The Science Behind Next-Generation Biomanufacturing

A look at the key scientific and technical achievements that have enabled Amgen to introduce a new biotech manufacturing paradigm in Singapore and soon, Rhode Island.

High-Performing Cell Lines

The trillions of cells used in manufacturing a biologic medicine are all descendants of one cell line. It’s important to start with a cell line that offers the optimal mix of quality and quantity—robust cells that produce the desired drug molecule in abundance.

In the early decades of biotech, it was tedious and difficult to screen large numbers of cells in order to find the top performers. Innovations have since enabled us to engineer host cell lines that can reliably make large amounts of a quality product. Amgen now uses a proprietary expression system using unique plasmid vectors—loops of DNA that combine the product gene with expression-enhancing genes. This system allows us to pressure the cells into making multiple copies of our product gene, effectively transforming the cells into medicine-making machines.

Amgen also uses sophisticated cell-sorting technology and customized biomarkers, which can measure protein generation at a rate of tens of thousands of cells per second. This enables scientists to screen hundreds of millions of cells to find the outliers that are peak producers.

 

New Insights Into the Care and Feeding of Cells

Throughout the early decades of the industry, cells used in making medicines were nourished with animal serum or hydrosylates—plant matter treated with enzymes to produce a complex mixture of peptides and nutrients. These formulations supported cell growth, but they also made it more difficult to ensure a consistent process from batch to batch. Moreover, since these mixtures were too complex to define precisely, it was hard to assess how changes in the formulation affected the cell line’s performance. Newer processes employ chemically defined media, or nutrients that can be characterized precisely in terms of their chemical composition. Well-defined cell nutrition can provide important benefits including:

  • Precise testing of raw materials to reduce the risk of unwanted variations.
  • Experimenting with different formulations to optimize processes.
  • The ability to monitor the depletion of key nutrients and replenish them as needed.
  • Processes that are more robust and reproducible.
  • More reliable product quality.

 

Process Intensification

The yield from a process depends on how much protein a cell can produce, the number of cells that can thrive per volume of media, and how long the cells can survive. Earlier cell lines and processes were limited in the cell density they could support. When the density of cells in the bioreactor increased beyond a fairly low level, the environment inside became less conducive to cell survival. Consequently, the output of the desired protein would peak after roughly one week and then quickly decline.

Amgen has deployed new process intensification technologies to maintain an environment inside the bioreactor that enables more cells to thrive. These technologies, combined with more robust cell lines, can provide a five-fold or greater increase in the number of cells that can thrive on a per-volume basis. Other process modifications related to intensification can also help cells survive longer, further boosting how much protein a process can yield.

 

Quality by Design

The complexities involved in manufacturing biotech medicines gave rise to the view that “the process is the product.” In other words, to reliably make the same high-quality medicine time and again, you needed to execute the exact same process in all its details. This paradigm made it challenging to introduce improvements that would lead to more efficient or higher-yield processes.

That former view is giving way to a new understanding of how the process affects the product and how to control it to get good results. Novel insights from this shifting paradigm include a deeper grasp of a product’s key quality attributes, or the features of a molecule that most affect its efficacy and safety. Research has also helped to unravel the complex interactions between cell biology, cell nutrition, the bioreactor environment, and product quality.

 

Downstream Improvements

In the harvesting process, the protein is extracted from the cells and cellular debris and then purified. In current manufacturing plants, centrifuges are typically used to separate the cells and larger particles from the cell broth. But with newer processes that have high cell densities, using a centrifuge may lead to significant loss of the protein you’re trying to recover.

To advance the new manufacturing paradigm, Amgen is re-engineering the downstream process by adopting two technologies. One method helps to separate cells and particles while in the bioreactors so that the protein-rich broth can be siphoned from the vessel for further purification. Another method, filtration, uses specialized membranes to retain cells and debris while allowing the protein to pass through and be collected for final purification. Next-generation facilities are flexible and modular, so the equipment needed to implement either approach can be wheeled into place as needed.

 

Analytics of the Future

To ensure the quality of medicines, biotech plants conduct many tests across every step of the manufacturing process. These analytical tests are typically done in quality control labs, and it often takes days or weeks to get results. The old paradigm required more testing to ensure no deviation in any aspect of the process or product attributes. These are some of the reasons that quality testing has traditionally been reactive, expensive, and time-consuming.

Amgen has been pilot testing technologies that will make analytical testing more proactive, less expensive, and faster. Many tests once sent to labs can be shifted to the manufacturing floor, including real-time tests for endotoxin, protein concentration, water quality, and product titers. By developing deeper insights into the critical quality attributes of each medicine, scientists can design a leaner series of test that are focused on those key attributes.

These innovations can lower costs and cycle times and get medicines to patients more quickly. Timely test results and continuous process monitoring can also enable early correction of any process that is starting to veer off track. These improvements are being implemented in Amgen’s new Singapore plant, and many can also be used in Amgen’s established facilities.

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