A design space claim spanning multiple unit operations can be supported when the linkage between the unit operations is well characterized and robust. The design and rationale for process linkage studies are based on the properties of the biopharmaceutical product and capabilities of the manufacturing process. The studies leverage experience gained during process development, production of manufacturing-scale batches, and characterization studies of unit operations, as well as platform knowledge. The specific experiment or set of experiments conducted for a given product critical quality attribute (CQA) is designed to challenge the manufacturing process to an extent at or beyond what is expected to occur when manufacturing within the design space. For each CQA that is impacted by multiple unit operations, each unit operation is evaluated individually in a multivariate study, which will identify the worst-case conditions. The worst-case output from each unit operation is assessed downstream either experimentally or by mathematical assessment of downstream capability. The worst-case output selected for experimental study is generally the sample observed to have the highest (or worst) CQA level from among the unit-operation and hold time studies. In general, the experimental linkage of downstream unit operations is conducted with parameters at target. Three experimental approaches are considered: spiking experiments, polishing step removal experiments and unit-op worst-case linkage experiments. The presentation will summarize the rationale of the overall approach and provide examples from case studies for each of the experimental studies.

Process linkage experiments to support the design space of a biopharmaceutial manufacturing process

253rd National Meeting (2017)

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