Highlights of the 14th Japan Bioanalysis Forum Symposium

Toward implementation of the ICH M10 guideline: latest discussion in bioanalytical communities (day 1)

The ICH M10 guideline [1] for bioanalytical method validation and study sample analysis reached step 4 in May 2022, and the implementation of the ICH M10 guideline is currently ongoing worldwide. In this session, four presenters gave an overview of ICH M10 and shared up-to-date discussions in the Japan Bioanalysis Forum (JBF) and bioanalytical communities of the European Bioanalysis Forum (EBF) and American Association of Pharmaceutical Scientists. Akiko Ishii-Watabe (National Institute of Health Sciences [NIHS], Japan), the rapporteur of the ICH M10 Expert Working Group, overviewed the ICH M10 guideline, highlighted the differences from the current Japanese guidelines and then explained future issues related to regulated bioanalysis. Makoto Takahashi (Daiichi Sankyo, Japan) presented the feedback from the JBF workshop on ICH M10 (October 2022, Kyoto, Japan), including discussions of highly interesting topics. Chad Briscoe (Celerion, on behalf of the American Association of Pharmaceutical Scientists) presented the feedback on ICH M10 discussion from the Land O’ Lakes Bioanalytical Meeting (July 2022, Madison, WI, USA), three open scientific discussions and the PharmaSci360 meeting (October 2022, Boston, MA, USA), including up-to-date discussions. Philip Timmerman (EBF) provided a historical perspective on the challenges of global harmonization and gave feedback on EBF’s discussions from the workshop on ICH M10 (November 2022, Barcelona, Spain).

JBF–Japan Pharmaceutical Manufacturers’ Association collaboration session (day 1)

From Dec 2021 to Jan 2022, the Drug Evaluation Committee of the Japan Pharmaceutical Manufacturers’ Association (JPMA) conducted a questionnaire on the strategy of bioanalytical method development for pharmaceutical companies which belonged to the JPMA. In this collaboration session, Kairi Nakamura and Miyuki Tamura (Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, JPMA) introduced the results of the questionnaire, focusing on the policy of analytical method development and metabolite analysis. The current situations were shared about outsourcing of bioanalysis, cross-validation of bioanalytical methods in global development, revision of policy against switching to ICH M10, selection criteria of metabolites adding to quantification method and so on.

The JPMA is an association of pharmaceutical companies that create new drugs, and opportunities to disclose detailed research outcomes by JPMA member companies are limited to academic conferences. Therefore this session became a valuable opportunity for CRO members of the JBF community to receive information.

Electronization in bioanalysis (day 1)

Kazuo Tokuda (Chugai Pharmaceutical, Japan) introduced a case study of a laboratory information management system (LIMS). A LIMS enables consolidation management of sample information, workflow records and analysis results, which makes data transfer between different systems unnecessary. Also, workflows and times (time stamp) can be recorded as electronic data. It was introduced that a LIMS has a potential for significant contribution to improve efficiency and reliability of studies.

Katsunori Ieki (Shin Nippon Biomedical Laboratories, Japan) introduced a case study of a LIMS in a CRO. Workflow records and analysis histories as well as analytical results are managed by the LIMS. The LIMS enables data export in a data format meeting the client’s request. Shin Nippon Biomedical Laboratories, which is a CRO, is providing clients with highly reliable studies by using a LIMS. In addition, the introduction of electronic management systems for sample information (chain of custody) was promoted.

Katsutomo Hata (Shionogi, Japan) introduced the company’s efforts on digitalization and automation for bioanalysis workflow. At present, automation of pretreatment and digitalization of records/reports (paperless) are implemented without using a LIMS. The company is aiming at a highly streamlined bioanalysis workflow, proceeding with further transformation and applying automation/digitalization more extensively in the future.

Bioanalysis of oligonucleotides: various approaches & advancements (day 2)

Hiroaki Aikawa (LSI Medience, Japan) presented a case study of imaging mass spectrometry using nusinersen as a tool compound. He also explained quantitative analysis of imaging MS.

Suguru Fukuda (Shin Nippon Biomedical Laboratories, Japan) explained points to note in the bioanalysis of oligonucleotides using LC–MS/MS. Selection of internal standard, separation of analytes and internal standards by HPLC, and prevention of ion-pair reagent deterioration were noted as critical points. He also explained that the injection of stripping reagent reduces carryover effects.

Yoshiharu Hayashi (CMIC Pharma Science, Japan) explained the rationale of using hybridization-based methods and presented case studies such as dual hybridization ligand-binding assay (LBA) and hybridization liquid chromatography-fluorescence. He also presented a case study to optimize extraction method in LC–MS analysis. He emphasized the importance of selecting the right approach in relation to the profile of the analytes and the required characteristics of the assay.

Eric Thomas (Labcorp Drug Development, IN, USA) provided a wide range of case studies such as optimization of solid-phase extraction conditions, ion-pairing reagents in LC–MS and the complementary use of LBA and LC–MS. He also presented the features of the Simoa^® assay. Reported analytes included N-Acetylgalactosamine-conjugated antisense oligonucleotide, interfering RNA and aptamers.

Bioanalysis of biomarkers & application to translational research (day 2)

In this session, four presenters provided case studies of biomarker bioanalysis aligning with context of use and presented episodes of biomarker translation. Tatsuya Ikehara (Shionogi, Japan) presented a case study of developing and validating an analytical method of 24S-hydroxycholesterol, mechanism investigation of the biomarker using a rat pain model and cultured microglial cells, and evaluation of its usefulness as a clinical biomarker in chronic pain patients. Makoto Yamazaki (Mitsubishi Tanabe Pharma, Japan) presented case studies of biomarker bioanalysis with various methodologies including qPCR, flow cytometry and immunohistochemistry.

Yohei Kosugi (Takeda Pharmaceutical, Japan) presented a highly sensitive bioanalytical method development of glucosylsphingosine and galactosylsphingosine and their use as translational biomarkers. Motohiko Morihara (Ono Pharmaceutical, Japan) presented challenges and strategy to select fit-for-purpose bioanalytical methods for successful measurement of translational biomarkers, with the examples of prostanoids and urinary biomarkers.

Data integrity (day 2)

This was a collaborative session with the Japan Society of Quality Assurance to discuss considerations when implementing a computerized system.

Subcommittee 3 in the GLP Division of the Japan Society of Quality Assurance is studying the points to be considered for data integrity (DI). The Organisation for Economic Cooperation and Development issued DI Guidance no.22 [2] which provided guidance on a basic approach to DI that should be followed in GLP testing facilities. Tomoharu Shimokawa (Toray Research Center, Japan) presented the requirements of the guidance for the following seven items: data, audit trail, electronic signature, access control, backup, archiving and education. He also presented the requirements specification of equipment that should be considered from the viewpoints of DI when newly implementing HPLC data management systems and bio-related equipment.

What’s new in immunogenicity assessment (day 2)

Mauricio Maia (Genentech, CA, USA) presented the immunogenicity profile of the port delivery system (PDS) with ranibizumab in patients with neovascular age-related macular degeneration. The immunogenicity profile of PDS 100 mg/ml was compared with that of monthly intravitreal ranibizumab 0.5-mg injections. Three anti-drug antibody (ADA) assays (screening, confirmatory and neutralizing antibody) were used in Susvimo™ clinical trials. The immunogenicity profile of PDS 100 mg/ml was similar to that of monthly intravitreal ranibizumab 0.5-mg injections. Incidences of ADAs and neutralizing antibodies with PDS 100 mg/ml were generally low and comparable with those seen with monthly intravitreal ranibizumab 0.5 mg in clinical trials.

Immunogenicity assessment employs a cut-point approach to determine positivity or negativity of a potential immune response, instead of evaluation with a surrogate positive control. The cut point is a clinically meaningful immunogenicity assessment rather than focusing on the incidence of responses and how the cut point can impact such assessment. The EBF held a focus workshop dedicated to points to consider for immunogenicity cut points in April 2022. Joanne Goodman, presenting on behalf of the EBF, presented on discussions for immunogenicity cut points at the focus workshop. The discussions focused around three key areas: understanding the current challenges and the strategic points to consider; case studies covering disease state, cross-validation, false-positive rates, in-study cut points and pre-existing antibodies; and regulatory expectations and challenges.

Patient-centric sampling (day 3)

In this session, two presenters were invited to introduce recent examples of ‘patient-centric sampling’ in real clinical studies. First, Katty Wan (Pfizer, USA) presented implementations of dried blood sampling using the Tasso-M20 device to support clinical development of Paxlovid™. The device was successfully applied to three phase III and several special population studies by managing the sample logistics, data analysis flow and site trainings. Second, Sharin Roth (Otsuka Pharmaceutical Development & Commercialization, USA) introduced strategies and challenges associated with microsampling in decentralized clinical trials. A Mitra^® device was utilized to collect small volumes of blood by clinic staff and subjects on remote. The applicability of at-home self-collection of blood in the clinical development of small-molecule drugs was discussed.

Development strategy for antibody–drug conjugates (day 3)

In this session, two presenters were invited to give presentations which focused on antibody–drug conjugate (ADC) bioanalysis.

First, Hideo Takakusa (Daiichi Sankyo, Japan) presented a bioanalytical approach to ADCs. The general components and characteristics of ADCs were overviewed, and he introduced the actual analysis method development for trastuzumab deruxtecan by LC–MS for quantitative bioanalysis, evaluation of the average drug–antibody ratio (DAR) reduction profile as biotransformation, and biodistribution of payload in tumor. The slow decrease of the average drug–antibody ratio in monkey plasma was also shared, and its potential mechanism was discussed based on the physicochemical and biotransformation profiles.

Next, Masanori Nagata (Astellas Pharma, Japan) presented the bioanalysis of enfortumab vedotin as an ADC molecule. He introduced the structural elements of enfortumab vedotin and the bioanalysis for the whole molecule of ADC (LBA), payload (LC–MS) and ADA (LBA) along with the US FDA’s draft guidance [3]. He also introduced the points of consideration on the bioanalysis for enfortumab vedotin, and future perspectives in ADC bioanalysis. The necessity to obtain anti-payload antibodies for each situation and domain specificity for ADA-positive samples were also mentioned.

Update of public–private joint research: bioanalytical researches on development & standardization of analytical methods for pharmacokinetic evaluation of four new-modality drugs (day 3)

Yoshihiro Saito (NIHS) introduced the objectives and an overview of this joint research.

Yuchen Sun (NIHS) presented an update on standardization of bioanalytical methods for oligonucleotides using LC–MS/MS. He explained the results of multisite validation of mipomersen and fitusiran. He also explained about comprehensive structure determination of metabolites using fitusiran as a tool compound.

Kosuke Saito (NIHS) explained a plan for standardization of bioanalytical methods for complex modalities of peptides. He explained how his team are developing a bioanalytical method for BT1718 as a tool compound of peptide–drug conjugates. He also explained a bioanalytical method development for cyclorasin 9A5, which was initiated in six sites in parallel to identify potential issues of method development for peptides.

Noritaka Hayashi (NIHS) explained a plan for standardization of bioanalytical methods for ADCs. He also explained that drug–antibody ratios can be determined using intact LC–MS. His team optimized a pretreatment method for trastuzumab emtansine as a tool compound.

Yoichi Tanaka (NIHS) explained a plan for standardization of bioanalytical methods for gene therapy products using Droplet Digital PCR™. He also explained a Droplet Digital PCR method development for adeno-associated virus encoding green fluorescent protein (serotypes 2 and 9) as a tool.

JBF discussion groups

The discussion group (DG) promotion committee (seven members from industries, led by Koji Arai of LSI Medience, Japan) organized this session. The four DGs (DGs 55–58) presented the results of their year-long discussions on priority themes and exchanged opinions with attendees on a variety of issues related to bioanalysis during the poster sessions held on the morning through the afternoons of the second and third days.

DG55, which consisted of four members (leader: Ryotaro Yagi, Toray Industries, Japan), presented outcomes of the topic ‘Bioanalysis using columns other than Octa Decyl Silyl (ODS)’, focusing on the differences between ODS and non-ODS columns. For example, the presentation introduced the status of use and recognition of various columns; what is important in column selection; target compound types; difficulties encountered in constructing analytical methods; and solutions to problems.

DG56 focused on the topic ‘Life-cycle management of ligand-binding assays’. The group consisted of six members (leader: Suguru Hanari, CMIC Pharma Science, Japan). They summarized and discussed the life-cycle considerations of LBA for pharmacokinetics/toxicokinetics (PK/TK), biomarkers and ADAs based on regulatory documents. Then they conducted surveys to check the current situation of the life-cycle management of LBA in regard to PK/TK, and shared the results.

DG57 discussed the topic ‘Digital transformation in the field of bioanalysis’. The group consisted of four members (leader: Yoshitaka Hashimoto, Ono Pharmaceutical, Japan). Based on the survey results targeting bioanalysts in Japan, they shared the current situation and challenges for digital transformation in the bioanalytical field. They also presented what kind of digital technologies and IT can be used to achieve operational efficiency in the bioanalysis field, considering examples from other industries.

DG58 discussed the topic ‘How to create a career path as a bioanalyst’. The group consisted of seven members (leader: Shinsuke Uchihashi, Maruho, Japan). They focused on turning points or work environments having a large impact on the career development of bioanalysts. They surveyed bioanalysts to collect diverse opinions and actual cases. The collected cases of concerns and tips were shared with the attendees to help them solve problems regarding career development of bioanalysts.

Posters for general presentation

Twenty-three posters for general presentation were submitted and presented at poster sessions and on the 14th JBF Symposium website. Two excellent presentations were awarded by JBF.

Conclusion

The modalities of pharmaceutical products and drug development strategies are evolving, and bioanalytical challenges are diversifying. The utilization of innovative approaches and collaboration between experts from diverse backgrounds are significantly important aspects for the solutions and quality of regulated bioanalysis to deliver medicines to patients worldwide faster. The 14th JBF symposium successfully brought together experts from various fields and provided hot topics and discussions. We believe that discussions in this symposium will contribute to enhanced innovation and global harmonization, and foster further collaboration in the various fields. Most of the presentation materials can be found on the official JBF website [4]. The 15th JBF symposium (theme: ‘Toward the New World’) will be held in Kyoto, Japan on 5–7 February 2024.

Future perspective

Bioanalysis plays an important role in drug development and needs to keep changing in accordance with changes in the surrounding environments of healthcare and technology. The JBF will continue to provide opportunities for learning, discussion and collaboration for the advancement of bioanalysis and drug development.