Use of Disposables
For an in-market supply production plant, the use of disposables is more limited than at smaller scales of operation. The
financial incentives and physical limitations for using plastic over steel are often high, particularly for chromatography
and tangential flow filtration (TFF) operations. There are still areas in the plant where disposables can be used effectively
as long as the space and flexibility has been pre-engineered into the facility.
In this instance, the use of disposables is limited to adding buffer hold vessels to the new process. After the processing
time bottlenecks have been overcome, the supply of buffer becomes limiting. For this plant, freeing up a large buffer hold
vessel by supplementing the hold tanks with 2,000 L of disposable storage enables batches of up to 4.3 g/L to be produced
without any bottlenecks (Table 3).
Table 3. Describes where the first bottleneck occurs in each step of the process evolution
This technique, developed by Pall Life Sciences (East Hills, NY) and based on patented technology, can be thought of as TFF
in a direct flow mode.4 One of the main applications of this technology is its use as a fully disposable retention ultrafiltration system for early-phase
material manufacture in flexible, low-capital-cost plants. Lonza (Basel, Switzerland) wanted to test the technology for application
in large-scale manufacture for the in-line concentration of significant volumes of process streams to allow them to fit in
the confines of existing intermediate product hold tanks. The premise of the system is shown in Figure 1—flat sheet membranes
are manifolded together to create a serpentine flow path of progressively smaller membrane areas. This maintains the cross-flow
across the membranes while the feed stream volume (and hence volumetric flow rate) is reduced.
Figure 1. A diagrammatic representation of a stack arranged in single pass mode. The stages are separated by special silicone
gaskets, which are displayed here in dark grey to add clarity. 3 x 2 means 3 cassettes in parallel, 2 cassettes in series.
Because the operation is pressure driven, the stack can be arranged as an in-line filter and controlled through the inlet
and outlet pressures or flow rate. In this analysis, the operation of such a rig becomes part of the transfer of product from
one unit operation to the next and, as such, has no impact on the processing time.
Ultrafiltration processes for the production of MAbs have typically been used to concentrate the product and diafilter it
into a buffer suitable for the next processing step. Because of the conventional wisdom that separation ratios of 10:1 (retained
solute molecular weight to transmitted solute molecular weight) are necessary, the industry has paid relatively little attention
to the abilities of ultrafiltration membranes to purify process streams. Many researchers have shown that by controlling the
hydrodynamic operation and build up of the fouling layer and the feed stream conditions, this ratio can be greatly reduced
and even reversed.5–7 It has also been demonstrated that charged membranes can achieve two-dimensional separation, although there are currently
few such membranes available on the market.8
Commercially available membranes have been used to avoid the complex wash buffers required by high-capacity Protein A resins
when combined with a membrane process performed under appropriate conditions using no more automation than is available with
an existing ultrafiltration rig. Because these wash buffers are not suitable for in-line dilution, they can become a limitation
to plant throughput. Therefore, including an additional unit operation in a process can actually improve plant throughput.