A Phase I clinical manufacturing approach gaining in popularity is pure API in a capsule. This approach can be known as Powder In Capsule (PIC), or Chemical In Capsule (CIC). Reduced drug product development time is one reason why this technique is so appealing. Additionally, because it is a two component system (API and capsule shell), analytical test methods for the API can be leveraged to simplify method development for the drug product. With the ever increasing pressure to reduce timelines, this manufacturing technique is a viable path forward for producing Phase 1 and small Phase 2a supplies used in Proof Of Concept (POC) clinical studies. Although there are many advantages to this approach there are also some disadvantages. One such disadvantage is the manufacturing processes are dependent on the physical properties of the API. Particle size, flow, density and compressibility of the API play a large role in the success of these projects. The technology employed at Kansas City is the Powdernium™ precision dispensing system. Our scientists have vast experience with this approach and technology. They are capable of solving many problems commonly encountered.

The Challenge

In this particular case Aptuit was manufacturing Phase I clinical supplies with an API possessing physical properties which were very challenging. The API had ~70% of the particles less than 60 microns (Figure 1) with a bulk density of 0.257 g/cc and a tap density of 0.494 g/cc (Figure 2). The resulting Carr’s index was 48% so the material was quite compressible and poor flowing. The targeted fill weight per capsule was 15 mg of pure API. Upon manufacturing the feasibility batch, it was discovered that the material was so compressible that the dispensing head would develop a thick wall of material at the outer edge and the system would encounter a “time out” error and shut down. This would have doubled the manufacture time and potentially resulted in the entire batch being rejected due to the very low yield.

The solution recommended was to reduce the fill of the dispensing heads to half full and double the number of dispensing heads (Figure 3). The theory was the lower fill volume would result in a reduced residence time, which would limit the amount of consolidation which could occur.

At Aptuit’s Kansas City site, the Powdernium Precision System (Figure 4) was employed to ensure precise dispensing of the API in powder form. Aptuit scientists have substantial experience in using this technology to solve many problems.

The client received pure API in capsule form (Figure 5) in blister packaging (Figure 6).

Conclusion

The theory was correct and the reduced fill volume allowed for the successful fill of capsules prior to the consolidation of the material and a time out error occurring. The clinical supplies were manufactured with a yield of >97% of acceptable capsules. The batch was also successfully completed and released for the client in twelve weeks from start.

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