Continuous twin screw granulation: Impact of microcrystalline cellulose batch-to-batch variability during granulation and drying - A QbD approach

Christoph Portier; Tamas Vigh; Giustino Di Pretoro; Jan Leys; Didier Klingeleers; Thomas De Beer; Chris Vervaet; Valérie Vanhoorne

doi:10.1016/j.ijpx.2021.100077

Continuous twin screw granulation: Impact of microcrystalline cellulose batch-to-batch variability during granulation and drying - A QbD approach

Int J Pharm X. 2021 Mar 19:3:100077. doi: 10.1016/j.ijpx.2021.100077. eCollection 2021 Dec.

Authors

Christoph Portier¹, Tamas Vigh², Giustino Di Pretoro², Jan Leys², Didier Klingeleers², Thomas De Beer³, Chris Vervaet¹, Valérie Vanhoorne¹

Affiliations

¹ Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
² Drug Product Development, Janssen Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
³ Laboratory of Pharmaceutical Process Analytical Technology, Department of Pharmaceutical Analysis, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.

Abstract

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs.

Keywords: API, Active Pharmaceutical Ingredient; BET, Brunauer Emmett and Teller; Batch-to-batch variability; Com, Commercial batch; Continuous manufacturing; Design of experiments; DoE, Design of Experiments; Dx (d10, d50, d90), Size in microns at which x volume% of the particles is smaller than dx; Formulation development; HR, Hausner Ratio; L/D, Length-to-diameter; L/S, Liquid to solid; LOD, Loss on drying; MCC, Microcrystalline Cellulose; PCA, Principle Component Analysis; PSD, Particle size distribution; QbD, Quality-by-Design; Quality-by-Design; RTD, Residence Time Distribution; SCE, Size Control Element; SSA, Specific Surface Area; Twin screw granulation; WBC, Water Binding Capacity; Wet granulation; rpm, Revolutions Per Minute.