Webinar Highlights – Improving Analytical Method Performance Through Quality Risk Management and a Design of Experiments Approach

By November 7, 2019


In our most recent Method Lifecycle Management webinar held Improving Analytical Method Performance Through Quality Risk Management and a Design of Experiments Approach, Joseph A. Turpin, Director of Chromatography Products and Services at S-Matrix Corporation and Tran Pham, Business Development Manager at Waters Corporation, presented an overview of Quality by Design approaches to analytical method development (AQbD), the regulatory views on this approach, examples of design of experiments in AQbD, and case studies demonstrating software assisted AQbD method development.

The webinar can now be accessed on-demand and we have compiled the top 10 questions from the webinar and answered them in more detail below:

1. What was the system used in the case study? The system used was the Waters ACQUITY H-Class PLUS, PDA and QDa detectors, Empower chromatographic software, and Fusion QbD software.

2. Does AQbD only apply to chromatographic methods? No. AQbD approaches apply to any analytical procedure needed to test and ensure product quality. When developing analytical methods using an AQbD approach, risks assessments and design of experiments are conducted to understand method performance limits and to establish control strategies to ensure good method performance. In return, confidence in product quality is increased because these reliable methods are generating good quality data.

3. Developing methods using AQbD approaches seem to require more work and longer development times. How can the added time and labor be justified? Developing methods with AQbD approaches initially requires more time when compared to traditional approaches. However, once an AQbD approach is implemented per a company’s unique analytical workflow, the amount of time it takes to develop a method is reduced. In addition, the benefits of using an AQbD approach are realized. These include increased method robustness and method performance understanding, reliability and decreased method failures.

4. Do you use Empower to do your DOE studies? Fusion QbD fully automates the creation of the instrument methods and method sets in Empower with the QbD-aligned method parameters. The experiments are exported to Empower as ready to run Empower Sample Sets. Fusion QbD also fully automates import and modeling of any desired chromatographic results from the Empower integrated chromatograms.

5. Please share what you know of clients submitting AQbD based method development in their regulatory filing and how the regulatory agency responded. Did the client company receive regulatory relief in allowing post-approval method changes as long as the changes were within the operating space? Overall, applying AQbD helps minimize risks and promotes finding the right method conditions the first time. This helps reduce the need to make any post approval changes. Also, the AQbD approach and generation of an operating space demonstrates control and understanding of your method which ultimately builds confidence with regulatory agencies.

6. How do I select a parameter range for selected factors in DoE study? Consider the major effectors of selectivity for initial chemistry system screening. For example, in RPC you would include:

    1. Different column chemistries
    2. A broad pH range – using a maximum of 1.0 unit of pH between study levels
    3. Gradient Time as the slope variable. Note – set the Initial % strong solvent as low as possible to assure retention of early eluting peaks, and the Final % strong solvent has high as possible to assure all peaks elute before the end of the gradient.

7. Is the AQbD currently available for LC-MS/MS methods? Fusion QbD experiment automation is primarily focused on the LC portion of the method. Fusion QbD also supports automated acquisition of MS data from integrated TICs when using the ACQUITY SQD or QDa. However, you can also manually transfer other critical MS results and incorporate them directly into the method development analysis and robustness modeling along with the LC elements of the study.

8. Is this software only useful for chromatography application connected by Empower? Fusion QbD with PeakTracker is currently focused on the seamless integration with Empower to provide a fully automated method development tool that allows for automatic method creations and automatic peak tracking via MS data collected by the Waters QDa mass detector.

9. What approach to use when after DOE there is no unshaded (white) areas which means all our criteria are failed? In this case, you would evaluate the selected experiment parameters and ranges. You would shift the study ranges and/or change the parameters. For example, in a screening study you may not have included the stationary phase, or included only closely related C18 columns. In this case you should consider including columns of very different stationary phases which would be consistent with your sample compounds. Given a variable such as pH, you should consider shifting – and possibly broadening the pH range, while being careful to not exceed a maximum of 1.0 unit of pH between study levels.

10. Can you recommend another DOE software to use? There are many other DOE or statistical modeling software that communicates with Empower and have unique features. It is best to research and find which software best suites your unique method development work flow and requirements.

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Categories: Pharmaceutical