Bioanalytical validation personal perspective
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This document summarizes four case studies involving issues with bioanalytical method validation: 1) An analyst constructed standard curves inconsistently between assay runs, using a varying number of calibration standards. 2) An analytical method was used for multiple studies over many years without re-validation, despite changes in equipment and assay conditions. 3) Subject concentration-time curves showed implausible "U-shaped" profiles, indicating an unresolved analytical problem. 4) Hundreds of samples were rendered below the lower limit of quantification due to the laboratory failing to specify and follow procedures for sample acidification using hydrochloric acid. The document emphasizes that proper standard operating procedures, ongoing method monitoring,
Bioanalytical validation personal perspective
- 1. Bioanalytical Method Validation: A Personal Perspective on Small Molecules E. Dennis Bashaw, Pharm.D Director, Division of Clinical Pharmacology-3 Office of Clinical Pharmacology Office of Translational Sciences US Food and Drug Administration
- 2. Disclaimer: The presentation today should not be considered, in whole or in part as being statements of policy or recommendation by the US Food and Drug Administration. The examples given in the presentation today are based on actual situations seen by the presenter. All identifying information has been removed to protect the confidentiality of the applicants involved.
- 3. Trends in Drug Discovery Scannell, JW, et al “Diagnosing the decline in pharmaceutical R&D efficiency” Nature Reviews Drug Discovery, 11:191-200 (March 2012)
- 6. Drug Development in the 21st Century Risk/ Benefit Do No Harm Science Conservative Innovation Clinical Pharmacology
- 7. INNOVATIVE ANALYSES •Improved Computing Resources •Quantitative drug-disease-trial models • Exposure-response models INNOVATIVE TRIAL DESIGNS • Clinical trial simulations • Enrichment, adaptive, dose-response KNOWLEDGE MANAGEMENT • Leverage prior data New Clinical Pharmacology Tools
- 8. House of Cards If you do not have confidence in the validation of the analytical method, how can you have confidence in the concentration values? If you do not have confidence in the concentration values, how can you have confidence in the derived pharmacokinetic parameters or dose? Safety & Efficacy Clinical Pharmacology Bioanalytical Validation
- 10. Relevant FDA Guidances Bioanalysis. 2013 Mar;5(6):645-59. doi: 10.4155/bio.13.19. J Pharm Sci. 2011 Mar;100(3):797-812 Anal Chem. 2012 Jan 3;84(1):106-12
- 11. The Importance of Methods Validation to Clinical Pharmacology Bioanalytical Methods Validation Guidance, pg 2
- 12. MDS Canada
- 13. Cetero
- 14. Bioanalytical Review Problems Mis-labeled samples Improper Shipping Flawed Extraction Analytical Problems Calculation Issues Analysis/Reporting
- 15. Case Study #1 The Case of the “Come As You Are” Standard Curve
- 16. Case Study #1 IV drug, relative bioavailability study in patients with varying degrees of renal insufficiency Analytical plan called for daily standard curves to be constructed at 2, 5, 10, 25, 100, 500, and 1000ng/ml using triplicate samples. Analysis consisted of 5 runs over the course of 3 weeks by the same analyst
- 17. Case Study #1 Target (ng/mL) 2 5 10 25 100 500 1000 Run 1 1.76 4.2 10.2 22.3 120 515 1100 1.5 5.13 8.7 24.11 111 517.2 1070 2.13 4.8 11.4 27.2 102 505 1012 Mean 1.84 4.78 10.08 24.65 108.25 509.3 1045.5 Run 3 1.55 1005 2.42 1089 2.59 1070 Mean 2.19 1054.67 Run 4 1.76 4.76 10.35 21.45 114 535 1093 1.23 4.22 11.2 22.76 110 503 1125 1.16 3.98 10.22 31.22 102 487 1200 1.94 4.25 27.86 99 493 1103 1.87 5.15 22.4 1114 5.6 26.4 4.9 5.55 Mean 1.59 4.80 10.59 25.35 106.25 504.5 1127 NO DATA ! TRIPLICATE SAMPLES???
- 18. Case Study #1 Analyst chose the number of standards he would use to construct a standard curve differently between each assay run. Worst case was two samples (low & high)! Assay was essentially out of control Over 5 runs over two weeks no two “standard” curves were constructed the same way Report was “signed-off” by analyst, lab supervisor, Director of Analytical Services, and Vice-President for Pharmaceutics!
- 19. Case Study #2 The Case of History Repeating Itself
- 20. Case Study #2 Initial assay developed in the mid 1980s using, for the time, state of the art HPLC system Original assay validation report showed adequate accuracy, precision, sensitivity, selectivity, etc. Drug approved, but due to poor absorption the sponsor immediately began a series of formulation studies to improve bioavailability Assay validation of the later studies was a copy of the earlier report, a table of standard curve results but no tracings
- 21. Case Study #2 Why didn’t the sponsor submit individual study validation reports or tracings? A. They didn’t have them B. The assay conditions had changed C. The assay performance had changed Due to changes in equipment/column the retention time for the parent had gone from 3 minutes to 10 minutes. While this is certainly manageable, the sponsor decided to not provide this data to the FDA.
- 22. Case Study #3 The Case of the “U” Shaped Concentration Time Curve
- 23. Case Study #3 “U” Shaped Plasma Concentrations (mean of 12 subjects) Not surprisingly, the calculation of half-life was “difficult” for Group 2!
- 24. Case Study #3 In two studies done in support of this NDA more than a quarter of the subjects in a treatment leg in both trials (assayed at the same time, by the same analyst) showed these results. The sponsor chose to increase the half-life and denied there was an analytical problem! What this is, is the “black box phenomena” of data collection and analysis. A computer gets the output from the detector, runs the statistical & pharmacokinetic analysis modules, produces standard tables that a report is written from. But the report writer is not necessarily exposed to the primary data. Study A Study B
- 25. Case Study #4 The Case of The Missing Reagent
- 26. Case Study #4 A study was conducted in 24 subjects 12 normal and 12 with renal insufficiency. Due to irreversible protein binding, the extracted plasma samples had to be acidified with 0.1N HCl within an hour of extraction. Because of analytical problems at their prior lab, the company elected to send their samples to Europe for analysis. A total of approximately 320 samples were shipped.
- 27. Case Study #4 Upon analysis, out of 300+ samples all concentrations were BLOQ! Subsequent investigation revealed that the SOP did not specify an acidification target and that the stock bottle of HCl was sub-potent (age) and contaminated. The cost of a bottle of acid and a proper SOP was approximately $1 Million and six months of development time.
- 28. Lessons Case #1-Written SOPs are only effective when followed. The fact that an analyst could change procedures on a daily basis and yet all levels of management signed off on the report should not be possible. Case #2-Analytical methods need to be constantly monitored for changes in performance and when found must be investigated. Hoping the FDA will not ask questions is not a risk management strategy.
- 29. Lessons Case #3-Data analysis should include a program of primary data examination. Over-reliance on the computer to catch errors is totally dependent upon an exhaustive programming of failure modes and is unlikely to ever be all inclusive. Case #4-Common laboratory reagents play a key role in analysis. A seemingly small detail caused a costly delay. Does your lab have an SOP on reagents and how well is it followed? Last inventory?
- 30. An Observation on Quality Quality is neither necessarily expensive nor time consuming Lack of Quality is always Costly Financial, Cost to re-do work Time, Delay to market Reputational, Client loss of confidence in ability Business, Loss of clients
- 31. Closing Thoughts “It is not enough to do your best; you must know what to do, and then do your best.” W. Edwards Deming Would you stake your reputation/ lab/ company right now on the quality of your bioanalytical work? If, not then WHY do you tolerate it? WHY do you think anybody else will?