New technologies in upstream biopharmaceutical production continue to increase yields and protein product quantities at the bioreactor. However, these higher titers, larger yields, and shorter production times are not always making it through as end-product.
As improvements in upstream manufacturing continue to show results, the slower advancements in downstream purification have created a bottleneck (see GEN, January 1, 2006, p. 1).
The mass of product that needs to be recovered is getting higher and higher, says Joanne Beck of Abbotts (www.abbott.com) bioresearch center. The entire purification train is slowly becoming a bottleneck.
Biopharmaceutical manufacturing capacity and production purification problems are adversely affecting about 51% of biopharmaceutical developers and contract manufacturers, according to the 3rd Annual Report and Survey of Biopharmaceutical Manufacturing by BioPlan Associates.
As you get higher titers and lower volumes, youre going to get higher biomass to deal with as well, pointed out Duncan Low, Amgens (www.amgen.com) scientific director of process development at a conference of biomanufacturers in Boston. He noted that, in the 1980s, titers from 550 mg/L were common. In the future, volumes of 1020 g/L are expected.
However, an exponential improvement in titer volumes may not lead to greater overall efficiencies, because increased biomass will exceed the capacity of downstream protein purification, especially the chromatography and filtration steps. This will lead to repeat chromatography steps for high-volume bioreactor runs.
At a certain point, the number of chromatography cycles required will outstrip all the gains achieved by the greater bioreactor capabilities. Its mass-driven, explained Low. If you want to put 28 kilos in a column, youre going to need one thats twice as big as one that would take 10 kilos.
As Low suggested, downstream bottlenecks are raising industry eyebrows with the protein purification process receiving considerable attention. More than half of the respondents to the BioPlan survey of 187 manufacturers worldwide, indicated that there was an opportunity to improve this step. For an industry that has annual returns of $87 billion and depends on these downstream steps, success could result in millions more in returns.
Chris Conroy, Acambis (www.acambis. com) supervisor of viral manufacturing, agrees. He sees trouble on the horizon for protein purification. With these higher titers and more biomass, purification is going to become considerably more difficult in the future. Its simply harder to filter these volumes and put them through the columns.
In the production of most biopharmaceuticals, retaining the biological activity of large volumes of proteins and maintaining consistency is critical to manufacturing success. The high level of consistency required is both expensive and unwieldy. Moreover, the processes that are proven on the lab bench must work as well, scaled-up to the production floor.
Protein purification weighs in at about 50 percent of the workload of making and formulating the product, says Erica Shane, director of process biochemistry at Medimmune (www.medimmune.com). There is room for improvement, especially with cell cultures that have higher titers.
One manufacturer surveyed felt that the biggest problems in the capture step are the binding capability of the protein A and the specificity of protein A for Mabs. The multitude of different properties makes the pretreatment of the purified broth to the column a significant issue.