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Q&A: Successful Strategies for Developing a Continuous Manufacturing Process

Andy Birkmire, GEA

Q: When scaling up a continuous wet granulation what can be used as scale up factor and what should stay consistent (no change upon scale up)?
A: For most Pharmaceutical applications, there won’t be a scale factor necessary if you are in the range of 25-30 kg/hr. If you do need to increase to 50-200 kg/hr, then you would look at keeping the work input constant (Degree of Fill).

Q: What is the impact of material’s density in terms of adjusting the motor speed and mass flow?
A: For high bulk density/freely flowable materials, the feeding will be quite easy. When you have low bulk density materials which are not free flowing, the hopper will need to be refilled more frequently in order to generate enough head pressure to fill the screws.

Q:  Can you clarify further the DOE model you used? Was this a factorial design? How the independent parameters and ranges were selected?
A: That case study was using a factorial design. The DoE parameters were selected by looking at degree of fill, liquid to solid ratio, and then with the quantity of materials available, a factorial design was selected.

Q:  Does excipients property impact the process? As you said no need to use processed API, then how we can control the CQA?
A: Of course, excipient quality impacts the process and CQAs. You would just need to perform feeding/granulation studies to understand how the excipient quality/variability.

Q: What are the biggest scale challenges between Consigma 25 and 50,100, etc.?
A: This hasn’t been a big question, for most process ranges we see 25-50 kg/hr is more than adequate, and there aren’t many considerations in scaling in this range.

Q: How to make stage wise yield?
A: I’m not sure about this question – you can certainly break down each unit operation and calculate the micro-yields within a single processing line.

Q: What is the role of barrel heating during the wet granulation? Will the system also be useful for melt granulation?
A: Typically, the role is that you want to keep the barrel temperature constant, so adding or removing heat as appropriate to maintain process stability. Barrel heating is definitely useful for melt granulation.

Q: What are the critical parameters that would allow us to know if continuous manufacturing works for certain formulations?
A: You would have to select a manufacturing route (direct compression, wet granulation/drying, melt granulation, etc.) and then we could easily break down the critical parameters for each scenario.

Q: Which is currently the main limit of CPF?
A: I think the answer to your question is there is a large installed base of Batch equipment, but for new applications, the speed of development and reduced footprint and reduced consumption of API makes continuous processing very attractive.

Q:  Are there examples of approved products with PFL system? Compositionally, how is the amount of lubricant per unit dose reported?
A: I didn’t intend on the presentation to be around PFL applications, I just shared where powder feeding was applicable in continuous processing.

Q:  Did you apply a moving average filter on the feeding data? Do you offer the software for the feeder analysis?
A: Yes, you always apply a moving average filter on the feeder data, which changes based on the throughput. Any feeder vendor will have software available for this purpose.

Q:  How popular is continuous process today in pharmaceutical industry vs batch processes?
A: I don’t know how to quantify this. We certainly see a lot of interest/activity in continuous processing, based on the flexibility/speed to market, reduced API consumption. But I can’t quantify that unfortunately. Our lab is certainly busy!

Q: What would be the starting point for developing a high shear granulation process using continuous manufacturing?
A: Start with a given formulation, and run at different Liquid to Solid ratios, and Degrees of Fill. This will give you a quick demonstration of the types of granules that are possible. If the granulation isn’t where you want it to be, you can then look at different screw configurations, etc. This process is very quick vs. Batch process development.