Downstream Processing in Biopharma

Ensuring the Yield, Safety and Quality of Large Molecule Therapeutics

Biopharmaceutical downstream processing (DSP) refers to the isolation, purification and concentration of a previously synthesized drug substance or other product from a complex bulk matrix – e.g. animal or bacterial cells – once cell growth and expansion are complete. It is typically used in mAb or protein processes, as well as in the manufacture of oligonucleotides, polysaccharides and vaccines.

Downstream processing involves many steps before isolation, purification and concentration of the end-product is complete. It may also include formulation, enabling the transition from drug substance to drug product, as well as resource management and management of multiple waste streams and biohazards. Process Analytical Technology (PAT) and Manufacturing Science and Technology (MSAT) teams focus on process optimization, scale-up and troubleshooting, transforming day-to-day DSP activities performed at laboratory, pilot and manufacturing scales.

DSP generally includes a combination of the following steps, depending on the nature of the product and the method of synthesis:

Harvest and filtration

Separation of the product from bulk debris while optimizing retention of yield and quality.

Primary capture

Capture of the desired product with retention of minimal impurities and by-products. 

Buffer exchange and up-concentration

Comprises ultrafiltration (UF) – concentration of a dilute product stream and separation of the molecules in solution based on membrane pore size or molecular weight cut-off – and diafiltration (DF), the exchange of products from an existing buffer into a new buffer for a subsequent process or a final formulation buffer.

Purification

The removal of residual impurities while minimizing any potential loss of yield.

Bioconjugation (molecule dependent)

Bioconjugate molecules are a new class of biologics, designed to increase efficacy through the combined function of two or more molecules with different mechanistic actions. Antibody-drug conjugates (ADCs), synthesized by biochemically modifying an antibody and covalently linking it to another active pharmaceutical ingredient (API), are among the more common bioconjugates.

Formulation

The transition from a drug substance into a formulated drug product suitable for clinical administration.

This guide discusses how PAT can help laboratories transform their daily workflows and make significant improvements to DSPs. Topics include:

• Protein concentration monitoring

• Buffer exchange process optimization

• Vaccine adjuvants composition, distribution and morphology

• Automation of viral inactivation

• Bioconjugation process development