Optimizing Continuous Feeding of Poorly Flowing Excipients: Impact of Batch-To-Batch Variability and Process Design

Purpose

Understanding batch-to-batch variation of excipients and correlating this to process performance is a key concept of Quality-by-Design for pharmaceutical product development. In this study, the effect of batch-to-batch variation in material properties of milled lactose monohydrate on continuous feeding is investigated. The small particle size and poor flow properties of the milled lactose grades make consistent feeding challenging.

Methods

The impact of material properties on feeding performance is evaluated by testing three different grades of lactose monohydrate in three volumetric feeding set-ups. Furthermore, nine batches of the same lactose grade are selected from a total of 435 batches to test the effect of batch-to-batch variability on the feed factor. The nine batches are tested in three feeder set-ups, with different screw configurations and rotational speed. The batch-to-batch variation of the feed factor is compared to the intra-batch variability, which is obtained by measuring the feed factor of the same lactose batch multiple times.

Results

The effect of batch-to-batch variation on the measured feed factor is dependent on the feeder set-up. In an optimized set-up, different batches of lactose monohydrate can be fed with high consistency, showing little variation in feed factor. In a more challenging feeder set-up, however, the inter-batch variability of the feed factor is larger than the intra-batch variability. This indicates that batch-to-batch variation does affect the consistency of the feeding process.

Conclusion

It is found that a combination of process set-up and excipient consistency determines the variability of a feeding process. By optimizing the feeder configuration and minimizing batch-to-batch variability, different batches of a poorly flowing excipient can be fed with high consistency.

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Materials

From a total of 435 batches, nine batches of milled lactose monohydrate (Pharmatose® 200 M (EU), DFE Pharma, Germany) were selected for testing feeding performance. Batches numbered 1–7 are used for testing the inter-batch variability of feeding performance. Batches labeled A and B are used to test the intra-batch variability of feeding performance, and are also included in the inter-batch variability analysis. The nine batches were selected to cover maximal batch-to-batch variability based on principal component analysis (PCA). Two different grades of milled lactose monohydrate (Pharmatose® 200 M (NZ) and Pharmatose® 350 M) were selected to test the effect of varying lactose grades on feeder performance. Pharmatose 200 M (NZ) shows a similar particle size distribution as Pharmatose® 200 M (EU), but since the two grades are produced at different geographical locations, they are not identical. Pharmatose® 350 M shows a finer particle size distribution compared to the other two lactose grades tested. Three batches of Pharmatose® 200 M (NZ) and one batch of Pharmatose® 350 M were selected for feeding tests, based on availability.

Jaspers, M., Starsich, F., Fathollahi, S. et al. Optimizing Continuous Feeding of Poorly Flowing Excipients: Impact of Batch-To-Batch Variability and Process Design. J Pharm Innov 20, 30 (2025). https://doi.org/10.1007/s12247-025-09927-0