Philippe Cappuyns

Impact of screw configuration on the particle size distribution of granules produced by twin screw granulation.

Twin screw granulation (TSG) has been reported by different research groups as an attractive technology for continuous wet granulation. However, in contrast to fluidized bed granulation, granules produced via this technique typically have a wide and multimodal particle size distribution (PSD), resulting in suboptimal flow properties. The aim of the current study was to evaluate the impact of granulator screw configuration on the PSD of granules produced by TSG. Experiments were performed using a 25 mm co-rotating twin screw granulator, being part of the ConsiGma™-25 system (a fully continuous from-powder-to-tablet manufacturing line from GEA Pharma Systems). Besides the screw elements conventionally used for TSG (conveying and kneading elements), alternative designs of screw elements (tooth-mixing-elements (TME), screw mixing elements (SME) and cutters) were investigated using an α-lactose monohydrate formulation granulated with distilled water. Granulation with only conveying elements resulted in wide and multimodal PSD. Using kneading elements, the width of the PSD could be partially narrowed and the liquid distribution was more homogeneous. However, still a significant fraction of oversized agglomerates was obtained. Implementing additional kneading elements or cutters in the final section of the screw configuration was not beneficial. Furthermore, granulation with only TME or SME had limited impact on the width of the PSD. Promising results were obtained by combining kneading elements with SME, as for these configurations the PSD was narrower and shifted to the size fractions suitable for tableting.

Exergetic sustainability assessment of batch versus continuous wet granulation based pharmaceutical tablet manufacturing: a cohesive analysis at three different levels

Identifying better performing Active Pharmaceutical Ingredient (API) synthesis routes with reference to green chemistry and green engineering principles was of the highest importance in the pharmaceutical industry during the past decade. However, very little attention was paid to other life cycle stages such as the Drug Product (DP) production, packaging and distribution. In this case, the environmental sustainability of batch versus continuous granulation based tablet manufacturing is quantified from a resource point of view by conducting Exergy Analysis (EA) and Exergetic Life Cycle Analysis (ELCA) at three different levels in order to identify and locate resource losses throughout the pharmaceutical supply chain. Assessing the potential implementation of the continuous production line ConsiGma™ at the Janssen-Cilag SpA pharmaceutical manufacturing plant and thereby replacing the conventional batch manufacturing mode would result in a resource consumption reduction of 10.2% (65.6 to 58.9 kJex per tablet), 15.2% (111 to 94.0 kJex per tablet) and 2.2% (2.3 to 2.2 MJex per tablet) at the process (α), plant (β) and overall industrial level (γ) respectively. Focusing on DP production processes by excluding transiting exergy in API, excipients and packaging materials resulted in a reduction of 34.0%, 25.9% and 14.7% at the respective system boundaries. The API dose seemed to be the parameter with highest sensitivity towards environmental burden. From an emission point of view, a Carbon Footprint (CF) reduction of 2.0% (0.22 to 0.21 kg CO2-eq per tablet) was obtained at the γ level in shifting from batch to continuous manufacturing of Tramacet®. Focusing on DP production revealed a CF reduction of 16.2%.

Use of a continuous twin screw granulation and drying system during formulation development and process optimization

Since small scale is key for successful introduction of continuous techniques in the pharmaceutical industry to allow its use during formulation development and process optimization, it is essential to determine whether the product quality is similar when small quantities of materials are processed compared to the continuous processing of larger quantities. Therefore, the aim of this study was to investigate whether material processed in a single cell of the six-segmented fluid bed dryer of the ConsiGma™-25 system (a continuous twin screw granulation and drying system introduced by GEA Pharma Systems, Collette™, Wommelgem, Belgium) is predictive of granule and tablet quality during full-scale manufacturing when all drying cells are filled. Furthermore, the performance of the ConsiGma™-1 system (a mobile laboratory unit) was evaluated and compared to the ConsiGma™-25 system. A premix of two active ingredients, powdered cellulose, maize starch, pregelatinized starch and sodium starch glycolate was granulated with distilled water. After drying and milling (1000 μm, 800 rpm), granules were blended with magnesium stearate and compressed using a Modul™ P tablet press (tablet weight: 430 mg, main compression force: 12 kN). Single cell experiments using the ConsiGma™-25 system and ConsiGma™-1 system were performed in triplicate. Additionally, a 1h continuous run using the ConsiGma™-25 system was executed. Process outcomes (torque, barrel wall temperature, product temperature during drying) and granule (residual moisture content, particle size distribution, bulk and tapped density, hausner ratio, friability) as well as tablet (hardness, friability, disintegration time and dissolution) quality attributes were evaluated. By performing a 1h continuous run, it was detected that a stabilization period was needed for torque and barrel wall temperature due to initial layering of the screws and the screw chamber walls with material. Consequently, slightly deviating granule and tablet quality attributes were obtained during the start-up phase of the 1h run. For the single cell runs, granule and tablet properties were comparable with results obtained during the second part of the 1h run (after start-up). Although deviating granule quality (particle size distribution and Hausner ratio) was observed due to the divergent design of the ConsiGma™-1 unit and the ConsiGma™-25 system (horizontal set-up) used in this study, tablet quality produced from granules processed with the ConsiGma™-1 system was predictive for tablet quality obtained during continuous production using the ConsiGma™-25 system.

Environmental sustainability assessments of pharmaceuticals: an emerging need for simplification in life cycle assessments.

The pharmaceutical and fine chemical industries are eager to strive toward innovative products and technologies. This study first derives hotspots in resource consumption of 2839 Basic Operations in 40 Active Pharmaceutical Ingredient synthesis steps through Exergetic Life Cycle Assessment (ELCA). Second, since companies are increasingly obliged to quantify the environmental sustainability of their products, two alternative ways of simplifying (E)LCA are discussed. The usage of averaged product group values (R(2) = 3.40 × 10(-30)) is compared with multiple linear regression models (R(2) = 8.66 × 10(-01)) in order to estimate resource consumption of synthesis steps. An optimal set of predictor variables is postulated to balance model complexity and embedded information with usability and capability of merging models with existing Enterprise Resource Planning (ERP) data systems. The amount of organic solvents used, molar efficiency, and duration of a synthesis step were shown to be the most significant predictor variables. Including additional predictor variables did not contribute to the predictive power and eventually weakens the model interpretation. Ideally, an organization should be able to derive its environmental impact from readily available ERP data, linking supply chains back to the cradle of resource extraction, excluding the need for an approximation with product group averages.

Model development and prediction of particle size distribution, density and friability of a comilling operation in a continuous pharmaceutical manufacturing process

Graphical abstract Figure. No Caption available. Abstract The comilling process plays an important role in solid oral dosage manufacturing. In this process, the granulated products are comminuted to the required size distribution through collisions created from a rotating impeller. In addition to predicting particle size distribution, there is a need to predict other critical quality attributes (CQAs) such as bulk density and tapped density, as these impact tablet compaction behavior. A comprehensive modeling approach to predict the CQAs is needed to aid continuous process modeling in order to simulate interaction with the tablet press operation. In the current work, a full factorial experiment design is implemented to understand the influence of granule strength, impeller speed and residual moisture content on the CQAs. A population balance modeling approach is applied to predict milled particle size distribution and a partial least squares modeling approach is used to predict bulk and tapped density of the milled granule product. Good agreement between predicted and experimental CQAs is achieved. An Symbol value of 0.9787 and 0.7633 is obtained when fitting the mean particle diameters of the milled product and the time required to mill the granulated material respectively. Symbol. No caption available.