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Bioanalytical method validation guidance language and a decade of progress

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Keywords: BMV, harmonization, regulations

Pver the last 10 years, bioanalytical method validation (BMV) has evolved in terms of science and health authority guideline language. Bioanalysts in 2019 need to be cognizant of a multitude of guidance and the associated interpretations around the globe. The transgression from a single regulatory document in effect in 2009, to today’s status has been documented through many publications in Bioanalysis. As such, this reflection paper recalls some of the pivotal points that have impacted regulated bioanalysis and what may lie ahead. At the time of writing, a single harmonized global BMV guideline is proposed and while appealing in concept, the complexity and diversity of bioanalytical approaches challenges any detailed prescriptive instructions on how to validate all assays. However, the fundamental attributes of a BMV that generate trustworthy data, have sustained the last decade and we can expect them to serve us well into the future. The authors reflect on key regulatory language developments and consider the lessons served as we take the bioanalytical discipline forward.

It is interesting to track back through the volumes of the Bioanalysis journal to see the frequency of reference to regulations and BMV Guidance. There, it is in Bioanalysis Volume 1 issue 1 (April 2009); the conference report on the second Calibration and Validation Group workshop held the previous year in Toronto, Canada [1]. The report outlines where we were a decade ago in discussing and debating current topics around BMV regulations. Of course, along with the Calibration and Validation Group workshop evolving into the Workshop on Recent Issues in Bioanalysis, the regulatory aspects of bioanalysis have also developed in coverage and complexity. At least, it seems that way. Fundamentally, however, we are still tasked with demonstrating the performance of a bioanalytical method against the criteria pillars of accuracy, precision, sensitivity, selectivity, stability and reproducibility, as we were in 2009 (and before). Considering what has changed and what remains consistent over the last decade, this reflection paper summarizes some of the key milestones that stand out to the authors and speculates what may lay ahead.

10 years ago, bioanalysts were operating to a single BMV Guidance (US FDA) [2] but the scene was set for a modernization of regulatory language that would reflect the ongoing practice of many bioanalytical laboratories. Pivotal White Papers that accommodated the expectations from the early Crystal City workshops and from the ligand-binding assay (LBA) community were considered essential complements to the 2001 BMV Guidance [3–6]. Then came the EMA contribution to BMV regulatory guidance (effective in 2012) [7] and the ensuing debates around harmonization began. That discussion has not stopped to this day. With several other global health authorities issuing BMV Guidance, which largely replicated EMA, an inordinate amount of workshop and conference sessions would focus on any actual or interpreted differences. The FDA issuance of their updated BMV Guidance in draft form in 2013 [8] added further debate and introduced the most significant changes, since the 2012 EMA BMV Guidance. However, the US FDA document remained in draft until last year (2018), leaving some degree of ambiguity and confusion. With finalization of the FDA 2018 BMV Guidance [9], a new round of debate has begun against the background appeal for BMV harmonization and consistency of scope.

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  1. Savoie N, Booth BP, Bradley T et al.2008 White paper: the 2nd Calibration and Validation Group Workshop on recent issues in good laboratory practice bioanalysis. Bioanalysis 1(1), 19–30 (2009).
  2. US FDA. Guidance for Industry: Bioanalytical Method Validation (2001).
  3. Viswanathan CT, Bansal S, Booth B et al.Quantitative bioanalytical methods validation and implementation: best practices for chromatographic and ligand binding assays. Workshop/Conference Report. AAPS J. 9(1), E30–E42 (2007).
  4. Fast D, Kelley M, Viswanathan CT et al.Workshop report and follow-up: AAPS workshop on current topics in GLP bioanalysis; assay reproducibility for incurred samples – implications of Crystal City recommendations. AAPS J. 11(2), 238–241 (2009).
  5. DeSilva B, Smith W, Weiner R et al.Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm. Res. 20, 1885–1900 (2003).
  6. Smolec J, DeSilva B, Smith W et al.Bioanalytical method validation for macromolecules in support of pharmacokinetic studies. Pharm. Res. 22(1), 1425–1431 (2005).
  7. European Medicines Agency. Guideline on Bioanalytical Method Validation (2011). www.ema.europa.eu/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf
  8. US FDA. Draft Guidance for Industry: Bioanalytical Method Validation (2013).
  9. US FDA. Guidance for Industry: Bioanalytical Method Validation (2018). www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf
  10. Findlay J, Dillard R. Appropriate calibration curve fitting in ligand binding assays. AAPS J. 9(2), E260–E267 (2007).
  11. Booth B, Arnold ME, DeSilva B et al.Workshop report: Crystal City V – quantitative bioanalytical method validation and implementation: the 2013 Revised FDA Guidance. AAPS J. 17(2), 277–288 (2015).

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