Focusing on powder processing in dry powder inhalation product development, manufacturing and performance.

Dry powder inhalers (DPI) are well established products for the delivery of actives via the pulmonary route. Various DPI products are marketed or developed for the treatment of local lung diseases such as chronic obstructive pulmonary disease (COPD), asthma or cystic fibrosis as well as systemic diseases targeted through inhaled delivery (i.e. Diabetes Mellitus). One of the key prerequisites of DPI formulations is that the aerodynamic size of the drug particles needs to be below 5 µm to enter deeply into the respiratory tract. These inherently cohesive inhalable size particles are either formulated as adhesive mixture with coarse carrier particles like lactose called carrier-based DPI or are formulated as free-flowing carrier-free particles (e.g. soft agglomerates, large hollow particles). In either case, it is common practice that drug and/or excipient particles of DPI formulations are obtained by processing API and API/excipients. The DPI manufacturing process heavily involves several particle and powder technologies such as micronization of the API, dry blending, powder filling and other particle engineering processes such as spray drying, crystallization etc. In this context, it is essential to thoroughly understand the impact of powder/particle properties and processing on the quality and performance of the DPI formulations. This will enable prediction of the processability of the DPI formulations and controlling the manufacturing process so that meticulously designed formulations are able to be finally developed as the finished DPI dosage form. This article is intended to provide a concise account of various aspects of DPI powder processing, including the process understanding and material properties that are important to achieve the desired DPI product quality. Various endeavors of model informed formulation/process design and development for DPI powder and PAT enabled process monitoring and control are also discussed.

Filling of lactose-based formulations in a tamping-pin capsule filler.

We studied three lactose-based formulations in terms of bulk powder properties and capsule-filling behavior in a tamping-pin capsule filling system, to which several mechanical adaptions were made for process optimization in light of future continuous production. The model formulations were thoroughly characterized and filled into size 1 capsules according a well-defined design of experiments (DoE). Overall, the three entirely different formulations were successfully filled within the selected design space. The fill weight and fill weight variability can be adjusted by fine-tuning the process settings, like the pin immersion depth and the maximum compaction pressure (pneumatic or spring-controlled), and by using the appropriate powder bed height and mechanical adaptions. This study demonstrated that selection of process parameters and mechanical adaptions could enhance the filling performance, especially in continuous production, since they reduce the powder volume in the process. Moreover, we showed that a tamping-pin system is capable of successfully filling a broad range of powders with various material characteristics and can potentially be used in a continuous production mode.

Predicting capsule fill weight from in-situ powder density measurements using terahertz reflection technology.

The manufacturing of the majority of solid oral dosage forms is based on the densification of powder. A good understanding of the powder behavior is therefore essential to assure high quality drug products. This is particularly relevant for the capsule filling process, where the powder bulk density plays an important role in controlling the fill weight and weight variability of the final product. In this study we present a novel approach to quantitatively measure bulk density variations in a rotating container by means of terahertz reflection technology. The terahertz reflection probe was used to measure the powder density using an experimental setup that mimics a lab-scale capsule filling machine including a static sampling tool. Three different grades of α-lactose monohydrate excipients specially designed for inhalation application were systematically investigated at five compression stages. Relative densities predicted from terahertz reflection measurements were correlated to off-line weight measurements of the collected filled capsules. The predictions and the measured weights of the powder in the capsules were in excellent agreement, where the relative density measurements of Lactohale 200 showed the strongest correlation with the respective fill weight ( R 2 = 0.995 ). We also studied how the density uniformity of the powder bed was impacted by the dosing process and the subsequent filling of the holes (with excipient powder), which were introduced in the powder bed after the dosing step. Even though the holes seemed to be filled with new powder (by visual inspection), the relative density in these specific segments were found to clearly differ from the undisturbed powder bed state prior to dosing. The results demonstrate that it is feasible to analyze powder density variations in a rotating container by means of terahertz reflection measurements and to predict the fill weight of collected capsules.

Material tracking in a continuous direct capsule-filling process via residence time distribution measurements.

Continuous production of pharmaceuticals requires traceability from the raw material to the final dosage form. With that regard, understanding the residence time distribution (RTD) of the whole process and its unit operations is crucial. This work describes a structured approach to characterizing and modelling of RTDs in a continuous blender and a tamping pin capsule filling machine, including insights into data processing. The parametrized RTD models were interconnected to model a continuous direct capsule-filling process, showing the batch transition as well as the propagation of a 2 min feed disturbance throughout the process. Various control strategies were investigated in-silico, aiding in the selection of optimal material diversion point to minimize the material waste. Additionally, the RTD models can facilitate process design and optimization. In this work, adaptions to the capsule filling machine were made and their influence on the RTD was examined to achieve an optimal machine setup.

Residence time distribution of a continuously-operated capsule filling machine: Development of a measurement technique and comparison of three volume-reducing inserts.

This paper presents the measurement and analysis of the residence time distribution (RTD) of a tamping-pin capsule filling machine. The tamping speed and the amount of material inside the powder bowl proved to have a significant effect on the RTD. Various inserts into the powder bowl that reduce the volume and alter mixing and transport in the bowl were experimentally investigated. To obtain the RTD, a tracer-based measurement method was applied and a sophisticated data processing strategy was developed. The tracer-based method also allowed investigations of stagnant zones in the powder bowl, another important aspect in continuous manufacturing (CM). The suitability of tracer material was assessed based on a detailed characterization of bulk and tracer material. Characteristic parameters of the RTD were extracted and compared, proposing a systematic strategy for selection of a suitable insert.

Carrier-based dry powder inhalation: Impact of carrier modification on capsule filling processability and in vitro aerodynamic performance.

This study aims to investigate the effect of carrier characteristics and dosator capsule filling operation on the in vitro deposition of mixtures containing salbutamol sulphate (SS) and lactose and mannitol as model carrier materials. The carrier surfaces of lactose and mannitol were modified via wet decantation. The impact of the decantation process on the properties of carriers was investigated by laser diffraction, density and powder flow measurements, N2 physisorption, small and wide angle X-ray scattering (SWAXS) and scanning electron microscopy (SEM). Differences in carrier type and untreated and decanted materials were identified and the SAXS measurements proved to be a promising technology confirming the successful removal of fines. Adhesive carrier API mixtures with carrier-to-API ratio of 99:1 wt% were prepared, mixture homogeneity was tested and subsequently the mixtures were filled into capsules at different process settings. Finally, the influence of the decantation process on the in vitro performance of the adhesive mixtures was tested with a next generation impactor. For lactose, the decantation decreased the fine particle fraction (FPF) of SS, whereas the FPF of mannitol as a carrier was only affected by the capsule filling process. In summary, the DPI formulation based on untreated lactose, especially by capsule filling using a dosing chamber to powder layer (compression) ratio of 1:2, proved to be superior in terms of the dosing accuracy (RSD<0.8%) and the in vitro aerodynamic performance (FPF of 12%).

Low-dose capsule filling of inhalation products: critical material attributes and process parameters.

The aim of the present work was to identify the material attributes and process parameters of a dosator-nozzle capsule filling machine that are critical in low-fill weight capsule filling for inhalation therapies via hard-gelatin capsules. Twelve powders, mostly inhalation carriers, some fines and one proprietary active pharmaceutical ingredient (API), were carefully characterized and filled into size 3 capsules. Since different process conditions are required to fill capsules with powders that have very different material attributes, the powders were divided into two groups. A design of experiments (DOE) based exclusively on process parameters was developed for each group, to identify the critical material attributes (CMA) and critical process parameters (CPP). The fill weight (4-45 mg) of the group I powders (larger particles, higher density, better flowability and less cohesion) correlated with the nozzle diameter (1.9-3.4mm), the dosing chamber length (2.5-5mm), the powder layer depth (5-12.5mm) and the powder density (bulk and tapped density). The RSDs were acceptable in most cases, even for very low doses. The fill weight (1.5-21 mg) of group II powders (very fine and low dense particles with a particle size <10 µm, poor flowability and higher cohesion) depended also on the nozzle diameter (1.9-2.8mm), the dosing chamber length (2.5-5mm) and the powder layer depth (5-10mm), albeit in a different way, indicating that for these powders dosator filling was not volumetric. Moreover, frictional (wall friction angle) and powder-flow characteristics (bulk density and basic flowability energy) have an influence on the mass. Thus, in summary, group I and group II powders can be filled successfully via dosator systems at low fill weights. However, the group II powders were more challenging to fill, especially without automated process control. This study is the first scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling.

The effects of material attributes on capsule fill weight and weight variability in dosator nozzle machines.

The goal of this work is to identify and understand the complex relationship between the material attributes, capsule fill weight and weight variability of capsules filled with a dosator nozzle machine. Six powders were characterized and filled into size-3 capsules in three volumes of dosing chambers and at two filling speeds. Subsequent multivariate data analysis was used to identify the influence of the material attributes on the capsule fill weight and weight variability. We observed a clear correlation between the capsule fill weight and the particle size, the air permeability and the compressibility. As the fill weight decreases, more factors affect capsule fill weight. For example, the wall friction angle, the tapped density, and the particle shape proved to be important factors. Larger fill weights were more affected by density while lower fill weights by flow and friction characteristics. No correlation was found between the material attributes and the weight variability. Rather, we could also see the major effect of process parameters on capsule fill weight and weight variability.

The effects of powder compressibility, speed of capsule filling and pre-compression on plug densification.

This paper describes the effect of powder compressibility and two process parameters of a dosator nozzle capsule filling machine on powder densification during plug formation. One process parameter was the ratio between the powder bed's depth and the length of the nozzle dosing chamber, hereinafter referred to as F. The other one was the speed of capsule filling. This paper demonstrates that powder densification during the capsule filling process is a function of the powder compressibility and the above process parameters (increasing them leads to higher plug density). The Walker model was used to characterize the compressibility of powders at low compression forces and the obtained compressibility coefficient W proved to be a good predictor of powder densification during the capsule filling process.

The effect of capsule-filling machine vibrations on average fill weight.

The aim of this paper is to study the effect of the speed of capsule filling and the inherent machine vibrations on fill weight for a dosator-nozzle machine. The results show that increasing speed of capsule filling amplifies the vibration intensity (as measured by Laser Doppler vibrometer) of the machine frame, which leads to powder densification. The mass of the powder (fill weight) collected via the nozzle is significantly larger at a higher capsule filling speed. Therefore, there is a correlation between powder densification under more intense vibrations and larger fill weights. Quality-by Design of powder based products should evaluate the effect of environmental vibrations on material attributes, which in turn may affect product quality.