Innovation in pharmaceutical manufacturing of solid dosage forms via continuous wet granulation

For decades, the manufacturing of solid dosage forms in the pharmaceutical industry has been synonymous with batch processing. However, batch processes are often sensitive to variability (possibly resulting in batch rejection or reprocessing), high labor costs (due to the multiple manual interventions during processing), high production costs, excessive inventories and scale-up issues. On the other hand, many advantages are associated with continuous processing which are all related to important economic drivers for change (i.e. quality, cost and time). However, implementation of new technologies, methodologies and equipment is needed to allow transfer from batch to continuous manufacturing within the pharmaceutical industry. As wet granulation is the most popular method to improve material properties (flow, homogeneity, compressibility) prior to tableting, it is obvious that a continuous wet granulation process is of high importance for a manufacturer of solid dosage forms. At the Laboratory of Pharmaceutical Technology (Ghent University) a continuous twin screw wet granulation process using a modified twin-screw extruder was developed. Based on this research work, GEA Pharma Systems developed a fully integrated ‘from-powder-to-tablet’ manufacturing line, the ConsiGmaTM system, using twin screw granulation as an intermediate step for wet granulation of raw materials. The overall objective of this project was to bridge the gap between the existing technology and its industrial implementation. Although technical know-how about the continuous granulation system is available at the manufacturer of this system, process knowledge (certainly towards specific pharmaceutical formulations) about this innovative manufacturing technique is limited within the pharmaceutical industry. Also in scientific literature the number of papers dealing with continuous wet granulation is limited. Therefore, the continuous granulation of pharmaceuticals by means of the ConsiGmaTM system was investigated in order to (a) improve process knowledge and process understanding of this novel manufacturing tool for solid dosage forms and (b) simplify scale-up and transfers in pharmaceutical manufacturing. To meet these objectives, the parameters affecting the quality of the end product manufactured via continuous wet granulation using the ConsiGmaTM system were determined via a series of experiments which evaluated the different aspects of this granulation technique: influence of formulation, process and equipment parameters on granule and tablet quality, visualization and understanding of granulation liquid mixing and distribution, use of continuous granulation for formulation development and process optimization, stability and repeatability of the continuous granulation process and in-line blending capacity of the granulation unit

Real-time assessment of critical quality attributes of a continuous granulation process

There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from traditional batch production towards continuous production. The currently applied conventional quality control systems, based on sampling and time-consuming off-line analyses in analytical laboratories, would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production. This manuscript evaluates strengths and weaknesses of several complementary Process Analytical Technology (PAT) tools implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line. The use of Raman and NIR-spectroscopy and a particle size distribution analyzer is evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline− lactose blend. The solid state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the active pharmaceutical ingredient (API). A higher barrel temperature and a higher powder feed rate, resulted in larger granules

Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. (C) 2017 Elsevier B.V. All rights reserved