Implementing Feedback Granule Size Control in a Continuous Dry Granulation Line Using Controlled Impeller Speed of the G
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ORIGINAL ARTICLE
Implementing Feedback Granule Size Control in a Continuous Dry Granulation Line Using Controlled Impeller Speed of the Granulation Unit, Compaction Force and Gap Width Annika Wilms 1,2 & Andreas Teske 3 & Robin Meier 3 & Raphael Wiedey 1 & Peter Kleinebudde 1 Accepted: 29 November 2020 # The Author(s) 2020
Abstract Purpose In continuous manufacturing of pharmaceuticals, dry granulation is of interest because of its large throughput capacity and energy efficiency. In order to manufacture solid oral dosage forms continuously, valid control strategies for critical quality attributes should be established. To this date, there are no published control strategies for granule size distribution in continuous dry granulation. Methods In-line laser diffraction was used to determine the size of granules in a continuous roll compaction/dry granulation line (QbCon® dry). Different process parameters were evaluated regarding their influences on granule size. The identified critical process parameters were then incorporated into control strategies. The uncontrolled and the controlled processes were compared based on the resulting granule size. In both processes, a process parameter was changed to induce a shift in median particle size and the controller had to counteract this shift. Results In principle, all process parameters that affect the median particle size could also be used to control the particle size in a dry granulation process. The sieve impeller speed was found to be well suited to control the median particle size as it reacts fast and can be controlled independently of the throughput or material. Conclusion The median particle size in continuous roll compaction can be controlled by adjusting process parameters depending on real-time granule size measurements. The method has to be validated and explored further to identify critical requirements to the material and environmental conditions. Keywords Continuous manufacturing . Roll compaction/dry granulation . Process analytical technologies . Laser diffraction . Process control . Feedback control
Introduction Continuous manufacturing (CM) in the production of pharmaceutical solid oral dosage forms is characterized by the connection of individual processes into one line, ideally from raw excipients and active pharmaceutical ingredient (API) to final
* Peter Kleinebudde [email protected] 1
Heinrich Heine University Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
2
INVITE GmbH, Drug Delivery Innovation Center, Chempark Building W32, 51368 Leverkusen, Germany
3
L.B. Bohle Maschinen + Verfahren GmbH, Industriestraße 18, 59320 Ennigerloh, Germany
dosage form. Potentials of this production concept include higher flexibility of production volume and time as well as increased quality due to tight monitoring and control strategies [1–4]. Regulatory agencies and the International Council of Harmonization (ICH) have shown support of this approach [5–11]. A new guideline, ICH Q13, is currently developed for continuous manufacturing processes
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