SQA opinion paper on global harmonization of the bioanalytical method validation guidances

Abstract

BioanalysisVol. 2, No. 12 EditorialFree AccessSQA opinion paper on global harmonization of the bioanalytical method validation guidancesChristopher Tudan, Stephen Rogenthien and Anthony JonesChristopher Tudan† Author for correspondence125A–1030 Denman Street, Vancouver, BC, V6G 2M6, Canada. Search for more papers by this authorEmail the corresponding author at bioaccurate@gmail.com, Stephen RogenthienQA Manager, Ricerca Biosciences, LLC, 7528 Auburn Road, Concord, OH 44077, USASearch for more papers by this author and Anthony JonesPharmanet Development Group, Inc., 301D College Road East, Princeton NJ 08540, USASearch for more papers by this authorPublished Online:26 Nov 2010https://doi.org/10.4155/bio.10.162AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: bioanalytical method validationFDA/EMA regulationsglobal harmonizationmethod validation guidelinesSociety of Quality Assurance (SQA)This opinion paper states the Society of Quality Assurance’s (SQA) recommendations for the global harmonization of bioanalytical practices and provides some detailed areas for consideration in this exercise.BackgroundThe US FDA’s 2001 Bioanalytical Method Validation (BMV) Guidance [101] and the subsequent ‘Crystal City’ workshop consensus white papers [1–6] have formed the basis for establishing best practices in bioanalysis. Pharmaceutical companies and contract research organizations have followed the recommendations in these documents as there were no other standards readily applicable to bioanalysis. For example, the International Conference on Harmonisation (ICH) Q2(R1) [102] standard was written for analytical methods used for drug product characterization, rather than for drug assay in biological matrices.Although many of the specifics of execution were left up to industry, interpretations of these documents have been accepted by both bioanalysis practitioners and regulators, providing some harmonization for global bioanalytical processes. This approach to harmonization lasted until 2009 when two documents were published by the European Medicines Agency (EMA): the January 2009 concept paper on the need for a Committee for Human Medicinal Products (CHMP) guideline on the validation of bioanalytical methods [103] and the subsequent Draft Guidance on Bioanalytical Method Validation [104].The existence of two guidance documents (FDA and EMA) that would inevitably have contradictory content resulted in the emergence of a movement for harmonization of the BMV guidances, which was introduced by the European Bioanalytical Forum (EBF) in their 2009 meeting and published in an editorial the same year [7]. Platforms for discussions via meetings and workshops have since been established to drive this paradigm [8–10].Current situationThe current bioanalytical landscape is ripe for the global harmonization of a bioanalytical guidance document. Key aspects of this landscape include:▪ Pharmaceutical companies and CROs are conducting regulatory bioanalysis internationally.▪ Analysis performed in one country is usually part of submissions to others, since new drug applications and abbreviated new drug applications are no longer targeting local markets and patients, but international markets and global illnesses.▪ Regulatory agencies and pharmaceutical Quality Assurance Units (QAUs) are performing global inspections, and therefore regulations are no longer limited to national borders.▪ Regulatory guidances are supplemented with conference reports that have equal weight in guiding bioanalysis.▪ Although there are multiple guidances pertaining to bioanalysis now in existence, there is not a single, comprehensive guidance. The EMA draft guidance remains a ‘work in progress’, and the FDA guidance is currently under revision. These guidances are, and likely will remain, inconsistent with some current industry practices, and each other.▪ There remains no substantial guidance on BMV applicable to ligand binding and immunoassays.▪ New approaches to bioanalysis now exist that require guidance and regulations since their results impact safety and will be part of regulatory submissions. These include biomarker assays, immunoassays, flow cytometry and dried blood spot analyses.▪ A comprehensive guidance pertaining to the bioanalysis of human clinical samples is not available; many of the principles applied to bioanalysis have been derived from the Good Laboratory Practice (GLP) regulations that apply to nonclinical safety studies.▪ There remains insufficient regulatory agency guidance on the processes associated with incurred sample reanalysis, repeat analysis for pharmacokinetic (PK) reasons and sample reanalysis.▪ EBF member companies would prefer to perform analyses according to one global guidance.A role for quality & the Society of Quality AssuranceBioanalysis provides essential regulatory data for toxicokinetic, pharmacokinetic (PK), bioavailability and bioequivalence (BE) studies, and relevant data is consistently submitted to various regulatory agencies around the world. However, the initiative for the harmonization of the BMV guidances has been driven by organizations that are rooted in the scientific aspects of regulated bioanalysis. These include the American Association of Pharmaceutical Scientists (AAPS), Calibration and Validation Group (CVG), EBF, Canadian LC–MS Group, European Federation for Pharmaceutical Sciences (EUFEPS), Boston Society for Advanced Therapeutics (BSAT) and Applied Pharmaceutical Analysis (APA). In addition, regulatory agencies have been invited to participate in the applicable workshops and meetings and have included the EMA, FDA, Medicines and Healthcare products Regulatory Agency, Japanese Ministry of Health, Labour and Welfare, and the Health Canada Therapeutic Products Directorate. Unfortunately, from a compliance perspective, associations representing quality assurance (QA) professionals have been largely absent from much of the debate and consensus-forming that has occurred to date.The largest association of quality assurance professionals in the world that is impacted by the BMV guidances and will be advocates of a harmonized BMV document is the SQA. Current membership of SQA exceeds 2300 active and affiliate members in over 30 countries working in industry, government, academia, and consulting. The Society includes general membership, special interest and administrative committees, regional chapters, and specialty sections, including the Bioanalytical Specialty Section (BASS). SQA/BASS serves as a network resource for QA professionals involved in bioanalytical regulatory compliance and its members have significant experience interacting directly with their respective global regulatory agencies. The group consists of QA professionals who are typically accountable for assuring compliance of bioanalytical data, as well as the associated regulatory training of scientists and management, at their respective facilities. Therefore, the SQA wishes to provide its perspectives and support towards a common understanding of the best approach to bioanalytical method validation and sample analysis.The SQA is supportive of the global harmonization of BMV guidances initiative, and asks health authorities and laboratories worldwide to consider the urgency of this initiative, specifically the need for a comprehensive global bioanalytical guidance document. The SQA sees this as an opportunity to establish a working relationship with the scientific community during the development of a single bioanalytical guidance document. This is in contrast to the current paradigm of merely taking responsibility for its enforcement after its development, especially considering its members’ regulatory experience that can be lent to building a more complete guidance in partnership with the scientific community.A recommended approach to globalizationHarmonization should be accomplished in a reasonable amount of time by defining a simple, focused, unified and global process that facilitates a finalized guidance. The SQA believes that global harmonization should be science-driven and include the rationale behind each requirement. This globalization should therefore not be conducted as a harmonization of varied perspectives on nonclinical and clinical bioanalytical guidelines, but as the consensus of representatives from all disciplines affected and simultaneously forwarded to all regulatory and governing bodies for implementation. It will therefore be necessary to involve all global stakeholders by creating an all-inclusive consortium (e.g., the AAPS, CVG, EBF, EUFEPS, BSAT and SQA) with worldwide influence to merge the FDA and EMA guidances with other applicable standards to create a unified guidance.The structure of the guidance document should also be considered, and to this end, there is still a lack of consensus. The SQA members, having functioned under the umbrellas of the FDA, Organization for Economic Co-operation and Development, ICH, Brazil, Russia, India and China, and WHO, advocate that an ICH document would most easily facilitate a single global document that could be implemented into all regulatory processes and enforced by all respective governing bodies. Since a standardized framework would be best developed to address the bioanalytical guidance pertaining to nonclinical and clinical samples, it is recommended that any reference to GLP and good clinical practice be avoided except where the respective compliance is required.Key topics to consider for a global BMV guidance documentListed below are topics that the SQA/BASS recommends be considered by such a consortium. These topics are a constant source of industry discussion and are listed below.▪ Human clinical samplesThere is already some framework for clarification regarding guidance for the bioanalysis of human clinical samples [11,105], and it is the hope of the SQA/BASS that a globalized BMV guidance would provide a consistent, unified approach.▪ Incurred sample reanalysisAcceptance criteria; details about the selection of incurred sample reanalysis (ISR) samples; definition of the complexity, scope, and duration of investigation to address failed ISR assessment.▪ Manually integrated chromatogramsClarification on the definition and acceptability of reintegration practices.▪ MetabolitesClarification on acceptable practices associated with the effect of metabolites on quantitation.▪ BiomarkersRegulatory challenges associated with biomarkers that are distinct from the measurement of xenobiotics. If biomarker assay requirements are defined by regulatory guidances, then their unique analytical challenges must be taken into account. Remaining nonprescriptive with such guidelines becomes more significant in that, depending upon how the data are to be used, method validation or various levels of method qualification need to be considered. A guidance document that describes biomarkers could clarify the definitions of ‘quantitative validation’ and ‘nonquantitative qualifications’ or ‘quantitative qualifications that cannot be validated’.▪ Stability▪ Ensuring that stability assessments mimic actual sample processing steps and are not merely ‘checkbox’ assessments against arbitrary times and conditions;▪ Establishing a position on long-term matrix stability questions (e.g., whether stability should be established at -70°C, -20°C or both); whether stability must be conducted in the presence of other drugs when the administered drug is a combination product;▪ Defining appropriate blood, urine and solid tissue stability testing: including the need for a collection process stability experiment to be performed before or during method validation to ensure method integrity during sample analysis;▪ Identifying potential stability issues and their resolution prior to method validation (determined before or during method development);▪ Establishing a position on how study results should be reported when stability is in progress.▪ ImmunoassaysLigand-binding assays, including the use of kits for immunoassays.▪ Distinction between method validation & qualificationRequirements for varying degrees of validation and qualification of new paradigms (e.g., proteins, antibody–drug conjugates, siRNA and peptide-mimetics). Specifically, consensus should be obtained on whether a method should be validated or qualified, and if a method can be qualified, to what degree. Furthermore, consensus should be obtained on commercial kits that come ‘qualified’ for an intended use, but nonetheless are used as a ‘validated’ method. In these cases, the validation of a kit needs to be defined if it is expected to be distinguished from a qualified method.▪ OutliersAgreement on when and how outliers can be applied to method validation and sample analysis.▪ ReanalysisIncluding PK repeats, reanalysis investigation procedures and associated documentation.▪ Surrogate matricesDescription for appropriate use.▪ Dried blood spot analysisInclusion of parameters to be evaluated.▪ Reporting of resultsContent-driven for consistent reporting worldwide; consideration of a likely difference of reporting BE and biomarker studies.▪ Matrix effectsIncluding binding assays and methodologies to address them. The impact of hemolysis and lipemic effects on matrix effects should be considered and documented (if identified).▪ Solid tissuesClarification to the extent that the validation of a method that is used for the analysis of an analyte(s) within a solid matrix is feasible only if the matrix being analyzed is a homogenate of the solid tissue, or if the collection of the tissue is controlled and validated. Otherwise, methods used for solid tissue analysis should be qualified rather than validated.▪ UrineConsidering the validation of a method associated with urine, collection conditions must be adequately controlled; otherwise, the integrity of the data associated with the respective method must be considered with this caveat and documented accordingly. The collection, storage stability, stability during collection and preparation, buffering and/or volumes should be regulated to the point that the applicable method can be appropriately validated, and this should be clarified in the guidance document. The validation of methods for urine may not always be feasible, requiring instead a qualification of the method, as defined in the BMV guidance.ConclusionGlobal harmonization of BMV and sample analysis practices has to occur in an efficient, effective and balanced fashion. If we are to obtain a comprehensive yet useable document that improves, not impedes, drug development, all scientific and regulatory stakeholders need to be actively involved in the process. Balance must be achieved between scientific and regulatory concerns; between current and future bioanalytical technologies; between detailed prescription and flexibility; between absolute rigor and pragmatism. The SQA can play an important role in attaining such a balance, bringing a practical, compliance-based perspective to complement other industry and regulatory agency input to this complex and worthwhile undertaking.DisclaimerThe opinions expressed in this article are those of the SQA BASS and do not necessarily reflect the respective authors’ company’s position on the subject matter.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.Bibliography1 Viswanathan CT, Bansal S, Booth B et al. 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LinkGoogle ScholarFiguresReferencesRelatedDetailsCited ByThe European Bioanalysis Forum community’s evaluation, interpretation and implementation of the European Medicines Agency guideline on Bioanalytical Method ValidationPeter van Amsterdam, Arjen Companjen, Margarete Brudny-Kloeppel, Michaela Golob, Silke Luedtke & Philip Timmerman13 March 2013 | Bioanalysis, Vol. 5, No. 6Bioanalysis of drug in tissue: current status and challengesY-J Xue, Hong Gao, Qin C Ji, Zamas Lam, XinPing Fang, Zhongping Lin, Matthew Hoffman, Daniel Schulz-Jander & Naidong Weng23 November 2012 | Bioanalysis, Vol. 4, No. 21Aspects of bioanalytical method validation for the quantitative determination of trace elementsKeith E Levine, Christopher Tudan, Peter M Grohse, Frank X Weber, Michael A Levine & Yu-Seon J Kim9 August 2011 | Bioanalysis, Vol. 3, No. 15Conference Report: Bioanalytical Procedures and Regulation: Towards Global HarmonizationHoward M Hill21 February 2011 | Bioanalysis, Vol. 3, No. 4 Vol. 2, No. 12 Follow us on social media for the latest updates Metrics History Published online 26 November 2010 Published in print December 2010 Information© Future Science LtdKeywordsbioanalytical method validationFDA/EMA regulationsglobal harmonizationmethod validation guidelinesSociety of Quality Assurance (SQA)DisclaimerThe opinions expressed in this article are those of the SQA BASS and do not necessarily reflect the respective authors’ company’s position on the subject matter.Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download