FDA’s bioanalytical method validation guidance provides an approach for pharmaceutical companies and CROs to employ during drug development. Additionally, it ensures the quality and veracity of acquired data and results. The FDA released the current guidance document in May 2018.
The goal of the guidance is to help sponsors aiming for Investigational New Drug applications (INDs), Abbreviated New Drug Applications (ANDAs), Biologic License Applications (BLAs), etc. It is applicable for studies that require quantitative evaluation of drugs or analytes.
It can help evaluations related to toxicokinetic, pharmacokinetic, and biomarker concentration. FDA’s guidance also illuminates the road for the development of bioanalytical methods used in non-clinical studies.
Scope and Principles
It is worth noting that these guidelines on bioanalytical method validation are non-binding. Where scientifically justified, a different approach or a modification of the guidelines is welcome. However, the method and justification should match the goals of the regulatory requirements.
FDA’s guidance document has several applications but is especially important for sponsors considering investigational new drug applications (INDs) or applicants of new drug applications (NDAs).
Carefully constructed and well-detailed method development is the cornerstone of method validation. FDA recommends that the sponsor (or CRO) should “understand” the analyte of interest before going into method validation. This includes several factors, including the physicochemical properties of the analyte.
A better understanding of the analyte is immensely helpful in method development and creating a standard operating procedure (SOP). The process also makes it possible to check if an existing method can be applied, rather than spending time developing or validating a new method. Method development considers several bioanalytical parameters to establish the suitability of the method and thus its validation.
On the Use of Assays
Bioanalytical method development and validation often use chromatographic assays (CCs) and Ligand Binding Assays (LBAs). As such, FDA bioanalytical method validation guidance emphasizes on these assays. These assays help provide various factors by quantitative determination involving biomarkers, drugs, their metabolites, and therapeutic proteins. Several biological matrices can be used, including blood, serum, plasma, urine, and tissue such as skin.
Given their role in method validation, bioanalytical parameters specific to these assays are important to consider. These include:
- Reference standards and critical reagents
- Calibration curve
- Selectivity and Specificity
- Accuracy, Precision, and Recovery
- Quality control samples
- Dilution Effects
Method Validation and Expectations
Generally, a validated method should show system suitability using a specific SOP. Calibration curves should find their way to analytical runs. It is important to use the same curve fitting and weighting during the study as with validation.
QCs should form at least five percent of the samples, with room to add more. An analytical run can fail if the QC and/or calibration acceptance criteria are not met.
Understanding Partial Validation
Partial validation is useful when changes are made to a validated method. The scope of the partial validation can vary from a small change in assay accuracy and go all the way to near full validation. This is done to accommodate small changes in the method or for method transfers and similar procedures.
Cross-validation is employed in specific circumstances. This includes situations where the same experiment or method is being used in two different laboratories. It can also apply to the use of different methods within a study or using the same method across studies.