The main benefit experienced through implementation of EMD Millipore's single-use facility is reduction in changeover time,
which delivers increased flexibility within the production facility. The changeover time for our 200-L seed bioreactor has
been reduced from greater than 24 hours for our stainless-steel bioreactor to less than three hours. Also, set-up times are
significantly reduced; for example, a TFF step that previously took at least 12 hours and required a 12-hour shift can now
be done in less than 7 hours for exactly the same process, just by using the single-use equipment.
With single-use technology, capacity can be increased very quickly by adding new bioreactors and, in addition, capitol costs
are significantly lower. For example, a new bioreactor can be in installed for under €350,000 ($451,000). With single-use
technology, one can increase capacity within two to three months rather than the 6 to 12 months typical for a stainless-steel-based
With a single-use facility, if a bigger filtration system is needed, for example, one that has been validated for use in the
facility, it can simply be wheeled in without the need to reengineer the room or utilities. Within a fixed stainless-steel
plant there is limited flexibility and it is much more difficult to make modifications.
With increased speed in changing out from one batch to another, multiple small batches can be run through an existing facility,
so scheduling within the manufacturing plant becomes less of an issue.
Another benefit of single-use technology is the ability to develop a process in one location and then when a facility is ready,
easily move the equipment to that second location. With single-use technology, process development can be conducted in parallel
with construction of the new facility. Traditionally, with a stainless-steel facility, everything is done in series, and very
little can be done in parallel. In an off-line location, a process can be developed using the equipment and once the production
facility is ready, equipment is dropped in, plugged into the wall for the air and the electricity, and effectively it is up
Single-use systems have a limitation of 1000 to 2000 L and scaling beyond that would typically incorporate either traditional
stainless steel or a hybrid approach. EMD Millipore has taken the same approach to scaling up the single-use systems as it
would for stainless steel. Predesigned systems make this approach easier, where one designs the experiment around the systems
rather than designing the systems around the experiment. When designing the Martillac facility and the processes that are
run in it, engineers defined a set of operating ranges and targets that were not scale dependent.
A number of best practices can be applied when considering implementation of a single-use process train. To begin with, it
is necessary to think differently about how the facility will be run and what the facility must do. The traditional approaches
of engineering are not necessarily applied. The designer must consider how to get flexibility, how to move equipment in and
out of rooms and maintaining the integrity of those operations—as an example. In designing the facility it is some of the
simple things that can make a big difference. At Martillac, the same utility panels (i.e., gases, power, water) are installed
in the upstream and downstream suites to reduce maintenance and provide manufacturing flexibility. The sizes of doors and
corridors and systems are aligned to enable bioreactors to be moved between the suites.
Another consideration is how the manufacturing process will be scaled up: by leveraging larger bioreactors or replicating
the manufacturing process by adding more production lines? And then, will that process be run in one location or in multiple
SINGLE-USE AND TEMPLATED PROCESSES
In addition to implementing a full single-use process train, EMD Millipore leveraged a templated downstream process for monoclonal
antibody (mAb) production at the facility. This approach reduced process development time, reduced the time and effort required
for equipment specification and procurement, and most importantly, enabled these activities to be conducted in parallel, thus
shortening overall project timelines. The process template was designed for both laboratory and production scale. A scaled-down
version of the system was developed to confirm that the processes will scale from 3 L to 50, to 200, and 1000 L; that model
enables parallel process development and a rapid move into the production environment.
The templated process helps optimize integration of the purification technologies. For example, there must be a good fit between
clarification and the capture protein A step. The right processing conditions then ensure that when the protein A is eluted
off, it is done at the right concentration and pH to enable for viral activation, and then with minimal adjustment in processing
can move straight into the ion exchange purification, for example.
The systems must also be flexible to be sized appropriately. Typically at this stage, the preclinical and phase one materials
have expression level ranges from less than 1 g/L to up to 3 g/L. The single-use systems need to be connected in such a way
that they are flexible enough to change the size of the chromatography column or the size of the filtration system depending
on the output of the bioreactor.
The advantages of applying a template approach to the downstream processing of mAbs are well known and include standardization
of unit operations, buffers, certain operating parameters, and equipment. This standardization allows streamlining and minimizing
process development, rapid scale-up, and facilitation of technology transfer.
In the development of clinical supply, speed is more important than creation of a fully optimized process. Clearly, the process
must deliver material of acceptable quality, yield, and purity but optimization for a commercial process can be left until
the molecule shows promise in the clinic. As such, a pragmatic approach to minimize time and effort makes sense.
Such an approach can be facilitated through a combination of single-use technologies and a template approach to downstream
processing in which operating parameters can be preselected to reduce process development efforts. This approach is expected
to be of value for smaller, emerging drug manufacturers who are unlikely to have the extensive experience needed to establish
a downstream processing template. Furthermore, use of prepackaged devices, systems, and ancillaries can reduce the time and
effort required for specification, procurement, and installation.
In the approach described here, devices and operating parameters were preselected based on experience. In doing so, the number
of devices and parameters to screen was effectively reduced. Preconfigured standard systems reduce the specification, delivery,
and implementation time and effort. The risk element is considerably reduced through use of well-established protocols, data
collection, analyses, and scale-up tools.