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FDA, in cooperation with IPEC, is building a spectral library of excipients to detect improper ingredients within a drug product on site.
Globalization of the pharmaceutical supply chain has increased the challenges to FDA to ensure that drug products and ingredients are not contaminated, counterfeited, or mislabeled (1, 2). To help in this effort, the agency has developed rapid screening methods for pharmaceutical products and ingredients that can be deployed on portable instruments by field laboratories and inspectors for the screening of dietary supplements, pharmaceutical ingredients, and finished products on site (e.g., at border crossings, import centers, foreign manufacturing sites). Examples include detection of toxic and catalytic metals by X-ray fluorescence, detection of weight-loss drugs in dietary supplements by ion mobility spectroscopy, detection of diethylene glycol and ethylene glycol in glycerin, sorbitol or propylene glycol by Raman or near-infrared (NIR) spectroscopy (3–7). The deployment of such instruments will allow FDA inspectors to screen a large number of ingredients and products at the site of importation, in domestic commerce, or even at foreign drug manufacturing sites, and to determine which are suspect and should be detained, sampled, and sent to laboratories for confirmatory testing by traditional methods such as US Pharmacopeial testing. FDA is concerned about diversion into the legitimate supply chain of excipients that are unsuitable for use, as well as the possibility of tampering with an excipient during transit.
During the past year, FDA's Division of Pharmaceutical Analysis (DPA) has developed a deeper understanding of the value and limitations of library-based Raman and NIR spectral-correlation methods for rapid spectroscopic screening of pharmaceutical ingredients (8–10). The division has developed procedures for transferring spectral libraries across instruments from different vendors and platforms (e.g., laboratory, portable, and handheld).
DPA would now like to build an excipient library to be deployed on NIR and Raman portable instruments and used at points of entry or storage. To ensure a robust library, DPA is partnering with the International Pharmaceutical Excipients Council (IPEC) to reach out to manufacturers and distributors of common excipients to provide authentic samples to the agency to help build these libraries. This article provides details on how to participate, and some anticipated questions and answers.
Benefits of participation
Development and deployment of an excipient library to monitor for possible contamination, adulteration, tampering, and diversion into the qualified pharmaceutical supply chain will improve safety of the drug supply, and thus, patient safety. Additional benefits include the following:
Creation of this library will provide added assurance that a given excipient is of the expected quality. Consumers will have increased confidence in the quality of drug products based on this increased surveillance of the excipient supply chain.
Details of participation
Materials (i.e, excipient samples) would be shared with DPA in St. Louis using a Material Transfer Agreement (MTA). This agreement would allow DPA to accept material from vendors and distributors and protect intellectual property. A copy of the MTA and contact information can be obtained on the FDA's Office of Testing and Research website under Hot Topics, at www.fda.gov/AboutFDA/CentersOffices/CDER/ucm136930.htm.
Manufacturers are asked to provide multiple lots (at least three) of approximately 2 g each of excipients with a Certificate of Analysis for the lot. In the case where manufacturers do not supply directly to the US pharmaceutical industry, distributors may submit the excipient samples. Material should be representative of the potential spectral variability that might be expected in their product. Variables that might affect spectral variability would include the following:
Samples should conform to market standards and/or standards filed with the agency. DPA is ready to begin receiving excipient samples for this project.
Questions and answers
The following section addresses anticipated questions about the spectral library project and the collection of samples. Answers are provided by the authors, representing DPA and IPEC.
What instruments will be used for screening excipients?
DPA plans to build two libraries, one for NIR and one for Raman spectroscopy. These are both common techniques used in library searches because their spectral features are highly sensitive to chemical structure. Both have become increasingly common in portable instrumentation due to their ability to sample through various common sampling media. Some excipients may not be suitable for both libraries because of some inherent limitations of each technique that must be taken into account when populating spectral libraries. An NIR spectrum is dependent on moisture content and particle size, for example. It contains broad and generally weak spectral features (due to sampling of overtone and combination bands). Raman features tend to be sharper and do not depend on moisture or particle size, but if a sample fluoresces, Raman spectral features can be obscured and limit the effectiveness of the library method. Some of the limitations for these two techniques can be reduced using common preprocessing techniques, such as multiplicative scatter correction or first derivative preprocessing. The results of library searches are strongly dependent on (and often enhanced by) spectral preprocessing.
How will a sample spectrum be matched to the libraries?
The typical library search consists of correlating the full spectrum of a test (unknown) sample to a reference (library) spectrum using the Hit Quality Index (HQI), shown in the following equation:
where the × indicates the scalar product of the two vectors. As such, library searches are aimed at gauging the full spectrum correlation of two spectra as opposed to focusing on a particular region or peak. The HQI values in the above equation range from 0 to 1.000, with 1.000 indicating a perfect match. This match is achieved when the unknown spectrum is identical to the library spectrum. FDA plans to use this concept when it implements its libraries.
How many materials are expected to be in the library?
DPA has identified 166 excipients that fit in one or more of the following categories: most commonly used, most vulnerable to adulteration, or needing an update of the US Pharmacopeia monograph. From this list, FDA has narrowed down a priority list of excipients (see Table I). Once library entries for these priority materials have been obtained, the library will be deployed to field inspectors along with any other excipients that have been received. The library will continue to be expanded as additional excipients are received.
Table I: List of priority excipients to be collected for spectral library.
What additional types of data are being considered for this library?
Both an NIR and Raman library will be built. These libraries will contain the spectrum of each excipient. In addition to the spectrum, each entry will contain the chemical name, date added, and spectrometer details. When the library search algorithm can distinguish between different manufacturers and/or sites of manufacture of the same excipient, such further identifying information will be included.
Will the library be available to everyone?
The agency does not plan to share the library at this time. If industry and the agency see value in sharing the library in the future, FDA will conform to any provisions in the MTAs.
Will others be able to contribute to the spectral library?
FDA prefers to obtain excipients directly from manufacturers or distributors to be certain of their identity and provenance of the manufacturer and/or manufacturing site to minimize the possibility that a contaminated or subpar quality excipient is included in the library. As far as contributing spectral entries into the spectral database, FDA will not be accepting spectra.
How will the materials be used and/or evaluated?
Both Raman and NIR spectra of the excipients received will be generated without further testing or qualification of the material. As the scope of this effort is to establish a spectral library database, FDA does not plan to perform quality testing.
Would there be a time factor for the samples (i.e., would the manufacturer need to send samples every year)?
For most samples, this step would not be required. However, manufacturers could send new samples if they felt a process or raw material change could affect the spectrum of their material.
John Kauffman, Jason Rodriguez, Steve Wolfgang, William Busch, Karen Richardson, Chris Moreton, Patrick Rice, Ken Crook, Chi-san Wu, Asenicion Koenig, Carl Perini, Bret Clark, Justin Denault, Irwin Silverstein, Priscilla Zawislak, Art Falk, Dale Carter, Dave Schoneker, Alan Potts.
Lucinda F. Buhse is director of the Division of Pharmaceutical Analysis in FDA's Office of Testing and Research. Philip H. Merrell is a subcommittee chair at the International Pharmaceutical Excipients Council of the Americas and a technical market manager at Jost Chemical, tel. 314.428.4300.
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