The 18(th) Workshop on Recent Issues in Bioanalysis (18(th) WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on "IVDR Implementation in EU & Changes for LDT in the US" and on "Harmonization of Vaccine Clinical Assays Validation" were the special features of the 18(th) edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2024 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2024 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers in Part 1A the Recommendations on Mass Spectrometry Assays and Regulated Bioanalysis/BMV and in Part 1B the Regulatory Inputs on these topics. Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) and Part 2 (Biomarkers/BAV, IVD/CDx, LBA and Cell-Based Assays) are published in volume 17 of Bioanalysis, issues 3 and 4 (2025), respectively.

The 16th Workshop on Recent Issues in Bioanalysis (16th WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on the ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Mass Spectrometry and ICH M10. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (LBA, Biomarkers/CDx and Cytometry) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 15 of Bioanalysis, issues 15 and 14 (2023), respectively.

With the globalization of clinical trials, regulators have increased collaboration to evaluate the adequacy of clinical trial conduct and to optimize regulatory oversight. The 2020 joint Good Clinical Practice (GCP) symposium of the US Food and Drug Administration and the UK Medicines and Healthcare products Regulatory Agency provided the agencies' perspectives on the challenges in ensuring data quality in novel clinical trial designs and the importance of the management and documentation of protocol deviations, sponsor oversight of clinical trials, and use of electronic source data, including electronic health records. This paper summarizes considerations of both agencies on these topics, along with case examples. This paper touches upon considerations when using real-world data to support regulatory decisions. It also discusses the impact of the coronavirus disease 2019 (COVID-19) pandemic on clinical trial conduct and underscores the importance of well-designed, resilient, and adaptable systems for GCP compliance and data integrity.

The 15th edition of the Workshop on Recent Issues in Bioanalysis (15th WRIB) was held on 27 September to 1 October 2021. Even with a last-minute move from in-person to virtual, an overwhelmingly high number of nearly 900 professionals representing pharma and biotech companies, contract research organizations (CROs), and multiple regulatory agencies still eagerly convened to actively discuss the most current topics of interest in bioanalysis. The 15th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on biomarker assay development and validation (BAV) (focused on clarifying the confusion created by the increased use of the term "Context of Use - COU"); mass spectrometry of proteins (therapeutic, biomarker and transgene); state-of-the-art cytometry innovation and validation; and, critical reagent and positive control generation were the special features of the 15th edition. This 2021 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2021 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1A) covers the recommendations on Endogenous Compounds, Small Molecules, Complex Methods, Regulated Mass Spec of Large Molecules, Small Molecule, PoC. Part 1B covers the Regulatory Agencies' Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine. Part 2 (ISR for Biomarkers, Liquid Biopsies, Spectral Cytometry, Inhalation/Oral & Multispecific Biotherapeutics, Accuracy/LLOQ for Flow Cytometry) and Part 3 (TAb/NAb, Viral Vector CDx, Shedding Assays; CRISPR/Cas9 & CAR-T Immunogenicity; PCR & Vaccine Assay Performance; ADA Assay Comparabil ity & Cut Point Appropriateness) are published in volume 14 of Bioanalysis, issues 10 and 11 (2022), respectively.

The 14 th edition of the Workshop on Recent Issues in Bioanalysis (14 th WRIB) was held virtually on June 15–29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14 th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by Mass Spectrometry (hybrid assays, LCMS and HRMS) were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 1) Hybrid Assays, Innovation in Small Molecules, & Regulated Bioanalysis. Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation), Part 2B (Regulatory Input) and Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 5, and 6 (2021), respectively.

BioanalysisVol. 13, No. 24 Ask the ExpertsFree AccessConduct of remote inspections: challenges and progressJason Wakelin-Smith & Stephen VinterJason Wakelin-Smith*Author for correspondence: E-mail Address: jason.wakelin-smith@mhra.gov.ukMedicines & Healthcare products Regulatory Agency (MHRA), Library, National Institute for Biological Standards & Control (NIBSC), Blanche Lane, South Mimms, Potters Bar, Hertfordshire, EN6 3QG, UK & Stephen Vinter**Author for correspondence: E-mail Address: stephen.vinter@mhra.gov.ukInspection, Enforcement & Standards, Medicine & Healthcare products Regulatory Agency, 10 South Colonnade, Canary Wharf, London, E14 4PU, UKPublished Online:17 Nov 2021https://doi.org/10.4155/bio-2021-0244AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: complianceinspectionMHRApandemicremoteJason Wakelin-SmithJason joined the MHRA in November 2006 as a GCP Inspector, became a Senior Inspector in 2015 and a Lead Senior Inspector in 2017. Jason has a split role between the GCP and laboratories inspection teams within the MHRA conducting a variety of inspections including GCP inspections of trial sponsors, CROs and analytical laboratories, bioequivalence trials as well as conducting GLP inspections as part of the UK GLP Monitoring Authority.Jason has a BSc (Hons) in Biomedical Science and a Postgraduate Diploma in Pharmaceutical Technology & Quality Assurance. Prior to joining the MHRA Jason spent seven years in the UK National Health Service working in hospital pharmacy.Stephen VinterStephen is Operations Manager for the GLPMA and Laboratories Group at the MHRA and is Head of the United Kingdom Good Laboratory Practice Monitoring Authority.Prior to joining the Agency in 2012, Stephen worked in Operations Management at a CRO. Stephen has also worked in the manufacturing sector and is a Chartered Chemist and Chartered Quality Professional.In his role as a Lead Senior Inspector, Stephen conducts GCP and GLP inspections of organizations and laboratories within the UK and overseas facilities as part of the MHRA inspection program for organizations conducting Bioequivalence studies. He has worked on several regulatory guidance documents and represents the Pharmaceutical Inspection Co-operation Scheme as an observer on the ICH M10 Expert Working Group.How have the methods of inspection changed to maintain regulatory standards despite the restrictions faced by both laboratories & regulatory bodies over the course of the pandemic?We had the same challenges as all organizations during the pandemic, and the most significant challenge being the inability to travel unless for a critical reason. Laboratory inspections over the pandemic have, by necessity, become more focused with inspections reprioritized to those supporting the development of COVID-19 vaccines and treatments alongside our normal inspection programs. Our first goal was to develop remote approaches to allow us to continue our inspection programs during travel restrictions.Even before the pandemic within the wider Inspectorate, we had started to use office-based inspections as part of our inspection processes. For example, we would often carry out the first day of a GCP inspection remotely, to review data or information requested in advance so as to maximize our time on site. We were also running a pilot of focused pharmacovigilance inspections that was entirely office based. Across the Inspectorate we had started to develop some of the basic tools and techniques necessary to conduct remote inspections so we felt we were in a strong position at the start of the pandemic to implement a suitable remote inspection program in our team.A key aspect that has been worked on for several years across industry and the MHRA has been the development of effective tools for the transfer of electronic data and documents to support inspection activity. When we started developing remote (or office based) inspections, we would often use portals or commonly available platforms provided by the organization being inspected supported by video conferencing facilities and remote access to electronic systems where this could be supported by the organization being inspected. The MHRA have introduced the use of Microsoft® Teams as our inspection platform, which has permitted the integration of file sharing, the conduct of interviews via videoconference and online chat between the inspectors and inspection host into a single platform.The basics of laboratory inspection have not changed during the pandemic; they continue to consist of reviews of analytical data and supporting documentation alongside discussions with site staff to understand the systems and processes that underpin the conduct of the study analysis. Some aspects of traditional surveillance style inspections are harder to carry out such as tours of facilities or readily available access to laboratory systems where a degree of technical support or infrastructure is required. We have conducted several bioequivalence inspections during the pandemic and at each have managed to undertake tours of the clinical and bioanalytical facilities supported by the site staff using mobile phones or tablets, microphones and with willing assistants to act as the camera crew!Probably the biggest changes have been associated with the adoption of electronic ways of working wherever this can be supported. We have changed the type and format of data that we request allowing the transfer of data onto our MS Teams platform and subsequent data review using our own software. We have also requested remote access to any electronic systems at the laboratory from our desktops where possible, and where this not possible then we use shared desktop sessions to allow us to interact with software.We have identified significant findings during remote inspections, so, although they have their challenges, remote inspections are an effective tool and one which is likely to remain as part of a hybrid inspection program going forward. They work well for focused inspections, for example to follow-up to specific issues, CAPA review or those that are very data orientated.What have been the key challenges of conducting regulatory inspections amidst a global pandemic?We have to recognize that it is not just the inspectors that have been forced to work remotely but also the companies themselves so we have made sure that staff at the organizations being inspected were not making unnecessary journeys traveling into the laboratory or office purely to access documentation on our behalf and potentially putting themselves (and others) at risk during the process. We have not experienced significant issues with accessing staff, data or documentation but we suspect there have been plenty of people behind the scenes trying to provide us with access to the information we require whilst complying with pandemic related restrictions.How easily can inspection protocols & assessment criteria be adapted to remote inspections?Readily – once we have appropriate access to staff, data and documentation then the inspection is conducted in a similar manner to that of an on-site inspection minus the ad hoc face-to-face interactions.What are the key challenges of conducting remote inspections from a regulatory perspective?It takes a little longer to conduct a remote inspection, we may not spend so much time traveling, but the time spent accessing, requesting documentation, asking questions and obtaining clarifications, can take longer. We recognize this when we schedule inspections and also take into account that we can sometimes be in different time zones.Technology is incredibly important. Poor internet connections can cause significant problems with video conferencing, facility tours and access to data, and this is something that is discussed with the organization during inspection planning.We have also been challenged by the number of systems that we need to gain access to in order to inspect the selected processes remotely and in full along with the ability of the organization to grant us remote access to these. From a laboratory perspective, we have seen a lot of instrument platforms which are not networked let alone set up for remote access by an external organization along with compartmentalized access to broader systems such as those containing standard operating procedure or training records.There are also plenty of paper-based processes in place within some of the laboratories we have inspected, which may require scanning before they can be provided to us for review. This is often not just associated with the trial or study records but also any supporting logbooks and equipment records.All these challenges are discussed during planning with the facility to allow us to reach a suitable solution that works for the inspectors and the facility.Are there any advantages of remote inspections over traditional face-to-face inspections?They have a place in the inspector's toolbox for focused assessment of particular aspects of a study, such as the review of analytical data. We have copies of various types of analytical software at the MHRA which enables us to inspect the data remotely in our own system without causing an increased burden on the laboratory by us having to be on site to conduct this part of the inspection. Certainly, with inspections overseas there is a greater flexibility found when trying to schedule inspections with the laboratory as complex travel requirements are not required!Do you have any advice for laboratories on best practice when preparing for a remotely conducted inspection?It is important to discuss with the lead inspector as early as possible about how the inspection will be conducted remotely. These discussions during the planning phase ensure the inspection platform is set up accordingly to allow a smooth exchange of information, to schedule the various interviews and tours required and also to conduct checks on the system performance before the inspection starts.Make sure that you understand the data flows associated with the studies selected for inspection and work out how access to the analytical data and supporting metadata, such as audit trails, can be given. This may be in the form of remote access to your systems, transfer of data for review using software held by the MHRA or agreement that guided access may be the only possible route available (although this is not ideal and should be discussed with the lead inspector). Ultimately, the inspector will want to follow the generation of data from the source documentation through to its eventual inclusion in the study report via all of the transfers and transformations it goes through.Identify what records are likely to be required in order to support the inspection. If you are unsure what is likely to be required, then a discussion with the lead inspector is always encouraged early in the process of setting up the inspection.If remote tours are to be conducted then ensure sufficient Wi-Fi coverage exists throughout the facility and consider the use of a 'presenter' for the tour who is provided with a microphone and the ability to hear the inspection team with another member of staff operating the camera.Do you think remote inspections will reshape the future of the bioanalytical regulatory landscape, to become the 'new norm'It is likely that the 'hybrid' inspection model, with inspections consisting of both remote and on-site components, will continue after the pandemic. Improvements in technology are likely to increase the use of remote tools, making the inspection more efficient for both inspectors and the laboratory alike. - This interview was conducted by Sankeetha Nadarajah, Managing Editor of Bioanalysis.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.FiguresReferencesRelatedDetailsCited ByImplementation of automation, IT support and cybersecurity in bioanalysisNaamah Maundrell15 June 2022 | Bioanalysis, Vol. 0, No. 0Special Focus Issue - COVID-19: bioanalytical considerations, contributions and lessons – part 2Chad J Briscoe & Matthew Barfield22 November 2021 | Bioanalysis, Vol. 13, No. 24 Vol. 13, No. 24 Follow us on social media for the latest updates Metrics Downloaded 597 times History Received 2 November 2021 Accepted 2 November 2021 Published online 17 November 2021 Published in print December 2021 Information© 2021 Newlands PressKeywordscomplianceinspectionMHRApandemicremoteFinancial & 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

The 14th edition of the Workshop on Recent Issues in Bioanalysis (14th WRIB) was held virtually on June 15-29, 2020 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. The 14th WRIB included three Main Workshops, seven Specialized Workshops that together spanned 11 days in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy and vaccine. Moreover, a comprehensive vaccine assays track; an enhanced cytometry track and updated Industry/Regulators consensus on BMV of biotherapeutics by LCMS were special features in 2020. As in previous years, this year's WRIB continued to gather a wide diversity of international industry opinion leaders and regulatory authority experts working on both small and large molecules to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance and achieving scientific excellence on bioanalytical issues. This 2020 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the Global Bioanalytical Community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2020 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication covers the recommendations on (Part 2A) BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation and (Part 2B) Regulatory Input. Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 3 (Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity) are published in volume 13 of Bioanalysis, issues 4, and 6 (2021), respectively.

Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting clinical trials. Regulatory agencies conduct GCP inspections to verify the integrity of data generated in clinical trials and to assure the protection of human research subjects, in addition to ensuring that clinical trials are conducted according to the applicable regulations. The first joint GCP workshop of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) and the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA‐UK) was held in October 2018 and provided the agencies’ perspectives on the importance of data quality management practices on data integrity. Regulatory perspectives on data blinding to minimize introduction of bias, and the role of audit trails in assessing data integrity in global clinical trials were discussed. This paper summarizes considerations of both agencies on these topics, along with case examples.

BioanalysisVol. 11, No. 18 ForewordFree AccessCrucial importance of evaluating internal standards (IS) response and troubleshooting in effective LCMS method development, validation and sample analysisSeongeun Julia Cho, Stephen Vinter & Fabio GarofoloSeongeun Julia ChoUS FDA, Silver Spring, MD, USASearch for more papers by this author, Stephen VinterUK MHRA, London, UKSearch for more papers by this author & Fabio Garofolo*Author for correspondence: E-mail Address: fabiogarofolo@hotmail.comAngelini Pharma, Rome, ItalySearch for more papers by this authorPublished Online:22 Oct 2019https://doi.org/10.4155/bio-2019-0245AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Internal standards (IS) are commonly used in chromatographic analytical methods to correct for variability in sample processing and analysis. To achieve this, a constant amount of IS is added to all samples – except for a double blank in a batch – including calibration standards (CALS), quality controls (QCs), and subject samples prior to the initiation of extraction procedures. Therefore, by design, the responses of IS from all samples in an analytical run are anticipated to be similar to each other. However, in some instances, we observe variability in IS responses, even among samples processed and analyzed concurrently. It is worthwhile to note that since the IS selected for a method should have similar physicochemical properties of the analyte of interest, variability of IS response in many cases may not impact the accuracy of the data, provided that IS behaves in a similar fashion as the analyte and reflects changes to the analyte that occur during sample processing and analysis. Under these conditions, for example, if ranges of IS responses for CALS, QCs and subject samples are comparable across an entire analytical run, IS variability in subject samples is unlikely to impact the accuracy of the data. In other circumstances, however, IS response variability may require additional investigations to ensure measurements of subject sample concentrations are accurate. These situations may include when the range of IS responses for subject samples is substantially wider than the range of IS responses for CALS/QCs in the same analytical run or when IS responses for subject samples are consistently lower or higher than IS responses for CALS/QCs in a run. Often, analytical laboratories rely on a pre-set acceptance rule specified in standard operating procedures (SOP) to identify study samples with unacceptable IS responses. However, handling IS irregularity solely based on a pre-set criteria and subsequent routine repeat analysis are not always effective in detecting potential problems nor provide sufficient information regarding the root causes of the variability or data accuracy.Recently, the US FDA published a final guidance for industry, ‘Evaluation of internal standard responses during chromatographic bioanalysis: questions and answers' [1]. The guidance explains when observed IS response variability may impact the accuracy of data and whether it warrants further investigation. In addition, an excerpt from the WRIB Decennial Index [2] highlights the numerous industry/regulators' discussions over the years:“There has been much discussion between regulators and industry regarding internal standard (IS) variability, with little concrete recommendations regarding criteria. In 2011, the consensus was that when properly using a stable-labeled IS, there may not be a need for IS response acceptance criteria, as long as the stable-labeled IS and the drug of interest coelute [3]. This was reconfirmed in 2015 [4]. Discussions on this topic continued in 2014, where it was concluded that IS response evaluation is a complex topic with many scenarios to consider. A single set of criteria for IS acceptance or triggering an investigation may not be practical. A variety of approaches have been employed/discussed as appropriate acceptance criteria for IS response variation. These include numerical boundaries based on the IS variation of known samples, trend analysis and statistical methods to identify outliers. Whatever the approach taken, and whether a general set of criteria or assay-specific criteria are established, the IS response should be closely monitored; abnormal variability and outliers should be investigated [5]. Discussions in 2015 elaborated that trends and systemic differences should be investigated to identify their root causes and to determine effects on the accuracy of the drug/analyte concentration results in matrix. Investigations should be science-driven with clear rationale and documentation. SOPs with acceptance limits for IS response variation should be established to identify technical problems during sample processing” [4].IS Variability was revisited in 2017 with further clarifications on this topic by US FDA. The case studies and scientific discussions among the community led to the recommendations that “During study sample analysis, thorough and consistent approaches with predefined acceptance criteria for IS responses are important to ensure accuracy of results,” and “A priori criteria should consider scientific merits. Additional investigations and proper documentation may be warranted when unusual IS responses are observed” [6]. Moreover, it was decided that more training was needed to harmonize industry practice and regulatory expectations. Hence, a full day industry/regulators training session with numerous case studies and panel discussions were organized during the 12th WRIB (2018) in Philadelphia [7]. This session, entitled ‘Crucial importance of correct internal standards (IS) response troubleshooting & interpretation in effective LCMS method development, validation and sample analysis’, has been extremely successful, and it has been expanded in this special issue aimed to heighten an appropriate attention to IS responses during method development and need for critical evaluation during the sample analysis.Articles in this issue have been inspired by the industry/regulators' interactive discussion during the 12th WRIB and they discuss specific case studies and in-depth evaluations of the findings on IS variability. In an editorial, Stephen Vinter (MHRA; London, UK) provides an insight into inspectors' experiences and expectations of this important topic [8]. It describes the crucial role inspections play in the regulatory process and invites the reader to consider the impact IS response variations can have on bioanalytical data. Alongside this, Gustavo Mendes Lima Santos and Eduardo Fernandes (Brazilian Health Regulatory Agency [ANVISA]; Brasilia, Brazil) discuss the perspective of the ANVISA and their regulation monitoring [9]. Specifically, this article considers requirements regarding IS monitoring in CROs. Fraier et al. (Roche Innovation Center; Basel, Switzerland) demonstrates how IS response variations should trigger investigations into the root cause [10]. Through two cases, they conclude determining the cause may not always be possible, however, assay accuracy and reliability of results should be demonstrated, and re-development of an assay may be required in some situations. Similarly, Buonarati and Schoener (Intertek USA Inc, CA, USA) present examples of atypical IS responses, including biomarker assays, and conclude that close monitoring of IS response should be routine practice and unusual and substantial trends should always be evaluated [11]. Woolf (Merck & Co, PA, USA) describes cases in his article in order to illustrate how variable IS responses cannot always be attributed to compensation of matrix effects [12]. He details that anomalous IS responses, even for stable label IS, should be investigated and the root cause should be determined where possible. Verhaeghe (Janssen Research & Development, Beerse, Belgium) goes on to present two case studies where there was a clear response difference between study samples and CALS and QCs [13]. Verhaeghe concludes that IS acceptance criteria is useful for enabling unbiased rejection of results, however, there is no one-size-fits-all criteria and scientific judgement should be used. Similarly, van de Merbel et al. (PRA Health Sciences, Assen, The Netherlands) discuss examples of complex and extreme variation of IS responses in their article [14]. van de Merbel et al. goes on to recommend a decision-tree covering four major general areas of IS variability to assist with root cause analysis. In a Perspective by Green et al. (LGC Limited, Fordham, UK), considerations for selecting an IS in bioanalytical assays and similar challenges that Green and her team have experienced are discussed [15]. Finally, Le Blaye (French National Agency for Medicines and Health Products Safety [ANSM]; Saint-Denis, France) discusses how objective numerical criteria are useful for deciding to re-analyze individual samples, however, a visual inspection of plots of IS response could be better for monitoring trends or systematic differences [16]. This perspective concludes standard operating procedures are only capable of describing the standard response to standard situations and should not be used to justify blindly accepting data.AcknowledgmentsThe guest editors would like to thank Rhiannon Finnie (Commissioning Editor, Bioanalysis) for her great enthusiasm, dedication and continuous support during the various development stages of this Special Issue on Internal Standards Variability.DisclaimerThis article reflects the views of the author and should not be construed to represent FDA's views or policies.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.References1. US Department of Health and Human Services FDA Center for Drug Evaluation and Research (CDER). Evaluation of internal standard responses during chromatographic bioanalysis: questions and answers guidance for industry (2019). www.fda.gov/media/130451/downloadGoogle Scholar2. Garofolo W, Savoie N. The decennial index of the White Papers in bioanalysis: a decade of recommendations (2007–2016). Bioanalysis 9(21), 1681–1704 (2017).Link, Google Scholar3. Garofolo F, Rocci M, Dumont I et al. 2011 White Paper on recent issues in bioanalysis and regulatory findings from audits and inspections. Bioanalysis 3(18), 2081–2096 (2011).Link, CAS, Google Scholar4. Welink J, Fluhler E, Hughes N et al. 2015 White Paper on recent issues in bioanalysis: focus on new technologies and biomarkers (part 1 – small molecules by LCMS). Bioanalysis 7(22), 2913–2925 (2015).Link, CAS, Google Scholar5. Fluhler E, Hayes R, Garofolo F et al. 2014 White Paper on recent issues in bioanalysis: a full immersion in bioanalysis (part 1 – small molecules by LCMS). Bioanalysis 6(22), 3039–3049 (2014).Link, CAS, Google Scholar6. Welink J, Yang E, Hughes N et al. 2017 White Paper on recent issues in bioanalysis: aren't BMV guidance/guidelines ‘scientific’? (part 1 – LCMS: small molecules, peptides and small molecule biomarkers). Bioanalysis 9(22), 1807–1825 (2017).Link, CAS, Google Scholar7. Welink J, Xu Y, Yang E et al. 2018 White Paper on recent issues in bioanalysis: ‘a global bioanalytical community perspective on last decade of incurred samples reanalysis (ISR)’ (part 1 – small molecule regulated bioanalysis, small molecule biomarkers, peptides & oligonucleotide bioanalysis). Bioanalysis 10(22), 1781–1801 (2018).Link, CAS, Google Scholar8. Vinter S. Variations in internal standards: an inspector's perspective. Bioanalysis 11(18), (2019).Link, Google Scholar9. Santos GML, Fernandes E. Internal standards (IS) monitoring in CROs: ANVISA perspective. Bioanalysis 11(18), (2019).Google Scholar10. Fraier D, Ferrari L, Heinig K, Zwanziger E. Inconsistent internal standard response in LC–MS/MS bioanalysis – an evaluation of case studies. Bioanalysis 11(18), (2019).Link, Google Scholar11. Buonarati M, Schoener D. Investigations beyond SOP on internal standard response. Bioanalysis 11(18), (2019).Link, Google Scholar12. Woolf E. Learning how to interpret “dangerous” internal standard behaviors. Bioanalysis 11(18), (2019).Link, Google Scholar13. Verhaeghe T. Systematic IS variability and issue resolution. Bioanalysis 11(18), (2019).Link, Google Scholar14. van de Merbel NC, Koster RA, Ohnmacht C. Very complex internal standard response variation in LC–MS/MS bioanalysis: root cause analysis and impact assessment. Bioanalysis 11(18), (2019).Google Scholar15. Green R, Wright M, Wheller R, Wallace G. Putting in place a decision-making process during method development based on internal standard response. Bioanalysis 11(18), (2019).Google Scholar16. Le Blaye O. Variations in internal standard response: some thoughts and real-life cases. Bioanalysis 11(18), (2019).Google ScholarFiguresReferencesRelatedDetailsCited ByDevelopment and Validation of a Method for Quantification of Favipiravir as COVID-19 Management in Spiked Human Plasma22 June 2021 | Molecules, Vol. 26, No. 13Evaluation, identification and impact assessment of abnormal internal standard response variability in regulated LC−MS bioanalysisYunlin Fu, Deborah Barkley, Wenkui Li, Franck Picard & Jimmy Flarakos30 April 2020 | Bioanalysis, Vol. 12, No. 8 Vol. 11, No. 18 Follow us on social media for the latest updates Metrics History Received 21 September 2019 Accepted 27 September 2019 Published online 22 October 2019 Published in print September 2019 Information© 2019 Newlands PressAcknowledgmentsThe guest editors would like to thank Rhiannon Finnie (Commissioning Editor, Bioanalysis) for her great enthusiasm, dedication and continuous support during the various development stages of this Special Issue on Internal Standards Variability.DisclaimerThis article reflects the views of the author and should not be construed to represent FDA's views or policies.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

BioanalysisVol. 11, No. 18 EditorialOpen AccessOpen Access licenseVariations in internal standard: an inspector's perspectiveStephen VinterStephen Vinter*Author for correspondence: E-mail Address: stephen.vinter@mhra.gov.ukMHRA, 10 South Colonnade, Canary Wharf, London, E14 4PU, UKPublished Online:16 Oct 2019https://doi.org/10.4155/bio-2019-0232AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit Keywords: bioanalysischromatographygood clinical practicegood laboratory practiceinternal standardregulatory inspectionInspections play a crucial part in the regulatory process ensuring studies are conducted in accordance with relevant regulations and allowing verification of the data generated by a laboratory. If these requirements are satisfied, then the assessment of data supplied to support regulatory decisions is a more straightforward process for both applicants and the regulator.Medicines & Healthcare products Regulatory Agency (London, UK) inspections cover several areas of laboratory activity to enable an assessment to be made of the facility's systems, its staff and the integrity of the data it has generated. Inspections will often include tours of the facility, interviews with staff, review of the Quality Management System, equipment reviews, data integrity checks and reconstruction of the data generation.What part do internal standards and a review of their response play in an inspection? The answer to this question is highlighted throughout this special issue, but the short answer is that they play an important part in supporting the quality of the data by giving information related to the assay performance, so there is an expectation that a laboratory reviews this response and acts accordingly.Inspectors continue to identify issues where an inconsistent internal standard response within an assay has not been reviewed by a laboratory, where current guidance has been incorrectly interpreted or where there is a lack of transparency in how the variation in response was assessed and mitigated. In some cases, this has resulted in rejection of data from the impacted studies.How a laboratory manages, documents and reports internal standard response review can provide important information to inspectors about the data, systems and the level of compliance of the laboratory being inspected.It is important to consider the underlying principles associated with regulatory studies in addition to specific requirements of guidance documents. If all these principles are incorporated into a laboratory's systems and culture successfully, then a significant step will have been taken in generating reliable and compliant data.Good laboratory practice & good clinical practiceThe quality and validity of study data, plus the ability to verify study conduct, are important factors when we consider the principles of both good laboratory practice (GLP) and good clinical practice (GCP).If we consider the Organisation for Economic Co-operation and Development (Paris, France) principles of GLP; the conduct of the study is the responsibility of the Study Director. When the Study Director signs and dates the final report, they are indicating acceptance of responsibility for the validity of the data [1]. In addition, a key principle of GCP can be found in the International Council for Harmonisation (ICH) E6 (2.13), which requires that systems with procedures that assure the quality of every aspect of the trial should be implemented [2].An assessment of internal standard response can aid the Study Director while making the statement of compliance to confirm the validity of the data, which is a key statement used by regulators when assessing the compliance of a GLP study. The internal standard response assessment will also support the requirements discussed in ICH E6 to ensure the quality of every aspect of the trial. Therefore, poor internal standard response may undermine the validity and quality (reliability) of the data, so without making this assessment and appropriately assessing the impact, a study may not be compliant with the principles of GLP or GCP. An assessment of internal standard response is therefore considered necessary and should be effectively documented.Contemporaneous and accurate recording of study events is extremely important when considering effective documentation. This recording of events and study decisions is extremely important when considering that an inspector will need to verify the study conduct. During GLP facility inspections, the quality and integrity of data generated by the facility are assessed and during study audits, an inspection will need to establish whether practices were employed in the development of data that would impair their validity [3]. ICH E6 (2.10) requires that all clinical trial information should be recorded, handled and stored in a way that allows its accurate reporting, interpretation and verification [2].What can we take from these principles regarding internal standard response?There are many components to an inspector's assessment of the study conduct and the validity of the data generated. It is reasonable to conclude that by assessing internal standard response, a laboratory has both a powerful tool for internal decision making and also valuable information to allow verification of the study activities and results. When suitable documentation, including the subsequent decisions, are combined with the assessment, an inspector will be able to use this information to support their inspection activities to verify the quality and validity of the reported data.Current guidance from regulators in Europe & the USACurrent regulatory guidance includes reference to internal standard response, so it is useful to pay attention to the content of these documents, especially if there is a requirement for an assay to comply with them.The European Medicines Agency Guideline on Bioanalytical Method Validation [4] allows sample re-analysis if the internal standard response of the unknown is significantly different from the response of the calibration standard and quality control samples, when criteria for re-analysis have been predefined in a Standard Operating Procedure (SOP). The European Medicines Agency Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples [5], also reflects the ICH E6 principles that we have already discussed, in that in all cases sufficient documentation should be available to confirm that the conduct of the analysis is performed in a manner which assures its quality. The current US FDA Bioanalytical Method Validation guidance [6] also requires that internal standard response of calibration standards are monitored for variability and that a SOP is in place to address such issues.So using these guidelines and reflection papers as examples and then adding the principles of GLP and GCP, plus any other local regulatory requirements, it is fairly clear that laboratories should have procedures in place to assess internal standard response to ensure the quality and validity of data and suitable documentation of the assessment to support decision making.Inspection experiences & expectationsThis inspector's experience has seen well-established SOPs, good documentation and technically sound decision making which is fully transparent to allow straightforward verification of study conduct. Unfortunately, there are numerous examples where inspection findings have been raised and, in some cases, resulted in the rejection of data. Inspection findings have included no assessments being made at all, limited assessment where simple outlier tests are applied without taking into account significant trends in the internal standard response, no documentation retained to support decision making, inappropriate acceptance criteria within SOPs or misinterpretation of guidance leading to unjustified repeat analysis or re-injection of samples.When should this assessment take place?Obviously this should take place during sample analysis as decisions will be made on whether repeat analysis is required and the assessment will also provide information about the performance of the assay and potential analytical issues. It is also advisable to assess internal standard response during method validation as there have been examples observed on inspection of internal standard response issues not being detected during the validation of the method which have then also occurred during sample analysis, leading to lengthy analytical investigations, repeated validation experiments and lost data.As an expectation, an inspector would expect to see a procedure in place (that is in compliance with regulatory requirements) for internal standard response assessment, which looks for outliers and assesses any trends in the response, which then triggers appropriate actions (such as investigations, repeat analysis or the acceptance of data). These decisions should be suitably documented to allow verification of the study conduct, to understand the rationale behind the decision and to provide evidence that the data are valid and of suitable quality. It is useful to also give some attention to final report transparency. Information regarding issues or investigations should be accurately and completely described so that the decision maker, whether it is another scientist or a regulator, has all the necessary information to enable them to understand the full conduct of the study.If these are all in place, then an inspector will be able to review the study documentation effectively, discuss any decision making with the laboratory and avoid significant inspection findings and subsequent issues with gaining regulatory approval.It should also not be forgotten that the quality of data are of high importance as there will be an animal, volunteer, patient or the environment impacted by the laboratory's results. These data can be used before any inspection or regulatory submission so there is a responsibility to ensure that the data are of suitable quality to avoid any harm to the study subjects.Hopefully this issue will provide information on how best to meet the needs of regulators, laboratory best practice and things to look out for when considering the impact internal standard response can have on bioanalytical data.By sharing our combined experiences on this issue, we can hopefully all understand the challenges that laboratories face in this technically demanding field and generate reliable and compliant data.AcknowledgmentsI would like to thank the Medicines & Healthcare products Regulatory Agency laboratories inspection team for their ongoing support and input to enable the writing of this editorial.Financial & competing interests disclosureThe author has 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.Open AccessThis work is licensed under a Crown Copyright protection and licensed for use under the Open Government License unless otherwise indicated. Where any of the Crown copyright information in this work is republished or copied to others, the source of the material must be identified and the copyright status under the Open Government License acknowledged.References1. Organisation for Economic Co-operation and Development. Principles of good laboratory practice (1998). www. oecd.org/chemicalsafety/testing/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htmGoogle Scholar2. International Council for Harmonisation. Guideline for good clinical practice E6(R2) (2017). www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4_2016_1109.pdfGoogle Scholar3. Organisation for Economic Co-operation and Development. Guidance for GLP monitoring authorities, revised guides for compliance monitoring procedures for good laboratory practice (1995). www.oecd.org/chemicalsafety/testing/oecdseriesonprinciplesofgoodlaboratorypracticeglpandcompliancemonitoring.htmGoogle Scholar4. European Medicines Agency. Guideline on bioanalytical method validation (2012). www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdfGoogle Scholar5. European Medicines Agency. Reflection paper for laboratories that perform the analysis or evaluation of clinical trial samples (2012). www.ema.europa.eu/en/documents/regulatory-procedural-guideline/reflection-paper-laboratories-perform-analysis-evaluation-clinical-trial-samples_en.pdfGoogle Scholar6. US FDA, Department of Health and Human Services, Center for Drug Evaluation and Research. Bioanalytical method validation guidance for industry (2018). www.fda.gov/media/70858/downloadGoogle ScholarFiguresReferencesRelatedDetailsCited ByDevelopment and validation of a HILIC-MS/MS method for the quantitation of fructose in human urine in support of clinical programsJournal of Pharmaceutical and Biomedical Analysis, Vol. 208Crucial importance of evaluating internal standards (IS) response and troubleshooting in effective LCMS method development, validation and sample analysisSeongeun Julia Cho, Stephen Vinter & Fabio Garofolo22 October 2019 | Bioanalysis, Vol. 11, No. 18 Vol. 11, No. 18 Follow us on social media for the latest updates Metrics History Received 19 September 2019 Accepted 30 September 2019 Published online 16 October 2019 Published in print September 2019 Information© Crown CopyrightKeywordsbioanalysischromatographygood clinical practicegood laboratory practiceinternal standardregulatory inspectionAcknowledgmentsI would like to thank the Medicines & Healthcare products Regulatory Agency laboratories inspection team for their ongoing support and input to enable the writing of this editorial.Financial & competing interests disclosureThe author has 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.Open AccessThis work is licensed under a Crown Copyright protection and licensed for use under the Open Government License unless otherwise indicated. Where any of the Crown copyright information in this work is republished or copied to others, the source of the material must be identified and the copyright status under the Open Government License acknowledged.PDF download

The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA on 1-5 April 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations on the 2018 FDA BMV guidance, 2019 ICH M10 BMV draft guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy. Part 1 (Innovation in small molecules and oligonucleotides and mass spectrometry method development strategies for large molecules bioanalysis) and Part 3 (New insights in biomarker assay validation, current and effective strategies for critical reagent management, flow cytometry validation in drug discovery and development and CLSI H62, interpretation of the 2019 FDA immunogenicity guidance and gene therapy bioanalytical challenges) are published in volume 10 of Bioanalysis, issues 22 and 24 (2019), respectively.

The 2018 12(th) Workshop on Recent Issues in Bioanalysis took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for PK, PD and ADA assays by hybrid LBA/LCMS and regulatory agencies' input. Part 1 (LCMS for small molecules, peptides, oligonucleotides and small molecule biomarkers) and Part 3 (LBA/cell-based assays: immunogenicity, biomarkers and PK assays) are published in volume 10 of Bioanalysis, issues 22 and 24 (2018), respectively.

The 2018 12th Workshop on Recent Issues in Bioanalysis (12th WRIB) took place in Philadelphia, PA, USA on April 9-13, 2018 with an attendance of over 900 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day full immersion in bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LC-MS, hybrid ligand binding assay (LBA)/LC-MS and LBA/cell-based assays approaches. This 2018 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2018 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for LC-MS for small molecules, peptides, oligonucleotides and small molecule biomarkers. Part 2 (hybrid LBA/LC-MS for biotherapeutics and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis, biomarkers and immunogenicity using LBA and cell-based assays) are published in volume 10 of Bioanalysis, issues 23 and 24 (2018), respectively.

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California from 3 April 2017 to 7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis, Biomarkers and Immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid LBA/LCMS and ligand-binding assay (LBA) approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 1) covers the recommendations for Small Molecules, Peptides and Small Molecule Biomarkers using LCMS. Part 2 (Biotherapeutics, Biomarkers and Immunogenicity Assays using Hybrid LBA/LCMS and Regulatory Agencies' Inputs) and Part 3 (LBA: Immunogenicity, Biomarkers and PK Assays) are published in volume 9 of Bioanalysis, issues 23 and 24 (2017), respectively.

The 2017 11th Workshop on Recent Issues in Bioanalysis (11th WRIB) took place in Los Angeles/Universal City, California on 3-7 April 2017 with participation of close to 750 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - a full immersion week of bioanalysis, biomarkers and immunogenicity. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecule analysis involving LCMS, hybrid ligand binding assay (LBA)/LCMS and LBA approaches. This 2017 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2017 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 2) covers the recommendations for biotherapeutics, biomarkers and immunogenicity assays using hybrid LBA/LCMS and regulatory agencies' inputs. Part 1 (LCMS for small molecules, peptides and small molecule biomarkers) and Part 3 (LBA: immunogenicity, biomarkers and pharmacokinetic assays) are published in Volume 9 of Bioanalysis, issues 22 and 24 (2017), respectively.

The 2016 10th Workshop on Recent Issues in Bioanalysis (10th WRIB) took place in Orlando, Florida with participation of close to 700 professionals from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations, and regulatory agencies worldwide. WRIB was once again a 5-day, weeklong event - A Full Immersion Week of Bioanalysis including Biomarkers and Immunogenicity. As usual, it is specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small and large molecules involving LCMS, hybrid LBA/LCMS, and LBA approaches, with the focus on biomarkers and immunogenicity. This 2016 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. This White Paper is published in 3 parts due to length. This part (Part 2) discusses the recommendations for Hybrid LBA/LCMS and regulatory inputs from major global health authorities. Parts 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) have been published in the Bioanalysis journal, issues 22 and 23, respectively.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 1 covers the recommendations for small molecule bioanalysis using LCMS. Part 2 (hybrid LBA/LCMS and regulatory agencies' inputs) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will also be published in volume 7 of Bioanalysis, issues 23 and 24, respectively.

The 2015 9th Workshop on Recent Issues in Bioanalysis (9th WRIB) took place in Miami, Florida with participation of over 600 professionals from pharmaceutical and biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. It is once again a 5-day week long event - a full immersion bioanalytical week - specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest in bioanalysis. The topics covered included both small and large molecules, and involved LCMS, hybrid LBA/LCMS, LBA approaches including the focus on biomarkers and immunogenicity. This 2015 White Paper encompasses recommendations that emerged from the extensive discussions held during the workshop, and is aimed at providing the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to advance scientific excellence, improve quality and deliver better regulatory compliance. Due to its length, the 2015 edition of this comprehensive White Paper has been divided into three parts. Part 2 covers the recommendations for hybrid LBA/LCMS and regulatory agencies' inputs. Part 1 (small molecule bioanalysis using LCMS) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in volume 7 of Bioanalysis, issues 22 and 24, respectively.