Downstream Processing in The Development of Biopharma

Downstream processing of biopharmaceuticals (also known as DSP) refers to the recovery and purification of drug substances (DS) from natural resources such as animal or bacterial cells. Biopharmaceutical downstream processing is suitable for monoclonal antibody or protein processing, as well as the manufacture of oligonucleotides, polysaccharides and various vaccines.

Downstream processing is generally defined as the unit operations following the completion of cell growth and expansion, and the completion of drug substance synthesis or other product formation. The purpose of downstream processing is to separate, purify and concentrate previously synthesized drug substances or other products from complex bulk matrices.

Downstream processing may also include formulation activities, marking the transition from drug substance to drug product (DP). In addition, downstream processing considerations include resource management and management of various waste streams and biohazards. Depending on the nature of the product and the method of synthesis, downstream processing (Dsp) typically involves a combination of the following steps:

Harvest and filtration: Harvest is the first step in separating product from bulk debris while optimizing product yield and quality retention

Primary capture: Capture refers to retaining the desired product while minimizing the retention of impurities and by-products. It differs from "harvest" in that basically all bulk debris has been removed.

Buffer exchange and concentration: Ultrafiltration (UF) concentrates the diluted product stream and separates molecules in solution based on membrane pore size or molecular weight cut-off. Diafiltration (DF) exchanges product from existing buffers into new buffers for subsequent processing or final formulation buffers.

Purification (and removal of contaminants or impurities): Purification removes residual impurities while retaining as much product as possible through each continuous process employed. The goal is to achieve product purity while minimizing potential yield losses.

Bioconjugation (molecule dependent): Bioconjugates are a class or new generation of biomolecules designed to achieve greater efficacy through the combined function of two or more different therapeutic types of molecules. Antibody-drug conjugates (ADCs) are one of the more common bioconjugates, synthesized by biochemically modifying an antibody and covalently linking it to another active pharmaceutical ingredient (API).

Formulation: Formulation is the process of converting a drug substance (DS) into a dosed product (DP). Formulations transform product molecules from the environment, solvent, or other physical states into a form suitable for clinical administration.

The biopharmaceutical industry is adopting new technologies to gain greater process insight by successfully applying continuous processing methods and enabling comprehensive data capture and electronic record keeping. Through automated laboratory reactors, in situ spectrometers, particle characterization tools, and advanced software, Process Analytical Technology (PAT) allows precise control and comprehensive visibility into the optimization of downstream operations.