Dispruptive technology
Manufacturers of future high-titer mAbs will have the option of using traditional stainless-steel equipment, single-use equipment,
or a hybrid combination of the two. Availability of single-use bioreactors with working volumes of 1000–2000 L makes them
a compelling alternative as a production platform. In reality, the important issue is not stainless steel or single-use technology,
but rather how technologies can be combined to provide the most productive and cost-effective process. Choosing one or the
other technology concept depends on both strategic considerations and feasibility studies of each individual case.
Stainless steel.
A stainless-steel manufacturing facility for biotechnology products is based on well-known design principles originating
from the petrochemical and dairy industries, with additional considerations for cross-contamination prevention and sterility.
The facility is characterized by having a fixed piping and tank layout (mobile vessels are possible below the 1000-L scale).
Once the investment is made and the installation is finalized, the strategic safety of having all process equipment in-house
is obtained. Only a few dependencies for consumables and spare parts remain.
Stainless-steel technology is well suited for automation applied to improve safety, ergonomics, process reproducibility, and
to reduce training scope. Because instrumentation for cleaning and sterilization does not contribute directly to the production
process, the technology carries some overhead and requires significant maintenance and validation. Cleaning stations for utensils
and mobile tanks add to the complexity.
Single-use.
Compared with stainless steel, single-use technology has obvious advantages, primarily a reduced investment cost and an inherent
elimination of risk from cross-contamination because the product-contacting surface is disposed of after each batch. Piping
between process steps may be eliminated with plastic tubing and manual transport to move bag containers between process stations.
Working volumes as much as 3000 L for simple solution hold are available. Bioreactors with capacities as high as 2000 L have
been proven suitable for running many processes.
Being highly flexible, single-use technology can be reconfigured for a new process or product in a few days. Another important
feature is that installation is simplified because of a reduced need for cleaning and sterilization, which again translates
into reduced capacities for clean steam, clean-in-place, and waste collection and treatment.
Still, there are a number of challenges for single-use technology. The technology is less orderly, so the arrangement of tubing
must not interfere with operator activities, and process accuracy must be considered. The technology has limitations for demanding
mixing and heat-transfer applications. Large-range reliable single use sensors are just starting to become available.
The complexity of single-use technology is that the core process-contacting elements are essentially built up again for each
batch so instruction and training demands become more important factors. The flexible and more manual nature of processing
is also reflected in increased material handling and tracking challenges. For critical components, a dual-vendor strategy
is desirable but not always possible because not all single-use inserts will fit all supports or racks to hold them.
Feasibility considerations.
Estimating the economic prospects of single-use technology can be done with feasibility studies, which typically can be simplified
if specific cost of goods values are not required. It is important to consider the entire production scenario before simplifications
are made. In many cases, not including high batch-frequency operations, single-use technology is a more favorable concept.
Such is the case with respect to investment cost but also with respect to variable costs when the cost of the capital that
would otherwise go into the investment of the comparable stainless-steel operation is included. Amortization and interest
of stainless equipment over time must be added to variable costs, and many case studies will show that it exceeds variable
cost related to increased consumables for a single-use design.
Assumptions regarding the cost of cleaning chemicals and water for injection are often included in feasibility studies but
are seldom the deciding factor, because the cost is usually low compared with other consumables and cost of capital. It is
important to use cost data that reflect the scale of operation. Sometimes, estimates about reductions in operator time are
introduced in to the feasibility study. Although personnel costs are important, such estimates can be difficult to realize
in real life. It is a more conservative approach to state that operators may be freed up to improve process operation and
monitoring instead of handling cleaning processes.
Designing the next-generation facility
A new facility design paradigm arises from the combination of high-titer processes and single-use technology. Jagschies has
addressed the question of realistic estimates for future mAb product volumes (8). The viewpoint is that most products will
require less than 500 kg annually capacity with few products requiring as much as 1000 kg. Assuming 5 g/L titer and typical
process conditions places an annual output of 1000 kg within the reach of a facility based on six bioreactors with 2000-L
working volume. Not surprisingly, the 10+ fold yield increase over the titers from earlier times is reflected in a facility
housing significantly smaller bioreactors, thus paving the way for an upstream process based on single-use technology instead
of traditional stainless-steel technology.
Figure 2
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Figure 2 illustrates the conceptual differences between the traditional and the next-generation facility. The three-dimensional
model shows typical equipment simplistically lined up to compare floor space and room height between a traditional 6 × 20,000
L bioreactor facility and a single-use 6 × 2000 L bioreactor facility. The scenario illustrates that the next-generation facility
will exhibit both a reduced footprint and reduced building complexity by being able to fit into a one production-level facility,
because the bioreactors will not protrude through several levels.
This design would require in-line dilution of concentrated buffers and potentially a series of product pool bags for downstream
processing of the large product volumes arising from the individual bioreactor. Depending on production strategy, the volumes
involved also open up for supply of ready-made media and buffers. Therefore, the media and buffer preparation suites may be
eliminated from the facility or reduced significantly.
Compared with the traditional mAb facility, next-generation single-use facilities will be more generalized with a series of
process stations where utilities are presented and process equipment can be hooked up to form the required process. There
will be an added emphasis on logistics and workflows, resulting from changed requirements for storage, manual transport of
process liquids, and equipment, waste, and personnel flows.
Life in the next-generation facility
Automating single-use technology.
In changing from stainless-steel to single-use operation, manufacturers may lose aspects of the orderly process hook up and
the easy tracking of when actions and process events happened, when operators intervened, and when valves (clamps in the single-use
case) were opened and closed.
Figure 3
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As it stands, the state of the art for single-use technology, written procedures and training are the cornerstones to ensuring
the process remains reproducible. In this capacity, automation enables technology to create a type of comfort zone around
the low-automation level process step (see Figure 3).
As facilities go from pilot plant-scale to full-production scale, the industry will see automation strategies in which the
process itself is handled by the vendor-supplied local control and a central manufacturing execution system (MES) forms a
process support system guiding the operator through all steps necessary for the process (see Figure 3). Tracking and material-handling
technologies such as barcode systems are already available to ensure good housekeeping for materials, equipment, and new and
used consumables. The most recent development is that single-use items are also available with RFID tags.
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