Portable Raman spectroscopic devices have become part and parcel of every pharmaceutical manufacturer’s QA/QC toolbox. These mobile devices are being embraced for an increasing range of applications, from raw materials identification to API classification to counterfeit detection. They may soon become more prevalent even as a means of characterizing finished-dosage forms.
Portable Raman is experiencing somewhat of a heyday, thanks to an obvious need within industry for better, faster quality and inspection tools, and thanks to regulators who have pushed vendors and manufacturers to collaborate in order to develop these tools.
Inside FDA, a leading proponent of Raman as a solution for ensuring the safety and purity of raw materials, APIs, and finished product is John Kauffman, a research chemist within CDER’s Division of Pharmaceutical Analysis (DPA). Kauffman has written and presented extensively on Raman and other analytical technologies. Here, Pharmaceutical Manufacturing Senior Editor Paul Thomas asks Kauffman about what manufacturers need to know about portable Raman as technology improves and becomes easier to use.
PhM: Portable Raman and other spectroscopic devices have rapidly gained in popularity for pharmaceutical raw material inspection (with increasing encouragement by FDA). How significantly have these devices improved over the past few years? Would you say that it’s possible to get “lab quality” results in the field?
J.K.: The technologies that enabled the development of portable Raman spectrometers were holographic sharp cutoff and notch filters and battery powered, narrow-band laser diodes. These components have been available for many years. Incremental improvements in the sharpness of the filter cutoff can improve the wavelength range of portable Raman spectrometers, and frequency stabilization of the diode lasers may improve the instrument resolution if it is laser bandwidth limited.
But many recent innovations in portable Raman spectrometers have focused on other design elements that often depend on the vendors’ target markets. For example, some instruments are designed for ruggedness, while others are designed to be small enough to fit in a pocket. One encouraging development is that vendors are improving the user interface to simplify the use of these instruments by non-experts, and some vendors are also developing chemometric tools that offer flexibility for method development scientists.
The typical figures of merit for Raman spectrometers are spectral range, resolution, signal collection times and signal-to-noise ratio. Vendors of portable instruments must also consider the size, weight and form factor of their instruments, and are therefore faced with a set of trade-offs between measurement characteristics and portability during instrument development. Signal collection times depend on laser power, detector sensitivity and the optical throughput of the instrument, and this consideration is often more important in field applications than in lab applications.
Signal-to-noise ratio can be improved by cooling the detector to temperatures at which thermal noise is negligible. Unfortunately this feature generally requires heavy components and has a high power demand. There are some portable instruments with low temperature detectors (i.e., less than -40 °C) but they tend to be larger and heavier. Most portables with cooled detectors use single-stage thermoelectric cooling to drop the temperature by 20 °C or so below ambient temperature, and this helps, but very few portable spectrometers can match the signal-to-noise performance of laboratory instruments.
Resolution is determined in part by the focal length of the spectrograph, so vendors of portable instruments have to strike a compromise between size and resolution. Laboratory instruments usually do not have these constraints, so one can expect better resolution and better signal-to-noise ratios from benchtop Raman spectrometers. Similarly, if spectral range is important for a given application, laboratory spectrometers with double or triple monochromators are available.
Having said this, we have utilized portable Raman instruments from a number of vendors, and their resolutions, ranges, signal-to-noise ratios and collection times have been adequate for most of our applications.
PhM: Are drug manufacturers making use of these portable inspection technologies to the degree that they should—with APIs and also with excipients?
J.K.: Nearly every major pharmaceutical innovator firm has a program in Raman spectroscopy. These programs support applications such as raw materials identification, API characterization, counterfeit detection, and characterization of finished dosage forms. Raman spectroscopy is often very useful for APIs because they are often strong Raman scatterers, whereas many excipients exhibit Raman spectra with broad features and high background.
I am not aware of any applications of Raman spectroscopy for excipient characterization within the pharmaceutical industry, with the exception of excipient identification. As you know, the FDA Division of Pharmaceutical Analysis initiated an Excipient Library program about 1 year ago, in collaboration with IPEC. We hope to develop chemometric methods that allow us to assess certain quality attributes of excipients.
With respect to the use of Raman spectroscopy in process control, it’s best to consider this question by comparison to near infrared (NIR) absorbance applications. NIR has been utilized in the pharmaceutical industry since the late 80s and early 90s, but it has only been in the last 8-10 years that we have seen a significant number of NIR methods in new drug applications. Raman spectroscopy is probably 10 years behind NIR in terms of its development as a tool for pharmaceutical manufacturers, so while we have seen very few Raman methods in new drug applications to date, we anticipate an increasing number in the future.