For a multiproduct cGMP manufacturing facility, measures to prevent risk of cross-contamination between products are a high
priority. Single-use technology can provide a simple method of achieving this goal for many processing operations (1). This
case study describes how the transition from multi-use to single-use tangential flow filtration (TFF) was evaluated and implemented
for a buffer exchange step in a 500-L production-scale recombinant protein manufacturing facility (PF1) at CMC Biologics,
a contract manufacturing organization (CMO).
A typical monoclonal antibody (mAb) or recombinant protein manufacturing process uses ultrafiltration/diafiltration (UF/DF)
by TFF for final product concentration and formulation of bulk drug substance (see Figure 1A). The primary criteria for such
a TFF system are suitability for cGMP, product compatibility, and reliable performance, including high yield and efficient
buffer exchange. Additional criteria of almost equal importance, particularly for a CMO, include rapid and predictable setup
and operation, a platform system with multiple filter options to accommodate a wide range of protein products, and low total
operating costs, including materials, labor, buffer usage, and overhead due to changeover between products. These last criteria
are particularly well addressed by single-use technology. A primary objective of single-use systems is to simplify and reduce
costs associated with product changeover, because cleaning and cleaning validation requirements are significantly reduced
when product-contact surfaces are discarded after use. Additionally, for TFF, total operating time in routine usage is reduced
through elimination of many of the steps required to clean and store membranes between manufacturing batches (see Figure 1B).
As re-usable TFF membranes are typically product-dedicated, the significant logistics of storing and tracking multiple use
TFF membranes for different protein products between manufacturing campaigns is completely eliminated by a single-use system.
The economics of single-use TFF technology are also favorable relative to re-usable membranes for intermediate-scale manufacturing
with relatively few batches in a campaign (2).
Figure 1: Process flow diagrams. (A) A typical process flow for a monoclonal antibody or recombinant protein. Ultrafiltration
and diafiltration (UF/DF) for buffer exchange is performed at the end of the manufacturing process for formulation of bulk
drug substance. (B) Processing steps for UF/DF by tangential flow filtration (TFF). Steps that differ between re-useable
and single-use filters are indicated on the right. Brackets on the left indicate processing times for pre- and post-use operations.
The PF1 cGMP manufacturing facility at CMC Biologics was designed for mammalian cell-culture processes up to 500-L production
scale based on single-use technology. Typical PF1 clients have clinical-stage protein therapeutics with a need for relatively
few (e.g., two to five) batches in a manufacturing campaign. Thus, between frequent needs for product changeover and favorable
economics for short campaigns, a single-use TFF system was an obvious fit. However, to streamline facility commissioning,
single-use technology was initially emphasized more heavily in upstream production and buffer preparation, allowing many of
the downstream purification operations to leverage existing equipment and methodology from the re-useable systems already
established in a parallel 3000-L production facility. Once the PF1 facility was in full operation, a strategic plan to transition
multi-use operations to single use was implemented, with the final TFF buffer exchange step being one of the first to make
the switch. The approach for transitioning was simple and straightforward. First, vendor descriptions were used to identify
a TFF system which would best meet the needs of a CMO, and then performance was evaluated in three stages: 1) demonstrating
suitability in scale-down models, 2) scale-up to a PF1 manufacturing process, and 3) assessing reliability over multiple runs
with multiple lots of TFF filters.