Maths: Validation Challenges for Bioassays

Validation of test methods is a critical requirement for the drug development process. Bioassays are used to support biologics in the drug development process and in post-market analytical support.

Unlike analytical test methods for small molecules, bioassays have unique requirements due to the variable nature of some critical components. Although some variability may be inherent, careful attention to setting appropriate limits and to robust qualification of critical components enhances the likelihood of success during validation.

Regulatory agencies expect pharmaceutical companies and biopharmaceutical companies to use validated methods for late phase work. The methods are used to test large molecule drug substance or drug product for identity, purity, and potency. Poorly developed and inadequately validated methods often have high failure rates when in production. Data submitted from poorly developed/validated methods is subject to additional scrutiny due to the excessively high failure rate that lowers confidence in the data that is produced.

Cell-based methods may be difficult to validate due to a lack of extensive testing during the development phase. Method validation requires careful design of the method during development and seamless implementation to meet regulatory agency expectations for the quality of assay methods used in testing of biopharmaceutical or pharmaceutical compounds.

Cell-based methods have additional complexities that may contribute to variability. With appropriate controls in place in the method variability can be minimized leading to successful validation and sample analysis using the cell-based method.

Why you should Attend:

Bioassays, especially cell-based methods are a necessary component of assays providing data supporting large molecule therapeutics. Typically, these methods are required to establish potency, a critical quality attribute, in either release or stability assays. The live cell quality of these assays may introduce a layer of uncertainty regarding the ability to build a method that meets requirements for ruggedness.

Cells that express the receptor responsible for the mechanism of action may be a transfected clonal line or may be a cell expressing the native protein. The growth characteristics of the cell that promote expression levels with good signal-to-background in the method are an important quality to address as development of the assay begins.

A key question may be how much prework to perform to guide development of the assay. Live cells are not as simple to control as individual reagents in a method. Live cells respond to components in media, environmental factors, and seeding densities in a manner that may have an impact on growth characteristics, receptor expression, and signals in cell-based methods.

These issues should be assessed fully and examined in early development work to direct the lab toward the parameters likely to produce an assay with a low rate of failure. This complexity often leads to problems when factors that contribute to ruggedness in cell-based methods are not assessed and addressed during the development phase. Successful validation is achievable with careful consideration of the cells as the primary critical reagent.

Control of the assay starts with control of the cells. While sufficient time is needed to perform development using design of experiments, moving from development to validation should be based on the quality of the data observed in the assay and not inordinately pushed forward.

Areas Covered in the Session:

• Method selection
• Understanding the variable nature of cell-based methods
• Understanding the critical characteristics of cell-based assays that may affect performance
• Characterization of the cell line
• Details of cell maintenance, cell culture prior to performing the method
• Defining parameters to monitor
• Defining critical reagents
• Selection and certification of the reference standard
• Setting appropriate limits for reagents
• Reagent supply and sample handling
• Pre-test of critical reagents
• Setting intermediate performance controls
• Testing robustness/ruggedness/selectivity/specificity prior to validation
• Analyst training
• Peer review of the test method
• Statistical analysis
• Validation protocol and templates
• Preplanning
• Documentation of deviations and failures

• Validation scientists in bioanalytical or clinical laboratories
• Development scientists in bioanalytical or clinical laboratories
• QA Documentation Specialists
• Regulatory Specialists
• Consultants
• Directors of Outsourcing
• Method trainers
• Statistical staff

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Certificate of completion

Digital certificate - Included