Patrick L. Heider

End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation†

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

Rapid Flow‐Based Peptide Synthesis

A flow‐based solid‐phase peptide synthesis methodology that enables the incorporation of an amino acid residue every 1.8 min under automatic control or every 3 min under manual control is described. This is accomplished by passing a stream of reagent through a heat exchanger into a low volume, low backpressure reaction vessel, and through a UV detector. These features enable continuous delivery of heated solvents and reagents to the solid support at high flow rate, thereby maintaining maximal concentration of reagents in the reaction vessel, quickly exchanging reagents, and eliminating the need to rapidly heat reagents after they have been added to the vessel. The UV detector enables continuous monitoring of the process. To demonstrate the broad applicability and reliability of this method, it was employed in the total synthesis of a small protein, as well as dozens of peptides. The quality of the material obtained with this method is comparable to that for traditional batch methods, and, in all cases, the desired material was readily purifiable by RP‐HPLC. The application of this method to the synthesis of the 113‐residue Bacillus amyloliquefaciens RNase and the 130‐residue DARPin pE59 is described in the accompanying manuscript.

The application of an automated plant-wide control strategy for a continuous pharmaceutical pilot plant

Continuous manufacturing has the potential to provide substantial improvements to the manufacturing of pharmaceutical products compared to traditional batch-wise manufacturing. A key challenge is the development of effective control strategies for this new type of process. This contribution presents the experimental application of an automated plant-wide control strategy for a continuous pharmaceutical pilot plant that produces a pharmaceutical product from start to finish in a continuous fashion. The performance of the automated control loops demonstrate the maintenance of the critical material attributes close to their desired setpoints for a sustained period of operation.