Revised FDA Guidance on the validation of analytical methods

The FDA has recently published the final version of their Guidance for Industry "Bioanalytical Method Validation". Extensive changes had been made to the guidance draft from 2013; these are the most important:

  • Chapter III, formerly "Chromatographic Methods", has been renamed to "Bioanalytical method development and validation" and supplemented by subsection "Bioanalytical Parameters of CCs und LBAs", which describes a total of nine parameters.
  • Chapter IV carries the title "Incurred Sample Reanalysis" (ISR) and, compared to the guidance draft of 2013 (here in chapter V), contains different requirements on how analyses must be repeated in order to verify the original analytical data. For example, samples for repeat analyses may not be pooled. Also, an ISR is expected for all studies submitted in the scope of an NDA, BLA or ANDA.
  • The tables included in the Annex have been completely revised and designed more clearly.
  • The glossary has been expanded considerably and contains 31 new terms (from "Autosampler stability" and "Hook effect" to "Zero calibrator").

Chapter II "Background" clearly points out the importance of validated analytical methods, which are indispensable for the successful execution of non-clinical, biopharmaceutical and clinical-pharmacological studies. These analytics offer critical data to demonstrate the safety and efficacy of medicinal products. To ensure that this data is completely reliable, the FDA lays down the following key questions:

  • Is the analyte being specifically and selectively captured by the method? Are there any interfering factors?
  • What variabilities are to be expected? How accurate and precise is the procedure?
  • What range in measurements provides reliable data? How sensitive is the method (detection and determination limits)?
  • How do the collection, handling and storage of a sample affect the reliability of the data? What steps need to be followed while collecting samples? Must samples be frozen before they are shipped? Storage time and temperature of samples?

The FDA expects that these questions are considered for proving the reliability of analytical data through method validation.

Following the fit-for-purpose (FFP) concept however, the proportionality should be considered: compared to analytical studies, which are paramount for gaining a marketing authorisation for a drug product, exploratory studies (e.g. in early stages of development) do not require a complete method validation in consideration of all key questions formulated in this guideline.

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