Learning from Vaccine Production
Many of the lessons learned in vaccine production could also be applied to monoclonal antibody manufacture, according to Alfred Luitjens, senior scientist, upstream process development at Crucell. He spoke of how the company is dealing with the need to manufacture a new TB vaccine for the global market because the old BCG vaccine is not effective.
Crucell, in collaboration with the Aeras Global TB Vaccine Foundation, has been developing an improved vaccine, now in Phase II, using recombinant adenoviral technology. The product is being manufactured in its PER.C6® human cell line.
Crucell knew that a scale-up to 10,000 L capacity would be needed at the original productivity of the process, in order to meet the demand for 100,000 to 200,000 doses a year. It wanted to fit the process into its existing facility, however, and chose to focus upon intensifying upstream and downstream processing to boost productivity, rather than merely scaling up.
The result is the iMAP (intensified manufacturing for adenovirus production) program, whose upstream elements include intensified PER.C6 production, large volume high density cell banks, and intensified virus production with adjustment of medium formulation to decrease the volume used.
Comparing standard production with iMAP reveals a decrease in process time from 44 days to 22 days and a decrease in cycle time from 14 days to seven days. In addition, the process can be carried out in a 1,000 L bioreactor, which, according to Luitjens, brings Crucell close to the goal of a 10–20 fold intensification of its manufacturing process.
Also of note were comments by Alahari Arunakumari, Ph.D., senior director at Medarex, about how increased titers required more attention to be given to downstream clarification processes. Medarex has found that a combination of depth filtration, tangential flow filtration, and centrifugation can be helpful here.
Non-protein A purification with combinations of columns and membranes is also being developed. Meanwhile, Ying Gao, Ph.D., research associate at MedImmune, spoke about how various software tools for COG analysis can help assess the cost of alternative purification strategies and contribute to short-, medium-, and long-term production planning.
Finally, manufacturing in all biopharmaceutical sectors is under increasing pressure to be green, lean, and clean. Flemming Junker, Ph.D., vp biopharmaceutical product supply, Novo Nordisk, spoke about how green manufacturing works at his company.
In 2003, Novo Nordisk set up a climate action program. “Climate change is our business and should be for all companies,” he said. “We need to do something about this, to mitigate the emission of carbon dioxide. It’s good business, because if we are not sustainable, then the price of energy will increase.”
At Novo Nordisk the aim is to decouple economic growth from a rise in carbon emissions. The company joined with the World Wildlife Fund’s Climate Savers Initiative in Denmark and set a goal of decreasing carbon emissions by 10% in 2014 (compared with 2004 figures). “A lot of people said this was not possible,” observed Dr. Junker.
Novo Nordisk approached its goal by looking at how overall production could be made cleaner by doing a deal with the Danish Oil and Natural Gas Organisation (DONG) where energy savings were earmarked for buying green energy and by identifying and implementing energy saving projects with a payback time of five years or less. The company’s efforts have already enabled DONG to build more wind turbines in the North Sea.
According to Dr. Junker, by 2014 all Novo Nordisk’s Danish production sites, including bulk insulin production, will be 100% powered by green electricity. He attested to the importance of small changes such as centralizing WFI production, using condensate for heating, other changes in the cooling systems, and regular leakage tests, in helping to achieve green manufacturing goals.
Responding to a question, Dr. Junker admitted that the environmental aspect of steel versus disposables was a difficult one for the industry. The chair of this session, Prof. Alois Jungbauer, head of the downstream processing group at the Austrian Center of Biopharmaceutical Technology, commented that most of the items used in lab work are disposable these days and these pose an environmental issue that is hardly ever discussed.