Publications by authors named "Michael Buonarati"

13 Publications

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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 ( - 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 2021 Feb 20;13(4):203-238. Epub 2021 Jan 20.

Merck, West Point, PA, USA.

The 14 edition of the Workshop on Recent Issues in Bioanalysis (14 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 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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http://dx.doi.org/10.4155/bio-2020-0324DOI Listing
February 2021

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

Bioanalysis 2019 Dec 9;11(23):2099-2132. Epub 2019 Dec 9.

US FDA, Silver Spring, MD, USA.

The 2019 13 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 , issues 22 and 24 (2019), respectively.
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http://dx.doi.org/10.4155/bio-2019-0270DOI Listing
December 2019

GCC Consolidated Feedback to ICH on the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline.

Bioanalysis 2019 Sep 30;11(18s):1-228. Epub 2019 Sep 30.

WuXi Apptec, Shanghai, China.

The 13 GCC Closed Forum for Bioanalysis was held in New Orleans, Louisiana, USA on April 5, 2019. This GCC meeting was organized to discuss the contents of the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline published in February 2019 and consolidate the feedback of the GCC members. In attendance were 63 senior-level participants from eight countries representing 44 bioanalytical CRO companies/sites. This event represented a unique opportunity for CRO bioanalytical experts to share their opinions and concerns regarding the ICH M10 Bioanalytical Method Validation Draft Guideline and to build unified comments to be provided to the ICH.
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http://dx.doi.org/10.4155/bio-2019-0207DOI Listing
September 2019

Investigations beyond standard operating procedure on internal standard response.

Bioanalysis 2019 Sep 26;11(18):1669-1678. Epub 2019 Sep 26.

Intertek Pharmaceutical Services, San Diego, CA, USA, 92121.

Internal standard response is routinely monitored in regulated studies to accept or reject individual samples with outlier results due to potential sample processing or instrumentation errors, and processes are typically governed by standard operating procedures. However, acceptance or rejection of individual samples is not always sufficient. Internal standard response trends and substantial systemic differences between spiked and incurred samples using a method with an otherwise stable internal standard response should be investigated. Investigations may range from informal evaluations to detailed studies with formal investigation reports. Atypical internal standard response can be an indicator of systemic problems with a bioanalytical method and modification to allow for a relatively stable internal standard response across an analytical run may be essential.
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http://dx.doi.org/10.4155/bio-2019-0187DOI Listing
September 2019

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 2018 Nov 29;10(22):1781-1801. Epub 2018 Nov 29.

UK MHRA, London, UK.

The 2018 12 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.
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http://dx.doi.org/10.4155/bio-2018-0268DOI Listing
November 2018

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 2017 Nov 17;9(22):1807-1825. Epub 2017 Nov 17.

UK MHRA, London, UK.

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.
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http://dx.doi.org/10.4155/bio-2017-4975DOI Listing
November 2017

2016 White Paper on recent issues in bioanalysis: focus on biomarker assay validation (BAV) (Part 1 - small molecules, peptides and small molecule biomarkers by LCMS).

Bioanalysis 2016 Nov 7;8(22):2363-2378. Epub 2016 Oct 7.

Novartis, Emeryville, CA, USA.

The 2016 10 Workshop on Recent Issues in Bioanalysis (10 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 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 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 1) discusses the recommendations for small molecules, peptides and small molecule biomarkers by LCMS. Part 2 (Hybrid LBA/LCMS and regulatory inputs from major global health authorities) and Part 3 (large molecule bioanalysis using LBA, biomarkers and immunogenicity) will be published in the Bioanalysis journal, issue 23.
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http://dx.doi.org/10.4155/bio-2016-4992DOI Listing
November 2016

LC-MS/MS determination of apixaban (BMS-562247) and its major metabolite in human plasma: an application of polarity switching and monolithic HPLC column.

Bioanalysis 2014 Aug;6(15):2071-82

Bristol-Myers Squibb, Route 206 Province Line Road, Lawrenceville, NJ 08543, USA.

Background: apixaban (BMS-562247) (Eliquis(®)) is a novel, orally active, selective, direct, reversible inhibitor of the coagulation factor Xa (FXa). A sensitive and reliable method was developed and validated for the measurement of apixaban (BMS-562247) and its major circulating metabolite (BMS-730823) in human citrated plasma for use in clinical testing.

Methodology/results: A 0.100 ml portion of citrated plasma sample was extracted and analyzed by LC-MS/MS. Run times were approximately 3 min. The lower limit of quantification (LLOQ) was 1.00 ng/ml for BMS-562247 and 5.00 ng/ml for BMS-730823. Intra- and inter-assay precision values for replicate QC control samples were within ≤5.36% for both analytes (≤7.52% at the LLOQ). The accuracy for both analytes was within ±9.00%.

Conclusion: The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies.
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http://dx.doi.org/10.4155/bio.14.66DOI Listing
August 2014

Qualification and application of a liquid chromatography-tandem mass spectrometric method for the determination of human Aβ1-40 and Aβ1-42 peptides in transgenic mouse plasma using micro-elution solid phase extraction.

Arch Pharm Res 2014 May 26;37(5):636-44. Epub 2013 Jul 26.

Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, Mail Stop 412A, South San Francisco, CA, 94080, USA,

A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and applied for the determination of human Aβ1-40 and Aβ1-42 peptides in transgenic mouse plasma to support preclinical pharmacodynamics studies. The method consisted of micro-elution solid phase extraction for sample preparation and LC-MS/MS analysis in the negative ion mode using electrospray ionization for analysis. (15)N53-Aβ1-40 and (15)N55-Aβ1-42 peptides were used as internal standards. A quadratic regression (weighted 1/concentrations), with an equation y = ax(2) + bx + c, was used to fit calibration curves over the concentration range of 0.500-100 ng/mL for both Aβ1-40 and Aβ1-42 peptides. For quality control samples at 6.00, 40.0 and 80.0 ng/mL from the qualification experiment, the within-run accuracy ranged from -2.69 to 0.583 % with precision values ≤8.23 % for Aβ1-40. Within-run accuracy ranged from -4.83 to 10.1 % with precision values ≤8.87 % for Aβ1-42. Samples from a pharmacodynamics study using Tg2576 transgenic mice were analyzed by this qualified LC-MS/MS method and concentrations were compared to those generated by ELISA. The two methods were shown to be comparable for Aβ1-40 quantification of samples from the Tg2576 amyloid precursor protein transgenic mouse model, but varied slightly for Aβ1-42.
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http://dx.doi.org/10.1007/s12272-013-0215-2DOI Listing
May 2014

Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0152 in human plasma using solid-phase extraction.

Biomed Chromatogr 2013 Jan 24;27(1):102-10. Epub 2012 May 24.

Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA.

A liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0152 in human plasma to support clinical development. The method consisted of a solid-phase extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSpray(TM) for analysis. d(7) -GDC-0152 was used as the internal standard. A linear regression (weighted 1/concentration(2) ) was used to fit calibration curves over the concentration range of 0.02-10.0 ng/mL for GDC-0152. There were no endogenous interference components in the blank human plasma tested. The accuracy at the lower limit of quantitation was 99.3% with a precision (%CV) of 13.9%. For quality control samples at 0.0600, 2.00 and 8.00 ng/mL, the between-run %CV was ≤8.64. Between-run percentage accuracy ranged from 98.2 to 99.6%. GDC-0152 was stable in human plasma for 363 days at -20°C and for 659 days at -70°C storage. GDC-0152 was stable in human plasma at room temperature for up to 25 h and through three freeze-thaw cycles. In whole blood, GDC-0152 was stable for 12 h at 4°C and at ambient temperature. This validated LC-MS/MS method for determination of GDC-0152 was used to support clinical studies.
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http://dx.doi.org/10.1002/bmc.2754DOI Listing
January 2013

Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of G-856 (Cur-61414) in human plasma using semi-automated solid phase extraction.

J Chromatogr B Analyt Technol Biomed Life Sci 2012 Mar 25;887-888:85-92. Epub 2012 Jan 25.

Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA 94080, USA.

A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of G-856 in human plasma to support clinical development. The method consisted of a solid phase extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSpray for analysis. d₈-G-856 was used as the internal standard. A linear regression (weighted 1/concentration²) was used to fit calibration curves over the concentration range of 5.00-2000 pg/mL for G-856. There were no significant endogenous interference components in the multiple lots of blank human plasma tested. The accuracy (%Acc) at the lower limit of quantitation (LLOQ) was 98.2% with a precision (%CV) of 5.38%. For quality control samples at 15.0, 800, and 1600 pg/mL, the inter-day %CV was ≤ 5.03%. Inter-day %Acc ranged from 96.9 to 99.3%. G-856 was stable in human plasma for 184 days at -20 °C and -70 °C storage. G-856 was stable in human plasma at room temperature for up to 16 h and through four freeze/thaw cycles. This validated LC-MS/MS method for determination of G-856 was used to support Phase 1 clinical studies.
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http://dx.doi.org/10.1016/j.jchromb.2012.01.016DOI Listing
March 2012

Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0834 and its metabolite in human plasma using semi-automated 96-well protein precipitation.

Biomed Chromatogr 2012 Nov 7;26(11):1444-51. Epub 2012 Feb 7.

Department of Drug Metabolism and Pharmacokinetics, Genentech, South San Francisco, CA, 94080, USA.

A liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the determination of GDC-0834 and its amide hydrolysis metabolite (M1) in human plasma to support clinical development. The method consisted of semi-automated 96-well protein precipitation extraction for sample preparation and LC-MS/MS analysis in positive ion mode using TurboIonSpray® for analysis. D6-GDC-0834 and D6-M1 metabolite were used as internal standards. A linear regression (weighted 1/concentration(2) ) was used to fit calibration curves over the concentration range of 1 - 500 ng/mL for both GDC-0834 and M1 metabolite. The accuracy (percentage bias) at the lower limit of quantitation (LLOQ) was 5.20 and 0.100% for GDC-0834 and M1 metabolite, respectively. The precision (CV) for samples at the LLOQ was 3.13-8.84 and 5.20-8.93% for GDC-0834 and M1 metabolite, respectively. For quality control samples at 3, 200 and 400 ng/mL, the between-run CV was ≤ 7.38% for GDC-0834 and ≤ 8.20% for M1 metabolite. Between run percentage bias ranged from -2.76 to 6.98% for GDC-0834 and from -6.73 to 2.21% for M1 metabolite. GDC-0834 and M1 metabolite were stable in human plasma for 31 days at -20 and -70°C. This method was successfully applied to support a GDC-0834 human pharmacokinetic-based study.
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http://dx.doi.org/10.1002/bmc.2716DOI Listing
November 2012

Urinary naphthalene mercapturates as biomarkers of exposure and stereoselectivity of naphthalene epoxidation.

Drug Metab Dispos 2002 Mar;30(3):247-53

Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, California 95616, USA.

Previous work has shown that the rate and stereochemistry of naphthalene epoxidation correlates with differences in susceptibility to cytotoxicity. The development of methods for measuring epoxide formation in vivo could provide a marker for assessing events critical to naphthalene cytotoxicity that are applicable to humans. Here, urinary diastereomeric mercapturates have been measured in mice (susceptible) and rats (nonsusceptible) after intraperitoneal administration (1.56-200 mg/kg) or inhalation exposures (0.8-110 ppm, 4 h) to naphthalene. No significant differences were observed in the percentage of the dose eliminated as mercapturate in urine between mice (25-34%) and rats (24-35%) or at varying doses after i.p. administration. The amounts of urinary mercapturate after 4-h exposures were considerably greater in mice than rats. In mice, the ratio of diastereomeric mercapturates derived from the 1R,2S- to 1S,2R-epoxide was 1:1 at low doses (1-3 mg/kg), increased to 3:1 at intermediate doses (50 mg/kg), and decreased to 2:1 at high doses (100 and 200 mg/kg). In rats, these ratios remained less than 1:1 at all doses. After inhalation, ratios were 5 to 6:1 at low concentrations (less than 15 ppm) and decreased to 3:1 at higher concentrations (15-100 ppm) in mice, whereas in rats, the ratios were 1:1 or less for all concentrations. These studies show that mercapturates provide good assessments of internal dose, that there are not significant differences between mice and rats in the percentage eliminated as mercapturate but that the ratios of mercapturates derived from the 1R,2S- versus 1S,2R-epoxide differ markedly and are consistent with previous in vitro metabolism studies.
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http://dx.doi.org/10.1124/dmd.30.3.247DOI Listing
March 2002