Abstract
Evolving immunogenicity assay performance expectations and a lack of harmonized anti-drug antibody validation testing and reporting tools have resulted in significant time spent by health authorities and sponsors on resolving filing queries. Following debate at the American Association of Pharmaceutical Sciences National Biotechnology Conference, a group was formed to address these gaps. Over the last 3 years, 44 members from 29 organizations (including 5 members from Europe and 10 members from FDA) discussed gaps in understanding immunogenicity assay requirements and have developed harmonization tools for use by industry scientists to facilitate filings to health authorities. Herein, this team provides testing and reporting strategies and tools for the following assessments: (1) pre-study validation cut point; (2) in-study cut points, including procedures for applying cut points to mixed populations; (3) system suitability control criteria for in-study plate acceptance; (4) assay sensitivity, including the selection of an appropriate low positive control; (5) specificity, including drug and target tolerance; (6) sample stability that reflects sample storage and handling conditions; (7) assay selectivity to matrix components, including hemolytic, lipemic, and disease state matrices; (8) domain specificity for multi-domain therapeutics; (9) and minimum required dilution and extraction-based sample processing for titer reporting.Graphical
Highlights
SUMMARYThe purpose of this publication is to provide a model framework for the anti-drug antibody (ADA) validation reports to be included in regulatory submissions and for marketing authorization applications
While it is not feasible to define acceptance criteria for system suitability controls that reflect the full diversity of appropriate fit-for-purpose practices, we provide examples of approaches that are consistent with current regulatory standards and would suffice for most ADA assay platforms
The 99% lower limit for the low positive control (LPC)/negative control (NC) ratio can be calculated as Mean − t(0.01,n − 1) × standard deviation (SD), where the LPC/NC ratio is calculated by dividing each LPC reportable result by the average of the NC results from the corresponding plate
Summary
The purpose of this publication is to provide a model framework for the anti-drug antibody (ADA) validation reports to be included in regulatory submissions and for marketing authorization applications. This model seeks to promote a harmonized scientifically sound approach by presenting illustrative examples that are consistent with current regulatory and pharmacopoeia guidance [1,2,3] but which does not preclude alternative approaches. Neutralizing antibodies are out of the scope of this paper and will be addressed in a separate manuscript. The proposed model acknowledges that the scope of information to be presented will depend on the therapeutic modality and the immunogenicity risk profile of the modality. While it is not feasible to define acceptance criteria for system suitability controls that reflect the full diversity of appropriate fit-for-purpose practices, we provide examples of approaches that are consistent with current regulatory standards and would suffice for most ADA assay platforms
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