Japanese Bioanalytical Method Validation Guideline: The World’s First Regulatory Guideline Dedicated to Ligand-Binding Assays

Imazato-Hirano, Mami; Taniguchi, Yoshihiro; Kakehi, Masaaki; Kuze, Yoji; Nakamura, Takahiro; Minamide, Yoshiyuki; Miya, Kazuhiro; Hosogi, Jun; Katashima, Masataka; Maekawa, Kotaro; Okuda, Haruhiro; Niimi, Shingo; Kawasaki, Nana; Ishii‐Watabe, Akiko; Katori, Noriko

doi:10.4155/bio.15.43

Cited by 4 publications

(2 citation statements)

References 9 publications

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“…All bioanalytical methods should be developed, validated and implemented according to regulatory requirements and industry standards [1][2][3][4][20][21][22][23][24][25][26][27][28][29] for preclinical and clinical studies assessing safety and efficacy. There are other considerations when utilizing automated liquid handling in regulated bioanalysis.…”

Section: Considerations In Methods Validation and Bioanalysismentioning

confidence: 99%

Application of Automated Liquid Handling in Ligand-Binding Assay-Based Bioanalytical Method Development: the Practical Considerations

et al. 2018

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The ligand-binding assay (LBA) is the standard bioanalytical methodology to support preclinical and clinical development of biologics. LBA methods are based on molecular interactions of specific and selective critical reagents, which are large proteins themselves, with intended analyte in often a complex biological matrix such as serum. There are several benefits of automation in LBA method development. Primarily the replacement of manual with automated liquid handling will result in improved accuracy and precision of the assay [1], reduced human errors and lowering of the physical stress due to manual steps conducted by bench scientists. The decreased variation in pipetting that will then be achieved leads to the generation of higher quality bioanalytical data having greater reproducibility within studies and therefore more comparability across studies over time. This commentary will highlight our experience in applying automated liquid handling to each of these critical components of LBA method development process in bioanalytical laboratories conducting pharmacokinetic (PK), anti-drug antibody (ADA) and target engagement (TE) method development using LBAs, from start of critical reagent screening/pairing, to reagent addition, to sample/quality control (QC) dilutions, preparation of standard calibrators and QC samples with a focus on implementation in regulated bioanalysis. Selection of automation platformsThere is a broad variety of automated liquid handling systems available in the market today. They mainly are either air-based system or liquid-filled system for pipetting with either/or a combination of fixed and disposable tips. Automation platforms with liquid detection system are used to not only provide a record of action of aspiration but also to aid when the volumes of bioanalytical samples are low.Numerous publications have promoted using automated robotic systems in bioanalytical laboratories with different platforms and logistics of set-up [2][3][4][5][6][7]. The 'total laboratory automation (TLA)' proposed for routine clinical chemistry laboratories [4] is not always the best strategy for the application of automation to the development of PK, ADA and TE methods based on LBA methods. Most of the leading manufacturers of integrated robotic and automated liquid handling systems have produced LBA-based systems and have the flexibility to work with multiple assay platforms, run multiple methods in a single operation and are designed to take advantage of the vertical space within a laboratory to achieve the capacity of functionality required.In our laboratory, we took the initial path of purchasing modular automated liquid handling systems which can serve several benefits to our bioanalytical operation. Focus upon the accuracy and precision of liquid handling and its laboratory-wide effect upon flexible operation and reproducibility for LBA methods that will be routinely employed over several years was one of the major reasons for choosing modular platforms over TLA. The breakdown of the preparation of ...

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Section: Considerations In Methods Validation and Bioanalysismentioning

confidence: 99%

Application of Automated Liquid Handling in Ligand-Binding Assay-Based Bioanalytical Method Development: the Practical Considerations

et al. 2018

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“…Guideline for bioanalytical method validation pertaining to LBA was released by the Ministry of Health, Labor and Welfare of Japan [5,6]. However, bioanalysis for ADA is out of its scope and currently, there are no regulatory guidelines on immunogenicity assessment in Japan.…”

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confidence: 99%

Immunogenicity of Therapeutic Protein Products: Current Considerations for Anti-Drug Antibody Assay in Japan

et al. 2017

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Immunogenicity assessment is an important issue for ensuring the safety and efficacy of therapeutic protein products. Although the reliability of the anti-drug antibody (ADA) assay is one of the key points, there are some difficulties in assessing its validity because the analytes are polyclonal antibodies with variable and unknown characteristics. To elucidate the points to consider for the ADA assay, a Japanese research group was established that discusses the issues raised on the immunogenicity assessment. In this review, we first introduce the current situation regarding the development and immunogenicity assessment of therapeutic protein products in Japan. We then present our current view and recommendations on the ADA assay by considering its unique features. Therapeutic proteins such as monoclonal antibodies are currently essential in the treatment of cancer, autoimmune disease and other diseases. Many therapeutic protein products intended to address unmet medical needs are being developed worldwide, including in Japan, and therefore, ensuring their safety and efficacy is of paramount importance. Since protein has its intrinsic feature of immunogenicity owing to its structure containing potential B-cell and T-cell epitopes, therapeutic proteins have the potential to induce ADA even if the protein has the same amino acid sequence as endogenous human proteins. Proteins can be recognized as antigens by B cells and are also incorporated and digested by antigen-presenting cells. This process leads to the production of T-cell epitope peptides that are presented on major histocompatibility (MHC) II molecules. Various patient-and product-specific factors are suggested to affect the process of ADA induction [1]. The emergence of ADA in patients can potentially lead to loss of efficacy and/or adverse events. Therefore, immunogenicity risk assessment and risk-mitigating strategies are required during the development of therapeutic protein products [2].The appropriateness of the ADA assay is a key issue in immunogenicity assessment. The ligand-binding assay (LBA) is often used for detecting ADA in biological samples. Unlike the assay used for drug concentration analysis, the ADA assay has unique features, for example: the actual characteristics of the analyte (human ADA) are variable and unknown; there is no real reference standard: the experimentally prepared positive control for ADA is used as a surrogate reference standard to evaluate and control the assay performance; and the evaluated validation parameters such as sensitivity and drug tolerance limit (DTL) vary depending on the characteristics, mainly the affinity of the used positive control. In addition, matrix components that interfere with the assay in the study samples may vary depending on the disease and/or the individual patients. Therefore, it is practically impossible to completely assess the validity of the ADA assay, and the assay is associated with certain risks of obtaining an inappropriate result. As mentioned in the European Medicines Agency (EMA...

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Collaborative study using common samples to evaluate the performance of anti-drug antibody assays constructed by different companies

Niimi

Nishimiya²,

Nishidate³

et al. 2018

Drug Metabolism and Pharmacokinetics

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Japanese Bioanalytical Method Validation Guideline: The World’s First Regulatory Guideline Dedicated to Ligand-Binding Assays

Cited by 4 publications

References 9 publications

Application of Automated Liquid Handling in Ligand-Binding Assay-Based Bioanalytical Method Development: the Practical Considerations

Application of Automated Liquid Handling in Ligand-Binding Assay-Based Bioanalytical Method Development: the Practical Considerations

Immunogenicity of Therapeutic Protein Products: Current Considerations for Anti-Drug Antibody Assay in Japan

Collaborative study using common samples to evaluate the performance of anti-drug antibody assays constructed by different companies

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