Continuous manufacturing of solid dosage forms gained a lot of attention and investments in continuous production lines in pharmaceutical industry during the last years. Benefits such as deeper process understanding due to development at final scale resulting in no scale-ups, leading to less API amounts and risks during product development. Nevertheless, a product destined to dedicated special production equipment is disadvantageous with regards to flexibility. A production process where a flexible switch of production mode (batch-vs. continuous) with equipment providing the same operation principle would be advantage. For the continuous production mode, a well-defined development – and control strategy of the production line is required, to gain a deeper process understanding and guarantee consistent product quality over production time. This study provides data insights of transferring a fluidized-bed granulation process from batch- to a semi-continuous process and investigates the effect of the production mode on product quality. Placebo and verum trials on batch – and (semi-)continuous production equipment were conducted and critical quality attributes of resulting granules and tablets (e.g. particle size distribution, dissolution of active pharmaceutical ingredient (API)) were investigated. After transfer from batch- to (semi-)continuous production equipment, “upscaling” to a pilot plant was performed including supervision of the production process via process-analytical technologies. A suggestion for a control-strategy at pilot scale was developed. MATERIAL & METHODS Case studies were conducted at batch-equipment: GPCG2 (Glatt), rotary press 102i (Fette) and (semi-) continuous production equipment: Xelum R&D-Kit (Syntegon, Schopfheim, Germany) and a Xelum Pilot Plant prototype (Syntegon) including tablet press TPR 200 (Syntegon). Moisture of the granulates was measured offline by IR-balance (HX204, Mettler Toledo) and online at pilot plant by NIR spectroscopy (MicroNIR PAT-W, VIAVI Solutions Inc.). Blend-uniformity of ready-to-press blend was monitored via SentroPAT FO, Sentronic NIR spectrometers. Particle size distribution of ready-to-press-blend was measured offline by image analysis (QicPic, Sympatec) and partly online by Parsum Probe. Height, diameter and weight of the tablets were determined with a tablet hardness tester. Tablet disintegration time was measured and dissolution tests were performed according to Ph.Eur. 8.0 using a paddle apparatus (75 rpm) and an acetate buffer pH 4.5 + 0.4% SDS. Drug content was determined by HPLC-Analysis.
RESULTS & CONCLUSION This study demonstrated the transfer from batch-to continuous manufacturing equipment and showed the development cycle during drug product development for a continuous manufacturing process. Comparable drug products regarding their critical quality attributes could be achieved, independent of the production mode. Furthermore, a control strategy could be developed for the pilot plant process, which allows a deep process understanding (NIR and Parsum probe incorporated in fluidized-bed granulation process at R&D-Kit, NIR-probe included in tablet press at Xelum pilot plant), a monitoring of critical quality attributes (NIR for moisture measurement of granules at receiver unit, NIR for blend uniformity and API-content analysis in second blender unit) and a control of the production line (data loss in weight feeder, yield determination after granulation, in-process controls of tablets) resulting in a consistent product quality over a production time of approx. 4 hours.
Learning Objectives:
Upon completion, participants will understand the differences between batch and semi-continuous production using the fluidized-bed granulation technique and learned how to transfer a batch-process to a semi-continuous manufacturing equipment.
Upon completion, participants will be able to understand the development process for a (semi-) continuous fluidized-bed granulation process – from small scale equipment (single fluidized-bed granulator) to pilot plant.
Upon completion, participants will understand the importance of a control strategy for a (semi-)continuous production process demonstrated by an example of an efficient control-strategy based on an experimental data set.