TANGIBLE BENEFITS

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 facility.

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 and running.

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 locations?

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.