For synthetic APIs, increasing attempts to move from traditional batch to continuous manufacturing are ongoing. Advantages besides lower CAPEX und OPEX are in particular higher product safety by enhanced process robustness, smaller foot print of the plants, lower cleaning costs and downtimes due to dedicated modular and flexible plants.
In manufacturing of biomolecules these concepts have so far only been applied for high-volume bulk or fine chemicals. However, with the upcoming cost issues in the manufacturing of biotherapeutics by low cost biogeneric manufacturers and stratified medicine scenarios, first approaches to industrialize continuous manufacturing for biologics like amino acids, peptides, proteins and monoclonal antibodies and fragments, are under investigation.
For the production of biopharmaceuticals, e.g. monoclonal antibodies, fermentation is already more often used in a continuous perfusion mode than is known to the public. Therefore, it is only consistent to apply continuous process concepts also for Downstream Processing operations. However, until recently the necessary unit operations and corresponding equipment has not been available. This is currently
undergoing through a substantial change. Besides a broad variety of continuous chromatography applications with or without protein A, also older well known unit operations like liquid-liquid extraction processes based on ATP (Aqueous-Two-Phase) systems or precipitation by aid of suitable auxiliaries have become available and begin to find their place in a full continuous process scheme.
To accelerate slower unit operations better system performance, e.g. in chromatography, rod- or radial chromatography columns together with modern packings, as well as membrane adsorbers in IEX- or HIC-mode are available or under development.
The role of single-use (SUS) / disposable concepts, which are more and more applied also in industrial scale up to 2000 L volumes, in a fully continuous operation have yet to be defined. Their fields of use will depend on an individual processrelated economic assessment.
New developments in manufacturing equipment, including analytics, as well as new process design concepts based on QbD-approaches can only be successfully integrated into efficient, reproducible, and robust continuous processes by the combination of modeling and simulations
with laboratory-scale experiments.