The FDA’s related initiatives in Process Analytic Technology (PAT) and Quality by Design (QbD) remain, nearly 20 years after their promulgation, largely unrealized. The technology exists for biopharma, as it has been available for decades to makers of potato chips, cement, and bobblehead dolls. The reason manufacturers have chosen inertia over innovation is purely economic: implementing and maintaining PAT and QbD costs more time and money than any potential reduction in cost of goods plus anticipated liability.
Yet, despite the unfavorable adoption climate, equipment vendors continue to innovate. A recent article describes a novel fiber optical nanoplasmonic sensor which developers are exploring for rapid immunoglobulin titer determinations. The sensors, which combine surface plasmon resonance (SPR) transduction and single-use Protein A-modified sensor chips, work with sample volumes as low as 1 µL, with reproducibility and sensitivity comparable to Protein G HPLC (with ultraviolet detection).
The sensors’ dynamic range, which is tunable by varying sample volume, covers protein concentrations ranging from 0.0015 to 10 mg/mL—pretty much every expected titer from discovery through production, without need for dilution or concentration. The sensor also appears immune from common interferences, works on unpurified culture broth, and correlates well with enzyme-linked immunosorbent assay (ELISA).
Daniel Aili, PhD, Laboratory of Molecular Materials at Linköping University, Sweden, “SPR is a real-time, label-free technique. In principle we can get results in less than 30 seconds, but it depends on the concentration of the IgG.”
In its current form the SPR sensors require sampling, currently a standard component of PAT, but improvements are on their way.
“The technique was originally developed with in-line analysis in mind and a spinout company, ArgusEye, will focus on in-line applications,” says Aili. “The flow cell and sensor system has already been tested up to pilot scale for various downstream process steps, for example to monitor product breakthrough.”
Using this type of sensor in-line is more challenging, yet even in its current embodiment it can be used to quantify IgG titers in crude samples, even with cells present. “The technique also works very well at small scale and low volumes, which can be very helpful during process development,” adds Aili.
Nor is SPR limited to interactions between antibodies and protein A. A protein G chip is under development, for example.
“We can use a wide range of biorecognition molecules, including antibodies, peptides, and aptamers to sense, essentially, any analyte of interest,” Aili tells GEN. “In addition to monitoring therapeutic products, we can use the sensor to detect side products and contaminants. Moreover, since it is an affinity-based technique with a very robust, non-fouling surface chemistry, we can measure in complex sample matrices without any sample preparation, for example for rapid at-line or on-line monitoring of product concentrations in unpurified upstream samples.”