Dr. Fadi Alkhateeb of Waters Corporation discusses his recent method development work.
What does it mean to develop a good LC method?
With Method Lifecycle Management (MLCM) we focus not only on the quality of the analytical method but also on the quality of the reportable result. The goal is to generate quality data across the life of a method. To achieve this, method development begins with an Analytical Target Profile (ATP) in which performance objectives are defined in terms of accuracy and precision, independent of the analytical technology chosen. The ATP is linked to the Critical Quality Attributes (CQA) of the drug product and the Critical Process Parameters (CPP) of the manufacturing process. The traditional method development goals of resolution and peak shape are critical method parameters, but what defines a good method under MLCM principles is one that achieves the accuracy and precision goals specified in the ATP. This leads to a quality reportable result throughout the method’s life.
Why are pharmaceutical companies adopting MLCM and Analytical Quality by Design (AQbD) approaches to method development?
Pharmaceutical companies are interested in ensuring product safety and efficacy, accelerating drug development, improving efficiencies, and controlling their risk. Efficient method development and developing fit-for-purpose analytical methods are essential to these goals. MLCM with an AQbD approach to method development achieves robust, well-designed, and well-understood methods that: are fit for their intended purpose; generate high quality data; minimize out-of-spec (OOS) and out-of-trend (OOT) results; can be utilized over years or even decades; and are durable regardless of the technology, lab or analyst running the method.
In much of your method development work you use 3rd party method development software, in addition to Empower CDS and the ACQUITY QDa Mass Detector. Please describe a key benefit of these tools.
A recent, exciting technological development is the ability to use automated MS peak tracking in AQbD method development. Waters Empower CDS is now seamlessly integrated with S-Matrix Fusion QbD PeakTracker software allowing automated DoE, automated method generation and both UV and ACQUITY QDa Mass Detection to identify each peak across the chromatogram, expediting method development and ensuring peaks are properly identified, and coelutions are not missed. Retention times change and peaks can co-elute during the method development process. Method development using only UV detection requires the time-consuming injection of sometimes expensive and not readily available standards to identify and track shifting peaks. Also, a mass detector is a very powerful risk mitigation tool to quickly identify unexpected and non-chromophoric chromatographic peaks. For more information, please see my applications work Automated Peak Tracking Using Mass Detection and Fusion QbD Software.
How does AQbD differ from other approaches to method development?
AQbD is a more comprehensive approach than one-factor-at-a-time (OFAT) or systematic method development. With AQbD, design space and control strategy are established as part of the method development, providing a broad knowledge about the multiple variables that are involved in this process. AQbD includes an upfront assessment to identify and classify the areas of risk in the analytical procedure. Subsequently it calls for the development and implementation of control strategies to mitigate the identified risks. The promise of this approach is that it may allow for some regulatory flexibility because it demonstrates understanding and control of the analytical procedure. If a systematic approach to method development includes DOE, risk assessment, and control strategies, it could also be considered an AQbD approach to method development.
Why is Design of Experiments (DOE) an important part of AQbD method development?
DOE reveals the effect that each variable has on a chromatographic method. For example, it provides details about how pH is affected when temperature or gradient time are adjusted. In my application note, Analytical Quality-by-Design Based Method Development for the Analysis of Formoterol, Budesonide, and Related Compounds Using UHPLC-MS, I found that below a certain temperature, the pH has a very significant impact on the separation. However, above that temperature, the pH doesn’t matter. I would never have known this without the data analysis and design of experiments in the software.
I understand that an important aspect of a lifecycle approach to analytical methods (MLCM) is understanding and controlling risk. What criteria should be used to evaluate a solutions partner when taking this approach?
I recommend partnering with a supplier who understands the customer’s goals and is knowledgeable in method lifecycle principles and AQbD method development. Also, one should choose a vendor who manufactures reproducible chromatographic instrumentation with robust, reliable performance, accurate UV and MS detection, compliant-ready software with data traceability, and reproducible column chemistries. Choosing a highly reproducible LC column is critical to the long-term reliability and robustness of an analytical method. Column variability can lead to OOS and OOT results and poor method performance, resulting in costly method revalidation. Some key considerations when choosing LC columns can be found in BEH C18 Batch to Batch Robustness for the Analysis of Rosuvastatin and Impurities. A good solutions partner will provide high quality tools and applications expertise in all of these areas.