Making Room for Improvement

An article in a recent issue of The Analytical Scientist – “Breaking Out of the Black Box” (1) – highlights the problem of users not understanding the underlying science in analytical techniques, blindly generating data without the appropriate context and interpretation. The article by Wolfgang Lindner – a pioneer in chiral analysis – caught my attention because black box thinking is one of the problems I’ve been working on for more than a year. I am looking for more flexibility in developing regulatory-approved analytical methods for the pharmaceutical industry. Approved methods are locked and don’t require much scientific knowledge – the user must follow them rigidly and there is little opportunity for improvement.

The core of this project, therefore (which was part of a larger study on molecular interactions) was to shift the focus to a more science-based approach that requires an understanding of the analytical methods, thereby enabling continuous improvements.

Anders Karlsson (AstraZeneca R&D in Mölndal, Sweden) came up with the idea that launched the project. He wanted to continuously improve his quality control procedures after the original methods had been approved by regulatory agencies. Actually, this is already possible to a certain extent, but only if the analytical method is filed according to the European Medicines Agency’s (EMA) Quality-by-Design guidelines. That is to say, the guidelines do allow post-approval changes if – and only if – the changes are inside the original design space, which can be limiting.

For example, a pharmaceutical company that had developed and filed a high-performance liquid chromatography (HPLC)-based quality control method a few years before the commercialization of ultra-HPLC  (UHPLC) would find it difficult, if not impossible, to upgrade its quality process simply because it would not have been able to include UHPLC conditions in the original design space. Done correctly, switching from HPLC to UHPLC is a minor modification because the essential difference lies in column dimensions and particle size – and yet it would offer significant improvements on analytical performance. However, according to the regulations, the changeover is not possible without resubmitting the method to the EMA.

Working with Karlsson and Mikael Nilsson, Cambrex Karlskoga, and my supervisors, Jörgen Samuelsson and Torgny Fornstedt, I launched a project with the goal of finding a way to develop analytical methods that allow minor post-approval changes – even if they are outside of the original design space.

We modified an original quality control method for esomeprazole magnesium (Nexium), by switching from HPLC to UHPLC. Our first and most important step was to investigate the differences between HPLC and UHPLC in depth, which allowed us to explain the differences scientifically, making method transfer easier.

I strongly agree with Lindner that we should strive to understand the underlying principles behind the analytical methods we use every day in drug development and manufacturing. Greater understanding is often the solution to creating smart and efficient analytical methods. On a personal note, the project has also taught me that you can’t be an expert on everything and that cooperation is needed to produce good and robust analytical methods. I believe that one of the reasons behind the success of the project was the diversity in backgrounds, perspectives and skills of the people involved.