Abstract
BackgroundDemonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. Physicochemical methods are preferred instead of biological assays to determine concentration of drugs in biological fluids, but it does not permit direct quantification of potency. Here, we report a microbiological assay using large plates designed to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator.MethodsThe assay is based on the concentration-dependent variation of the inhibitory effect of antibiotics on reference bacteria (B. subtilis ATCC 6633, S. aureus ATCC 6538p and S. epidermidis ATCC 12228) in a seeded agar (Difco™ Antibiotic Media), producing a concentration-response linear relationship with two parameters: y-intercept (concentration) and slope (potency). We compared the parameters of 22 generic products (amikacin 4, gentamicin 15, and vancomycin 3 products) against the innovator and the reference powder by Overall Test for Coincidence of the Regression Lines (Graphpad Prism 5.0).ResultsThe validation method yielded excellent results for linearity (r2 ≥ 0.98), precision (intra-assay variation ≤ 11%; inter-assay variation ≤ 10%), accuracy, and specificity tests according to international pharmacopoeial requirements. Except for one generic of vancomycin that had 25% more API (Py-intercept = 0.001), the pharmaceutical equivalence was demonstrated in 21 generics with undistinguishable slopes and intercepts (P > 0.66). Potency estimates were 99.8 to 100.5, 99.7 to 100.2 and 98.5 to 99.9% for generic products of amikacin, gentamicin and vancomycin, respectively.ConclusionThe proposed method allows rapid, cost-saving, precise, and accurate determination of pharmaceutical equivalence of drugs in pharmaceutical dosage-form, and may be used as a technique for testing generic antibiotics prior to their approval for human use.
Highlights
Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence
Pharmaceutical equivalence, defined as having equivalent amounts of the same active pharmaceutical ingredient (API) of the innovator, in the same dosage form, and produced under good manufacturing practices, constitutes the only criterion required for therapeutic equivalence of intravenous drugs [12]
We propose a new and more understandable interpretation of the parallel-line assay results to determine pharmaceutical equivalence, comparing the dose-response relationship obtained with the pharmaceutical form of innovator versus generic by curve fitting analysis and performing an intra-house validation of the procedure assessing the same criteria recommended by international pharmacopoeias
Summary
Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. The global anti-infective market is valued at US$66.5 billion with antibacterial agents accounting for over 50% of sales [1] This remarkable cost has resulted in a massive use of generic drugs trying to assure unlimited access to cheap treatments, to the point that currently over half prescriptions include at least one generic product [2,3]. Pharmaceutical equivalence, defined as having equivalent amounts of the same active pharmaceutical ingredient (API) of the innovator, in the same dosage form, and produced under good manufacturing practices, constitutes the only criterion required for therapeutic equivalence of intravenous drugs [12]. The quantification of API in standard samples or biological fluids is critical for drug regulatory agencies around the world
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