Scale-up successfully

Hartmut vom Bey & Barbara Fretter discuss scaling up in roller compaction

After a successful development phase, it is time to scale-up to larger batch sizes. Going from the first clinical batches to production-sized batches often poses questions such as ‘what equipment is needed?’ and ‘what are the risks in scale-up?’ There are several scale-up strategies for roller compaction.

Scale-up by production time

A common batch size for R&D is approximately 1kg. On the Mini-Pactor, a lab-scale roller compactor, this can be produced in approximately 15 minutes with a slow roll speed of 2rpm. This being a continuous manufacturing process, the easiest way to increase the batch size is to extend the production time. No other production parameters must be adapted and thus the product quality will remain constant. When extending the production time from 15 minutes to 15 hours for example, the batch size can increase from the initially assumed 1kg to 60kg. This results in a scale-up factor of 60 without changing the settings of the roller compactor. It therefore stands to reason that other scale-up factors are also possible by simply adjusting the production time based on desired batch sizes.

Scale-up by roll speed

The second easily changeable parameter is the roll speed. During R&D work, slower roll speeds such as 2rpm are typically used because the API is rare and only small batches are required. Increasing the roll speed often requires little to no adaptations to the roller compaction settings to gain the same granulate quality. The reason for this is that roller compaction is a slow densification process, especially compared to rotary tableting. Only at high speeds of about 30rpm will the overall densification time be comparable to that of rotary tablet presses. When leaving out these high speeds, an increase of roll speed from 2rpm to 20rpm increases the throughput by a factor 10. This means our starting batch of 1kg in 15 min can be increased to 10kg in 15 min. Combining these two strategies – ‘production time’ and ‘roll speed’ – a scale-up factor of 600 is easily possible without changing the equipment. In our example this means 600kg in 15 hours.

Scale-up by gap

Another possibility to increase the throughput and therefore the producible batch size in a certain time is to increase the gap. Doubling the gap from 2.5mm in R&D to 5mm in production means to increase the throughput by a factor of 2. For achieving the same ribbon quality, the at-gap density must stay the same. Consequently, for a larger gap the mass being manufactured through this gap must increase by the same factor. Please be aware that increasing the gap is not as easy as increasing the production time or roll speed. A change of gap generally leads to a change in the at-gap density. Therefore, an adjustment of the specific roll force must be made to achieve the same ribbon density and a constant granulate quality. Additionally, enlarging the gap is not always possible. For example, this might not be feasible for products that suffer from draw-in issues.

Scale-up by roll width

For the three activities of scale-up described above, (assuming that the product allows for increasing the gap), no change of equipment is necessary.

Generally, R&D is performed on a Mini-Pactor that has 2.5cm wide rolls. By changing this machine to a production machine, a Macro-Pactor having 10cm wide rolls, a factor of 4 times more material can be manufactured in the same amount of time. Design and the performance of both machines are engineered in such a way that a product transfer from the Mini-Pactor to the Macro-Pactor is straightforward and easily accomplished.

Overall scale-up factor

For a reasonable overall scale-up factor in roller compaction, the extremes should be omitted as the previously given examples already did. Without changing the equipment, a scale-up factor of 600 is achievable (increase of production time and roll speed, Fig. 1). Often it can even be twice as large by doubling the gap. But please be aware that this is not always possible. By changing the equipment from Mini-Pactor to Macro-Pactor the scale-up factor can be enlarged to 2,400 or even 4,800 if increasing the gap is possible.

Comparison to wet granulation

In wet granulation, a common production batch size is 400kg. This requires high shear mixing (HSM) an approximately 1,200L bowl or for fluid bed granulation (FBG) approximately a 1,000L product container. The R&D work for both of these wet granulation technologies is typically done with smaller scale 1kg batches. Scaling up this 1kg R&D batch to a production sized batch requires at least three scale-up steps, but more likely five (Fig. 2). Each of these steps is executed using different (stepwise larger) equipment.

Additionally, the scale-up transitions are more complex. A lot of influencing factors are identified, but they are difficult to predict when transferring to the next bowl or container size.

In roller compaction, a scale-up factor of 600 is easily achievable using the same equipment. Including for a change to a production-sized machine, the scale-up factor increases to 2,400 or more. In general, only one step is needed for scale-up. In contrast to the straightforward scale-up in roller compaction, wet granulation needs several steps with different equipment, resulting in a scale-up factor of only 400.

Hartmut vom Bey is with Gerteis Maschinen + Processengineering & Barbara Fretter is with Solids Development Consult

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