Our director of analytical services, Laurie Goldman, sheds light on some of the key considerations and challenges labs face when conducting analytical method validation and gives her thoughts on the future of method development and validation.

A solid foundation

Today we have more reference materials and regulatory direction to develop sound methods and validation exercises than ever before. The FDA has put increased focus on providing clarity and support to analytical method development and validation, including a number of new product-specific guidances. When supplemented with USP chapters, ICH guidelines, and industry publications, there is a strong foundation for steering validation and its different approaches. Companies are also better equipped to construct validation data packages thanks to advances in instrumentation software.

Investing time into cultivating robust methods during a product’s early development establishes a solid foundation that facilitates validation when moving to clinical and commercial production. This has been increasingly recognised by analytical chemists, formulators, and managers in recent years.

Design and planning

Document, review, repeat.

Before designing and planning analytical method validation, it is essential to ensure that all analytical methods are fit for purpose. For optimal performance, we carry out scouting experiments to ensure our methods perform with a known degree of certainty and to verify we can measure relevant product parameters within acceptable ranges. We also work closely with our formulation teams to develop analytical methods throughout the development stages of each project. This allows us to use, evaluate, and refine our methods through multiple research, scale-up, and engineering batches.

Poor method design that leads to the need for re-analysis, reperforming the validation, or reviewing invalid data will significantly impact a project timeline, but that is not the only negative effect. Particle Sciences is a contract development and manufacturing organization, so we often have multiple client projects utilizing the same analytical equipment. A rerun of any analysis can cause a ripple effect that impacts the timeline of other projects in the queue, so it’s especially critical that methods are designed to be reliable and consistent.

Overcoming challenges

One challenge that labs face when validating a method is sample preparation. This is because each aspect of the process can impact the reproducibility of a measurement. As such, considerations like sampling technique require a full exploration in the early method development stages. We apply orthogonality to sample preparation steps by evaluating alternate diluents, varying preparation times, or modifying treatment settings. This becomes a type of design of experiments (DOE) that enables us to select relevant factors and assess the response to assure the robustness of our sample preparation steps.

Complex dosage forms can present challenges for sample preparation, including harsh extraction techniques that can impact analyte stability. At Particle Sciences, our analytical team works closely with our formulators to fully understand the limitations of our methods. This often involves producing “alternate” samples with variations in drug loading, excipients, or physical properties relative to the target product profile. Characterizing these samples alongside the actual product enables us to fully assess analytical method capabilities.

The future

Advances in pharmaceutical technology have led to greater complexity in analytical method development and validation. Examples include the shift from small molecule analytes to biopharmaceutics, the rise in complex dosage forms, and the increased use of biodegradable polymers for devices and depot injections. Instrumentation and software developments make analytical method development and validation easier, but these systems also introduce new networking and administration challenges.

When developing reproducible methods, sample preparation for complex dosage forms is a key challenge. We expect that techniques for preparing complex dosage forms will be standardized across the board and that the results produced from these dosage forms will become more reproducible.

We are also starting to see some of the sample preparation approaches we developed for drug-eluting devices and biodegradable particles take hold in the industry – a different kind of validation that reinforces the excellent work of our team!

Authors: Laurie Goldman and Nick DiFranco