Analytical Method Lifecycle: A Roadmap for Biopharmaceutical Development - The authors propose a roadmap for analytical lifecycle development. - BioPharm International


Analytical Method Lifecycle: A Roadmap for Biopharmaceutical Development
The authors propose a roadmap for analytical lifecycle development.

BioPharm International
Volume 26, Issue 4, pp. 46-50


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 spend.

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.

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