Content variability of active drug substance in compounded oral 3,4-diaminopyridine products

摘要

What is known and Objective: 3,4-diaminopyridine (3,4-DAP; amifampridine) is used for symptomatic treatment of Lambert-Eaton myasthenic syndrome. Until recently, it was only available as a compounded product, which raises safety concerns because of possible high variability in active drug substance content. The objective of this study was to evaluate the variability in dosage form weight, active content variability and impurity of compounded oral 3,4-DAP drug products. Methods: Ten samples each of 9 oral 3,4-DAP compounded products were weighed, extracted with water and the 3,4-DAP content determined by ultra high-performance liquid chromatography. Results and Discussion: Variability in dosage form weight ranged from 0·81% relative standard deviation (RSD) to 4·82% RSD. In the 90 samples tested, 3,4-DAP content ranged from 22·2% to 125·2% of declared label content. All 10 samples of one compounded product had active drug substance content well below the declared label content (35·0%, 51·7% RSD). No compounded product achieved the Good Manufacturing Practice (GMP) standard of 95-105% range limit of declared label content; one achieved 90-110%, and four others achieved 80-120% of declared content for all 10 samples. There was no evidence of a significant presence of degradation products or related substances in any compounded product. What is new and Conclusion: Compounded 3,4-DAP products are subject to considerable variability in active drug substance content. This variability seems to be principally because of heterogeneous formulated material rather than variation in dosage form weight.