Novel process analytical technological approaches of dynamic image analysis for pharmaceutical dry particulate systems

With the introduction of Process Analytical Technology (PAT) and Quality by Design (QbD) concepts by the Food and Drug Administration (FDA) the pharmaceutical industry is thriving towards improved process understanding. Subsequently, the pharmaceutical industry shifted the focus on the implementation of new technologies for real-time process control of various unit operations. Enhanced process understanding will result in a robust process and eventually enable quality by design into the product.
Inline with this PAT concept of improving process understanding and enhancing manufacturing efficiency, the objectives of this research work were to introduce and implement novel technologies of dynamic image analysis (DIA). The novel DIA approaches would allow for real-time (on-line) particle size and shape monitoring in a pharmaceutical dry milling unit operation and subsequently flowability characterization (at-line) of the milled material for pharmaceutical powders and granules.
For the first objective we employed a pilot-scale conical mill and investigated two DIA sensors, one as on-line mode and the other as in-line mode, for real-time particle size and shape monitoring. We selected different pharmaceutical excipients and placebo granulates, spanning a wide range of particle characteristics, for milling. Various mill parameters such as feeder speed, impeller speed, and screen sizes were considered. The particle size distribution results obtained from both the on-line and in-line modes were compared with a commercially available DIA instrument, which served as an at-line reference. Additionally, the data was also compared with the traditional sieve analysis. The results from the on-line, in-line and at-line DIA measurement modes showed similar particle size distributions for the various materials studied. However, few differences among the different DIA modes were observed that were mainly attributed to sampling and particle dispersion. A high correlation of 0.975 (p<0.001) was observed between on-line d50 and at-line d50 when compared to 0.917 (p<0.001) between in-line d50 and at-line d50. Finally, the on-line sensor was chosen as it provided robust results. A novel concept of time evolving size and shape analysis (TESSA) was successfully proposed for the first time in dry milling. The TESSA approach was found to be useful in detecting changes in milling conditions including the successful detection of a damaged screen when intentionally introduced in the milling process.
In the second objective we introduced a modern instrument, which combines powder avalanching with DIA to enable a comprehensive understanding of the flow behaviour of pharmaceutical powder formulations. The flow characterization of such formulations is essential as they can pose a challenge for upstream solid dosage manufacturing such as tabletting (die filling) and capsulation (weight variation). A commercial powder avalanching instrument existed earlier, but it lacked dynamic image analysis and further provided very few avalanching parameters such as mean time to avalanche and scatter values. The novel instrument used in this study provides image analysis of the motion of a powder inside a rotating drum and results in several parameters associated with powder avalanching such as avalanche time, avalanche angle, and avalanche power in addition to several other parameters. We initially tested the suitability of this modern instrument for flow characterization of binary blends, comprising of a coarse excipient and fine drug particles, and further introduced the concept of critical flow concentrations (CFCs). At least three drug concentrations were identified for which the flow behaviour, of the binary blends, essentially changed. Accordingly, different flow regions were identified, which were explained on the basis of changed particle packing configurations. A theoretical model successfully provided a first estimate of the initial two CFCs. The novel avalanche testing instrument used in this work provided complementary information to conventional flowability methodologies such as flow through an orifice. A thorough assessment of pharmaceutical blends is needed to avoid CFCs in view of a robust formulation development and hence with respect to building quality into the design of the solid dosage forms. Later, we used the powder avalanching instrument for characterizing the flow behaviour of the milled materials produced from the conical mill.
In the third objective we implemented the on-line DIA sensor in the conical mill and further tested the feasibility of the avalanching instrument as a potential at-line PAT tool for powder flow characterization. We conducted a response surface design in combination with robustness testing (Taguchi design). Both of these designs employed the conical mill, together with the on-line DIA sensor and the powder avalanching instrument. The mill process parameters, namely impeller speed and screen sizes significantly affected the particle size distribution and flow rate of the milled placebo granules. Feeder speed did not affect the particle size, but displayed a statistically significant influence on the flow responses. Robustness testing was able to capture the effect of assigned noise factors (different placebo lots and temperature conditions) on the responses and showed clear differences between different lots of the placebo granulates in addition to temperature-dependent changes in flow behaviour. Eventually, the powder avalanching instrument was proved to be a successful at-line PAT tool.
The dynamic image analysis PAT tools investigated in this research work provided a novel source of understanding the particle characteristics (size and shape) and flow behaviour of pharmaceutical powders and dry milled granules. Adequate characterization of particle size as well as shape and flowability is essential for upstream solid dosage form manufacturing. Thus, on-line particle size monitoring and at-line flowability characterization using the presented novel DIA techniques together, as complementary process analytical tools, provides valuable information for industrial characterization of pharmaceutical dry particulate systems, namely powders and granules.