Real-time data for manufacturing

Craig Dobbs describes definitive technologies for PAT and QbD initiatives.

“In the current Six Sigma environment of manufacturing, facilities are constantly searching for process improvements to drive overall efficiencies and productivity”
-Craig Dobbs

Of all of the analytical techniques that are currently applied as Process Analytical Technology (PAT) tools in solid-dosage manufacturing, why is liquid chromatography of particular importance in drug development?
Craig Dobbs. Several analytical techniques can be used in PAT - liquid chromatography, mass spectrometry, near infrared spectroscopy and Raman spectroscopy to name a few. Throughout a therapeutic compound's lifecycle, liquid chromatography (LC) is the only advanced analytical technology that is routinely used in every phase of the process: in discovery, research, development, manufacturing, qc/release, and post shipment stability monitoring. The amount of meaningful information produced by LC systems during this process is nothing less than gold mine of data. It is imperative that such LC analytical data is secured, easily archived and searchable, can be quickly cross-referenced and overlayed, and is instantaneously available to support decision-making processes. The concept of a long-term, historical database focused specifically on full characterization of a therapeutic molecule is at the central core of the USFDA's Quality by Design Initiative (QbD). LC is the single analytical technique that supports QbD by consistently producing the same type of easily referenced and interpreted data from anywhere in a drug product's lifecycle.

The manufacture of an active pharmaceutical ingredient is invariably a solution phase based process, which is the ideal sample matrix for LC analysis. Analytical LC testing of inprocess material (IPM) is routinely performed today in an off-line manufacturing QC laboratory to monitor reaction progress, or to specifically measure individual parameters like IPM purity or concentration. During a single inprocess LC analysis, a remarkable breadth of information can be extracted: raw material consumption, IPM purity, IPM concentration, even the presence of low-level or trace concentrations of impurities can be measured and quantitated down to 0.01 percent. If a trace compound negatively impacts a critical quality attribute of the IPM, LC is the ideal technology for monitoring its presence. Leveraging all of this information is critical to understanding where your process is relative to the defined design space within a QbD strategy.

Are there limitations in applying traditional LC as a PAT tool?
CD. What generally keeps traditional LC from being adopted directly onto the manufacturing floor is that it simply takes too long to generate a result. LC may produce data with unrivaled breadth, specificity, sensitivity, and accuracy - but off-line QC Lab sample-to-answer times are typically in excess of four to six hours. That reality is rapidly changing. With new atline and online analytical LC tools, manufacturers can make a measurement, generate information, and make a decision in real-time or in less than five minutes.  Real-time LC capability was realized in 2004 when Waters Corporation introduced UltraPerformance LC, or UPLC technology. The ACQUITY UPLC System was the market's first real-time LC, followed by ACQUITY UPLC H-Class System for easy LC to UPLC migration in discovery and development labs. UPLC technology now extends to automated direct online and atline IPM analysis on the manufacturing floor with the PATROL UPLC System. PATROL UPLC is the first and only real-time LC system specifically designed for this environment.

How can PATROL UPLC technology address manufacturing business pressures?
CD. In the current Six Sigma environment of manufacturing, facilities are constantly searching for process improvements to drive overall efficiencies and productivity. Because of the throughput challenges that LC presents as described above, as well as resource and costs issues, the technique is not usually considered an appropriate candidate for manufacturing floor deployment. Realizing these limitations but desiring the many analytical benefits of LC, the PATROL UPLC System began as a collaborative effort between Waters and a major pharmaceutical company to deliver real-time speed, sensitivity, specificity, and accuracy to the manufacturing floor, with a focus on making it reliable and rugged with a simplified operator interface appropriate for the environment. The flexibility and automation engineered into the system was implemented to address existing SOPs, provide a continuum of real-time UPLC technologies across the entire drug development cycle, and convert a once considerable manufacturing bottleneck into a competitive advantage. 

For more information on the PATROL UPLC System, visit www.waters.com/patrol.

As a Senior Manager for both Biopharmaceutical Business and Process Analytics at Waters, Craig Dobbs partners with industry experts to develop technology solutions that address process analytical needs in manufacturing, as well as in the development of biotherapies.