There has been a dramatic increase in the range of what bioanalysis can measure. Bioanalytics has also witnessed remarkable progress in the emergence of new assays. Regulatory statutes have evolved accordingly.

Against this dynamic backdrop, we explore what the latest FDA guidelines on the validation of bioanalytical methods imply for biolab in practical terms. We have extensively researched industry responses to put this comprehensive article together.

FDA and Bioanalytics

The U.S. Food and Drug Administration (FDA) has been a leading agency in guiding and regulating bioanalysis since the 1980s. In 2001, the FDA had published its first comprehensive guidelines for bioanalytical method validation for both large and small molecules.

Since then, a lot has changed in the arena of bioanalytics. The emergence of liquid chromatography-mass spectrometry (LC-MS) and ligand binding assays (LBAs) for biologics deserve special mention in this context.

The FDA issued its latest guidelines biolab for bioanalytical method validation in 2018 as an improved version of its 2013 draft guidelines. The document stresses the criticality of appropriate validation parameters: lower limit of quantification (LLOQ) and upper limit of quantification (ULOQ).

It also emphasizes how sampling and storage can impact bioanalysis. The sample collection procedure and storage conditions at the clinical site need to be determined during assay development.

However, the most important aspect of the latest guidance document is its emphasis on the need for comprehensive reporting. That is the part that biolabs need to be particularly careful about.

FDA’s Latest Guidelines: New Additions

The draft guidelines published in 2013 present detailed evaluation parameters for chromatographic assays and ligand binding assays (LBAs). The 2018 guidance document maintains the majority of them. However, there are some changes that biolabs need to note with care.

Most Important Changes

  • The section on incurred sample reanalysis (ISR).
  • A new section focused on:
    • Biomarkers
    • Bridging data and dried blood spots (DBS)
    • Diagnostic kits
    • Endogenous compounds

Changes With Reference To Chromatographic Assays

  • The acceptance criteria for validation of dilution and carryover are different.
  • The clarification for the number of QC levels and their replicates is new.
  • The document does not offer any acceptance criteria for QCs during accuracy and precision runs. However, the bioanalytics industry feels that fresh QCs should be used for at least one accuracy and precision run.
  • During in-study analysis, QCs need to cover the concentration range of the study sample.
  • Each run needs to evaluate the lack of interference at LLOQ.
  • For distinct batches within a single run, new acceptance criteria have been added.
  • Monitoring need for IS (incurred sample) drift and response.

Changes With Reference To LBAs

  • Clearer description of accuracy and precision runs.
  • More clarity on anchor points.
  • Added emphasis on
    • Including appropriate and clearly defined controls for each parameter
    • Maintaining consistency in preparing calibrators for every run.

New Additions In Recommended Documentation

  • Concurrent and reconstructible records to ensure data integrity. A separate method development report is no necessary. However, unique aspects of method development need to be documented.
  • All information on rejected runs and investigations need to be included.
  • Information on reanalyzed data, rejected investigations, reinjections, and reintegration needs to be recorded for chromatographic methods. Data should justify the need for reinjections.
  • Emphasis on more details in the reporting to reduce the need for onsite data review.