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Q&A: The Importance of Particle Properties on the Biopharmaceutical Performance of Amorphous Solid

Dave A. Miller, DisperSol Technologies, LC.

Q: Why was hammer milling and cryomilling necessary? Are the KSD particularly difficult to mill?
A: KSDs are not typically difficult to mill. Hammer milling is standard for thermally processed ASDs, including those made by HME. Cryomilling was done for research purposes to establish an extreme case of particle size reduction.

Q: How KinetiSol compares to HME?
A: This requires a response too extensive for this format. There are over a dozen peer-reviewed articles on this topic. I’ll refer you to those. 

Q: Are there long term stability study on BI-639667 KSD?
A: Presumably, BI conducted these studies with acceptable results for SDD and KSD, but those data were not shared. Long-term stability was outside of the scope of the research conducted at the University of Texas.

Q: What is largest batch size that KinetiSol can produce per run?
A: Speaking in orders of magnitude, we have production history at the 100 kg scale and are operational at the 1,000kg scale. We’ve produced registration batches (100 – 200kg) at a partner commercial CMO for one of our own clinical stage assets.

Q: How do the final achievable particle sizes at commercially relevant spray drying and KinetiSol processes differ from those presented, and what differences would you expect in the gastric-intestinal dissolution performance?
A: SDD particle size may be larger. KSD particles sizes would remain the same. The key difference is surface area, which is governed by particle morphology, and that would be fairly constant on scale-up. 

Q: Can KinetiSol be operated as a pressurized system?
A: No

Q: Which polymer was used for the formulations?
A: HPMCAS

Q: Are there some specific polymers OR specific polymer property(s)/ which pose a compatibility issue with your KSD technology?
A: Low viscosity polymers like poloxamer or low MW PEGs can present challenges as primary carriers for ASDs. However, those polymers are no longer relevant for ASDs. 

Q: Are you able to scale up from research sizes to amounts that would be amenable to the clinic?
A: Yes. DisperSol has five clinical-stage assets of its own (two are late-stage) and has produced numerous GMP batches for partner companies; mostly large pharmas. Also, as stated above, one of our clinical stage assets has progressed to registration stage requiring a commercial KinetiSol train be installed at a partner CDMO where registration batches were successfully produced. 

Q: How does the physical stability of KSD compare to physical stability of SDD?
A: Similar in closed and/or low humidity conditions. Typically, better in open and high humidity conditions due to reduced water absorption. 

Q: Can you share anything about what added materials are used in KSD & MBP? Are they solvent free processes?
A: MBP is solvent-based process developed by Roche. I’ll refer you to the literature on that. KSD is a non-solvent process. 

Q: Based on presentation, you can say SDD is good for BCS class II drug but BCS IV?
A: SDD is good for both. In some cases, other technologies can yield better performing formulations. 

Q: How easy is it to control the milling process if more extreme forms of milling are necessary?
A: The milling operations employed in typical KinetiSol manufacturing are conventional and well understood. Controlling them is not an issue. Cryogenic milling, although rarely used, requires some expertise, but can be well managed on a commercial scale. 

Q: Can you comment on the difference between your process and HME (if HME is feasible)?
A: See question 2.

Q: Can you share anything about what you mean by thermal processing?
A: Synonymous with “fusion method” described in many review articles. See Chiou and Riegelman. JPharmSci. 1971, 60(9) 1281 – 1302 for the earliest reference 

Q: Will you see the difference between your process and the SDD for BCS II compounds?
A: In all cases? No. In a majority of cases? Probably not. In many cases? Yes. 

Q: Great presentation! Can you comment on kinetisol technology’s ability to process thermally labile drugs better than conventional hot melt extrusion? Also can you comment on the scale possible with this technology?
A: With regard to comparisons to HME for the processing of thermally labile drugs, see my response to question 2. With regard to the scale of the technology, see question 9.

Q: Are there commercial examples of KinetiSol?
A: No. Our first NDA approval is expected by 2023

Q: Can you talk about the scale-up of Kinetisol process compared to spray drying?
A: This would require a response too lengthy for this format. I’ll refer you to Ellenberger et al. Expanding the Application and Formulation Space of Amorphous Solid Dispersions with KinetiSol: A Review, AAPS PharmSciTech, Volume 19, Issue 5, June 2018, pp. 1933 – 1956.

Q: Should you add HME as a positive control if is the case?
A: I addressed this during the live Q&A. In short, none of the formulations in the case studies presented could be produced by HME due to drug and/or polymer degradation.

Q: Are there any requirement on the solid state of the drug substance going into the KSD process, e.g., amorphous or crystalline?
A: No. The process space is defined according to input material properties. The space shifts with a major change to input material properties. However, nothing about KinetiSol precludes the use of APIs with certain characteristics.