Development and Evaluation of an In-line and On-line Monitoring System for Granule Size Distributions in Continuous Roll Compaction/Dry Granulation Based on Laser Diffraction

Annika Wilms,Peter Kleinebudde,Robin Meier

doi:10.1007/s12247-020-09443-3

Abstract

PurposeRoll compaction/dry granulation is established in manufacturing of solid oral dosage forms and, within the context of continuous manufacturing, it has sparked interest as material is fed, processed, and ejected continuously while also providing large possible throughputs. However, this amount of material has to be adequately controlled in real time to assure quality.MethodsThis research aimed at monitoring the critical quality attribute granule size distribution in continuous roll compaction/dry granulation (QbCon®; L.B. Bohle, Ennigerloh, Germany) using in-line and on-line laser diffraction. The influence of varying process parameters and excipient formulations was studied and evaluated with the prospect of using this technique to develop control loops. For this purpose, residence time parameters were assessed. In- and on-line data was compared with off-line laser diffraction and dynamic image analysis data.ResultsThe system successfully monitored the granule size distribution in a variety of process parameters and throughputs (up to 27.5 kg/h). It was sensitive to changes in process parameters and changes in material blends, which could pose a potential threat to the final drug products’ quality. Average event propagation time from the compaction zone to the laser diffraction system of 17.7 s demonstrates the systems’ fast reaction time.ConclusionResults highlight laser diffraction as a valuable method of in- and on-line size determination and allow for the development of a control strategy using this principle.

Highlights

Shifting the mindset from batch to continuous manufacturing (CM), the pharmaceutical industry is rather slow, compared with, e.g., the food industry, as the highest standard of quality must be met and documented for every product [1,3 L.B
In- and on-line analysis, returning to a Specific compaction forces (SCF) led to granule size distribution (GSD) parameters that do not differ significantly from different experiment timings in which the same parameters were chosen (e.g., 2 kN/cm at minutes 6–12 and 24–30)
An in- and on-line GSD monitoring system based on laser diffraction was implemented successfully in a Roll compaction/dry granulation (RCDG) process with up to 27.5 kg/h of material throughput

Summary

Introduction

Shifting the mindset from batch to continuous manufacturing (CM), the pharmaceutical industry is rather slow, compared with, e.g., the food industry, as the highest standard of quality must be met and documented for every product [1,3 L.B. Shifting the mindset from batch to continuous manufacturing (CM), the pharmaceutical industry is rather slow, compared with, e.g., the food industry, as the highest standard of quality must be met and documented for every product [1,. In CM initiatives, proposals for continuous granulation were published [8]. The Food and Drug Administration (FDA) has been especially supportive of the CM approach [3, 5] and the International Council of Harmonization published quality guidance to help introducing advanced concepts [9, 10]. ICH Guideline Q13, Continuous Manufacturing, was announced and is currently under construction. Six small-molecule drug products are on the market that, at least to some extent, incorporate CM approaches [11]

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Conclusion