Step 1: Cell Culture Development
How do the cells get into the cell bank?
- At the beginning of each process development phase, one needs a production cell line or strain that is able to express the protein of interest.
- Genetic engineering is employed to produce cell lines and strains that are genetically stable, that grow to high densities in a tank environment, and are highly productive. These cells or strains are then frozen in hundreds of vials and stored.
- The process begins when a vial of cells is taken from the cell bank.
- Those protein-producing cell lines grow and divide, and subsequently express the product.
- Cell culture processes initially developed at a small 'lab scale' are refined and optimized to be consistent, precise and reproducible at a larger 'pilot scale.'
- The most effective methods are identified, seed train procedures and other protocols are developed, and the parameters repeatedly optimized—thus establishing the upstream manufacturing process.
Step 2: Harvesting
Developing efficient methods for product separation
- Once the antibody has been produced, it must be harvested from the cell culture fluid.
- In the harvest suite, methods such as standardized centrifuge technology are utilized. By taking advantage of gravity, centrifugation physically separates the solid (disposable) cell culture component from the liquid (antibody-containing) component.
- As with other equipment in our pilot and large-scale manufacturing facilities, harvest centrifuges are mounted on skids, allowing for easy replacement as technologies advance.
Synergies shorten timelines, lower costs, and minimize risk
- The pilot and large-scale manufacturing facilities are designed and built with comparable specifications. Everything is identical, though on a different scale.
- This consistency allows for seamless, trouble-free scale-up, minimizes process and site change risk, and facilitates technology transfer—with the goal of enhancing manufacturing quality and efficiency.
Step 3: Purification
Refining the procedures that eliminate impurities
- Once the biologically active antibody product has been harvested, impurities must be removed.
- Impurities are separated out in the purification suite. Multiple process operations are employed that are designed to take advantage of variations between antibodies (products) and other unwanted molecules (impurities)—including differences in bioaffinity, charge, hydrophobicitiy, and molecular size.
- Most often, downstream processes combine filtration and chromatography in a sequence designed for operational simplicity and optimal performance.
A standardized platform simplifies manufacturing
- Because of the nature of the antibody molecule, it is possible to 'industrialize' antibody manufacturing, creating in essence an 'antibody assembly line' or standardized platform.
- This is in contrast to the manufacture of other therapeutics, where manufacturing procedures must often be developed from scratch.
- Process development, analytical assays and batch records are just a few examples of the programs and processes that need to be standardized.
- Such standardization is instrumental in shortening timelines, reducing capital costs, lowering the cost of goods, and augmenting the chances of technical success.
Step 4: Fill and Finish
Determination of an ideal formulation
- Antibodies must be stored in a stable environment for the product to remain potent. Typically, antibodies are stored in a formulation buffer, which is poured into sterile glass vials.
- Liquid formulations are often used since they are relatively simple and inexpensive to produce. The alternative is a powder formulation, which is produced via lyophilization (freeze-drying), a process that can deliver a more stable product but is generally more difficult to develop.
Parallel development processes maximize efficiency
- To maximize efficiency, as new antibodies enter the pilot stage sample material is simultaneously provided to the cell culture, harvest purification and fill and finish groups.
- This allows us to develop multiple processes in parallel, and results in…
- … shortened timelines and a more rapid entry of the antibody into manufacturing operations.
Step 5: Commercial Scale
Consistencies enable seamless scale-up
- When transferring an antibody to our large-scale manufacturing facility, processes can be scaled up to volumes in the order of 15,000 liters.
- Multiple synergies (equipment, technologies, procedures, protocols) greatly simplify this scale-up process.
- Our pilot and large-scale facilities rely on proven equipment, standardized platforms and integrated quality control.
At Boehringer Ingelheim BioXcellence™, we are in a unique position to shorten timelines, lower costs, enable technology transfer and minimize the risk inherent in the antibody and recombinant protein manufacturing process.