title: Quality by design (QbD) based development and validation of an HPLC method for amiodarone hydrochloride and its impurities in the drug substance.
abstract: The USP monograph describes an HPLC method for seven impurities in the amiodarone drug substance using a L1 column, 4.6mm×150mm, 5μm packing (PF listed ODS2 GL-Science, Inertsil column) at 30°C with detection at 240nm. The standard contains 0.01mg/mL of amiodarone, and USP specified impurities D and E with a resolution requirement of NLT 3.5 between peaks D and E. Impurities in a 5mg/mL sample are quantitated against the standard. Impurity A peak elutes just before peak D. We observed two problems with the method; the column lot-to-lot variability resulted in unresolved A, D, and E peaks, and peak D in the sample preparation eluted much later than that in the standard solution. Therefore, optimization experiments were conducted on the USP method following the QbD approach with Fusion AE™ software (S-Matrix Corporation). The resulting optimized conditions were within the allowable changes per USP 〈621〉. Lot-to-lot variability was negligible with the Atlantis T3 (Waters Corporation) L1 column. Peak D retention time remained constant from standard to sample. The optimized method was validated in terms of accuracy, precision, linearity, range, LOQ/LOD, specificity, robustness, equivalency to the USP method, and solution stability. The QbD based development helped in generating a design space and operating space with knowledge of all method performance characteristics and limitations and successful method robustness within the operating space.
authors.affiliation: Baxter Healthcare, Round Lake, IL 60089, United States. Electronic address: Shreekant_Karmarkar@baxter.com.
authors.forename: S
authors.initials: S
authors.lastname: Karmarkar
authors.affiliation: Baxter Healthcare, Round Lake, IL 60089, United States.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Baxter Healthcare, Round Lake, IL 60089, United States.
authors.forename: R
authors.initials: R
authors.lastname: Garber
authors.affiliation: Baxter Healthcare, Round Lake, IL 60089, United States.
authors.forename: A
authors.initials: A
authors.lastname: Szajkovics
authors.affiliation: Baxter Healthcare, Round Lake, IL 60089, United States.
authors.forename: M
authors.initials: M
authors.lastname: Koberda
mesh_terms: D000638:Amiodarone / Q000032:analysis* / Q000592:standards; D000889:Anti-Arrhythmia Agents / Q000032:analysis* / Q000592:standards; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000379:methods* / Q000592:standards; D004340:Drug Contamination; D004355:Drug Stability; D017408:Guidelines as Topic; D057230:Limit of Detection; D015394:Molecular Structure; D011786:Quality Control; D012015:Reference Standards; D015203:Reproducibility of Results; D013678:Technology, Pharmaceutical / Q000379:methods* / Q000592:standards
chemical_list: D000889:Anti-Arrhythmia Agents; D000638:Amiodarone
keywords: Amiodarone; ICH; Impurities; Quality by design (QbD); USP; Validation