A New Analytical LC-MS/MS Method for Determination of Eight Standard Nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, NDBA) in a Commercial Small Molecule Drug Product Capsules and its Active Pharmaeceutical Ingredient for Treatment of Fabry: A Rare Disease.
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引用次数: 0
Abstract
Purpose: This study aims to develop and validate a highly sensitive LC-MS/MS method for quantifying eight nitrosamine (NA) impurities NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA in a small molecule commercial Active Pharmaceutical Ingredients (API) and Drug Product (DP) capsules used for the treatment of Fabry rare disease in global patients.
Methods: The method utilized gradient separation on a C18 column, ensuring optimum resolution between NAs and internal standards. Elution was monitored at precursor and product ions. The method was validated according to ICH Q2 (R1) guidelines, assessing specificity, linearity, recovery, and repeatability in both API and capsule matrices.
Results: Quantification of NAs ranged from 0.0215 to 0.780 ppm in relation to a 20.5 mg/mL sample concentration. Linearity coefficients ranged from 0.99 to 1.00. The Detection Limit (DL) was 0.154-0.560 ng/mL, and the Quantitation Limit (QL) was 0.438-1.590 ng/mL. Mean recoveries for all NAs were between 90 and 107%, and repeatability was under 15%. An Analytical Target Profile (ATP) concept was successfully employed to monitor Analytical Method Performance Characteristics (AMPC).
Conclusions: The validated LC-MS/MS method proved effective for quantifying NAs (NDMA, NMBA, NDEA, NEIPA, NDIPA, NMPA, NDPA, and NDBA) in both API and capsule matrices, with results consistently below the Quantitation Limit (QL) in confirmatory testing. This approach supports the elimination of routine NA testing, adhering to FDA and EMA's conservative Acceptable Intake (AI) limits, ensuring safety and regulatory compliance for global patients.
期刊介绍:
Pharmaceutical Research, an official journal of the American Association of Pharmaceutical Scientists, is committed to publishing novel research that is mechanism-based, hypothesis-driven and addresses significant issues in drug discovery, development and regulation. Current areas of interest include, but are not limited to:
-(pre)formulation engineering and processing-
computational biopharmaceutics-
drug delivery and targeting-
molecular biopharmaceutics and drug disposition (including cellular and molecular pharmacology)-
pharmacokinetics, pharmacodynamics and pharmacogenetics.
Research may involve nonclinical and clinical studies, and utilize both in vitro and in vivo approaches. Studies on small drug molecules, pharmaceutical solid materials (including biomaterials, polymers and nanoparticles) biotechnology products (including genes, peptides, proteins and vaccines), and genetically engineered cells are welcome.