Product Recovery: Is air management the key to liquid recovery?

Maximizing product recovery at the end of the drug substance manufacturing process during bulk filling is moderated by the basic laws of physics. Gravity is your friend but air, or at least air in the wrong place, or without adequate consideration for how it moves, is not.

Single-use bulk filling solutions are nominally constructed from complex, relatively narrow bore assemblies of tubing between the critical sterilizing grade filter and multiple receiving biocontainers, either bags or bottles.  Before the process begins, all components, most notably the tubing, are air filled so air is always present. We’ll start with the most basic arrangement. Visualize a filter capsule, connected to a single biocontainer bag with a length of tubing to form a closed process.

If we pump liquid through the filter, the air in the filter and the tubing is pushed into the bag.  When all the liquid has been pumped into the filter, the downstream volume of the filter and the connecting tubing are likely full with liquid, and the bag contains the filtered liquid and the air displaced by the liquid at the start of the process.

If the bag is lower than the filter, surely gravity will just cause the liquid in the filter and tubing to drain directly into the bag? In a fixed volume, such as the tubing and the filter capsule, for liquid to move, something needs to replace it or a vacuum will be formed. So, this means that air needs to enter the tubing and the filter to allow the liquid to flow out. At this point, there are three scenarios.

1)  If the bag is oriented with the inlet at the low point, the air in the bag simply has no way to enter the tubing.

2)  If the bag has the inlet at the high point of the bag, air could enter the tube. Its lower density compared to the liquid in the tubing would suggest that it would float up through the tubing, allowing the liquid to fall via gravity into the bag. However, with a relatively narrow bore tube, typically less than ¼-½ in. (8 – 13 mm) internal diameter, this does not happen.  The interfacial tension of the liquid and air interface inhibits the movement of the air into the tube and we have an air-lock.

3)  Can air pass through the filter instead? The short answer is no. A fully wet microporous membrane does not allow the passage of bulk air. This is a phenomenon that we use to our advantage when evaluating the filter for integrity, and pressures above the natural bubble point for the filter membrane, wetted with the liquid, will be required. This is typically greater than 2-3 bar, depending upon the surface tension of the liquid being used.

So let’s look at some solutions to each of the scenarios.

In our final scenario we temporarily concluded that air cannot pass through the filter at low pressures. This is not entirely true. Air can diffuse through a wet filter membrane, albeit at a slow rate. This rate increases if we apply a significant air pressure upstream of the filter but remains low, nominally <5 mL/min. If our tubing volume is small enough, a function of tubing length and internal diameter, and we are prepared to wait long enough, sufficient air can enter the tube to allow liquid to flow into the bag. The good news is that a post-use filter integrity test naturally creates such diffusive flow, however, for all but the smallest of assemblies this is not practically useful.  This changes if we consider testing the final filter using a bubble point test. This uses a higher pressure that eventually de-wets the membrane allowing the bulk flow of gas, but this introduces a different problem. The bubble point test can be unpredictable and a rapid and largely unpredictable transition from low gas flow to a much higher flow state adds significant risk to the process. This risks inflating and damaging the biocontainer bag if there is not a vent filter on this bag. Adding this is feasible, however again, this adds risk when compared to a truly closed system. If filling into bottles, these vent filters are naturally present so this naturally limits some of the additional risk but still may not be desirable. It should be noted that any volume recovered from pressurization of the filter or during the integrity test needs to be factored into the process validation for the sterilizing grade liquid filter to accommodate the impact of these pressures on the validated filter retention under these more challenging process conditions.

In the next blog we will look at some innovative designs that can lead to achieving recovery without accepting additional process risk.