Bioanalytical Concentrations Below the LLOQ:

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1 Bioanalytical Concentrations Below the LLOQ: Should they be reported? arguments against What are regulatory and technical issues? What should we do to verify a lower LLOQ? Jeff Duggan and Jim Hilbert Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT The Case for and Against the Release of Bioanalytical Data Below the LLOQ AAPS 2015 Annual Meeting and Exposition, (#23), Wed., October 28, 2015

2 Possible Restrictions Technical and Scientific Sensitivity Selectivity Stability Absorptive phenomena Regulatory LLOQ defined in validation Assay range validated Supporting QCs (3x LLOQ) Other critical validated parameters

3 Verapamil, High Sensitivity Test Sensitivity to 50 pg/ml, linearity 50-10,000pg / ml 3

4 How far Below the LLOQ can we Go? (Beteween LLOQ and LOD) What are the limiting factors of our method?

5 Chromatographic Peak Signal to Noise LLOQ >= 5:1 S/N Baseline variation Sporadic noise Nearby interference Skewed baseline IS/Analyte Peak Area

6 Sensitivity and Chemical noise S/N Background Matrix 5 ng/ml Interferences 2 ng/ml

7 Accuracy and Precision Data from Validation: Supporting QCs QCs at 4 levels across the curve Accuracy (%bias) Precision (%CV) LLOQ QC set Verifies low end Statistically supported n= 5 or 6 X 3 runs P&A Interrun Precision and Accuracy for Drug XYZ in Human EDTA Plasma Assay Drug XYZ Concentration, nm 1 Nominal QC Batch ID LLOQ QC Low QC Mid QC High QC ULOQ QC Run Run Run NA NA NA NA Mean S.D %RSD %RE N

8 Response (CPS) Matrix Suppression: Sample and Method Inhibition, suppression or enhancement of the signal due to co-eluting matrix components A. SPE B. PP C. LLE D. 1-Docetaxel, 2-IS Time (min) Eluent pump Extracted Blank Injector Column 250 ul / min. Syringe pump Tee 20 ul / min. MS Source 8

9 Other Validation Criteria Selectivity: Can the method selectively measure the signal of the analyte in the presensce of other components Disease matrices Different populations Ion Suppression, Human Plasma Extracts Co-medicants Metabolites C P S 5000 PPT SS-LLE LLOQ Chromatogram Min. All of these effects can be amplified at high sensitivity

10 Stability and Adsorption Stability is tested only at low QC value during validation, what about: Freezer stability Room temperature stability Freeze thaw Extract and A/S stability Does analyte adsorb at sub LLOQ concentrations? Does the analyte signal become non-linear at low concentrations?

11 Stability BI xxxxxx Human Plasma Sample Concentrations after Hour Storage in Autosampler (~10 C) after Extraction BI xxxxxconcentration, nm Nominal QC Mean SD %RSD %RE Batch ID: HL29Oct2013a BI xxxxx Human Plasma Sample Concentrations after Four Cycles of Freezing and Thawing BI xxxxx Concentration, nm Nominal QC Batch ID:HL25Oct Mean SD %RSD %RE N 6 6 BI Human Plasma Sample Concentrations after 635 days Storage in the Freezer set at -20 C BI xxxxx Concentration, nm Nominal QC Batch ID: HL09Jul Mean SD %RSD %RE N 6 6 BI xxxxx Human Plasma Sample Concentrations after 96.5 hours Storage at Room Temperature under Normal Lab Lights BI xxxxx Concentration, nm Nominal QC Batch ID:HL03Feb Mean SD %RSD %RE N 6 6

12 Concentration related non-linearity Adsorptive affects Precipitation Matrix related affects Endogenous interferents

13 Typical Validation Runs Summary of Batches Performed Batch ID Run Number 1 Status 2 Description HL23Jul2013 NA Accepted Internal standard suitability evaluation HL25Oct Accepted HL28Oct Accepted HL29Oct Accepted Core Validation Run 1; Dil.QC, Freeze/Thaw Stability, Specificity Blank, and Specificity Zero are Included. Core Validation Run 2; Hemolysis effect samples and Lipemic samples are included. Core Validation Run 3; Thawed Matrix Stability and Run Size are included. HL29Oct2013a 5 Accepted Processed Sample Stability HL30Oct Accepted Freezer Stability of Plasma Samples HL22Nov2013 NA Accepted Stock freezer stability and room temperature stability test HL05Dec2013 NA Accepted Recovery and matrix effect test HL08Jan Accepted Freezer Stability of Plasma Samples HL03Feb Accepted Thawed Matrix Stability Extension

14 When to extend and When not to Extend the LLOQ Never: Comparative PK Studies: BE, BA, Food Effect, DDI Seldom: Sometimes : Studies with PK as primary endpoint Studies in which PK endpoint is not pivotal (SRD, MRD) Usually acceptable: Pharmacometric modeling studies Careful controls and cautions must be applied, things to be considered: The extent to which LLOQ extrapolation is made Expected ruggedness of method and matrix impact at sub-lloq concentrations Regulatory consequences: are the data use outside the study? will data be subject to regulatory scrutiny?

15 Recommendations for extending LLOQ Be sure extended values > LOD? With VerificationVia Partial Ways to verify sub-lloq values: Validation New and old curves should be combined (carry over) Extended STDs for lower concentrations. Add QC at new LLOQ Add QC at 3x New LLOQ, more if necessary Verify freezer stability at 3x New LLOQ Verify Selectivity (patient matrix) Cross analyte or co-med interference, if necessary Matrix Effect Verify other validation parameters as required A/S, Extract Stability F/T stability Recovery

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