SWGDRUG Approach to Validation Scott R. Oulton SWGDRUG Secretariat and Associate Laboratory Director for the Drug Enforcement Administration (DEA) Southwest Laboratory Vista, California

SWGDRUG Scientific Working Group for the Analysis of Seized Drugs

Mission of SWGDRUG The mission of SWGDRUG is to recommend minimum standards for the forensic examination of seized drugs and to seek their international acceptance.

SWGDRUG Objectives Specifying requirements for practitioners’ knowledge, skills and abilities, Specifying requirements for practitioners’ knowledge, skills and abilities, Promoting professional development, Promoting professional development, Providing a means of information exchange within the forensic science community, Providing a means of information exchange within the forensic science community, Promoting ethical standards of practitioners, Promoting ethical standards of practitioners, Providing minimum standards for examinations and reporting, Providing minimum standards for examinations and reporting, Establishing quality assurance requirements, Establishing quality assurance requirements, Considering relevant international standards, and Considering relevant international standards, and Seeking international acceptance of SWGDRUG recommendations Seeking international acceptance of SWGDRUG recommendations

2005 SWGDRUG Process The SWGDRUG process is an international forensic science community endeavor The SWGDRUG process is an international forensic science community endeavor The role of the core committee is to vote to accept or reject subcommittee recommendations The role of the core committee is to vote to accept or reject subcommittee recommendations In order for a proposal to become an official recommendation, 3/4s of the full core committee must be present. 2/3s of those present must vote in the affirmative (YES) for a proposal to become a recommendation In order for a proposal to become an official recommendation, 3/4s of the full core committee must be present. 2/3s of those present must vote in the affirmative (YES) for a proposal to become a recommendation

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SWGDRUG Core Committee DEA – Nelson Santos Secretariat – Scott Oulton (non-voting) Secretariat – Scott Oulton (non-voting) FBI - Eileen Waninger FBI - Eileen Waninger ASCLD – Garth Glassburg ASCLD – Garth Glassburg NIST - Susan Ballou NIST - Susan Ballou ASTM and NEAFS- Jack Mario ASTM and NEAFS- Jack Mario Educator – Dr. Chris Tindall Educator – Dr. Chris Tindall Educator – Dr. Suzanne Bell

SWGDRUG Core Committee CAC & NWAFS - Jerry MassettiCAC & NWAFS - Jerry Massetti MAFS - Richard Paulas MAFS - Richard Paulas MAAFS - Linda Jackson MAAFS - Linda Jackson SAFS - Dr. Conrad Roberson SAFS - Dr. Conrad Roberson SWAFS - Gary Chasteen SWAFS - Gary Chasteen South Africa - Tshepo Shole South Africa - Tshepo Shole Connecticut DPS – Dr. Robert Powers Connecticut DPS – Dr. Robert Powers

SWGDRUG Core Committee Canada - Richard Laing Canada - Richard Laing Japan - Dr. Kishi Tohru Japan - Dr. Kishi Tohru United Kingdom - Dr. Sylvia Burns United Kingdom - Dr. Sylvia Burns Australia - Catherine Quinn Australia - Catherine Quinn Germany - Dr. Udo Zerell Germany - Dr. Udo Zerell ENFSI - Dr. Erkki Sippola ENFSI - Dr. Erkki Sippola UNODC - Dr. Iphigenia Naidis UNODC - Dr. Iphigenia Naidis

SWGDRUG Continued Success All forensic drug analysts must stay involved in the process by contributing comments, criticisms and suggestions All forensic drug analysts must stay involved in the process by contributing comments, criticisms and suggestions If you agree with the process, let us know If you agree with the process, let us know If you don’t agree with what you are reading in the publication sources, let us know If you don’t agree with what you are reading in the publication sources, let us know Write or any core committee member Write or any core committee member

Validation Definition and Purpose of Validation Definition and Purpose of Validation Validation is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use or application have been fulfilled [ISO 9000:2005(E)] Validation is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use or application have been fulfilled [ISO 9000:2005(E)][ISO 9000:2005(E)][ISO 9000:2005(E)] Studies to determine method performance must be carried out by qualified/competent analysts using appropriate calibrated equipment Studies to determine method performance must be carried out by qualified/competent analysts using appropriate calibrated equipment

Validation Why is validation necessary? Why is validation necessary? We make measurements every day that affect people’s lives (fines, incarceration, etc.) We make measurements every day that affect people’s lives (fines, incarceration, etc.) Decisions are made by our results. There can be a high cost if we are wrong Decisions are made by our results. There can be a high cost if we are wrong Our customers expect to be able to trust the results Our customers expect to be able to trust the results Methods must be sufficiently reliable that decisions can be made with confidence. Methods must be sufficiently reliable that decisions can be made with confidence.

Validation When to validate a method? When to validate a method? New method to address particular problem New method to address particular problem Revise existing method for improvements or new problem Revise existing method for improvements or new problem QA suggests method is changing with time QA suggests method is changing with time Use of another laboratory’s method or different instrument Use of another laboratory’s method or different instrument Demonstrate equivalence between two different methods Demonstrate equivalence between two different methods

Validation Who decides how and to what degree of validation is required for method validation? Who decides how and to what degree of validation is required for method validation? The Laboratory is responsible for ensuring methods are validated The Laboratory is responsible for ensuring methods are validated Clients Input Clients Input Laboratory and client should agree to method used Laboratory and client should agree to method used Usually done retrospectively Usually done retrospectively

SWGDRUG’s Approach to Validation See PART IV B See PART IV B QUALITY ASSURANCE/VALIDATION OF ANALYTICAL METHODS Analytical Scheme Analytical Scheme Laboratory Responsibility Laboratory Responsibility Operational Environment Operational Environment Documentation Documentation Validation Plan Validation Plan

SWGDRUG Analytical Scheme An analytical scheme shall be comprised of validated methods appropriate for the analyte An analytical scheme shall be comprised of validated methods appropriate for the analyte Identify analyte of interest, preclude false-positives and minimize false- negatives Identify analyte of interest, preclude false-positives and minimize false- negatives For quantification the method should reliably determine the amount of analyte present For quantification the method should reliably determine the amount of analyte present

SWGDRUG Analytical Scheme Verification – shall be conducted on methods from non-routine, published literature, another laboratory’s protocols Verification – shall be conducted on methods from non-routine, published literature, another laboratory’s protocols demonstrate that a representative set of reference materials has been carried through the process and yielded the expected results demonstrate that a representative set of reference materials has been carried through the process and yielded the expected results

SWGDRUG Validating Methods Laboratory responsibility to determine whether SOPs have been validated, verified or require further validation/verification Laboratory responsibility to determine whether SOPs have been validated, verified or require further validation/verification All methods shall be validated/verified to demonstrate performance in normal operating environments All methods shall be validated/verified to demonstrate performance in normal operating environments

SWGDRUG Validating Methods The entire validation/verification process shall be documented. Documentation shall include, but is not limited to the following: The entire validation/verification process shall be documented. Documentation shall include, but is not limited to the following: Personnel involved Personnel involved Dates Dates Observations from the process Observations from the process Analytical data Analytical data Conclusions and/or recommendations Conclusions and/or recommendations Authorization approval signature Authorization approval signature

SWGDRUG General Validation Plan Purpose/scope – introductory statement (what, purpose and results required) Purpose/scope – introductory statement (what, purpose and results required) Performance specification – list of specific objectives Performance specification – list of specific objectives Process review – after completion, revisit objectives to ensure they were satisfactorily met Process review – after completion, revisit objectives to ensure they were satisfactorily met Analytical method – state the method to be validated (each step shall demonstrate satisfactory performance) Analytical method – state the method to be validated (each step shall demonstrate satisfactory performance)

SWGDRUG General Validation Plan Reference materials – appropriate materials used for qualitative and quantitative procedures (traceability required) Reference materials – appropriate materials used for qualitative and quantitative procedures (traceability required) Selectivity – assess capability of method to identify/quantify the analyte Selectivity – assess capability of method to identify/quantify the analyte Matrix effects – assess impact of interfering components Matrix effects – assess impact of interfering components Recovery – Determine for quantitative analysis Recovery – Determine for quantitative analysis

SWGDRUG General Validation Plan Precision (Repeatability/Reproducibility) – determine: Precision (Repeatability/Reproducibility) – determine: Acceptable limits Acceptable limits Qualitative/Quantitative – run 10 times Qualitative/Quantitative – run 10 times Non-routing Methods – may differ Non-routing Methods – may differ Trueness – quantitative analysis, assessed by: Trueness – quantitative analysis, assessed by: Replicate measurements at different concentrations Replicate measurements at different concentrations Performance of standard addition method Performance of standard addition method Comparison to proficiency test results Comparison to proficiency test results Comparison with different validated methods Comparison with different validated methods

SWGDRUG General Validation Plan Range – determine concentration or amount limits for which the method is applicable Range – determine concentration or amount limits for which the method is applicable Limit of detection (LOD) – lowest amount of analyte to be detected and identified (not necessarily quantitatively accurate) Limit of detection (LOD) – lowest amount of analyte to be detected and identified (not necessarily quantitatively accurate) Limit of quantitation (LOQ) – lowest concentration that has acceptable level of uncertainty Limit of quantitation (LOQ) – lowest concentration that has acceptable level of uncertainty

SWGDRUG General Validation Plan Linearity – quantitative methods Linearity – quantitative methods Determine mathematical relationship (calibration curve) between concentration and response Determine mathematical relationship (calibration curve) between concentration and response LOQ forms lower end of working range LOQ forms lower end of working range Determine acceptable variation from calibration curve Determine acceptable variation from calibration curve Determine upper limits of working range Determine upper limits of working range Robustness – alter method parameters and determine any changes to accuracy Robustness – alter method parameters and determine any changes to accuracy

SWGDRUG General Validation Plan Ruggedness – assess the factors external to the method Ruggedness – assess the factors external to the method Uncertainty – assess contribution of random and systematic errors Uncertainty – assess contribution of random and systematic errors Quality control – establish acceptance criteria prior to implementation of the method Quality control – establish acceptance criteria prior to implementation of the method

Validation Type Qualitative analysis - the parameters that need to be checked are selectivity, limit of detection and reproducibility. Qualitative analysis - the parameters that need to be checked are selectivity, limit of detection and reproducibility. Quantitative analysis – the parameters that need to be checked are selectivity, matrix effects, recovery, precision, trueness, LOQ, linearity, robustness, ruggedness, reproducibility and uncertainty Quantitative analysis – the parameters that need to be checked are selectivity, matrix effects, recovery, precision, trueness, LOQ, linearity, robustness, ruggedness, reproducibility and uncertainty

SWGDRUG Supplemental Documents Adopted by the Core Committee in August 2005 Adopted by the Core Committee in August 2005 The supplemental documents are not SWGDRUG recommendations The supplemental documents are not SWGDRUG recommendations Intended to be a resource for those responsible for implementing SWGDRUG recommendations Intended to be a resource for those responsible for implementing SWGDRUG recommendations Not inclusive and SWGDRUG recognizes that there are many ways of implementing the recommendations Not inclusive and SWGDRUG recognizes that there are many ways of implementing the recommendations Living documents and as such, SWGDRUG invites comments. Send your comments to Living documents and as such, SWGDRUG invites comments. Send your comments to

SWGDRUG Validation of Analytical Methods Supplemental Document SD-2 for Part IVB entitled “Quality Assurance/Validation of Analytical Methods” was finalized for publication in February 2006 Supplemental Document SD-2 for Part IVB entitled “Quality Assurance/Validation of Analytical Methods” was finalized for publication in February 2006 Designed to assist laboratories develop a general validation plan which meet their individual requirements Designed to assist laboratories develop a general validation plan which meet their individual requirements Intended to be used in conjunction with SWGDRUG Recommendations, Part IVB, Section 2 Intended to be used in conjunction with SWGDRUG Recommendations, Part IVB, Section 2 The document is organized into two sections: The document is organized into two sections: Section I provides guidance on the issues to consider when using various analytical techniques Section I provides guidance on the issues to consider when using various analytical techniques Section II is an example of a completed validation plan Section II is an example of a completed validation plan

SWGDRUG Properties for Validation Process Section 1 of the document is organized into Categories of Analytical Techniques (IR, MS, HPLC, etc.) from Table 1 – Categories A, B and C Section 1 of the document is organized into Categories of Analytical Techniques (IR, MS, HPLC, etc.) from Table 1 – Categories A, B and C For each instrument or method, specific properties are detailed that could have an effect on how the validation process is formulated and executed For each instrument or method, specific properties are detailed that could have an effect on how the validation process is formulated and executed

SWGDRUG Properties for Validation Process Section II demonstrates a purpose-defined validation plan for a particular method. Section II demonstrates a purpose-defined validation plan for a particular method. The aim is to show how a complete validation plan may appear The aim is to show how a complete validation plan may appear The example should not be directly applied to methodology used by any laboratory without first considering the specific purpose of a method and its relevant operational environment The example should not be directly applied to methodology used by any laboratory without first considering the specific purpose of a method and its relevant operational environment

SWGDRUG Properties for Validation Process Supplemental Document SD-2 Supplemental Document SD-2

SWGDRUG Future Plans SWGDRUG intends on adding additional supplemental documents to help illustrate validations SWGDRUG intends on adding additional supplemental documents to help illustrate validations Actual validated method Actual validated method Example qualitative and quantitative validations Example qualitative and quantitative validations Uncertainty examples Uncertainty examples

US Validation Perspective Disclaimer: This information is solely based upon my personal experiences in different laboratories in the US Disclaimer: This information is solely based upon my personal experiences in different laboratories in the US Validation requirements generally thought of only for quantitative analysis Validation requirements generally thought of only for quantitative analysis Qualitative methods exist, but in a general manner Qualitative methods exist, but in a general manner Through influence of ISO, laboratory’s are developing more specific qualitative methods Through influence of ISO, laboratory’s are developing more specific qualitative methods

US Validation Perspective Smaller labs have simple qualitative methods, but only looking for a few specific drugs Smaller labs have simple qualitative methods, but only looking for a few specific drugs We previously relied upon the analyst’s training and experience We previously relied upon the analyst’s training and experience Analyst discretion on which instrument and/or method to utilize Analyst discretion on which instrument and/or method to utilize

US Validation Perspective Changing method parameter acceptable to achieve identification (e.g., GC oven temp.) Changing method parameter acceptable to achieve identification (e.g., GC oven temp.) Fear of developing technicians as opposed to scientists Fear of developing technicians as opposed to scientists

US Validation Perspective DEA Analytical Sufficiency Document DEA Analytical Sufficiency Document Originally thought sufficient for qualitative analysis Originally thought sufficient for qualitative analysis However, no specific qualitative validation determining selectivity, limit of detection and reproducibility at a minimum However, no specific qualitative validation determining selectivity, limit of detection and reproducibility at a minimum

US Validation Perspective DEA recently accredited in ISO DEA recently accredited in ISO Developed general guidelines for qualitative testing Developed general guidelines for qualitative testing Although we were accredited, we are currently deciding what constitutes a qualitative method validation Although we were accredited, we are currently deciding what constitutes a qualitative method validation Questions Questions Make methods instrument and drug specific? Make methods instrument and drug specific? Make methods only instrument specific? Make methods only instrument specific?

US Validation Perspective Problem with quantitative methods, we have numerous ones for the same analyte Problem with quantitative methods, we have numerous ones for the same analyte In upwards of 5-10 different methods varying minimal parameters In upwards of 5-10 different methods varying minimal parameters Considering standardizing methodology and limit number of choices Considering standardizing methodology and limit number of choices

Questions ?? Scott R. Oulton Phone: (760) A copy of this presentation, can be downloaded at: