An FDA Laboratory Approach to Uncovering Potential Fraud in the Generic Drug Industry

Abstract

The Division of Drug Analysis of the U.S. Food and Drug Administration In St. Louis, MO, has screened more than 1400 drug samples for potential generic drug fraud by a combination of physical, instrumental, and chemical techniques. The approach to fraud centered around the analysis of exciplents as opposed to the normal approach of analysis of active Ingredients. Approximately 80% of the drug formulation pairs (Innovator and generic) submitted for bloequlvalence testing could be differentiated by a combination of physical and instrumental analysis, mainly thermogravimetrlc analysis (TGA) and Fourier-transform Infrared (FTIR) spectrometry. TGA proved to be the single most useful instrumental technique to determine differences In formulations. Liquid chromatography, gas chromatography, chemical tests, and polarizing microscopy were found to be the most useful tools to differentiate formulations that could not be resolved by FTIR, TGA, or physical comparisons. Xray powder diffraction and nuclear magnetic resonance spectroscopy were found not to be useful techniques to differentiate formulations. No clear-cut evidence of direct fraud was found, but Inconsistencies and suspicious samples were noted. Follow-up inspections based on the laboratory findings will probably occur. The procedures discussed In this article could be streamlined and made more efficient for examining large numbers of potential problem formulations.

Modified secured principal component regression for detection of unexpected chromatographic features in herbal fingerprints

“…In eqn (7), the matrix E i_winsize denotes the part of original residuals E inside the i th narrow window, P i_winsize contains the parts of the PCs inside the same window, I is a unit matrix of size (winsize 6 winsize), D i_winsize is the recalculated residuals corresponding to the residuals E i_winsize after compensation for the systematic fit errors. Compared with sPCR, this modified algorithm is friendly to use, and the results are more reasonable.…”

“…5 Chromatography fingerprinting emphasizes an integral formulation of pharmacologically active and phytopharmaceutically characteristic components of samples with similar or different attributions. [6][7][8][9][10][11] The quality consistency and stability of herbal extracts or products can be assessed by their integral fingerprint patterns in quantified operation procedures. Therefore, it was formally introduced by WHO in Munich in 1991, 12 and subsequently accepted.…”

Process Patent Protection via Analysis of Stable Isotope Ratios

“…Because of these challenges, process patents have been difficult to defend. Common strategies to prosecute infringement involve evidence of organic impurities and/or trace metals that are argued to be foreign to the established manufacturing process. , These cases can be challenging due to ambiguities in the interpretation of what constitutes a trace impurity . In contrast, isotopic evidence can be more persuasive than other approaches because it is so quantitatively sensitive, typically requiring samples of less than 0.1 to only a few milligrams of material to be delivered to the mass spectrometer, with high quantitative resolution in the ability to distinguish between materials with different origins and production histories.…”

Application of a Pruning Algorithm To Optimize Artificial Neural Networks for Pharmaceutical Fingerprinting

“…It has been suggested that instances of fraud might be directly detectable from analytical "fingerprints" which could demonstrate sameness or differences between samples. [1][2][3] Consequently, recent initiatives have been directed toward an evaluation of computer-based methods that could be used to distinguish within-and between-batch product consistency, to examine the effects of process changes in the production of pharmaceutical products, and to determine whether a product marketed today is the same as that which was originally approved. 1 It is well-established that information on the microscopic chemical composition of products provided by chromatographic trace organic impurity patterns represents an important component of the product fingerprint.…”

“…The discovery of fraudulent practices at a generic pharmaceutical firm in 1989 led the U.S. Food and Drug Administration (FDA) to conduct large-scale investigations into the pharmaceutical industry. It has been suggested that instances of fraud might be directly detectable from analytical “fingerprints” which could demonstrate sameness or differences between samples. − Consequently, recent initiatives have been directed toward an evaluation of computer-based methods that could be used to distinguish within- and between-batch product consistency, to examine the effects of process changes in the production of pharmaceutical products, and to determine whether a product marketed today is the same as that which was originally approved…”