Developing a standardized analytical method is a cumbersome and lengthy business. Ironically, the actual development of a method may not be that hard. When, for example, developing a method for analysing a pharmaceutical product, there is likely already quite some experience with the analytical technology and putting together a fully described method may take a few months (although, of course, it may take longer if obstacles are encountered). However, most effort likely concerns the full validation of the method, which may easily take one or two years (see Figure 1).
Figure 1: Schematic of the process of developing and validating an analytical method.
The different stages of method validation are outlined in Table 10.10 of the book, which is reproduced below. Most of the validation work can be performed in house and is quite manageable with a focused effort. However, a reproducibility test (highlighted in yellow) is time consuming and costly. Contrary to repeatability, which tests the precision of a method (i.e. random variations in the results) when applied in a given laboratory, on a given instrument, by a single analyst, reproducibility involves multiple laboratories (often at least five), multiple instruments and multiple analysts. Setting up the test (including suitable samples and reference materials), getting different laboratories to participate, perform the required experiments correctly and submit the results, and analysing the data following strict statistical protocols requires effort, perseverance, and often patience. In short, reproducibility testing is a daunting task that should only be performed after all lights (stability test, intermediate precision, robustness) have turned green.
More information on validation procedures can be found in module 10.5 and in ICH Q2(R2) Guideline on validation of analytical procedures.
Figure 2: Illustration of the role of Life-Cycle Management in the development and maintenance of analytical methods.
The unintended, but understandable consequence has been that methods, once accepted by a standardization body, such as the European Medicines agency (EMA) or the Food and Drug Administration (FDA) in the USA, have hardly ever been updated. As a result, methods may be dated and sub-optimal.
The “ICH Q14 Guideline on analytical procedure development”, issued by the International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) has now opened the door for method updates without full validation in a process called life-cycle management (see Figure 2)
If a new method is developed using a different type of analytical technology (e.g. replacing a liquid-chromatography method by an immune assay) a full validation and a comparative analysis of the two methods is unavoidable. However, when the technology is updated, for example when progressing from a high-pressure liquid chromatography (HPLC) method to an ultra-high-pressure liquid chromatography (UHPLC) method, a much more limited revalidation may suffice. In the latter case, large savings in time and consumables needed come within reach.
The nature and extent of the revalidation need to be established on a case by case basis.
