Abstract
Recent concerns about the applicability of design space boundaries developed on small scale to commercial manufacturing processes have been raised by regulators worldwide. These concerns center around the scalability of unit operations and their corresponding process parameters, and the impact this has on the desired attributes of the drug substance or product. Requests have been made to verify design space boundaries with data generated at commercial scale. Because it is not always feasible to manufacture large-scale batches, alternative approaches to verification are necessary. The following article discusses various science-based strategies that could be used to verify design space boundaries. These approaches balance the requirements to address regulatory concerns and ensure that quality standards are maintained for both drug substances and products, within the operating constraints currently facing the pharmaceutical industry.
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Notes
The term “edge of failure” is used in this paper to describe a design space boundary that is associated with the acceptance criteria for an intermediate or release specification. Operating near this edge will result in intolerable reduction in the product yield. The point of failure is typically a gradient and not necessarily a sharp edge.
Defined as “An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated,” ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8(R2) Step 4, August 2009.
References
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Garcia, T., McCurdy, V., Watson, T.N.J. et al. Verification of Design Spaces Developed at Subscale. J Pharm Innov 7, 13–18 (2012). https://doi.org/10.1007/s12247-012-9123-0
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DOI: https://doi.org/10.1007/s12247-012-9123-0