Modern Perspectives on Method Development

By October 21, 2021

In method development, traditionally analytical developers have focused largely on the analytical method itself. However, with modern day, enhanced approaches to procedural development, our focus is now on the reportable result. We need to fully understand how aspects of sampling, storage, sample preparation, personnel training, analytical procedure, instrument parameters, and data handling affect the variability of the reportable value. We use Analytical Quality-by-design (AQbD) principles to identify and minimize areas of the entire procedure that could potentially introduce variability into our final result.

The goal of the analytical method developer is to design a method that can be used to check specific quality attributes of the drug, and therefore whether it is fit for purpose. A well-designed procedure will achieve the accuracy and precision and any other goals required to demonstrate that a product of consistently high quality is being manufactured.

Drivers for the adoption of enhanced approaches to method development

Many companies are interested in adopting enhanced approaches to methods, as outlined in the new ICH Q14 and USP 1220 guidelines, and are looking to benefit from potentially greater regulatory flexibility to make changes to validated methods. Through the adoption of modern approaches to designing and managing analytical procedures, companies will have a better understanding of their products and procedures as well as processes for change management.

Improved understanding will enhance regulatory confidence in their ability to ensure quality products. In addition, well-designed and -managed methods can be more readily transferred between laboratories and across different technology platforms and successfully utilized for decades. Risk management and risk mitigation are very strong motivating factors driving pharmaceutical companies to adopt modern approaches to method development.

I spoke recently with Dr. Fadi Alkhateeb, a colleague and Senior Separations Scientist within Waters Scientific Operations division. Fadi gave me his perspective on the approach and tools that the Separations team uses when designing and developing fit-for-purpose methods.

Dr. Stephanie Harden: How does Analytical Quality-by-Design (AQbD) differ from other approaches to method development?

Dr. Fadi Alkhateeb: While there are multiple approaches to analytical method development, the AQbD is a more comprehensive approach than the others. With this systematic approach, we define a region of chromatographic space where inadvertent changes will not affect results, this region is known as MODR. We define this space by performing DoE, we evaluate and sample the space efficiently. As a result, we gain knowledge about method performance characteristics and study factors limitations.

AQbD includes an upfront and ongoing assessment to identify and classify aspects of the analytical procedure that could contribute variability to the process, with the subsequent development and implementation of control strategies to mitigate the identified risks. The promise of this approach is that it may allow some regulatory flexibility to validated methods since it demonstrates a thorough understanding and control of the analytical procedure.

Some key considerations when choosing LC columns, for example, can be found in BEH C18 Batch to Batch Robustness for the Analysis of Rosuvastatin and Impurities. Column to column variability can lead to out of specification and out of trend results, resulting in costly remediation requirements.

Chromatograms of the USP method described on XBridge BEH C18 Columns from 10 different batches. The retention order is impurity A, rosuvastatin, impurities B and C.


Dr. Stephanie Harden: I know that you use method development software in addition to the ACQUITY QDa Mass Detector to help develop robust separations. Can you describe a key benefit these tools afford, in addition to the LC?

Dr. Fadi Alkhateeb: We take advantage of the modern technologies available to us to ensure we really develop a fit for purpose method and that we understand the limitations of the method and how the separation could be affected if any method parameters change. One recent, exciting technological development is the ability to use automated MS peak tracking in combination with Fusion method development software from SMatrix. Now that Waters’ Empower CDS is integrated with Fusion QbD PeakTracker software, we can benefit from automated DoE, automated method generation and both UV and ACQUITY QDa mass detection to identify each peak in the chromatogram. This helps to ensure that peaks are correctly identified, and coelutions are not missed. It’s especially important when we need to ensure the baseline separation of critical peaks, since retention times change and peaks can co-elute during the automated method development process.

When relying on UV detection alone, we’re often required to use standards to check peak ID as the peaks shift around, but this can be expensive, and standards are sometimes not readily available. We see the ACQUITY QDa Mass Detector as a very powerful risk mitigation tool to quickly identify known, unexpected and non-chromophoric chromatographic peaks. For more information, please see my applications work: Automated Peak Tracking Using Mass Detection and Fusion QbD Software.

Dr. Stephanie Harden: Why is Design of Experiments (DoE) an important part of AQbD method development?

Dr. Fadi Alkhateeb: A DoE approach reveals the effect that each variable has on a chromatographic method. For example, it provides details about how pH is affected when temperature and or gradient time are adjusted. DoE can also apply to other variables such as sample preparation and system to system differences.

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, pH is not a significant factor – I would never have known this without using a design of experiments approach.

Dr. Stephanie Harden: What do you see as the main benefits to customers of partnering with Waters when starting to adopt modern approaches to method development?

Dr. Fadi Alkhateeb: At Waters we specialize in compliance and regulatory requirements and have a full understanding of the needs of our customers, as well as the challenges they face when it comes to adopting new approaches and tools/technologies. We partner with third-party software companies to ensure that we can offer fit-for-purpose integrated solutions for our customers looking to introduce method development software into their workflows. Our global professional services team specializes in training and supporting customers to achieve the outcomes they need.

Risk mitigation is an important consideration for pharmaceutical companies today, and at Waters we pride ourselves on the quality and consistency of our consumables and the reproducibility and reliability of our separations technologies. Our focus on quality and innovation is a significant factor driving companies to standardize on Waters technologies as they modernize their approach to methods and realize the benefits of controlling variability.

I’d like to thank Fadi for his time and invite you to connect with me on LinkedIn if you have any questions or would like more information about the adoption of modern technologies and enhanced approaches to managing your methods.

To learn more about the components of a successful workflow based on the use of AQbD principles, subscribe to the Method Lifecycle Management Podcast. Listen here.

Categories: Pharmaceutical