Title:Quality by Design-driven Analytical Method: A Quality Risk
Management-Based Liquid Chromatography Method for Daclatasvir and
Characterization of its Putative Degradants by LC-MS/MS
Volume: 20
Issue: 3
Author(s): Prashant Chaturvedi, Shruti Chopra*, Kalyani Joshi and Savita Tauro
Affiliation:
- Centre for Pharmaceutical Chemistry & Pharmaceutical Analysis, Amity Institute of Pharmacy, Amity
University Noida, Uttar Pradesh, 201303, India
Keywords:
Quality by Design (QbD), Critical Quality Attributes (CQA), Critical Process Parameters (CPPs), Quality Risk Management (QRM), Design of Experiment (DoE), Daclatasvir Dihydrochloride (DCV), LC-MS/MS.
Abstract:
Background: Antiviral drugs can cure more than 95 percent of people with hepatitis
C, but the inaccessibility of quality affordable medicines and the lack of their uninterrupted
supply poses a major challenge. Impurities in drugs have a significant impact on their quality
and are one of the substantial causes of drug recalls, ultimately leading to the unavailability of
the drug in the market. Hence, there is a need for a robust, quality risk management and quality
by design-driven analytical method that can detect the antiviral drug, Daclatasvir dihydrochloride,
in the presence of its probable impurities.
Objective: This study aimed to develop a Quality by Design-driven stability- indicating liquid
chromatography method for Daclatasvir dihydrochloride and the characterization of its putative
degradants by LC-MS.
Method: The fishbone diagram and quality risk assessment investigated twenty-four process
parameters and concluded that three risk parameters, i.e., flow rate, buffer pH, and stationary
phase type, were the critical process parameters. The critical quality attributes viz. resolution
between impurity 6 and DCV and impurity 2 & 3 (Rs˃1.5), the shape of the peak of DCV
which is decided by the Number of Theoretical Plates (NTP˃5000), and the retention time of
Daclatasvir (tR14-23 mins) were optimized using a two-level three-factor full factorial design
with five center points.
Results: The optimized method is stability-indicating in its true sense as it can separate the sample
with its degradants generated in basic (three), acidic (two), oxidative (H2O2: three, Azobisisobutyronitrile:
one), photo (three), and dry heat (one) conditions. Degradants structures were elucidated,
and degradation routes were established, using LC-MS and LC-MS/MS analyses.
Conclusion: The drug is highly susceptible to acid, base hydrolysis, and oxidation degradation
conditions and poses a significant risk to the analytical method to fail in system suitability criteria.
Hence, a robust and flexible chromatographic method with the capacity for continuous
improvement was developed and successfully validated within the criteria of design space.
