FDA: Draft guidance on bioanalytical validation reflects tech advances

By Zachary Brennan

- Last updated on GMT

FDA calls for fully validated bioanalytical methods
FDA calls for fully validated bioanalytical methods

Related tags Chromatography

The updated draft guidance calls for fully validated bioanalytical methods for any pivotal studies used to obtain approval or labelling, though less validation may be sufficient for a sponsor’s internal decision making.

Originally issued in 2001, the US Food and Drug Administration (FDA) updated the draft guidance​ following a meeting from 2006 on best practices for chromatographic and ligand binding assays and a workshop in 2008 on incurred sample reanalysis.

The guidance is meant for those working in gas chromatography (GC); high-pressure liquid chromatography (LC); combined GC and LC mass spectrometric (MS) procedures; and ligand binding assays, and immunological and microbiological procedures that are performed for the quantitative determination of drugs and/or metabolites, and therapeutic proteins in biological matrices, such as blood, serum, plasma, urine, tissue, and skin.

The guidance outlines examples where full, partial and cross-validation should be used. For instance, an example of cross-validation would involve a situation in which an original validated bioanalytical method serves as the reference, and the revised bioanalytical method is the comparator.

When sample analyses within a single study are conducted at more than one site or more than one laboratory, cross-validation with spiked matrix standards and subject samples should be conducted at each site or laboratory to establish inter-laboratory reliability​,” the FDA says

Cross-validation should also be considered when data generated with different analytical techniques, such as LC­MS/MS vs. ELISA, from different studies are included in a regulatory submission.

More Details

The guidance also offers more specific detail on the various chromatographic methods, ligand binding assays, incurred sample reanalysis, and other issues that should be considered and how best to document validation methods.

In terms of the other issues, the FDA offers advice when analytes are also endogenous compounds and the accuracy of the measurement of the analytes poses a challenge when the assay cannot distinguish between the therapeutic and the endogenous counterpart.


As for biomarkers, the agency says they “can be used for a wide variety of purposes during drug development; therefore, a fit-for-purpose approach should be used when evaluating the extent of method validation that is appropriate​.

When biomarker data will be used to support a regulatory action, such as the pivotal determination of safety  and/or effectiveness or to support labeled dosing instructions, the assay should be fully validated​.”

Other new technologies, however, such as the Dried Blood Spot (DBS) methodology “has been successful in individual cases, the method has not yet been widely accepted​,” the FDA says.

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