The manufacturing of recombinant protein is traditionally divided in two main steps: upstream (cell culture and synthesis of the target protein) and downstream (purification and formulation of the protein into a drug substance or drug product). Today, cost pressure, market uncertainty and market growth, challenge the existing manufacturing technologies. Leaders in the field are active in designing the process of the future and continuous manufacturing is recurrently mentioned as a potential solution to address some of the current limitations. This review focuses on the application of continuous processing to the first step of the manufacturing process. Enabling technologies and operation modes are described in the first part. In the second part, recent advances in the field that have the potential to support its successful future development are critically discussed.

Polyethylene furanoate (PEF) represents a promising renewable resource-based bioplastic as replacement for fossil-based polyethylene terephthalate (PET) with improved material properties. However, the synthesis of PEF through conventional polycondensation remains challenging, since the time-intensive reaction leads to degradation and undesired discolouration of the product. Here we show the successful rapid synthesis of bottle-grade PEF via ring-opening polymerisation (ROP) from cyclic PEF oligomers within minutes, thereby avoiding degradation and discolouration. The melting point of such mixture of cyclic oligomers lies around 370 °C, well above the degradation temperature of PEF (~329 °C). This challenge can be overcome, exploiting the self-plasticising effect of the forming polymer itself (which melts around 220 °C) by initiation in the presence of a high boiling, yet removable, and inert liquid plasticiser. This concept yields polymer grades required for bottle applications (M_n > 30 kg mol⁻¹, conversion > 95%, colour-free products), and can be extended to other diffusion-limited polymer systems.

The checkpoints for polymer nanoformulations from synthesis to clinic application are proposed as guidelines to develop safe and effective therapeutics.