The first option is to add a dedicated air filter, connected immediately downstream of the sterilizing grade liquid filter. With the right tubing valves, this filter is isolated until required and then permits the flow of air into the system as the liquid in the tube and filter flow under gravity into the biocontainer bag. This is a robust solution, however, as this breaks into the sterile side, it would be expected that a sterilizing grade gas filter be used and that this also be integrity tested, before and after use. This can be achieved but adds significant process complexity and a small amount of risk to the process. Our remaining options will aim to support a fully closed system.
The next option is to review the orientation of the receiving biocontainers. Bottles are only installed one way, and any air in the system is naturally at the top of the container in contact with the inlet tubing. Biocontainer bags are typically laid flat or often oriented with the inlet at the low point of the assembly during filling. If oriented with the inlet at the high point, or on a tiltable configuration to change orientation after filling, any air in the biocontainer could also be accessible to aid displacement of the retained volume. In the first blog, we mentioned the air-lock scenario where this air does not naturally rise up to displace the liquid. This is usually the case, however if the tubing diameter is large enough, this can facilitate this natural recovery. Traditionally, tubing dimensions are minimized to reduce nonrecoverable volumes, however perhaps counterintuitively, larger bore tubing may actually aid product recovery and minimize losses by allowing such gravity assisted draining.
The maximum internal diameter of the tubing, however, is often limited by the size of the inlet connections of the receiving biocontainer bag. So, is there another way? Recent patents have been granted describing a design that uses dedicated tubes for air movement between the receiving biocontainers and the downstream of the sterilizing grade filter. These tubes can be external or co-located in a ‘tube-in-tube’ design to allow unhindered passage of air and liquid in opposite directions simultaneously. When optimized these can bypass the air-lock scenario and support simple gravity driven drainage.
One final design uses an additional biocontainer bag connected immediately downstream of the filter. This can be partially inflated by collecting air during the first priming of the system. This air reservoir then supplies the air to displace the retained liquid without the need to disrupt the closed process.
While our filling model is very basic, these same solutions can be applied to more complex arrangements with multiple receiving vessels and is largely volume agnostic. Combining good fluid recovery designs with optimized tubing management controls, valving, automation, and sensing, it is possible to achieve the robust and reproducible recovery of valuable process fluids. Risk associated with the manual manipulation of tubing to move bubbles through the system is eliminated and, above all, more precious drug substance is available to increase productivity and treat waiting patients.