Mass Spectrometry Helps Drug Manufacturers Meet New Demands

Quality control in drug manufacturing has always been important: After all, if something goes wrong, lives could be on the line. Accordingly, new emphasis is being placed on pharmaceutical quality control, especially in light of a pending regulation from the Food and Drug Administration (FDA) that is designed to help pharmaceutical manufacturers improve their products. To push the industry toward the use of objective standards, the FDA recently released its Process Analytical Technologies initiative, a set of guidelines that encourage the manufacturers to develop systems of analysis and control. The FDA describes the initiative as the monitoring of processes taking place on line, in line or at line for the purpose of improving product quality of manufactured drugs.

Major drugmakers have been using spectroscopic technologies for years, according to Katherine Bakeev, product specialist at Foss NIRSystems of Silver Spring, Md. But modern near-IR spectrometers offer better light sources and imaging detectors, enabling rapid results on the assembly line.

By moving their analysis closer to the line, drugmakers put themselves in a “win-win-win situation,” said Carl Anderson, assistant professor at the Duquesne University Center for Pharmaceutical Technology in Pittsburgh. The quality of the drugs is improved, products are available for sale faster and the cost to the end user is decreased. And as the need for using the tools right on the assembly line increases, companies such as Carl Zeiss GmbH of Jena, Germany, Brimrose Corp. of America in Baltimore and Foss NIRSystems are responding with spectrometers that attach at specific points on the assembly line, such as to driers, where they monitor the water or alcohol level in the drugs as they are drying, or to blenders, where they monitor the mixing of powders.

Zeiss offers a sensor unit that attaches to the mixing and drying units. Called the Corona, the device incorporates a photodiode array detector that covers the visible and near-infrared regions with spectra collected at speeds as fast as 30 ms. It can acquire a full spectrum between 950 and 1700 nm for monitoring moisture and blending. A measuring head transmits a 25-mm-diameter beam through a window of up to 30 mm, which measures the diffuse reflectance from the sample. Further, a wireless configuration of the Corona can be installed on moving process equipment: Data transmits via radio frequency, and electricity is supplied through either an internal battery or an electrical generator.

The Corona is a near-IR spectrometer that attaches to the blending or drying units on an assembly line for real-time monitoring.

The position of spectrometers on the assembly line is dictated by factors such as the components of the drugs being sampled, the type of data needed and the amount of time required for analysis. The control system and software can be situated in one central location in a facility, with analyzers to monitor at-line, online, in-line or in a lab.

During at-line monitoring, a spectrometer is placed close to the line so it can monitor a particular sample for specific transmittances. Pattern-recognition techniques also may be applied to confirm that the product is what it should be or to confirm the information that is on the bar-code label.

On-line analysis is performed by running a group of samples through a flow cell. Results can be obtained in real time as the assembly line moves. In-line analysis is often performed in a vessel and requires a fiber optic probe or direct mounting of the sensor head to the static or moving sample vessel. In this method, analysis is optimized for the particular sample or function, such as measurement of liquid in a drying process.

Infrared is most widely used in the vibrational spectroscopic technique, said Emil Ciurczak of Integrated Technical Solutions in Goldens Bridge, N.Y., with near-IR being the most common in pharmaceutical manufacturing applications. Raman methods offer “a reasonably good light source,” he said, “but with its small spot size, you won’t see a true representation of material in a semi-heterogeneous glob.” And traditional midrange infrared is absorbed by water and is less effective with pure powder.

Anderson added that near-IR is favored because it delivers rapid, nondestructive analysis: Tablets can be measured without preparation and without being crushed.

Bruker Optics of Billerica, Mass., offers a variety of spectroscopic tools designed specifically for the FDA’s initiative, including one Raman, four near-IR and two IR analyzers. The Matrix-F is a near-IR spectrometer based on fiber optic probe technologies and suitable for the process monitoring of liquids, solids and gases. One leading pharmaceutical company already uses it to measure a process-critical control parameter inside a glass-lined reactor.

For that installation, Bruker Optics supplied a custom-designed transmission probe inside a 2-m pipe, which is inserted into the reactor through a flange at the top. The fiber optic Fourier transform spectrometer is housed in an environmental enclosure 100 m from the sample point. Data is gathered and used to develop and validate the model. Results are transmitted to the process control system, and the control parameter operates through a closed loop based on the near-IR result.

Thanks in part to the Matrix-F, the company claims to have cut down on the number of flawed batches that must be discarded at the end of the production process. Cutting steps from the process helps manufacturers reduce cycle times and increase production capacity; at the same time, consumers benefit from lower prices and higher-quality products.

New methods are on the horizon, too. Ciurczak sees wireless as the way of the future in production environments, indicating that a number of major drug manufacturers are already experimenting with paperless labs.

Bakeev claims that what drugmakers really want are reliable data management and archival systems, along with various digital protocols for integrating with the plant process control systems.

Though near-IR is the dominant standard on pharmaceutical assembly lines, new tools and combinations will soon infiltrate the industry, based on technologies such as acousto-optics and photon migration. Their purpose is “building in quality, rather than testing it in,” Ciurczak said, so that drug companies manufacture batches that meet specifications the first time around.