A recent stimulus to the review process article by the United States Pharmacopoeia (USP) expert committee proposes a major
change to the way regulated laboratories develop, validate, and control analytical procedures. Is this Quality by Design (QbD)
for the chromatography laboratory?
In this column I want to focus on the heart of chromatographic analysis: The analytical method or procedure. Analytical procedure
development, validation, and transfer are key parts of the traditional process that starts, if you're lucky, with defining
what you want the method to do and ends up with the operational use of the procedure. In the middle is the stuff that should
be done properly but usually is not, as evidenced by how poorly a method operates in routine use. This is typically because
the method development and validation is performed by one group and the operation of the procedure is carried out by another.
In many instances the two groups rarely talk to each other except when things go wrong — and blame each other for the problems.
Of course, this never happens in your organization, does it?
In the Beginning .....
Validation of analytical procedures in the pharmaceutical industry was harmonized with the agreement of the International
Conference on Harmonization (ICH) quality publications Q2A and B covering the text and methodology of validation of analytical
procedures (1,2) in 1994 and 1996, respectively. These two publications were merged into a single revised document ICH Q2
(R1) in 2005 without any text being amended (3).
Robustness of an analytical procedure is defined in ICH Q2(R1) as:
A measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication
of its reliability during normal usage.
In the methodology section there is more information on the topic of robustness:
The evaluation of robustness should be considered during the development phase and depends on the type of procedure under
study. It should show the reliability of an analysis with respect to deliberate variations in method parameters. If measurements
are susceptible to variations in analytical conditions, the analytical conditions should be suitably controlled or a precautionary
statement should be included in the procedure. One consequence of the evaluation of robustness should be that a series of
system suitability parameters (for example, resolution test) is established to ensure that the validity of the analytical
procedure is maintained whenever used (3).
This is the interesting part — for a document focused on the validation of analytical procedures we have the statement that
robustness is actually a job to be performed during method development. How many people actually conduct robustness studies
when under time pressures? However, it does say that robustness depends on the method but then goes on to mention some variables
that could be considered when looking at high performance liquid chromatography (HPLC) procedures:
In the case of liquid chromatography, examples of typical variations are:
Influence of variations of pH in a mobile phase;
Influence of variations in mobile phase composition;
Different columns (different lots and/or suppliers);
Flow rate (3).
Therefore, in my view, robustness should be undertaken for chromatographic methods, especially those involved in generating
data for making critical decisions.