April 15, 2005 (Vol. 25, No. 8)

Making Profitable Biopharmaceuticals a Reality

To continue to be profitable in the future, biomanufacturers should take some tips from the food business.

That was one of the take home messages at the recent “Biologicals Manufacturing Summit,” which was held in London and organized by Vision in Business (www. visioninbusiness.com).

“In the food industry, staff are asked to look at the overheads and reduce process costs by one to two percent every year,” continued Casper Leuenhagen, project manager from Diabetes API Manufacturing Development at Novo Nordisk (www. novonordisk. com).

“To improve biopharmaceutical yields and reproducibility from batch to batch and therefore reduce those overhead costs, I believe that process analytical technology (PAT) could play a key role.

“PAT is nothing new in the pharma industry. We have always been taking measurements throughout the manufacturing process but we have not been feeding the results back into the process soon enough.

“If this type of proactive approach is implemented across the biotech and pharma industries, the real business benefits of PAT will be felt because the cost of manufacturing will decrease significantly,” noted Leuenhagen.

To support his argument, Leuenhagen presented a case study from a recent Ph.D. project, where a fermentation run was continuously monitored using a grid of linear modeling so that fast corrective action could be taken. This meant the batch stayed within specification and was used rather than being thrown away when minor process deviations occurred.

Leuenhagen also discussed a second study where PAT was used at Novo Nordisk to control the mixing of active raw ingredients. This process had two manual steps, low yield repeatability, and no secondary control. But by using PAT with at-line near infrared (NIR) measurement as a secondary control to check the mixing of three raw ingredients and water, the process was reduced to one manual step and the yield reproducibility improved.

The study significantly improved the knowledge of the most important critical parameters. It also identified several programming errors in the control system, which were easily fixed and allowed batches to be saved after incorrect starting conditions were identified and quickly rectified.

“Using PAT you will always learn something you didn’t want to know about your process, but finding it out and correcting for it sooner rather than later will nearly always make your manufacturing cheaper,” concludes Leuenhagen.

Reducing Cycle Time

Other speakers at the summit pushed home the point that decreasing cycle times can also aid profitability. Friedrich Nachtmann, Ph.D., head of biotech cooperations at Sandoz (www.sandoz.com), presented data to show that by beginning the next primary protein isolation at the same time as the protein purification run, Sandoz could produce three batches of protein in 15 days instead of two.

“By making small investments and organizational changes in the plant we have reduced our cycle time from seven days to four and significantly reduced our manufacturing costs,” Dr. Nachtmann says.

Martin Wrankmore, continuous improvement lead at Lonza Biologics (www. lonza.com), proposed an alternative method of cutting down cycle time. Wrankmore presented a number of applications where the use of disposable technology is saving Lonza time with cleaning and cleaning validation, plus increasing process robustness.

For example, Lonza uses plastic tank liners and bioprocess containers to replace precleaned stainless steel tanks. The tank liners are used for cell culture medium and feed preparations and the bioprocess containers for medium, feeds, buffers, and sample collection.

In addition, there is also an increasing use of tube welding and disposable bioreactors. The tube welding is used to connect disposable to stainless steel reactors, and according to Wrankmore, using it saves more than two hours of traditional cleaning time.

The bioreactors replace two sets of inoculum fermenters, and although they have a 50-L capacity, are used like a large shake flask. To complete the upstream process, Lonza is also using disposable harvest systems for harvesting 200 L of fed batch fermentation.

“Using disposable technology in much of our upstream process is saving days of on-site preparation work so that we can decrease turn-around times, reduce the potential risk of product cross-contamination, and focus on product delivery,” says Wrankmore.

“The ongoing challenges we now face are an increasing reliance on our suppliers for delivery and flexibility in their design approach. We also have to carefully balance out the cost of the plasticware against the time and resources it would have taken to clean our process plant. However, due to the proven benefits of disposables to date, we are evaluating their use in our downstream purification processes.”

Mix and Match

At the downstream side of bioprocess manufacturing, Peter Levison, Ph.D., head of chromatography R&D, Pall Life Sciences (www.pall.com), believes that there are still ways of increasing profitability by expeditious use of purification technology.

Dr. Levison cited several examples where the use an oversized chromatography column could significantly reduce the protein purification time and in turn, the manufacturing costs. He also presented data to show that using membrane chromatography can reduce the purification time from hours to minutes.

Dr. Levison explains, “To make purification quicker it is always best to get rid of as much water as possible, as this is a major contaminant of most protein preparations. If the water is removed by a membrane chromatography capture step, then subsequent purification steps get easier to handle as there is less volume.

“In the future, we will see more and more use of an integrated sequence of process steps leading to an affordable process solution. Although membrane chromatography technology may appear more expensive per unit of capacity, these prepacked disposable units can frequently save so much time that it is a cost-effective investment.

“To get the optimum from a purification process it is often best to mix and match columns and membranes, as these are complementary technologies which will save a great deal of time if they are used together wisely,” Dr. Levinson concludes.

The Pressure is On

All the delegates at the “Biologicals Manufacturing Summit” agree that to improve profitability in biologicals manufacturing, biotechs and pharmas face a tough time as they will have to squeeze every last cent out of their manufacturing processes.

This will include having continuous monitoring methods in place such as PAT to improve yield, increasing the use of disposable technologies in the upstream as well as downstream processes, and reducing system down time.

“In the future process economics and process intensification are key drivers for change. Manufacturing will need to minimize down-time, and disposable technologies have a good application here, especially in CMOs,” Dr. Levison says.

“Optimizing the use of manufacturing plants will always increase capacity, and this is one of the most intelligent ways to increase profits when producing biopharmaceuticals,” concludes Dr. Nachtmann.

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