Biopharmaceuticals differ significantly from chemically produced pharmaceuticals in terms of complexity, size and requirements for processing technologies. Therefore, the biopharmaceutical industry utilizes microbial or animal cell culture technologies to produce these biopharmeuticals. Biogen uses mammalian cells as expression system for production.
The production of biopharmaceuticals requires state of the art processes and technologies and is strictly regulated by health authorities. A large and highly qualified staff is required to operate the equipment and control the manufacturing process to ensure product quality.
Since the biopharmaceutical manufacturing of proteins and antibodies utilizes mammalian cells with specific characteristics it differs sharply from traditional chemical production. The production occurs in large scale bioreactors utilizing customized liquid nutrient solutions. The cultivation conditions are usually close to physiological conditions – for example the culture temperature is controlled at 37 degrees Celcius, a sufficient supply of oxygen is guaranteed and pH is controlled. Operating pressures rarely exceed a few bar.
Flammable organic solvents and toxic substances are usually not found in biotechnological production because both the manufacturing cells and the protein products are only stable in an physiological environment. As a result, biotechnological production poses no substantial environmental risks when compared to chemical manufacturing.
Four-step production
Production in the next-generation biologic manufacturing facility in Luterbach will encompass multiple steps:
- Inoculation and seed train operations: Since Biogen’s biopharmaceuticals are produced from mammalian cells, a large number of these cells is needed for production. In the inoculation and seed-train operation, the mammalian cells are grown in specific cultivation vessels and bioreactors of various sizes in order to create a large number of cells that are suitable for manufacturing the product.
- Production Culture: During this production phase, the cells produce the desired product in the final large-scale bioreactor (volume of 18,500 liters). Typically, the cells are fed at regular intervals with nutrients that they need for growth and for the production process. This is known as a fed-batch process.
- Purification: In order to ensure for the product to be used in humans, very high purity levels are required. During the purification phase, the product is separated from cells and impurities are removed in a series of purification steps until the final purity specifications are guranteed.
- Formulation: In this step, the product is converted into a stable form and transferred into specific containers in which it can be stored for extended periods of time. This is the form in which the product is then transported for final processing, which involves filling it into a suitable devices or containers (often a vial or syringe), labeling and packaging. These final steps are performed at a different facility.
The entire manufacturing process from the start of the seed train to the final product takes many weeks, mostly because mammalian cells grow slowly compared to bacteria and it takes a long time to create enough cells to make large quantities of product in the final bioreactor. For this reason, modern biomanufacturing facilities have several bioreactors that gradually feed into one purification unit. At Biogen’s new facility, one manufacturing cell has four production bioreactors that supply one purification unit.