Bioanalytical Method Validation: A Guide For New Drug Development

Validated bioanalytical methods for quantitating analytes and biomarkers are crucial for the success of nonclinical and clinical studies. These validated bioanalytical methods are vital because they provide critical safety and efficacy data of drugs and pharmaceutical products. However, validating a bioanalytical method needs to address several key questions, including:

Measurement of intended analyte and selectivity and specificity of the method. Does the bioanalytical method measure the analyte without any interference?

Method accuracy and precision. Is there any variability in analyte measurement?

Reliability of dynamic assay range. What are the lower limit and upper limit of quantitation?

During the study, how are samples collected, processed, and stored? How do these parameters affect the method? What are the storage temperatures? Any specific shipping requirements?

Irrespective of the drug discovery phase, bioanalytical method validation needs to address many vital questions during bioanalytical analysis. While modifying an already validated assay, the sponsor can conduct partial or cross assay validation. Besides, assay method development for complex molecules such as biomarkers needs a specialized approach to method validation. 

Thus, laboratories and assay validation services developed a fit-for-purpose concept for validating bioanalytical methods. This approach metamorphoses according to the intended goal and different phases of drug development. Pivotal studies needed for NDA, ANDA, or BLA submissions should be fully validated. Thus new drug development will need full validation. However, sponsors may not conduct such a stringent assay validation for exploratory studies.

Bioanalytical method validation

An adequate bioanalytical method validation ensures that the method is thoroughly optimized to assess a given study sample. Sponsors must strictly adhere to certain aspects of method validation. These requirements are discussed below.

  • Sponsors must perform full method validation for analyzing new drug compounds and their metabolites or biomarkers.
  • Sponsors must perform full method validation if revisions are made to an existing validated method by adding an analyte or metabolite.
  • Establish a detailed standard operating procedure before initiating bioanalytical method validation. The protocol must mention factors that control the matrix environment, procedural variables, and other parameters from sample collection to sample analysis. Such an approach minimizes associated effects on analyte measurement.
  • Document and report experiments performed to draw or claim conclusions regarding method validity.
  • Validate analyte measurement in the intended biological matrix.

Bioanalytical method validation includes optimizing and validating assay parameters to ensure their reliability in bioanalysis. These parameters include

  • Reference standards
  • Calibration curve
  • Critical reagents
  • Quality control samples
  • Sensitivity
  • Selectivity and specificity
  • Precision
  • Accuracy
  • Stability
  • Recovery

As mentioned earlier, sponsors can perform partial or cross-validation under certain circumstances. Sponsors conduct partial validation while modifying an already validated method. Partial validation can range from validating a single parameter to nearly full method validation. Cross-validation compares validation parameters among two or more bioanalytical methods used within the same study or covering different studies. Besides, sponsors also execute cross-validation when assessing samples within the same study but at different testing sites. In such cases, sponsors must conduct cross-validation at each experimental site  using nonpooled subject samples and shared matric quality controls to establish the reliability of a bioanalytical method.

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