Optimization of a Liquid Chromatography Method for the Analysis of Related Substances using Design of Experiments Integrated with the Steepest Ascent Method and Monte Carlo Simulation
Trupti Tol,
QBD Team leader,
Cipla Ltd
An
analytical method for the determination of related substances (RS) was
optimised using quality by design (QbD) approach. The selectivity issue encountered
during oxidative degradation was a stumbling block, with a few poorly resolved degradant
peaks (each greater than 1.0%) eluting very close to the main peak and the
known impurities. Selectivity (resolution) was considered as a critical quality
attribute (CQA). Buffer pH, column oven temperature, gradient slope and flow rate
were the critical method variables (CMVs) studied through design of experiments
(DoE). The DoE study uncovered hidden peaks and unknown criticalities, which
would eventually lead to method and product failure. Since this was a sensitive
case of method development it was treated accordingly, and techniques such as
method of steepest ascent were adopted to attain the optimum condition.
Finally, the method robustness was proved and fortified through capability
analysis and Monte Carlo simulations.
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