Mastering Process Development: Six Months from Transfection to Pilot

In biomanufacturing today, there is increasing focus on improving process development. The goal is to accelerate development and reduce costs, without compromising the ability to scale up to a robust commercial process later on.

One company that seems to have gone a long way toward mastering these challenges is Wyeth.

At the American Chemical Society conference in August, Wyeth’s Jeff Deetz talked about what his group has done to achieve these goals. He was there to accept the Biochemical Technology Division’s Industrial Biotechnology Award on behalf of Wyeth BioPharm Development, where he is vice president of Technology and Innovation.

“We invested in a lot of steel early, so now we have to make the most efficient and effective use of it,” he said. “We want to ensure that we can supply future market growth and new product introductions without having to build more facilities.”

In its quest for efficiency, Wyeth’s process development group has taken several different tacks. One of these has been placing a strong emphasis on standardization for their antibody-dominated pipeline. That standardization includes not just platforms for specific unit operations-such as upstream and downstream processes, raw materials, buffers, and resins-but also work processes like cell line screening and selection, and how much time is invested in process development at each stage.

“We don’t keep optimizing a process before it’s known if the molecule will go forward into Phase 3,” he said.

The result is several rounds of “hurry up and wait” as they rush to develop a process to a required level of robustness for a given stage in product development, then wait to see if the molecule makes it to the next stage.    

For the first round, the internal standard is to go from transfection to pilot in six months. Then, after a one-month pilot to provide materials for toxicology studies, the team  invests another 10 months to manufacture clinical materials and prepare the IND filing. Only if the product makes it to Phase 3 do they go through another round of “enhanced” platform process development.

Wyeth’s ability to meet these deadlines is also the result of the company’s investments in science. One example has been the development of a defined cell culture medium, balanced to eliminate lactic acid inhibition, which allows for high cell densities and consistently yield high titers. High-throughput screening for cell line selection, purification conditions, and drug product formulation also speeds up the work.

The need for process development excellence was driven both by the company’s focus on antibodies, which require high productivity, and a growing pipeline. In 2004, Wyeth had 31 biotech products at various stages of development. By 2007, that number had grown to 57.

As a next advance, Wyeth’s process development team is using transcriptomics, proteomics, and metabolomics to select or engineer better production lines. They are also working on “manufacturing process intensification” to minimize the consumption of water, media, and buffers, and to reduce the upstream process volumes that have to be purified. “There is a lot of interest in the facility of the future, which includes disposables,” Deetz said.

In the future, the trend toward antibody fragments also may require that the group revisit some of its platforms.

“If we have an antibody fragment that does not include the Fc portion, which is what binds to Protein A, we would have to adapt our downstream platform,” Deetz said.