Speeding up quality control for biologics

NANOFLUIDIC filters have been shown to allow the rapid testing of protein drugs produced by living cells, which could lead to more efficient processes in the pharmaceutical industry.

One of the fastest-growing areas of the pharmaceutical industry is biologics – drugs manufactured by living cells. Biologics typically consist of small organic molecules such as antibodies or other proteins, and can be used to treat diseases such as cancer and arthritis. They are often produced in large quantities in bioreactors, but this can be difficult to control and take months to complete, while there is currently no mechanism for checking their quality during manufacture.

However, engineers at the Massachusetts of Technology in the US have successfully tested a nanofluidics method that could analyse biologics on a continuous, automatic basis for the first time.

Their system was based on a series of nano-scale filters in an array device, whereby proteins would enter a small channel and encounter a series of pores 15–30 nm in size. Smaller proteins stay closer to the side where they started, while larger proteins drift toward the opposite side. By varying the size of the pores, the researchers were able to determine whether the proteins had formed large clumps that could provoke a dangerous immune response in patients.

Jongyoon Han, who led the project, said: “In terms of size analysis, our system is either exceeding or matching the detection sensitivity of the conventional technologies such as SDS PAGE or HPLC. But our system is uniquely designed to operate in a continuous flow, continuous analysis mode, with no manual intervention.”

Han added that he believes his system could serve as one of the critical analytics technologies for biologics production in the future, and that it would be possible to directly connect the monitoring system to bioreactors for online quality control. In their Nature Nanotechnology paper, the researchers demonstrated this by showing it was possible to analyse the cell-free supernatants in a continuous flow.

This continuous stream of analysis could lead to improved manufacturing efficiencies due to the current nature of production in a bioreactor. Han said: “In the current batch mode of production, delays in quality analysis mean production would have to complete before learning about any issues, often yielding a lot of waste from bad batches.

“With continuous biomanufacturing, we would learn of quality issues such as aggregation and folding almost immediately. This would allow manufacturers to act more quickly, either by fixing the issue, via culture conditions, or starting a new run.”

The researchers tested their device on three proteins: human growth hormone; interferon alpha-2b, a cytokine that is being tested as a cancer drug; and granulocyte-colony stimulating factor (GCSF), which is used to stimulate production of white blood cells. Their nanofluidic system was found to analyse a small protein sample in 30–40 minutes, plus the few hours it takes to prepare the sample.

However, Han believes his team can speed that up by further miniaturising the device, which could open up further applications, such as testing drugs immediately before administering them, to ensure they haven't degraded before reaching the patient. He said: 'We may be able to do it in tens of, or even a few, minutes. If we realise that, we may be able to do real point-of-care checks.'

In terms of making steps towards commercialisation of the technology, Han believes that collaboration could be key. He said: “We are hoping to work with pharmaceutical companies to test, validate and demonstrate our system. Recently, there have been new endeavours such as NIIMBL (The National Institute for Innovation in Manufacturing Biopharmaceuticals), which promotes public-private partnership and collaboration toward developing new biopharmaceutical technologies. I would like many fruitful collaborations with industry partners through these and other channels.”

Nature Nanotechnology: http://doi.org/b7gq