio-decontaminated in place to achieve the required SAL.
The fundamental feature of all SBVs is that they consist of two halves, namely the active (Alpha) unit and the passive (Beta) unit. Each part consists of half of the ‘butterfly’ disc, which is sealed against the main body via an elastomeric seal to create the sterile barrier. Typically the active unit is attached to the stationary process equipment, such as a stopper processing 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 most advanced SBV designs have a range of mechanical interlocks on both the active and passive unit, which serve to ensure that neither half can be accidentally opened unless the two halves are docked together. The operation principle (see Figure 1) is as follows:
1. The two disc halves are locked in place to form a single sealed unit. The previously exposed interfaces are then sealed together.
2. The active unit is the driving half of the valve. Once operated (manually or automatically), the disc will open to allow the transfer of material through the valve. Once the transfer has taken place the valve is closed.
3. The active and passive units are unlocked and undocked.
The area of concern exists with the small area where the outer circumferences of the disc interfaces (that are exposed to the room environment) seal together and rotate into the open critical area. This is known as the ‘ring of concern’, which is common to any transfer device of this nature. Highly specialised SBVs utilise specific techniques to ensure that this concern is eliminated or reduced to ensure the SAL is met.
Two fundamental types of SBV design exist for the transport of aseptic products or components. The first iteration of the valve employs a steam-in-place (SIP) process, ensuring that all internal surfaces together with the ring of concern have been sterilised. On closure, it can withstand an over-pressure from the container or process device to maintain the integrity of the sterile boundary when moving through less classified areas, typically moving from a grade C/D area to grade A. This also means that filled containers can be stored prior to transfer without the risk of breach.
To maintain this integrity throughout repeated steam sterilisation cycles the seat of the valve needs to be manufactured from an FDA, US Pharmacopoeia compliant material. Fluoroelastomers (FPM/FKM) or perfluoroelastomers (FFKM) are most commonly utilised due to their elastomeric properties and high level compression set under repeated steam cycles.
In travelling through the respective room grades there is a risk that the exposed faces of the discs may pick up contaminants
In travelling through the respective room grades, however small, there is a risk that the exposed faces of the discs may pick up contaminants during transit. Consequently, it is common practice when transferring any product or component into the aseptic core (within the Grade A/Class 100 boundary, typically the isolator/RABs wall) to include a vertical laminar air flow (VLAF) system above the transfer point, ensuring HEPA filtered air washes over the disc faces prior to final connection.
Additionally, the procedure of spraying and wiping the discs with a sporicidal solution can be undertaken. In employing these techniques and standard operating procedures, a SAL of 3–4 can be expected, which is ideal for the transfer of many products or components to the next phase of manufacture.
A new bio-decontamination approach
The challenge for the next iteration of the aseptic SBV is to remove the cumbersome VLAF and bring about a validated 6 log reduction to the transfer process. This would remove the need for any additional capital expenditure in the form of a high level cleanroom together with its associated validation and ongoing consumable costs. It would also mean that if the operator is removed from the decontamination process and a more robust validatable process could be introduced then the SAL of the process could be improved.
After several years of research, design and testing a second iteration of aseptic split valve has now bridged this gap, using existing sterilisation and pressure hold techniques together with an integrated bio-decontamination process of the potentially contaminated exposed disc faces.
This new approach involves partially docking the two disc faces, creating a sealed chamber that can be bio-decontaminated prior to final docking. Due to the unique way the active portion of the valve is designed, the high sides of the body of the valve form walls that, when the passive section is introduced, create a sealed chamber allowing a decontamination process to take place (see Figure 2).
Figure 2: Illustration of valve cross section showing bio-decontamination gas between valve faces
Hydrogen peroxide gas (H2O2) has been used as the bio-decontamination media in view of the following attributes:
- Residue free (breaks down to oxygen and water)
- Safe: non-carcinogenic
- Repeatable and validatable results (6 log kill)
- Rapid decontamination cycle times
- Low-temperature execution: ideal for isolator/RABs transfers or temperature-sensitive products
This is also one of the most widely used bio-decontamination techniques on isolators and RABs, which over the last decade have overtaken the use of cleanrooms, due to the increased separation of the operator and product. Designing the valve to have fast decontamination cycles in conjunction with the isolator gassing system also means that hardly any additional hardware would be required, just an extension of the gassing system and a separate cycle developed for the transfer process.
During docking a sensor on the active portion of the valve identifies that the passive valve and transfer container are located in the partially docked position. Gassing valves located at either side of the valve then open and allow gas to be transferred through the sealed chamber, bio-decontaminating the internal surfaces of this area. This decontamination process goes through four distinct phases to ensure not only that the space has been decontaminated but also that the H2O2 gas has been fully removed in a timed sequence, as follows:
- Setting the humidity level for the introduction of VHP/VHPV (Dehumidification/Conditioning)
- Introduction of VHP/HPV (Conditioning /Gassing)
- Bio-decontamination/Dwell period. Where biological deactivation occurs
- Aeration. Removal of VHP/HPV to less than 1ppm. This time includes any out-gassing from material
Validation – small space gassing
Although bio-decontamination with H2O2 gas is widely accepted as a robust method for surface decontamination, the different suppliers of this technology use slightly different techniques to achieve the same result. As such, a number of different gas generators have been tested to ensure their effectiveness on the small space that is gassed. The validation of these systems involves the following methodology:
1. Biological indicators (BI) inoculated with 106 Geobacillus stearothermophilus spores as well as stainless steel strips also inoculated with 106 spores placed within the 5mm high chamber created in the partially docked position.
2. A gassing process executed going through the four distinct phases of the process. On completion the BIs are placed in growth media and then incubated and examined for growth after five days.
3. H2O2 monitors are placed above the seat of the valve to ensure there is no leak of H2O2 past the seat of the valve to where any product or component would reside.
Results for the various gas generator trials concluded that a 6 log reduction is established in the space and that no leak of gas had been detected past the seat of the valve. The times taken for the process varied from 6 to 30 minutes dependent on the generator used. As a bio-decontaminated process time, between 6 and 30 minutes is considered extremely fast gassing when compared with the conventional airlock approach of transfer into the aseptic core, which would typically be in the region of 30–60 minutes due to the overall volume and surface area being transported.
The applications for this type of sealed transfer are varied, but the system is now being used in the product transfer of non-terminally sterilised products direct from process dryers into intermediate containers and then into filling lines together with stopper transfers into RABs and isolator filling lines.
Manufacturers are now benefiting from the introduction of a closed handling method that not only achieves the required SAL along with a reduction or elimination of manual intervention, but also offers the opportunity to reduce the resource associated with cleaning and validating large volume areas, by utilising a compact and efficient split valve system that is also capable of ensuring a high level of protection while handling potent ingredients that pose a risk to operators.
