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Document History,Code History Date, M10 Endorsement by the Members of the ICH Assembly 26 02 2019. under Step 2 and release for public consultation,document dated 15 01 2019. Legal notice This document is protected by copyright and may with the exception of the ICH. logo be used reproduced incorporated into other works adapted modified translated or. distributed under a public license provided that ICH s copyright in the document is acknowledged. at all times In case of any adaption modification or translation of the document reasonable. steps must be taken to clearly label demarcate or otherwise identify that changes were made to. or based on the original document Any impression that the adaption modification or. translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided as is without warranty of any kind In no event shall the ICH or the. authors of the original document be liable for any claim damages or other liability arising from. the use of the document, The above mentioned permissions do not apply to content supplied by third parties Therefore. for documents where the copyright vests in a third party permission for reproduction must be. obtained from this copyright holder,1 ICH HARMONISED GUIDELINE. 2 BIOANALYTICAL METHOD VALIDATION,4 ICH Consensus Guideline.
5 TABLE OF CONTENTS,6 1 INTRODUCTION 4,7 1 1 Objective 4. 8 1 2 Background 4,9 1 3 Scope 4,10 2 GENERAL PRINCIPLES 5. 11 2 1 Method Development 5,12 2 2 Method Validation 6. 13 2 2 1 Full Validation 6,14 2 2 2 Partial Validation 7. 15 2 2 3 Cross Validation 7,16 3 CHROMATOGRAPHY 7,17 3 1 Reference Standards 7.
18 3 2 Validation 8,19 3 2 1 Selectivity 8,20 3 2 2 Specificity 9. 21 3 2 3 Matrix Effect 10,22 3 2 4 Calibration Curve and Range 10. 23 3 2 5 Accuracy and Precision 11, 24 3 2 5 1 Preparation of Quality Control Samples 11. 25 3 2 5 2 Evaluation of Accuracy and Precision 12. 26 3 2 6 Carry over 12,27 3 2 7 Dilution Integrity 13. ICH M10 Guideline,28 3 2 8 Stability 13,29 3 2 9 Reinjection Reproducibility 16.
30 3 3 Study Sample Analysis 16,31 3 3 1 Analytical Run 16. 32 3 3 2 Acceptance Criteria for an Analytical Run 17. 33 3 3 3 Calibration Range 18,34 3 3 4 Reanalysis of Study Samples 19. 35 3 3 5 Reinjection of Study Samples 20,36 3 3 6 Integration of Chromatograms 20. 37 4 LIGAND BINDING ASSAYS 21,38 4 1 Key Reagents 21. 39 4 1 1 Reference Standard 21,40 4 1 2 Critical Reagents 21.
41 4 2 Validation 22,42 4 2 1 Specificity 22,43 4 2 2 Selectivity 23. 44 4 2 3 Calibration Curve and Range 23,45 4 2 4 Accuracy and Precision 24. 46 4 2 4 1 Preparation of Quality Control Samples 24. 47 4 2 4 2 Evaluation of Accuracy and Precision 25. 48 4 2 5 Carry over 25,49 4 2 6 Dilution Linearity and Hook Effect 25. 50 4 2 7 Stability 26,51 4 3 Study Sample Analysis 27. 52 4 3 1 Analytical Run 27, 53 4 3 2 Acceptance Criteria for an Analytical Run 28.
54 4 3 3 Calibration Range 29,55 4 3 4 Reanalysis of Study Samples 29. ICH M10 Guideline,57 5 INCURRED SAMPLE REANALYSIS 30. 58 6 PARTIAL AND CROSS VALIDATION 32,59 6 1 Partial Validation 32. 60 6 2 Cross Validation 33,61 7 ADDITIONAL CONSIDERATIONS 34. 62 7 1 Analytes that are also Endogenous Compounds 34. 63 7 1 1 Quality Control Samples 35,64 7 1 2 Calibration Standards 36.
65 7 1 3 Selectivity Recovery and Matrix Effects 36. 66 7 1 4 Parallelism 37,67 7 1 5 Accuracy and Precision 37. 68 7 1 6 Stability 37,69 7 2 Parallelism 37,70 7 3 Recovery 38. 71 7 4 Minimum Required Dilution 38,72 7 5 Commercial and Diagnostic Kits 38. 73 7 6 New or Alternative Technologies 39,74 7 6 1 Dried Matrix Methods 40. 75 8 DOCUMENTATION 40,76 8 1 Summary Information 41.
77 8 2 Documentation for Validation and Bioanalytical Reports 42. 78 9 GLOSSARY 50,ICH M10 Guideline,81 1 INTRODUCTION. 82 1 1 Objective, 83 This guideline is intended to provide recommendations for the validation of bioanalytical assays. 84 for chemical and biological drug quantification and their application in the analysis of study. 85 samples Adherence to the principles presented in this guideline will improve the quality and. 86 consistency of the bioanalytical data in support of the development and market approval of both. 87 chemical and biological drugs, 88 The objective of the validation of a bioanalytical assay is to demonstrate that it is suitable for. 89 its intended purpose Changes from the recommendations in this guideline may be acceptable. 90 if appropriate scientific justification is provided Applicants are encouraged to consult the. 91 regulatory authority ies regarding significant changes in method validation approaches when. 92 an alternate approach is proposed or taken,93 1 2 Background. 94 Concentration measurements of chemical and biological drug s and their metabolite s in. 95 biological matrices are an important aspect of drug development The results of pivotal. 96 nonclinical toxicokinetic TK pharmacokinetic PK studies and of clinical trials including. 97 comparative bioavailability bioequivalence BA BE studies are used to make regulatory. 98 decisions regarding the safety and efficacy of drug products It is therefore critical that the. 99 bioanalytical methods used are well characterised appropriately validated and documented in. 100 order to ensure reliable data to support regulatory decisions. 101 1 3 Scope, 102 This guideline describes the method validation that is expected for bioanalytical assays that are.
103 submitted to support regulatory submissions The guideline is applicable to the validation of. 104 bioanalytical methods used to measure concentrations of chemical and biological drug s and. 105 their metabolite s in biological samples e g blood plasma serum other body fluids or. 106 tissues obtained in pivotal nonclinical TK PK studies that are used to make regulatory. 107 decisions and all phases of clinical trials in regulatory submissions Full method validation is. 108 expected for the primary matrix ces intended to support regulatory submissions Additional. 109 matrices should be partially validated as necessary The analytes that should be measured in. 110 nonclinical and clinical studies and the types of studies necessary to support a regulatory. 111 submission are described in other ICH and regional regulatory documents. ICH M10 Guideline, 112 For studies that are not submitted for regulatory approval or not considered for regulatory. 113 decisions regarding safety efficacy or labelling e g exploratory investigations applicants. 114 may decide on the level of qualification that supports their own internal decision making. 115 The information in this guideline applies to the quantitative analysis by ligand binding assays. 116 LBAs and chromatographic methods such as liquid chromatography LC or gas. 117 chromatography GC which are typically used in combination with mass spectrometry MS. 118 detection and occasionally with other detectors. 119 For studies that are subject to Good Laboratory Practice GLP or Good Clinical Practice GCP. 120 the bioanalysis of study samples should also conform to their requirements. 121 The bioanalysis of biomarkers and bioanalytical methods used for the assessment of. 122 immunogenicity are not within the scope of this guideline. 123 2 GENERAL PRINCIPLES,124 2 1 Method Development. 125 The purpose of bioanalytical method development is to define the design operating conditions. 126 limitations and suitability of the method for its intended purpose and to ensure that the method. 127 is optimised for validation, 128 Before the development of a bioanalytical method the applicant should understand the analyte. 129 of interest e g the physicochemical properties of the drug in vitro and in vivo metabolism and. 130 protein binding and consider aspects of any prior analytical methods that may be applicable. 131 Method development involves optimising the procedures and conditions involved with. 132 extracting and detecting the analyte Method development can include the optimisation of the. 133 following bioanalytical parameters to ensure that the method is suitable for validation. 134 Reference standards,135 Critical reagents,136 Calibration curve. 137 Quality control samples QCs,138 Selectivity and specificity.
139 Sensitivity,140 Accuracy,ICH M10 Guideline,141 Precision. 142 Recovery,143 Stability of the analyte in the matrix. 144 Minimum Required Dilution MRD, 145 Bioanalytical method development does not require extensive record keeping or notation. 146 However the applicant should record the changes to procedures as well as any issues and their. 147 resolutions to provide a rationale for any changes made to validated methods immediately prior. 148 to or in the course of analysing study samples for pivotal studies. 149 Once the method has been developed bioanalytical method validation proves that the optimised. 150 method is suited to the analysis of the study samples. 151 2 2 Method Validation,152 2 2 1 Full Validation. 153 Bioanalytical method validation is essential to ensure the acceptability of assay performance. 154 and the reliability of analytical results A bioanalytical method is defined as a set of procedures. 155 used for measuring analyte concentrations in biological samples A full validation of a. 156 bioanalytical method should be performed when establishing a bioanalytical method for the. 157 quantification of an analyte in clinical and in pivotal nonclinical studies Full validation should. 158 also be performed when implementing an analytical method that is reported in the literature and. 159 when a commercial kit is repurposed for bioanalytical use in drug development Usually one. 160 analyte has to be determined but on occasion it may be appropriate to measure more than one. 161 analyte This may involve two different drugs a parent drug with its metabolites or the. 162 enantiomers or isomers of a drug In these cases the principles of validation and analysis apply. 163 to all analytes of interest, 164 For chromatographic methods a full validation should include the following elements.
165 selectivity specificity if necessary matrix effect calibration curve response function range. 166 lower limit of quantification LLOQ to upper limit of quantification ULOQ accuracy. 167 precision carry over dilution integrity stability and reinjection reproducibility. 168 For LBAs the following elements should be evaluated specificity selectivity calibration curve. 169 response function range LLOQ to ULOQ accuracy precision carry over if necessary. 170 dilution linearity parallelism if necessary conducted during sample analysis and stability. ICH M10 Guideline, 171 The matrix used for analytical method validation should be the same as the matrix of the study. 172 samples including anticoagulants and additives In some cases it may be difficult to obtain an. 173 identical matrix to that of the study samples e g rare matrices such as tissue cerebrospinal. 174 fluid bile In such cases surrogate matrices may be acceptable for analytical method validation. 175 The surrogate matrix should be selected and justified scientifically for use in the analytical. 176 method, 177 A specific detailed written description of the bioanalytical method should be established a. 178 priori This description may be in the form of a protocol study plan report or Standard. 179 Operating Procedure SOP,180 2 2 2 Partial Validation. 181 Modifications to a fully validated analytical method may be evaluated by partial validation. 182 Partial validation can range from as little as one accuracy and precision determination to a. 183 nearly full validation Refer to Section 6 1 The items in a partial validation are determined. 184 according to the extent and nature of the changes made to the method. 185 2 2 3 Cross Validation, 186 Where data are obtained from different methods within or across studies or when data are. 187 obtained within a study from different laboratories applying the same method comparison of. 188 those data is needed and a cross validation of the applied analytical methods should be carried. 189 out Refer to Section 6 2,190 3 CHROMATOGRAPHY,191 3 1 Reference Standards.
192 During method validation and the analysis of study samples a blank biological matrix is spiked. 193 with the analyte s of interest using solutions of reference standard s to prepare calibration. 194 standards QCs and stability QCs Calibration standards and QCs should be prepared from. 195 separate stock solutions However calibration standards and QCs may be prepared from the. 196 same stock solution provided the accuracy and stability of the stock solution have been verified. 197 A suitable internal standard IS should be added to all calibration standards QCs and study. 198 samples during sample processing The absence of an IS should be technically justified. 199 It is important that the reference standard is well characterised and the quality purity strength. 200 identity of the reference standard and the suitability of the IS is ensured as the quality will. 201 affect the outcome of the analysis and therefore the study data The reference standard used. 202 during validation and study sample analysis should be obtained from an authentic and traceable. ICH M10 Guideline, 203 source The reference standard should be identical to the analyte If this is not possible an. ICH HARMONISED GUIDELINE BIOANALYTICAL METHOD VALIDATION M10 Draft version Endorsed on 26 February 2019 Currently under public consultation At Step 2 of the ICH Process a consensus draft text or guideline agreed by the appropriate ICH Expert Working Group is transmitted by the ICH Assembly to the regulatory authorities of the ICH regions for internal and external consultation

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