STEPS IN ANALYTICAL METHOD QUALIFICATION
In contrast to analytical method validation where regulatory requirements are explicit, qualification requires the project
sponsor to have a clearly defined policy in the absence of well-defined regulatory boundaries. Ideally, qualification starts
with an initial method assessment for filing the IMP dossier for Phase I. This assessment can be done immediately after method
development, keeping in mind ICH Q2 parameters, with the aim of providing authorities with first results on method performance
and the setting of validation acceptance criteria for future ICH validation. Of course at this early stage, cost constraints
can be an impetus for reducing the burden related to cGMP (e.g., in terms of quality assurance oversight), provided that confidence
and reliability in data acquisition and management are ensured.
While not cited in ICH Q2, stability-indicating profile of methods used to demonstrate product stability should be addressed
as part of the analytical method lifecycle in accordance to ICH Q5C on stability, at the latest during validation. Conditions
known to affect product stability (that have been determined from prior preformulation development work, stress stability
studies, and accelerated stability studies) are useful for showing stability-indicating properties of analytical methods.
The whole project can always benefit from the confirmation that analytical tools are stability-indicating before initiating
pivotal stability studies or preferentially earlier during method development and initial performance assessment. A good practice
in sample selection is to include one batch of representative material as well as its degraded forms.
The next step in qualification can include method refinement and robustness assessment, preferentially performed during Phase
II. Refinement typically includes finding the optimal way to run the test method in the laboratory, whereas robustness assessment
allows identifying critical parameters affecting method performance. These complementary activities, however, do not supersede
results from the initial performance assessment since non-inferiority criteria (at least equal to) are applied. Moreover,
applying QbD principles at this stage (i.e., design of experiments, risk management) becomes less incompatible and cost-prohibitive
while the project is moving away from quick-to-clinic and Phase I towards a later clinical stage (9). Using risk-based tools,
such as Ishikawa or control, noise, and experimental (CNX) methods for the identification of critical factors followed by
failure mode effect analysis (FMEA) or risk ranking matrices for prioritization, combined with design of experiment, is an
important approach to rationalizing laboratory work, better understanding method performance, and ensuring optimal project
While a method cannot fail qualification, it should be ultimately scientifically sound and optimized to achieve acceptable
performance capability. Developing a well-designed qualification program is therefore crucial for ensuring that the method
is sufficiently robust for passing the validation step while cost incurred by the different qualification activities can be
distributed across the development roadmap as a function of the level of project risk.
Finally, if third parties have been involved in the development and qualification of analytical methods, a well-designed technical
transfer and appropriate documentation are required for maintaining the qualification status after the transfer of the method
and to enable the validation readiness assessment exercise before ICH validation takes place.