FILTER SELECTION
For a CMO which manufactures a wide range of biomolecules, key attributes for choosing a single-use TFF filter system were
suitability for cGMP manufacturing, cost, type of filter membrane, a large product line for both pore size and filter area,
and an option for a completely single-use flow-path. The Sius single use TFF system from Novasep addressed all of these points
and was thus chosen for experimental evaluation. These single-use cGMP TFF cassettes cost approximately one-fifth of typical
re-usable TFF cassettes, but use the same type of membrane chemistry (modified polyethersulfone [PES]) common to many other
filter applications and have a favorable flux performance when compared with traditional multi-use filters (3). In addition
to the standard mPES membrane (Prostream), a more hydrophilic version of the mPES membrane (Hystream) was also available for
challenging applications, such as very high final protein concentrations and particularly hydrophobic proteins. As a CMO with
both clinical and large-scale commercial manufacturing capabilities, a notable feature is that the vendor's re-usable TFF
cassettes are available with membranes identical to the single-use product (cassette construction methods distinguish the
single-use and reusable systems). This complete scalability provides a low-risk means of transitioning to re-usable filters
later in a product's lifecycle, if the protein therapeutic were to eventually need large-scale manufacturing where the economics
are more favorable for re-usable systems (2). Membrane pore sizes range from 1 kDa MWCO to 0.65 µm, and standard cassette
sizes range from 0.01 to 2.5 m2. This complete product offering provides the means of establishing a platform TFF process with built-in flexibility to handle
a wide range of client proteins. For the early stage clinical programs typical for the PF1 facility, rapid and economical
process development is usually an objective, and simple platform processes are one means of achieving this. Finally, although
the single-use TFF cassettes are compatible with traditional cassette holding devices, an optional single-use flow-path insert
is also available that provides the same type of sanitary connections. The disposable filter plate insert, made of USP Class
VI polypropylene, isolates the process fluid from contact with the clamping surface of the cassette holder, facilitating product
changeover and eliminating sanitization of the cassette holder as a process step.
Figure 2: Example of a single-use flow-path. A) Flow-path insert. B) Flow-path insert assembled with tangential flow filtration
(TFF) cassettes in nonproduct-contact stainless-steel holder. C) One example of a complete single-use flow path using a bioprocessing
bag as a retentate reservoir. Note: PT is single-use pressure transducer, FT is flow transmitter, TT is temperature transmitter,
Cd is conductivity sensor. D. Cost savings of single-use TFF relative to traditional multi-use TFF as a function of total
number of production batches (i.e., the number of times a multi-use filter would be used) and the degree to which single-use
technology is incorporated into the TFF system. Cassettes only: Sius single-use cassette as a straight replacement for a re-useable
cassette with a standard flow-path. Cassette + PFI: Sius filter cassette and single-use flow-path insert together as a replacement
for a standard filter. Complete flowpath: Single-use components for all product contact surfaces in the entire system used
to perform TFF. Assumptions for single-use cost savings: filter costs are 80% lower, labor is 60% lower, and buffer/water
for injection usage is 75% lower. As the Sius filter is provided presanitized, buffer usage assumes that pre/post sanitization
is not performed, although for re-useable flow path options, sanitization of certain components may be required and savings
for buffer usage may be somewhat less.
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Besides the filter itself, decisions were also required on the other components of the system that would be evaluated. Because
product changeover considerations were a key driver for single use TFF in PF1, a system consisting entirely of single-use
product-contact surfaces was the ultimate goal, including product containers, retentate reservoir, pump head and/or tubing,
and in-line sensors, as well as the TFF cassette and flow-path insert. Such a system is readily achievable with current technology,
although for this evaluation, the single-use sensors were omitted from the otherwise completely single-use flow-path. This
omission was to avoid the additional complexity in a cGMP setting of requiring metrology to simultaneously transition to new
sensor technology. A subsequent stepwise transition to fully single-use product contact surfaces is relatively straightforward,
as both single-use sensors and flow-path components use compatible connections. Including additional single-use components
does affect the economics of TFF operations to a single-use system. It was previously demonstrated that single-use TFF filters
alone (i.e., in a re-usable flow-path) had a cost advantage over re-usable filters for filter areas up to at least 3 m2 (2). This advantage is true for any number of annual production batches, although the cost advantage increased significantly
when campaigns were fewer than about five batches. For much larger filter areas, the effect of filter costs becomes more
significant than labor, so the single-use cost advantage was specific for short manufacturing campaigns. When adding a single-use
flow path into the equation (see Figure 2), overall costs are increased but are still favorable over a re-usable system for
the typical clinical campaign of two to five batches, the primary clients of the PF1 facility.
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