Justification of small-scale models: an industry perspective

This white paper provides an overview of current practices for the qualification and refinement of small-scale models (SSM) used in the development of biopharmaceutical drug substance manufacturing processes.

SSMs are utilized to meet regulatory expectations of:

• Selection of an appropriate manufacturing process
• Establishment of a control strategy, covering continued process verification and life cycle management
• Support of manufacturing process development and validation

It must be experimentally demonstrated that an SSM, running at the appropriate process parameter settings (inputs), has representative performance and quality attributes (outputs) to the manufacturing scale. It is important to understand the degree to which these models represent the commercial process, including any limitations or differences that might exist (e.g. offsets). These factors may have an impact on the relevance of information derived from the models in order to justify the use of SSMs to meet the above regulatory expectations. The procedure for qualifying SSMs should follow defined engineering rules and apply statistical methods when applicable.

To this end, this paper presents current understanding on how to successfully qualify an appropriate and applicable SSM, including design, execution, data analysis and justification of results. Both upstream and downstream unit operations are covered and supported by case studies. Detailed considerations for designing and executing process characterization studies are out of scope.

SSMs are a useful tool in biopharmaceutical process development. Design of the models requires careful choice of scaling parameters to best match large-scale outputs. Qualification of the models proves that they generate comparable performance and quality attributes, justifying their use to address regulatory expectations. Qualification is performed using statistical comparison to large-scale run data. A variety of statistical methods can be used for qualification with appropriate justification.

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• File Size 3.32 MB
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• Create Date 5th May 2021
• DOI https://doi.org/10.46220/2021DG003
• Last Updated