1 13 March 2019 2 EMA/CHMP/ICH/172948/2019 3 Committee for Human Medicinal Products 4 ICH guideline M10 on bioanalytical method validation 5 Step 2b Transmission to CHMP 28 February 2019 Adoption by CHMP 28 February 2019 Release for public consultation 14 March 2019 Deadline for comments 1 September 2019 6 7 Comments should be provided using this template. The completed comments form should be sent to [email protected] 8 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5505 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. 9 10 11 12 13 INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL 14 REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE 15 16 17 ICH HARMONISED GUIDELINE 18 19 20 BIOANALYTICAL METHOD VALIDATION 21 M10 22 23 24 Draft version 25 26 Currently under public consultation 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working 46 Group, is transmitted by the ICH Assembly to the regulatory authorities of the ICH regions for internal and external 47 consultation, according to national or regional procedures. 48 49 50 51 M10 52 Document History 53 Code History Date M10 Endorsement by the Members of the ICH Assembly under Step 2 and release for public consultation ( 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 Legal notice: This document is protected by copyright and may, with the exception of the ICH logo, be 81 used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a 82 public license provided that ICH's copyright in the document is acknowledged at all times. In case of any 83 adaption, modification or translation of the document, reasonable steps must be taken to clearly label, 84 demarcate or otherwise identify that changes were made to or based on the original document. Any 85 impression that the adaption, modification or translation of the original document is endorsed or 86 sponsored by the ICH must be avoided. 87 The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors 88 of the original document be liable for any claim, damages or other liability arising from the use of the 89 document. 90 The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for 91 documents where the copyright vests in a third party, permission for reproduction must be obtained from 92 this copyright holder. 93 94 ICH HARMONISED GUIDELINE 95 BIOANALYTICAL METHOD VALIDATION 96 M10 97 ICH Consensus Guideline 98 TABLE OF CONTENTS 99 1. INTRODUCTION ....................................................................................... 4 100 1.1 Objective ............................................................................................................. 4 101 1.2 Background .......................................................................................................... 4 102 1.3 Scope .................................................................................................................. 4 103 2. GENERAL PRINCIPLES ............................................................................. 5 104 2.1 Method Development ............................................................................................. 5 105 2.2 Method Validation ................................................................................................. 6 106 2.2.1 Full Validation ................................................................................................. 6 107 2.2.2 Partial Validation ................................................................................................ 7 108 2.2.3 Cross Validation ................................................................................................. 7 109 3. CHROMATOGRAPHY ................................................................................. 7 110 3.1 Reference Standards ............................................................................................. 7 111 3.2 Validation............................................................................................................. 8 112 3.2.1 Selectivity ......................................................................................................... 8 113 3.2.2 Specificity ......................................................................................................... 9 114 3.2.3 Matrix Effect .................................................................................................... 10 115 3.2.4 Calibration Curve and Range.............................................................................. 10 116 3.2.5 Accuracy and Precision ...................................................................................... 11 117 3.2.5.1 Preparation of Quality Control Samples ............................................................ 11 118 3.2.5.2 Evaluation of Accuracy and Precision ................................................................ 12 119 3.2.6 Carry-over ...................................................................................................... 12 120 3.2.7 Dilution Integrity .............................................................................................. 13 121 3.2.8 Stability .......................................................................................................... 13 ICH M10 Guideline 122 3.2.9 Reinjection Reproducibility ................................................................................ 16 123 3.3 Study Sample Analysis ........................................................................................ 16 124 3.3.1 Analytical Run .................................................................................................. 16 125 3.3.2 Acceptance Criteria for an Analytical Run ............................................................ 17 126 3.3.3 Calibration Range ............................................................................................. 18 127 3.3.4 Reanalysis of Study Samples ............................................................................. 19 128 3.3.5 Reinjection of Study Samples ............................................................................ 20 129 3.3.6 Integration of Chromatograms ........................................................................... 20 130 4. LIGAND BINDING ASSAYS ..................................................................... 21 131 4.1 Key Reagents ..................................................................................................... 21 132 4.1.1 Reference Standard .......................................................................................... 21 133 4.1.2 Critical Reagents .............................................................................................. 21 134 4.2 Validation........................................................................................................... 22 135 4.2.1 Specificity ....................................................................................................... 22 136 4.2.2 Selectivity ....................................................................................................... 23 137 4.2.3 Calibration Curve and Range.............................................................................. 23 138 4.2.4 Accuracy and Precision ...................................................................................... 24 139 4.2.4.1 Preparation of Quality Control Samples ............................................................ 24 140 4.2.4.2 Evaluation of Accuracy and Precision ................................................................ 24 141 4.2.5 Carry-over ...................................................................................................... 25 142 4.2.6 Dilution Linearity and Hook Effect ....................................................................... 25 143 4.2.7 Stability .......................................................................................................... 26 144 4.3 Study Sample Analysis ........................................................................................ 27 145 4.3.1 Analytical Run .................................................................................................. 27 146 4.3.2 Acceptance Criteria for an Analytical Run ............................................................ 27 147 4.3.3 Calibration Range ............................................................................................. 28 148 4.3.4 Reanalysis of Study Samples ............................................................................. 29 149 150 5. INCURRED SAMPLE REANALYSIS .......................................................... 30 151 6. PARTIAL AND CROSS VALIDATION ........................................................ 31 152 6.1 Partial Validation ................................................................................................. 31 153 6.2 Cross Validation .................................................................................................. 33 2 ICH M10 Guideline 154 7. ADDITIONAL CONSIDERATIONS ............................................................ 33 155 7.1 Analytes that are also Endogenous