The global contract manufacturing organization (CMO) market is growing at a compound annual growth (CAGR) of 12–13 percent between 2018 and 2022. The growth is attributed to increased outsourcing of generic drugs by Big Pharma companies. Additionally, medium and small pharma and biopharma companies, who do not possess adequate infrastructure, will also outsource, thereby driving the market. Presently, non-sterile drug manufacturing dominates the global CMO market. However, the sterile manufacturing market is expected to grow at a higher rate (15 percent) than the non-sterile market (9 percent) thru 2022.
 
Manufacturing environments
As sterile drug products are on the rise, manufacturing environments are challenged to ensure that suitable control measures are put in place to mitigate many sources of potential contamination.  These include operators, equipment and other materials present in the manufacturing environment. Should microorganisms, particles or endotoxins enter the manufacturing environment, patient safety could be put at risk.
 
Several technologies have been developed over the years to ensure the sterile transfer of products and their drug substance during aseptic processing.  Examples include restricted access barrier systems (RABS) and isolators. RABS provide a barrier between processing lines and operators, but also allow operators to interact with products where necessary. Isolators provide an airtight barrier around the processing line and when used in cleanroom environments can minimize the risk from contaminants. 
 
Both RABS and isolator technologies have disadvantages, however. Materials transfer can be a difficult process when using an isolator, which can delay the shut down and start up process between batches, and RABS technology relies on manual cleaning processes, which can create delays between uses if not carefully managed.
 
The advantages of Split Butterfly Valve technology
The aseptic Spilt Butterfly Valve (SBV) provides a safe method of transferring drug substance or product from one container, process vessel, isolator or RABS to another while ensuring the sterility of the transfer is not compromised.
 
Fundamentally the SBV consists of two halves, the active (Alpha) unit and the passive (Beta) unit. Each half consists of half of the ‘butterfly’ disc. The active unit is attached to the stationary process equipment such as a mixing vessel, while the passive unit is attached to the mobile container such as an intermediate bulk container (IBC) or flexible bag. When the two parts are brought together, the disc halves join to form a single disc, sealing any surfaces which may have been exposed to a compound during transfer. The two discs then operate as one disc and can be opened to allow transfer of product from one location to another. 
 
The unique design of the aseptic SBV enables decontamination to take place in a closed environment. Once sealed, a gap is created between the discs and hydrogen peroxide gas is flushed through this enclosure to decontaminate the space. Chemical indicators (Cis) are used to validate and confirm full coverage of the enclosure has been achieved, followed by the use of biological indicators (BIs) to ensure a 99.9999% reduction, known as a 6-log reduction, in bacterial spores has been successful.
 
Adoption of aseptic SBV technology allows manufacturers to 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 areas. The method minimizes cleaning requirements and, consequently, downtime, while also increasing flow and yield from product transfers.
 
Processing time varies between four and 30 minutes depending on the gassing system utilized. This is extremely fast when compared to a conventional airlock or isolator which could be in the region of 4–6 hours. SBVs can also contribute considerable cost savings in comparison to traditional approaches, being as much as three to five times cheaper than alternative methods. The aseptic SBV also makes it possible to downgrade the surrounding cleanroom environment because of the integrity of the approach.
 
Case study
A North American CDMO required a solution to ensure the sterile transfer of API’s at its facility.
 
The CDMO is a full-service pharmaceutical company that specializes in the supply of respiratory and ophthalmic products. Its capabilities extend well beyond manufacturing, with an in-house development team specializing in all aspects of bringing a product to market - from lab scale batches, regulatory filings, scale-up, manufacturing and distribution.
 
Initial challenges 
The CDMO was looking to solve the issue of charging sterile drug substance into a mixing tank. This is a widespread problem in aseptic processing and particularly in formulation.
 
It was vital that sterile conditions were maintained whilst docking a container to the vessel and then transferring solid drug substance to form a liquid suspension. With a fully dissolved liquid, the product could typically be sterile filtered as it was passed to the filler. Although in this case, the product being passed to the filler was a suspension and so this option was not possible.
 
This required the process to be performed under aseptic conditions. As such, this would normally mean one of the following upgrades would be required:
 
• Upgrade the entire room to a grade A cleanroom from a grade C;
• Introduce an over-pressurized grade A area around the point of fill and upgrade the whole room to a grade B environment;
• Implement a laminar flow system around the point of fill, plus additional control due to the lack of a barrier;
• Introduce a RABS system at the point of fill or full vessel and upgrade the room to a grade B environment; and
• Maintain the grade C cleanroom but introduce isolator technology around the point of fill or full vessel.
 
Generally, RABs and isolator technology would likely have been favored in this situation, due to the benefits both technologies can offer. This includes improved sterility assurance, employing the fundamental techniques of separation and decontamination. However, when considering some of the disadvantages associated with these technologies such as high initial investment, space, ergonomics and ongoing cost and energy consumption, the company decided to look for a solution that was more suited to the task.
 
The solution
The ChargePoint AseptiSafe Bio valve was selected as a solution to this problem. The valve provided a sealed powder transfer mounted to the inlet port of the vessel. The valve could be pre-steam sterilized along with the vessel, unlike traditional SBVs or other conventional connections (see illustration 1a/b). On final connection, it also eliminated any room contamination from the mating faces of the transfer in a controlled and validated manner (see illustration 2a/b).

 

The AseptiSafe Bio valve works by creating a sealed chamber between the passive section (transfer container) and the active section (vessel). The sealed chamber is bio decontaminated with vaporized hydrogen peroxide (VHP) when the two halves dock together.

 
This removes any biological contamination to a validated 6-log reduction and leaves the space and mating faces clean and ready to dock together. Once mated, the disc can be opened. This allows the product to be securely transferred from transfer container to vessel, eliminating the risk of contamination. Performing this transfer within the grade C space provided considerable cost and production benefits.

 
Process validation
The first step in microbiologically validating the process was to generate a validated decontamination cycle for the VHP gassing stage. This consisted of four distinct phases, which the generator will run through to ensure a validated gassing cycle is performed each time.
 
Dehumidification phase—The humidity is reduced within the chamber to provide ideal conditions for biological kill.
Conditioning phase—VHP is introduced into the chamber to build up to levels to achieve good decontamination.
Decontamination phase—VHP concentration is retained in order to deactivate any microbiological activity within the chamber.
Aeration—On completion of the biological decontamination, the VHP is removed from the system so that no harmful levels of residue are left. In this instance, 0.4ppm was used as the acceptance level, as the client used a lower residue limit to ensure they had a robust system and no chance of contamination of their product due to gas residue.
 
The full decontamination cycle can be accomplished in as little as four minutes although 20 minutes is more typical. For this application the process was only being performed once a day. To ensure a robust cycle was produced, additional time was added to each of the critical phases, ensuring that decontamination was confirmed, and gas was aerated from the system. This resulted in a 41-minute full cycle.

 
Project learnings
The installation is now in full production. The initial benefits predicted at the outset of the project, such as low capital equipment cost, smaller footprint and ease of installation, have been matched by improved sterility assurance, ease of use for operators, and low maintenance. The system is straightforward to use, easy to install and validate and has improved the CDMO’s process.
 
One learning from this project was at the dispensing stage. At the time of validation, the system installed was a rigid reusable solution where pre-sterilized drug substance was supplied to the client in bags. These bags were opened and then subdivided and dispensed within an aseptic isolator to the pre-autoclaved transfer container and bio valve. It would have been beneficial to sterilize the product, container and transfer connection in one step through gamma irradiation, although this was not possible due to the constraints associated with gamma sterilizing stainless steel and elastomeric assemblies as one item.
 
With the release of the ChargePoint disposable/single use range, the AseptiSafe Bio valve will be combined with single use passive and bag technology to allow this process to take place. This will allow the client to purchase the drug substance, bag (container) and passive in a pre-sterilized, gamma irradiated form which can be docked directly onto the active vessel and discharged.
 
Alternatively, the client could purchase nonsterile drug substance, which is easier to handle. This can be dispensed into pre-sterilized single use bags with the integral passive half of the valve which can be docked and product transferred. The whole package could then be sent away for gamma sterilization, instead of having multiple individual sterilization and aseptic assembly steps, again making the process more streamlined, easier to handle and more cost effective.
 
Final thought
It will become increasingly important for containment technologies to be agile in order to adapt to evolving biomanufacturing requirements. This is an area in which SBVs can offer considerable benefits, due to their flexibility and ease of implementation. 
 
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