Investigation of impact of roller compaction process parameters on critical product attributes

R. Dontireddy1,2, G.E. Oâ??Mahony1, M.E. Crowley1, A.M. Crean1,2

1School of Pharmacy, University College Cork, Cork, Ireland.

2Pharmaceutical Manufacturing Technology Centre

INTRODUCTION

There is an ever growing demand in pharmaceutical industry for increased quality and decreased variability. Also, higher manufacturing costs and expiry of patents of blockbuster drugs in recent years have shifted the momentum for continuous processing in manufacturing[1]. Continuous processing aims to improve efficiency of production and also minimize batch to batch variation that is associated with conventional batch manufacturing[2]. In this current work, we studied Roller Compaction as an applicable method for continuous processing.
The primary objective was to study the applicability of roller compaction for continuous process via monitoring critical quality attributes of in- process material. Critical quality attributes of the ribbons and granules were studied using novel in-line and at-line PAT techniques and the results were compared with similar off-line techniques. DoE (Design of Experiments) was applied to study the relationship of different process attributes and their influence on final quality.

MATERIALS AND METHODS

Blends (50:50 mixture of API to excipients) containing milled and unmilled API were investigated to study the influence of API particle size on process and product characteristics. Blends were compacted using a CCS
220 roller compactor at different process settings based on DoE. At-line N-IR measurements (as an indicator of ribbon density) were performed using a MultiEye® system and in-line particle size measurements (for granules) were obtained using the Eyecon® system. Envelope and true density measurements were performed using Geopyc 1360 and Accupyc II 1340 respectively. Sieve analysis was performed using an automatic sieve shaker (VE 1000). Off-line analysis was performed using a PerkinElmer Spotlight 400 FT- IR and PerkinElmer NIR analyser to compare off-line results with those obtained during process. Drug content and degradation was measured by HPLC (Waters 2360).

RESULTS AND DISCUSSION

From preliminary studies, roller speed and roll pressure showed greater dependence on the ribbon production. Second DOE was performed within the parameter space achieved after initial screening DOE. A correlation of MultiEye® in-line analysis and off- line NIR results was obtained and showed no significant influence of processing parameters on the density of the ribbons. Off-line analysis of porosity, envelope and true density results from DoE showed minimal effect of process settings on ribbon quality.
Particle size analysis using In-line particle size analyser Eyecon® showed no significant differences between samples. But a comparison between granules from milled and unmilled drug blends, milled drug blends showed lower particle size distribution at any given process condition. These results are interesting since density measurements showed no difference between milled and unmilled ribbons.

CONCLUSIONS

Variability in the process parameters has minimal effect on the measured density of the ribbons and granule particle size. Physical state of API has significant effect on the granulate properties but showed no effect on ribbon density. We successfully demonstrated the use of In-line and At-line PAT techniques for applicability in roller compaction process.

ACKNOWLEDGMENTS

Pharmaceutical Manufacturing Technology Centre (PMTC), an Enterprise Ireland (EI) and Industrial Development Agency (IDA) funding initiative.

REFERENCE

1. Ooi SM, Sarkar S, van Varenbergh G, Schoeters K, Heng PWS. Continuous processing and the applications of online tools in pharmaceutical product manufacture: developments and examples. Therapeutic Delivery. 2013

2013/04/01;4(4):463-70.

2. Vervaet C, Remon JP. Continuous granulation in the pharmaceutical industry. Chemical Engineering Science.

2005 7//;60(14):3949-57.