At the USP Science Meeting in Toronto last week, the topic of anticounterfeiting and assuring drug quality took center stage. A number of presentations addressed the use of analytical technologies to protect public health. Raman spectroscopy appears to be gaining use to help detect fakes in the field, although it can pose some method transfer and validation challenges.
Anthony Zook, director of anticounterfeiting for Merck’s Global Security Group, discussed the new toolkit that Merck has developed to prevent product and package counterfeiting. Merck is using image analysis, portable Raman with a dedicated laptop and USB-based microscope, 3-D Topomicroscopy (a technique that allowed some counterfeiters to reverse-engineer the tablet die of a key commercial product) and FT-IR spectroscopy. The company has also developed a certification program to train field investigators and uses six portable Raman devices for this purpose. Keeping up with all product manufacturing changes is key, Zook said.
David Bugay, scientist with the Triclinic Labs, a contract testing facility, discussed the growing importance of miniaturized instrumentation, both in pharma QC applications, whether on the plant floor or the loading dock. “The new testing philosophy is to bring the lab to the sample,” he said, and using methods that have already been used in the lab can help speed the validation and method transfer required with handhelds.
Today, the technologies available in handheld form include IR, Raman, visible NIR, X-Ray fluorescence, portable gas chromatography and portable mass spectrometry. “No single technique will solve all the world’s adulteration problems,” he said. One needs to look at an array of technologies and design a protocol.
Cost is often seen as a disadvantage with portable systems, Bugay said, because they run 20-30% more than traditional lab instruments. Nonetheless, costs for some systems—he singled out Raman—have moved from $250,000 in the 1980s to about $50,000 currently. IR and Raman are complementary techniques, he said. Bugay has studied use of Raman to identify a number of well-known drug tablets and capsules, with the eventual goal of using it for qualitative counterfeit analysis. His laboratory developed methods on two different instruments and transferred them to a third. Adecision algorithm was developed.
People often have misconceptions about the acquisition of reference spectra, Bugay says, and may take a “let’s acquire them quickly” approach. Instead, acquisition is the most important part of the project, he says.
Bugay noted that Raman has some limitations, particularly when being used by untrained personnel in the field. His team applied multivariate domain spectral matching, to determine whether the measured spectrum of the unknown sample lies within the multivariate domain of the reference spectrum, defined by the uncertainty characteristics of each. This method takes into account fluctuations in the laser and the operator performance, considering those uncertainties in a standard p-value statistical approach.
Also discussing Raman was Steven Choquette, Group leader of the Bioassay Methods Group within the National Institute of Standards and Technology’s Biochemical Science Division. He described efforts to provide a standard spectral library for Raman spectroscopy.
The request for such a library first came from the Coblentz Society in the 1990s, he said, and efforts to improve validation and calibration for Raman have continued as part of a joint effort with ASTM.
Raman is a single-beam emission method, Choquette explained, and each vendor’s equipment uses different optical elements and lasers, so Raman spectra from different vendors can look very different from each other, even when analyzing the same very simple molecules. There is a real need for performance validation standards, he said, and for improving traceability, accountability, quality systems and data transfer between different vendors’ systems.
While they may appreciate the fact that Raman provides qualitative answers quickly and without sampling, and that measurements can be taken directly through containers, some end users are troubled by the method's lack of specificity. This is particularly true for first responders who have not been trained in the subtleties of analytical science and who need answers, quickly, out in the field.
Choquette quoted one New York City fireman, “When I point two Raman [devices] at the same stuff [reportedly not the word he used] I should get the same answer,” he said.
At this point, Raman spectral libraries are all vendor-specific and there is no standard spectral library, but, NIST has responded to Coblentz’ request by studying ways to improve calibration and to “correct” for differences between spectra.
Progress is being made, Choquette says, in developing artifact standards to allow for calibration, although NIST must still work out algorithm issues, particularly for system-to-system calibration.
Using a calibrated irradiant light-bulb-like source has always been the traditional way to standardize spectra, but irradiance calibration systems are expensive (according to NIST, they cost $10,000 seven years ago). Although these sources can be used with any laser, they require quite a bit of power, and can be difficult to connect with any given experiment or situation in the field.
NIST has developed a less expensive alternative artifact method, using fluorescent glass Standard Reference Materials to facilitate calibration in the field. Although each glass must be matched with one specific laser, they cost a fraction of what calibrated irradiant sources cost. In a 2002 article, NIST said the first chromium-doped SRM (number 2241, designed to operate with red lasers at about 785 nm) cost about $500 and could be used repeatedly.
Since then additional SRM’s have been developed for FT Raman and for use with blue, green and near-infrared lasers.
Overall, Choquette says, continued progress will be important as Raman gains users in forensics and other fields. Vendors also realize the value of standardization and are participating in the research.
Ultimately, he says, the goal would be generating a community-supported Raman spectroscopy library, which could be used by academicians, industry and government scientists, forensics specialists and first-responders alike. And what about that New York City fireman? Said Choquette at the conclusion of his talk, “I couldn’t agree with him more.”
On a visual plane more basic than spectroscopy, David Hale, researcher and Web 2.0 pioneer at the National Library of Medicine, discussed Pillbox, a public health safety database, recently went into live public beta stage. Designed for the public, healthcare providers, first responders, law enforcement and drug industry professionals, Pillbox houses high-resolution photographs of drug capsules and tablets, sortable by imprint, color, shape, size and scoring, linking this data to online FDA drug databases, toxicological, clinical and drug info databases, to help prevent medication errors, speed response to accidental poisonings and facilitate identification of substandard, recalled or counterfeit medicines.
Also speaking at the conference was incoming chairman of IPEC, William Dale Carter of J.M. Huber, who will start his tenure next year. To help combat extreme product quality variability, IPEC is working on third party inspections for pharma-grade materials, and with ASTM on standards. A former high level FDA staffer will reportedly be joining the organization. For an interview with current chair Janeen Skutnik and Colorcon's David Schonecker, visit PharmaManufacturing.com.
