Experts in every stage

Upstream and downstream processing from Boehringer Ingelheim BioXcellence™

We work with a variety of different host cell and strain types, including cell culture and microbial organisms (bacteria and yeasts), producing a range of molecule types such as monoclonal antibodies, recombinant glycosylated and non-glycosylated proteins, peptides, antibody fragments, Fc-Fusion proteins, protein scaffolds and plasmid DNA.

Our platform solutions for monoclonal antibodies and tailor-made solutions use a large toolbox of manufacturing techniques, but most of them fall into two basic categories: upstream and downstream processing.

Upstream processing

The production of active pharmaceutical ingredients (API) of biopharmaceuticals typically starts with the ‘upstream process’ - generation of the API via living cells. It begins with mere milliliters of mammalian or microbial cells engineered to produce a specific molecule. Step by step, in the controlled environment of a bioreactor, these cultures are grown to a volume of several thousand liters to produce several kilograms of the desired API.

Mammalian cell culture

Mammalian cell culture is used to produce large, complex proteins like monoclonal antibodies. Using them allows for changes to the API - like those which may happen in human cells: glycosylation, for example. Mammalian cell production processes take several days or even weeks; growing them requires a complex and well-balanced mixture of nutrients as well as relatively gentle stirring and aeration.

Microbial Organisms

Microbial organism cultures can grow much faster, in days or even hours, producing smaller molecules like peptides, enzymes, antibody fragments and protein scaffolds very efficiently. Microbial organisms are usually very robust and can grow to high cell densities: generally, several orders of magnitude beyond mammalian cell cultures – but they typically have some limitations on the size of the protein and 'human-like' modification of the molecules.

After production of the desired molecule with the best suited organism, the product is separated from a complex mixture of host cell proteins, cells, cell debris, nutrients, and waste materials – which is known as the ‘downstream process’.

Downstream processing

This starts with separating the cells from the media. In most mammalian cultures, the protein is secreted into the media, and is collected for further purification. In microbial production, the protein can also accumulate inside cells, which need to be disrupted and the cell debris separated from the API. Insoluble product agglomerations known as inclusion bodies - including unfolded, pure proteins sticking together - must be refolded into the biologically active conformation.

A range of techniques are availble to purify the API, but chromatographic separation is widely used. Separation principles used for chromatography are based on charge, size, hydrophobicity, or by specific affinity of the API to the chromatographic resin. Impurities can also be removed using precipitation based on temperature, pH, or chemical interaction. Moreover, a wide range of filtration techniques are used to separate the protein from the remaining solids, remove impurities, and exchange buffers.

Meet the experts

Thanks to our decades of experience in developing, transferring and scale up of biological processes, utilization of cutting age modelling tools and state-of-the-art analytical methods, we can offer efficient platforms as well as customized solutions for a broad range of molecules, ensuring a fast and secure supply of material through the whole lifecycle of an API.