2020 White Paper on Recent Issues in Bioanalysis: Vaccine Assay Validation, qPCR Assay Validation, QC for CAR-T Flow Cytometry, NAb Assay Harmonization and ELISpot Validation (Part 3 – Recommendations on Immunogenicity Assay Strategies, NAb Assays, Biosimilars and FDA/EMA Immunogenicity Guidance/Guideline, Gene & Cell Therapy and Vaccine Assays)

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 (Part 3) covers the recommendations on Vaccine, Gene/Cell Therapy, NAb Harmonization and Immunogenicity). Part 1 (Innovation in Small Molecules, Hybrid LBA/LCMS & Regulated Bioanalysis), Part 2A (BAV, PK LBA, Flow Cytometry Validation and Cytometry Innovation) and Part 2B (Regulatory Input) are published in volume 13 of Bioanalysis, issues 4 and 5 (2020), respectively.

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2020 White Paper on Recent Issues in Bioanalysis: BMV of Hybrid Assays, Acoustic MS, HRMS, Data Integrity, Endogenous Compounds, Microsampling and Microbiome (Part 1 – Recommendations on Industry/Regulators Consensus on BMV of Biotherapeutics by LCMS, Advanced Application in Hybrid Assays, Regulatory Challenges in Mass Spec, Innovation in Small Molecules, Peptides and Oligos)

Bioanalysis ◽

10.4155/bio-2020-0324 ◽

2021 ◽

Vol 13 (4) ◽

pp. 203-238

Author(s):

Hendrik Neubert ◽

Stephen C Alley ◽

Anita Lee ◽

Wenying Jian ◽

Michael Buonarati ◽

...

Keyword(s):

Cell Therapy ◽

Small Molecules ◽

Regulatory Compliance ◽

White Paper ◽

Scientific Excellence ◽

Research Organizations ◽

Mass Spec ◽

International Industry ◽

Regulatory Input ◽

Biotechnology Companies

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, 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.

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2020 White Paper on Recent Issues in Bioanalysis: BAV Guidance, CLSI H62, Biotherapeutics Stability, Parallelism Testing, CyTOF and Regulatory Feedback (Part 2A – Recommendations on Biotherapeutics Stability, PK LBA Regulated Bioanalysis, Biomarkers Assays, Cytometry Validation & Innovation Part 2B – Regulatory Agencies’ Inputs on Bioanalysis, Biomarkers, Immunogenicity, Gene & Cell Therapy and Vaccine)

Bioanalysis ◽

10.4155/bio-2021-0005 ◽

2021 ◽

Author(s):

Susan Spitz ◽

Yan Zhang ◽

Sally Fischer ◽

Kristina McGuire ◽

Ulrike Sommer ◽

...

Keyword(s):

Cell Therapy ◽

Regulatory Compliance ◽

White Paper ◽

Regulatory Agencies ◽

Scientific Excellence ◽

Large Molecules ◽

Research Organizations ◽

International Industry ◽

Regulatory Input ◽

Biotechnology Companies

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.

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2019 White Paper on Recent Issues in Bioanalysis: FDA Immunogenicity Guidance, Gene Therapy, Critical Reagents, Biomarkers and Flow Cytometry Validation (Part 3 – Recommendations on 2019 FDA Immunogenicity Guidance, Gene Therapy Bioanalytical Challenges, Strategies for Critical Reagent Management, Biomarker Assay Validation, Flow Cytometry Validation & CLSI H62)

Bioanalysis ◽

10.4155/bio-2019-0271 ◽

2019 ◽

Vol 11 (24) ◽

pp. 2207-2244 ◽

Cited By ~ 4

Author(s):

Steven Piccoli ◽

Devangi Mehta ◽

Alessandra Vitaliti ◽

John Allinson ◽

Shashi Amur ◽

...

Keyword(s):

Gene Therapy ◽

Flow Cytometry ◽

Method Development ◽

Regulatory Compliance ◽

White Paper ◽

Large Molecule ◽

Regulatory Agencies ◽

Assay Validation ◽

Biotechnology Companies ◽

Management Flow

The 2019 13th Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA, USA on April 1–5, 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 3) covers New Insights in Biomarker Assay Validation, Current & Effective Strategies for Critical Reagent Management, Flow Cytometry Validation in Drug Discovery & Development & CLSI H62, Interpretation of the 2019 FDA Immunogenicity Guidance and Gene Therapy Bioanalytical Challenges. Part 1 (Innovation in Small Molecules and Oligonucleotides & Mass Spectrometry Method Development Strategies for Large Molecule Bioanalysis) and Part 2 (Recommendations on the 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy) are published in volume 11 of Bioanalysis, issues 22 and 23 (2019), respectively.

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2019 White Paper On Recent Issues in Bioanalysis: FDA BMV Guidance, ICH M10 BMV Guideline and Regulatory Inputs (Part 2 – Recommendations on 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and Regulatory Agencies' Input on Bioanalysis, Biomarkers and Immunogenicity)

Bioanalysis ◽

10.4155/bio-2019-0270 ◽

2019 ◽

Vol 11 (23) ◽

pp. 2099-2132 ◽

Cited By ~ 3

Author(s):

Brian Booth ◽

Lauren Stevenson ◽

Renuka Pillutla ◽

Michael Buonarati ◽

Chris Beaver ◽

...

Keyword(s):

Gene Therapy ◽

Flow Cytometry ◽

Method Development ◽

Regulatory Compliance ◽

White Paper ◽

Regulatory Agencies ◽

Draft Guideline ◽

Effective Strategies ◽

Biotechnology Companies ◽

Management Flow

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.

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Mission Accomplished: The ACVP/STP Coalition for Veterinary Pathology Fellows Completes Its Objectives, but Its Legacy and Spirit Live On

Veterinary Pathology ◽

10.1177/0300985820918314 ◽

2020 ◽

Vol 57 (4) ◽

pp. 472-475

Author(s):

Rick Adler ◽

Elizabeth Clark ◽

Mark Cline ◽

Michael Conner ◽

Torrie Crabbs ◽

...

Keyword(s):

Support Groups ◽

Contract Research ◽

Research Organizations ◽

Veterinary Pathology ◽

Biotechnology Companies ◽

Training Position

After 15 years of existence, the ACVP/STP Coalition for Veterinary Pathology Fellows will dissolve, primarily due to lack of renewed financial sponsorship. While in operation, the Coalition organized 32 new training position for veterinary pathologists, supported by $7.4 M from sponsors, including pharmaceutical and biotechnology companies, contract research organizations, private individuals and allied veterinary pathology support groups. All residual funds will be donated to ACVP and STP with the understanding that the two organizations will use these funds to enhance training by collaborating on outreach efforts, thus maintaining the legacy and spirit of the Coalition.

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Mission Accomplished: The ACVP/STP Coalition for Veterinary Pathology Fellows Completes Its Objectives, but Its Legacy and Spirit Live On

Toxicologic Pathology ◽

10.1177/0192623320917970 ◽

2020 ◽

Vol 48 (4) ◽

pp. 603-606

Author(s):

Rick Adler ◽

Elizabeth Clark ◽

Mark Cline ◽

Michael Conner ◽

Torrie Crabbs ◽

...

Keyword(s):

Support Groups ◽

Contract Research ◽

Research Organizations ◽

Veterinary Pathology ◽

Biotechnology Companies ◽

Training Position

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Revised Response Criteria for Malignant Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.09.2403 ◽

2007 ◽

Vol 25 (5) ◽

pp. 579-586 ◽

Cited By ~ 2865

Author(s):

Bruce D. Cheson ◽

Beate Pfistner ◽

Malik E. Juweid ◽

Randy D. Gascoyne ◽

Lena Specht ◽

...

Keyword(s):

Flow Cytometry ◽

Study Groups ◽

Therapeutic Agents ◽

Emission Tomography ◽

Response Criteria ◽

Regulatory Agencies ◽

Positron Emission ◽

Group Response ◽

Biotechnology Companies ◽

New Guidelines

PurposeStandardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies.MethodsThe International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations.ResultsNew guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided.ConclusionWe hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

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Comparison of Technologies for SCC Threat Validation and Assessment

Volume 2: Integrity Management; Poster Session; Student Paper Competition ◽

10.1115/ipc2006-10434 ◽

2006 ◽

Author(s):

Shahani Kariyawasam ◽

Jose Larios ◽

Iain Colquhoun

Keyword(s):

Life Cycle Assessment ◽

Measurement Accuracy ◽

Regulatory Compliance ◽

Management Plan ◽

Management Process ◽

Direct Assessment ◽

Regulatory Processes ◽

Research Organizations ◽

The World ◽

Measurement Capabilities

Recent incidents and consequent regulatory processes have increased awareness and concern regarding the threat of SCC (Stress Corrosion Cracking). Throughout the world research organizations and operators are building processes to both validate the presence of SCC and, where present, assess the pipeline for the SCC threat. SCC is not a concern in the majority of the pipelines, however for the pipelines that do have SCC it is one of the major threats leading more often to ruptures than leaks. Therefore validating the presence of SCC is an important step in threat management. Where SCC threat has not been discovered operators need to check for susceptibility and where susceptible validate the threat of SCC. The validation of SCC threat does not require all the measurement capabilities required to assess the pipeline once cracking is discovered. This paper describes the benefits and limitations of ILI inspection, direct assessment (SCCDA), and hydrostatic testing in terms of detection, false indication, classification, measurement accuracy of defect sizes, and life-cycle assessment. The technologies are critically reviewed and compared using quantitative probabilistic methodologies. Case studies are simulated to demonstrate how the different technologies perform to provide immediate and future integrity. The performance characteristics are discussed and combined to form a comprehensive crack management plan that can provide safety, regulatory compliance and related economies to the crack management process.

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A Phase I Study of Allogeneic Natural Killer Cell Therapy Generated from Cord Blood Hematopoietic Stem and Progenitor Cells in Elderly Acute Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v126.23.1357.1357 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1357-1357 ◽

Cited By ~ 5

Author(s):

Harry Dolstra ◽

Mieke W.H. Roeven ◽

Jan Spanholtz ◽

Basav Hangalapura ◽

Marleen Tordoir ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Therapy ◽

Nk Cells ◽

Myeloid Leukemia ◽

Nk Cell ◽

Residual Disease ◽

Standard Chemotherapy ◽

Donor Chimerism ◽

Elderly Aml

Abstract Introduction Elderly acute myeloid leukemia (AML) patients have a poor prognosis due to high relapse rates following standard therapy. Natural Killer (NK) cell alloreactivity has found to control relapse in AML in the HLA-mismatched haploidentical allogeneic stem cell transplantation (allo-SCT) setting. Moreover, allogeneic NK cell infusions can induce complete remission (CR) inpatients with advanced AML. As a consequence, adoptive NK cell transfer may be a promising treatment for elderly AML patients, who are not eligible for allo-SCT. Most clinical studies exploited NK cell products enriched from leukapheresis of haploidentical donors containing low numbers of T cells that could have contributed to the observed therapeutic effects and potentially induced graft-versus-host disease (GVHD). Therefore, we have developed a GMP-compliant culture system for the generation of large batches of NK cells from umbilical cord blood (UCB)-derived CD34+ progenitor cells, without T cell contamination. Here, we report results of a phase I dose escalation study (Dutch Trial Register nr. NTR2818) to evaluate the feasibility, safety and toxicity of allogeneic UCB-NK cell infusion following an immunosuppressive preparative regimen in elderly AML patients. Secondary endpoints were NK cell lifespan and the effects on minimal residual disease (MRD). Methods Elderly AML patients not eligible for allo-SCT, and in morphologic CR after standard therapy, were given preparative chemotherapy consisting of Cyclophosphamide (Cy;900 mg/m2/day) and Fludarabine (Flu;30 mg/m2/day) on days -6 to -2. At day 0, UCB-NK cells at a dose of 3, 10 or up to 30x106/kg body weight were infused without IL-2 treatment to study if in vivo expansion could be obtained without IL-2 support. Patients were assessed for toxicity and GVHD. Donor chimerism was measured by Q-PCR for discriminating DNA polymorphisms. NK cell expansion and phenotype were analyzed by flow cytometry. MRD was evaluated by flow cytometry and molecular techniques. Results Twelve AML patients (68-76 years) have been included, all in morphologic CR after 2 to 3 standard chemotherapy courses (n=6), or 1 standard chemotherapy course followed by subsequent treatment with hypomethylating agents (azacitidine or decitabine) (n=6). Patients were treated with Cy/Flu and an escalating dose of partially HLA-matched UCB-NK cells. Four patients had good/intermediate risk, 4 poor risk and 4 very poor risk AML. To date, 9 patients received NK cell products containing a median of 74% highly activated CD56+ NK cells, with <1x104/kg CD3+ T cells and <3x105/kg CD19+ B cells. Remaining non-NK cells were CD14+ and/or CD15+ monocytic and myelocytic cells. Follow up did not show GVHD or toxicity attributed to the NK cells. As expected, preparative Cy/Flu induced a neutropenic period of 20 ± 16 days, but no severe infections were seen. A temporary repopulation and persistence of UCB-NK cells could be detected in peripheral blood between days 1 and 8 post-infusion, which was associated with increased IL-15 plasma levels observed in most patients. Interestingly, donor chimerism increased with higher doses of infused UCB-NK cells, and donor chimerism up to 3.5% was found in bone marrow (BM) at day 7/8. Further UCB-NK cell maturation in vivo was observed by acquisition of CD16 and KIRs, while expression of activating receptors was sustained. Of the 9 treated patients so far, 5 (56%) are still in CR after 43, 35, 31, 5 and 4 months, whereas 4 patients relapsed after 5, 6 (2 pts) and 15 months. Despite morphologic CR during azacitidine treatment, residual disease of 6-7% with a leukemia-associated phenotype could be detected by flow cytometry before NK cell infusion in BM of two patients. In both patients MRD was reduced to less than 0.05% at 90 days after UCB-NK cell therapy following Flu/Cy conditioning. Conclusion These results show that GMP-compliant UCB-NK cell products containing up to 30x106 NK cells/kg body weight can be safely infused in non-transplant eligible AML patients following immunosuppressive chemotherapy. After infusion, UCB-NK cells repopulate, mature and migrate to BM without supporting IL-2 infusion. Since we observed reduction in MRD in patients on treatment with hypomethylating agents, this UCB-NK cell therapy may induce or sustain CR in elderly AML patients, and could serve as an alternative consolidation therapy for patients with refractory AML or provide bridge to allo-SCT. Disclosures Spanholtz: Glycostem Therapeutics: Employment. Tordoir:Glycostem Therapeutics: Employment. Bohme:Glycostem Therapeutics: Employment. Kok:Glycostem Therapeutics: Employment.

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Flow cytometry in cell-based pharmacokinetics or cellular kinetics in adoptive cell therapy

Bioanalysis ◽

10.4155/bio-2018-0203 ◽

2018 ◽

Vol 10 (18) ◽

pp. 1457-1459 ◽

Cited By ~ 1

Author(s):

Vellalore N Kakkanaiah ◽

Kevin R Lang ◽

Patrick K Bennett

Keyword(s):

Flow Cytometry ◽

Cell Therapy ◽

Adoptive Cell Therapy ◽

Cellular Kinetics

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