Hybrid Modeling of the Reversed-Phase Chromatographic Purification of an Oligonucleotide: Few-Shot Learning From Differentiable Physics Solver-in-the-Loop.

Hybrid models integrate mechanistic and data-driven components, effectively addressing the challenges of limited process understanding and data availability typical of biopharmaceutical processes. In this study, we applied a hybrid modeling framework named differentiable physics solver-in-the-loop (DP-SOL) to describe the reversed-phase chromatographic purification of an oligonucleotide, overcoming the mentioned limitations of purely mechanistic and data-driven models. The framework establishes a connection between neural networks (NNs) and mechanistic models through differentiable physical operators and their gradients.

Model-based optimization strategy for intensification in the chromatographic purification of oligonucleotides.

Oligonucleotides (ONs) are acquiring clinical relevance and their demand is expected to grow. However, the ON production capacity is currently limited by high manufacturing costs. Since the purification of the target ON sequence from molecularly similar variants represents a major bottleneck, this work presents a resource-effective strategy for the optimization of their preparative reversed-phase chromatographic purification.

UV-based dynamic control improves the robustness of multicolumn countercurrent solvent gradient purification of oligonucleotides.

Therapeutic oligonucleotides (ONs) have great potential to treat many diseases due to their ability to regulate gene expression. However, the inefficiency of standard purification techniques to separate the target sequence from molecularly similar variants is hindering development of large scale ON manufacturing at a reasonable cost. Multicolumn Countercurrent Solvent Gradient Purification (MCSGP) is a valuable process able to bypass the purity-yield tradeoff typical of single-column operations, and hence to make the ON production more sustainable from both an economic and environmental point of view.

Role of the gradient slope during the product internal recycling for the multicolumn countercurrent solvent gradient purification of PEGylated proteins.

Protein PEGylation, i.e. functionalization with poly(ethylene glycol) chains, has been demonstrated an efficient way to improve the therapeutic index of these biopharmaceuticals.

Continuous countercurrent chromatographic twin-column purification of oligonucleotides: The role of the displacement effect.

Oligonucleotides (ONs) are breaking through in the biopharmaceutical industry as a promising class of biotherapeutics. The main success of these molecules is due to their peculiar way of acting in the cellular process, regulating the gene expression and hence influencing the protein synthesis at a pretranslational level. Although the Food and Drug Administration (FDA) already approved a few ON-based therapeutics, their production cost strongly limits large-scale manufacturing: a situation that can be alleviated through process intensification.